Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=CC.[CH2:4]([OH:8])[CH:5]([CH3:7])[CH3:6].[CH2:9]([OH:13])[CH2:10][CH2:11][CH3:12]>[Co].[Pd]>[CH:4](=[O:8])[CH:5]([CH3:7])[CH3:6].[CH:9](=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCO
Reactant: CC(C)CO
Agent: [Co]
Agent: [Pd]
Solvent: C=CC
Product: CC(C)C=O
Product: CCCC=O
Temperature: 10 °C
Reaction time: 24 h
Yield: 24.4 %
Yield: 60.2 %

Procedure:
In the first run, cobalt and palladium complexes were added in a large excess to saturate the supporting base with the cobalt catalyst species and the promoter. The cobalt and palladium supported on the base from the first run must be much less than the original amounts present in the liquid phase. It is quite simple to support these components quantitatively on the base by adding sufficient amount of the base to the soluble catalyst species. The second run was started by introducing 20 g. of propylene in 50 ml. o-xylene to the solid catalyst aged for 24 hours from the first run. The pressure of the reactor at this stage was 200 psig. and was raised to 800 psig. with a premixed gas (1:1 H2 /CO), and then to 1200 psig. with H2. The reactor was slowly heated to 100° C. from room temperature (10° C.) in a 2 1/2 hour period. The initial pressure drop was observed under 1660 psig. at 100° C. The pressure dropped from 1685 psig. to 1550 psig. (at the temperature range 100°-124° C.) within 3 1/2 hours. The reaction was allowed to proceed for an additional 2 hours at a little higher temperature range (124°-146° C.). The pressure of the reactor dropped to 800 psig. at this stage. A yellowish reaction mixture, indicating that no catalyst leaches away from the supporting base, was discharged from the reactor. Analysis of the two reaction mixtures discharged from the first and second runs showed that the product distributions are quite similar in both runs. In the first run, the propylene feed was reacted in 23% conversion to give 24.4% isobutanal, 60.2% n-butanal, 2.0% isobutanol, 8.9% n-butanol and 4.6% unidentified products; in the second run, the conversion of propylene was 21% and the product distribution was 14.6% isobutanal, 55.4% n-butanal, 3.7% isobutanol, 16.6% n-butanol, 0.2% 2-ethylhexanol and 10.4% unidentified products. It is obvious from these results that the cobalt carbonyl catalyst and palladium promoter are simultaneously supported on the same base and that the resulting supported solid catalyst exhibits an improved catalytic behavior. The co-supported solid catalyst (comprising cobalt and palladium) was capable of lowering the temperature required to initiate the hydroformylation of propylene by 40°-60° C. than the catalyst without the promoter (see Example V).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([OH:23])[C@@H:12]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:11][C@H:10]1[N:33]=[N+]=[N-])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(S)CCS.C(N(CC)CC)C>CO>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([OH:23])[C@@H:12]([CH2:24][O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:11][C@H:10]1[NH2:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=N[C@@H]1O[C@H](COCc2ccccc2)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: SCCCS
Solvent: CO
Solvent: CCN(CC)CC
Product: N[C@@H]1O[C@H](COCc2ccccc2)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 93.8 %

Procedure:
A mixture of 2,3,6-tri-O-benzyl-β-D-galactopyranosyl azide (3.00 g, 6.31 mmol), propane-1,3-dithiol (3.40 g, 31.50 mmol), and triethylamine (3.50 g, 31.5 mmol) in MeOH (31 ml) was stirred under nitrogen at room temperature for 10 hours. The reaction mixture was evaporated and purified by chromatography using CHCl3/EtOH 10:0.3 v/v to give 2,3,6-tri-O-benzyl-β-D-galactopyranosyl amine (2.66 g, 94%);
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C:12]([NH2:14])=[O:13])[CH2:7][CH2:6][CH2:5]2.[N:15]1([C:20]([C:22]2[CH:23]=[N:24][CH:25]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[N:15]1([C:20]([C:22]2[CH:27]=[C:26]([C:2]3[CH:3]=[C:4]4[C:9](=[N:10][CH:11]=3)[N:8]([C:12]([NH2:14])=[O:13])[CH2:7][CH2:6][CH2:5]4)[CH:25]=[N:24][CH:23]=2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC(=O)N1CCCc2cc(Br)cnc21
Reactant: CC1(C)OB(c2cncc(C(=O)N3CCCC3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=O)N1CCCc2cc(-c3cncc(C(=O)N4CCCC4)c3)cnc21
Temperature: 90 °C
Yield: 46.6 %

Procedure:
To a mixture of 6-bromo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (55 mg, 0.22 mmol) and pyrrolidin-1-yl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanone (78 mg, 0.26 mmol) in 1,4-dioxane (2 mL) is added 2.0 N aqueous sodium carbonate solution (0.23 mL, 0.46 mmol). Argon gas is bubbled through the solution for 5 min. To the mixture is added PdCl2(dppf) catalyst (12 mg, 0.02 mmmol) in one portion. The mixture is heated at 90° C. for 2 hrs. The mixture is filtered through short pad of diatomaceous earth, rinsing with EtOAC (3×1 mL). The filtrate is dried under reduced pressure. The reaction mixture is purified by Mass-triggered reverse phase HPLC to give 36 mg of the titled product.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[O:15]=[C:16]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[CH:24][C:23](C(O)=O)=[C:22]2[N:17]1[CH2:18][CH2:19][C:20]1[CH:38]=[CH:37][S:36][C:21]=12>C1(C)C=CC=CC=1>[F:32][C:28]1[CH:27]=[C:26]([C:25]2[C:16](=[O:15])[N:17]3[C:22](=[C:23]([C:6]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:5])[CH:24]=2)[C:21]2[S:36][CH:37]=[CH:38][C:20]=2[CH2:19][CH2:18]3)[CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1cc(-c2cccc(F)c2)c(=O)n2c1-c1sccc1CC2
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(-c2cccc(F)c2)c(=O)n2c1-c1sccc1CC2
Reaction time: 8 h

Procedure:
0.96 ml of N,N-dimethylformamide di-t-butyl acetal was added dropwise within 20 minutes to a boiling solution of 0.34 g of 4,5-dihydro-7-oxo-8-(m-fluorophenyl)-7H-thieno[2,3-a]quinolizine-10-carboxylic acid in 5 ml of toluene. The mixture was heated under reflux for an additional 30 minutes, left to stand at room temperature overnight and then washed once with water, twice with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized from ethyl acetate and there was obtained tert-butyl 8-(m-fluorophenyl)-4,5-dihydro-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylate of m.p. 135°-137°.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:22])([F:21])[CH:8]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[O:9]1>C(OCC)C>[Cl:1][S:2]([C:18]1[CH:19]=[CH:20][C:10]2[O:9][CH:8]([C:7]([F:22])([F:21])[F:6])[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[CH:17]=1)(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)C1=Cc2ccccc2OC1C(F)(F)F
Solvent: CCOCC
Product: O=C(O)C1=Cc2cc(S(=O)(=O)Cl)ccc2OC1C(F)(F)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To chlorosulfonic acid (50.0 mL) chilled to −15° C. was added 2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example 10) (4.0 g, 16.7 mmol). After stirring at −15° C. for 1 hour, the solution was warmed to room temperature and stirred for 16 hours. The resulting solution was added dropwise over ice (100 mL) with two diethyl ether(2×75 mL) extractions. The diethyl ether layers were combined, washed with water (2×75 mL), and brine (2×75 mL, dried over sodium sulfate and concentrated in vacuo. The resulting solids were triturated with hexane-ethyl acetate (9:1, 100 mL). The 6-chlorosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid was isolated as a white solid: mp 169-174. 1H NMR (CD3OD/300 MHz) 8.18 (d, 1H, J=2.7 Hz), 8.06 (dd, 1H, J=8.7, 2.7 Hz), 7.93 (s, 1H), 7.28 (d, 1H, J=8.7 Hz), 6.00 (q, 1H, J=6.6 Hz). EIHRMS m/z 324.9977 (M+, Calcd 324.9994).
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Mg]Br)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:2]2[C:6]3[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=3[CH2:4][CH2:3]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)CC2
Reactant: Clc1ccc([Mg]Br)cc1
Product: CCOC(=O)c1cc2c([nH]1)C(c1ccc(Cl)cc1)CC2

Procedure:
The title compound was synthesized in two steps. First, ethyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.3 g, 1.55 mmol) was reacted with 4-chlorophenyl magnesium bromide (6.2 mL, 1 M in ether, 6.2 mmol, 4 equiv) according to General Procedure 3 to give the endocyclic olefin-containing compound ethyl 6-(4-chlorophenyl)-1,4-dihydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation according to General Procedure 6, and was purified by column chromatography (Isco CombiFlash) using a 0-30% gradient (EtOAc/Heptane) over 22 minutes. 90.7 mg. LCMS m/e 312 (M+Na). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.11 Hz, 3H), 2.27 (dddd, J=12.83, 8.60, 6.36, 6.21 Hz, 1H), 2.58-2.83 (m, 2H), 2.85-3.01 (m, J=12.81, 8.47, 8.47, 4.28 Hz, 1H), 4.27 (tt, J=7.12, 3.63 Hz, 3H), 6.73 (d, J=1.64 Hz, 1H), 7.06 (q, J=4.42 Hz, 2H), 7.28 (d, J=8.35 Hz, 2H), 8.63 (br. s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:28][CH2:29][CH2:30][C:31](OC)=[O:32].[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:30]([CH2:29][CH2:28][C:20]3[S:19][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[C:31]2=[O:32])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CCCc1nc2ccccc2s1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCc2nc3ccccc3s2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 4-(2-benzothiazolyl)butanoate (1.5 eq., prepared in Synthetic Example 22) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[2-(benzothiazol-2-yl)ethyl]-1,8-naphthyridin-2(1H)-one, mp 178 to 179° C./DMF, wherein the product was purified through flash column chromatography and recrystallization.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].C[C:8](P(OC)(O)=O)([C:10]([O-:12])=[O:11])[CH3:9].[S:18]1[CH:22]=[CH:21][C:20](C=O)=[CH:19]1>C1COCC1>[S:18]1[CH:22]=[CH:21][C:20]([CH:9]=[CH:8][C:10]([O:12][CH3:1])=[O:11])=[CH:19]1
Reactant: CC(C)(C)[O-]
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: O=Cc1ccsc1
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccsc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.1 %

Procedure:
A suspension of potassium t-butoxide (61.5 g, 0.55 mol) in THF (800 mL) was cooled in an ice bath and trimethylphosphonoacetate (98 mL, 0.60 mol) in THF (100 mL) was slowly added. After 45 min, thiophene 3-carboxaldehyde (50 mL, 0.55 mol) in THF (100 mL) was slowly added while stirred in the ice bath. The mixture was allowed to warm to rt and stirred for 16 h. The reaction was quenched with 5% sulfuric acid (300 mL) and extracted twice with ether. The organic layers were each washed with brine, dried over magnesium sulfate, combined and concentrated. The residue was purified by FC (10% ethyl acetate in hexanes) and then crystallized from hexanes to give the title compound (71.3 g).
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:23]C)[N:13]2[CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18]2)=[C:9]([NH2:25])[N:8]=1)[CH2:3][O:4][CH3:5].Cl.[OH-].[Na+]>CO.O1CCOCC1.O>[NH2:25][C:9]1[N:8]=[C:7]([O:6][CH:2]([CH3:1])[CH2:3][O:4][CH3:5])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][O:19][CH2:18]1
Reactant: COCC(C)Oc1nc(N)c2nc(OC)n(CC3CCCOC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: COCC(C)Oc1nc(N)c2[nH]c(=O)n(CC3CCCOC3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-{[1-methyl-2-(methoxy)ethyl]oxy}-8-(methyloxy)-9-(tetrahydro-2H-pyran-3-ylmethyl)-9H-purin-6-amine (290 mg) in dry methanol (12 ml) at room temperature and under nitrogen was added 4.0M hydrogen chloride in 1,4-dioxane (5.0 ml). The reaction was left to stir at room temperature for 1 hour. The reaction was concentrated in vacuo and the resulting residue purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (10-45%) to afford a white solid. This was taken up in water (15 ml) and neutralised by the addition of 2.0M sodium hydroxide solution. The solid was filtered and dried on the rotary evaporator (60° C.) for 30 minutes (50 mg).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.[CH:21]([N:24](C(C)C)[CH2:25]C)(C)C.CNC>ClCCl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:24]([CH3:25])[CH3:21])=[N:6]2
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Agent: CNC
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N(C)C)nc2c1C#N
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.70 mmol) was dissolved in dichloromethane (7 ml), then diisopropylethylamine (0.15 ml, 0.88 mmol), dimethylamine (2.0 M tetrahydrofuran solution, 0.50 ml, 1.00 mmol) were added. After stirring in a sealed tube at an external temperature of about 60° C. for 3 hours, this was diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane) to obtain a colorless solid (0.18 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:9][CH:10]1[CH2:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:15][CH:16]=2)[O:11]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>CO.Cl.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:30])[N:7]([CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:15][CH:16]=2)[O:11]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC1CC(=O)c2ccc(S(=O)(=O)c3ccccc3)cc2O1)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CN(CC1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of (7-benzenesulfonyl-4-oxo-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (155 mg, 0.359 mmol) in MeOH (50 mL) were added Pd(OH)2 (10 mg) and HCl (concentrated, 5 drops) the mixture was shaken into a Parr apparatus under H2 atmosphere (50 PSI) for 3 hours. The reaction was filtered through a celite pad and the filtrate was neutralized with Na2CO3. The mixture was filtered and the filtrate was concentrated in vacuo. The residue purified via flash chromatography (DCM/MeOH, 99/1) to give (7-benzenesulfonyl-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (147 mg, 98% yield) as a clear glass.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[NH2:14]>CN1CCCC1=O.C(OCC)(=O)C>[NH2:14][C:6]1[CH:7]=[CH:8][C:9]([CH:11]([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:2]#[N:3]
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(N)c(C#N)c1
Yield: 88.5 %

Procedure:
Heat a mixture of copper (I) cyanide (2.5 g, 28.02 mmol), and 2-bromo4-isopropyl-phenylamine (5.0 g, 23.35 mmol) in 1-methyl-2-pyrrolidinone (20 ml) to 195° C. for four hours. Dilute the reaction mixture with 100 ml of ethyl acetate and wash the dark solution twice with 28% aqueous ammonium hydroxide, twice with saturated aqueous sodium chloride (brine) and twice with water. Collect the organic layer, dry over sodium sulfate and remove the solvent under reduced pressure. Purify the residue via flash chromatography eluting with a step gradient starting with hexanes and going to 80% hexanes with 20% ethyl acetate to obtain 3.31 g (20.66 mmol, 88% yield) of the title compound as an orange oil: Mass Spectrum (m/e): 161(M+1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:32](=[O:33])[N:31]([CH3:34])[C:23]4[N:24]=[C:25](S(C)=O)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]([CH2:39][CH2:40][NH2:41])[CH3:38].C(O)(C(F)(F)F)=O>CN(C=O)C.[Cl-].[Na+].O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:32](=[O:33])[N:31]([CH3:34])[C:23]4[N:24]=[C:25]([NH:41][CH2:40][CH2:39][N:37]([CH3:38])[CH3:36])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)c(-c2ccc(F)c(NC(=O)Nc3cc(C(C)(C)C)no3)c2)cc2cnc(S(C)=O)nc21
Reactant: CN(C)CCN
Agent: [Cl-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)no4)c3)c(=O)n(C)c2n1
Reaction time: 1 h
Yield: 23.5 %

Procedure:
To a stirring solution of 1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 43 (0.125 g, 0.251 mmol, 1.00 eq) in DMF (2.50 ml) at 0° C. was added unsym-dimethylethylenediamine (0.138 ml, 1.25 mmol, 5.00 eq). After 1 h, the completed reaction was diluted with brine (5 ml) and left to stir overnight. The solids were collected by filtration, rinsed well with H2O and dried on the filter to afford crude desired product (76 mg) as a pale pink solid. The crude product was purified by reverse phase chromatography (5-40% MeCN (w/0.1% TFA)/H2O (w/0.1% TFA)) to afford 1-(3-t-butylisoxazol-5-yl)-3-(5-(2-(2-(dimethylamino)ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)urea (37.3 mg, 0.059 mmol) as the TFA salt following lyophilization. The TFA salt thus obtained was treated with MP-Carbonate resin and certified 0.1N HCl (1.0 eq), frozen and lyophilized to afford the HCl salt. 1H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 9.56 (brs, 1H), 8.85 (brs, 1H), 8.76 (brs, 1H), 8.41 (dd, J=2.0 and 7.6 Hz, 1H), 8.01 (brs, 1H), 7.95 (s, 1H), 7.37-7.28 (m, 2H), 6.05 (s, 1H), 3.73 (m, 2H), 3.58 (brs, 3H), 3.41 (brs, 2H), 2.85 (brs, 6H), 1.24 (s, 9H); MS (ESI) m/z: 523.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:5](=[O:17])[NH:4][C:3]=1[C:18]1[N:22]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[N:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[K+].[CH2:37]1[CH2:41]O[CH2:39][CH2:38]1.ICCCC>O>[CH2:41]([N:4]1[C:3]([C:18]2[N:22]([C:23]3[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=3)[N:21]=[CH:20][CH:19]=2)=[C:2]([CH3:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:5]1=[O:17])[CH2:37][CH2:38][CH3:39]
Reactant: C1CCOC1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCI
Product: CCCCn1c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 7 h

Procedure:
4-(5-{5-Methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (Example 1) (102 mg, 0.25 mmol) was added to a stirred mixture of potassium tert-butoxide (42 mg, 0.375 mmol) and THF (2.0 mL) under a nitrogen atmosphere. This resulted in the formation of a yellow solution. 1-Iodo-butane (0.057 mL, 0.5 mmol) was added and the mixture was stirred for 7 h then left to stand for 16 h. Water (10 mL) was added and the mixture was extracted with DCM (3×10 mL). The combined organic phase was dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash column chromatography (2 g Si II SPE eluted with DCM). The crude product thus obtained was further purified by flash column chromatography (2 g Si II SPE eluted with 20% EtOAc in cyclohexane). Concentration of the appropriate fractions in vacuo gave the title compound which was freeze-dried from acetonitrile/water to afford a white solid (25 mg).
Reaction SMILES: CSC.[CH:4]1([Mg]Br)[CH2:6][CH2:5]1.Br[CH:10]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:17](=[O:27])[CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][N:22]=3)[N:20]=[C:11]12>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH:4]1([CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]3[C:17](=[O:27])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][N:22]=4)[N:20]=[C:11]23)[CH2:6][CH2:5]1
Reactant: O=c1cc(-c2ccncn2)nc2n1CCCCC2Br
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CSC
Solvent: C1CCOC1
Product: O=c1cc(-c2ccncn2)nc2n1CCCCC2C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
To a solution of 1.33 g (6.48 mmol) of CuBr.DMS in 25 mL of dry tetrahydrofuran at −78° C., was slowly added 12.45 mL (6.23 mmol) of cyclopropyl magnesium bromide (0.5 M in tetrahydrofuran). The resulting mixture was stirred at room temperature for 30 min. 0.800 g (2.49 mmol) of (+/−)-10-bromo-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one dissolved in 10 mL of dry tetrahydrofuran was added at −78° C. and the resulting mixture was stirred for 1.5 hours and allowed to warm to room temperature. The mixture was dissolved in a saturated solution of ammonium chloride and ethyl acetate. The organic phases were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography (dichloromethane/methanol/ammoniac in proportions of 99/1/0.1) to afford 0.230 g (33%) of a white solid.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)C=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([C:32]3[CH:37]=[C:36](SC)[CH:35]=[CH:34][N:33]=3)[N:29]([C:40]3[CH:41]=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=3)[N:28]=2)=[O:26])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[S:48]([O-:52])([O-])(=[O:50])=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([C:32]3[CH:37]=[C:36]([S:48]([CH3:2])(=[O:52])=[O:50])[CH:35]=[CH:34][N:33]=3)[N:29]([C:40]3[CH:41]=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=3)[N:28]=2)=[O:26])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1ccc(-n2nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2cc(SC)ccn2)cn1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2cc(S(C)(=O)=O)ccn2)cn1
Reaction time: 0.33 h

Procedure:
At 0° C., 3-chloroperbenzoic acid (0.260 g) was added to a solution of 4-[1-(6-methoxy-3-pyridyl)-5-(4-methylthio-2-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid tert-butyl ester (0.366 g) obtained in Example 47 in methylene chloride (7.3 mL), and the mixture was stirred for 20 minutes. Subsequently, the mixture was stirred at room temperature for a further 2 hours. At 0° C., 3-chloroperbenzoic acid (0.124 g) was added thereto, and the resultant mixture was stirred for 2 hours. Saturated aqueous sodium thiosulfate (10 mL) and saturated aqueous sodium hydrogencarbonate (10 mL) were added to the reaction mixture, followed by stirring. The reaction mixture was partitioned between water and chloroform. The organic layer was dried over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an amorphous product (0.387 g, 99%).