Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].Cl.[N:13]([O-])=O.[Na+].[OH:17][C:18]1[CH:23]=[C:22]([CH3:24])[O:21][C:20](=[O:25])[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH:9][N:13]=[C:19]2[C:18](=[O:17])[CH:23]=[C:22]([CH3:24])[O:21][C:20]2=[O:25])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(NN=C2C(=O)C=C(C)OC2=O)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
To a mixture of 3.78 g (0.025 mol) 4-carbomethoxy aniline and 10 ml of 12 N hydrochloric acid in 15 ml of water, cooled to 5° C., there is added dropwise a solution of 1.9 g (0.0275 mol) sodium nitrite in 5 ml of water. The solution formed is added to an ice cooled solution of 3.15 g (0.025 mol) 4-hydroxy-6-methyl pyr-2-one and 11 g (0.1025 mol) sodium carbonate in 65 ml of water. The suspension formed is stirred at 5° C. for 1 hr and at room temperature for 3 hrs. The suspension is vacuum filtered and the filter cake is air dried to afford 6.8 g (94.4% yield) of product, mp 230-240 decomp.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[C:16]([C:31]([OH:33])=O)[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:38][C:39]([F:49])([F:48])[C@H:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)C(C)C)(C)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>ClCCl.O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[CH2:21][CH2:20]3)=[C:16]([C:31]([NH:47][C@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:39]([F:38])([F:48])[F:49])=[O:33])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:34]([CH3:37])(=[O:35])=[O:36])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc2nc(-c3cccc(Br)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc2nc(-c3cccc(Br)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A mixture of 2-(3-bromophenyl)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-4-quinolinecarboxylic acid (0.250 g, 0.398 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.093 g, 0.438 mmol), and N,N-diisopropylethylamine (77 μL, 0.438 mmol) in dichloromethane (3.98 mL) was cooled to 0° C., and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (0.356 mL of 50% solution in ethyl acetate, 0.597 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 h, warmed to room temperature, and stirred overnight. The mixture was diluted with water (2 mL) and saturated aqueous NaHCO3 (1 mL) was added. After stirring for 30 min, the organic phase was removed, passed over a phase separator, and concentrated in vacuo. The residue was dissolved in acetonitrile, and water was added slowly until the mixture became cloudy. The solid precipitate was collected by filtration, washed with water, and dried to afford 2-(3-bromophenyl)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.260 g, 88% yield). MS (m/z) 747.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]2[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])S[C:19]([CH3:27])([CH3:26])[C:18]2=[O:28])[CH:10]=1.O[O:30][S:31]([O-:33])=O.[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]2[C:18](=[O:28])[C:19]([CH3:27])([CH3:26])[S:31](=[O:33])(=[O:30])[C:21]([CH3:25])([CH3:24])[C:22]2=[O:23])[CH:10]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)SC(C)(C)C1=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)S(=O)(=O)C(C)(C)C1=O
Yield: 29 %

Procedure:
A mixture of 4-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylthiopyran-3,5-dione (79 mg, 0.1816 mmol) and oxone (446 mg, 0.726 mmol) is stirred at ambient temperature for 20 hours as a solution in methanol/water (1 ml, 1:1 ratio). The reaction mixture is then partitioned between water and dichloromethane, the organic phase is separated and concentrated under reduced pressure. The residue is purified by preparative reverse phase HPLC to give 4-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethyl-1,1-dioxo-thiopyran-3,5-dione (24.6 mg) as a clear gum.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][N:7]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:5])[CH3:2].[CH3:26][N:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28](Cl)=[O:29]>>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:7]2[CH2:8][CH2:9][N:10]([C:28]([N:27]([CH3:26])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:29])[CH2:11][CH:6]2[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:13])=[O:14])=[CH:16][CH:17]=1)[C:23]#[C:24][CH3:25]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCNCC2C(=O)OCC)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)N(C)c3ccccc3)CC2C(=O)OCC)cc1
Yield: 98 %

Procedure:
In the same manner as described in Step 1 of Example 215, the 1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid ethyl ester (1.0 g, 2.7 mmol) was treated with N-methyl-N-phenylcarbamoyl chloride to provide 1.33 g (98%) of ethyl 1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(methylanilino)carbonyl]-2-piperazine-carboxylate as a brown oil. Electrospray Mass Spec 500.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[CH:21][C:22]([N+:24]([O-])=O)=[CH:23][C:15]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].I.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](SC)=[NH:34]>C(O)C.ClCCl.[Pd]>[OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[CH:21][C:22]([NH:24][C:33]([C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)=[NH:34])=[CH:23][C:15]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2ccc([N+](=O)[O-])cc21
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2ccc(NC(=N)c3cccs3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
A stirred suspension of tert-butyl 2-hydroxyethyl(2-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (590 mg, 1.539 mmol) and palladium, 10 wt. % on activated carbon (164 mg, 0.154 mmol) in ethanol (10 mL) was stirred at room temperature under an atmosphere of hydrogen (1 atm) for 2 hours (yellow color disappears). To this mixture was then added methyl thiophene-2-carbimidothioate hydroiodide (878 mg, 3.08 mmol), and the resulting mixture was stirred overnight at room temperature. The mixture was then diluted with dichloromethane and then filtered through Celite. The filtrate was then diluted with water and extracted with dichloromethane (4×). The combined organics were dried, filtered, concentrated, and then chromatographed in ethyl acetate, giving the desired product (339 mg, 47.6%) as a yellow foam. 1H NMR (DMSO-d6) δ 7.69 (s, 1H), 7.58 (d, J=4.8 Hz, 1H), 7.07 (t, J=4.2 Hz, 1H), 6.41-6.25 (m, 3H), 6.08 (d, J=8.1 Hz, 1H), 4.71-4.65 (m, 1H), 3.63-3.54 (m, 2H), 3.49-3.33 (m, 6H), 3.27-3.15 (m, 2H), 3.02-2.94 (m, 2H), 1.39-1.29 (m, 9H); ESI-MS (m/z, %): 463 (MH+, 100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][OH:20])[CH:13]=1)[CH2:8][CH2:9][F:10])([CH3:4])([CH3:3])[CH3:2]>CC#N.O=[Mn]=O>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=[O:20])[CH:13]=1)[CH2:8][CH2:9][F:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCF)Cc1ccc(Cl)c(CO)c1
Agent: O=[Mn]=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CCF)Cc1ccc(Cl)c(C=O)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100.5 %

Procedure:
MnO2 (1.22 g, 12.6 mmol) was added to a sol. of (4-chloro-3-hydroxymethyl-benzyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester (801 mg, 2.52 mmol) in CH3CN (50 mL). The mixture was stirred at rt for 4.5 h, and MnO2 (1.22 g, 12.6 mmol) was added again. The mixture was stirred for 1 h, and was filtered over celite. The precipitate was washed with CH3CN and CH2Cl2. The filtrate was evaporated under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (800 mg, quantitative yield) that was used further without purification. LC-MS: tR=1.01 min.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6]1)(=[O:4])=[O:3].[N:19]([C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1)=[C:20]=[O:21]>ClCCl>[CH3:1][S:2]([N:5]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]2([CH2:8][CH2:9][N:10]([C:20]([NH:19][C:22]3[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=3)=[O:21])[CH2:11][CH2:12]2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)N2CCC3(CC2)CN(S(C)(=O)=O)c2ccccc23)cc1
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a stirred solution of 1-methylsulfonyl-spiro[indoline-3,4′-piperidine] (2.66 g, 10 mmol) in dichloromethane (50 mL), was added ethyl 4-isocyanatobenzoate (1.91 g, 10 mmol) at room temperature. The resulting solution was stirred for four hours during which time precipitation occurred. The mixture was evaporated to remove dichloromethane, and then was suspended in methanol (20 mL), filtration followed by washing with cold methanol gave 1500 as a white solid (4.56 g, 100%)
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][Mg]Br)[CH3:2].[CH2:11]([C:19]#N)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC.C([O:23][CH2:24][CH3:25])C>>[CH2:1]([CH:3]([CH2:4][C:24](=[O:23])[CH2:25][CH2:19][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: CCCCC(CC)C[Mg]Br
Reactant: CCOCC
Reactant: CCCCCCCCC#N
Product: CCCCCCCCC(=O)CC(CC)CCCC
Reaction time: 12 h
Yield: 32 %

Procedure:
A Grignard solution of 2-ethylhexylmagnesiumbromide in diethylether (1.0 M, 110 mL, 0.11 mol) was slowly added via syringe to a stirred mixture of n-octylcyanide (4.66 g, 55 mmol) in diethyl ether (100 mL) at 0° C. under N2 atmosphere. After stirring for 12 h at reflux temperature, the reaction was quenched with an aqueous HCl-solution (2.0 M, 50 mL) at 0° C. and subsequently vigorously stirred for an additional 3 h at room temperature. The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with a saturated bicarbonate solution and brine, dried over MgSO4 and evaporated under reduced pressure to give a yellow solid. The resulting solid was purified by recrystallization from acetone to afford white crystals (IX) (4.51 g, 32%). 1H-NMR (CDCl3): δ=2.99-2.79 (m, 4H), 2.64-2.50 (m, 1H), 1.82-1.55 (m, 4H), 1.57-1.03 (m, 18H), 0.89-0.71 (m, 9H). 13C-NMR (CDCl3): δ=164.35, 34.89, 32.44, 30.31, 30.09, 29.90, 29.79, 28.48, 28.31, 25.71, 23.26, 14.71.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:13]=2[N:14]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(Cl)(Cl)Cl>[C:22]([N:10]1[CH2:11][CH2:12][C:13]2[N:14]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][C:8]=2[CH2:9]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1nc2c(s1)CNCC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc2c(s1)CN(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-tert-butyl 2-ethyl 6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-2,5(4H)-dicarboxylate obtained in step V of example 1 was deprotected to get the 4,5,6,7-Tetrahydro-thiazolo[5,4-c]pyridine-2-carboxylic acid ethyl ester. To a solution of 4,5,6,7-Tetrahydro-thiazolo[5,4-c]pyridine-2-carboxylic acid ethyl ester (1 eq) and triethyl amine (1 eq) in chloroform, acetic anhydride was added and the reaction mixture was stirred for 1 h at room temperature. Reaction mixture was then diluted with chloroform and washed with water. Organic layer was then separated, dried and concentrated under reduced pressure to afford the desired ethyl 5-acetyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylate.
Reaction SMILES: O.[NH:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[CH:9]1([CH:15]=O)[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1.C(CN)O>C(O)(C)C>[CH:9]1([CH:15]=[C:8]2[NH:2][C:3](=[O:4])[NH:5][C:6]2=[O:7])[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1
Reactant: O=C1CNC(=O)N1
Reactant: O=CC1CC=CCC1
Solvent: NCCO
Solvent: CC(C)O
Solvent: O
Product: O=C1NC(=O)C(=CC2CC=CCC2)N1
Temperature: 120 °C
Yield: 87.1 %

Procedure:
Fifty milliliters of water, 20 ml of isopropyl alcohol, 20.00 g of hydantoin, 24.22 g of 3-cyclohexene-1-carbaldehyde and 6.10 g of monoethanolamine were placed in a reactor equipped with a mechanical stirrer and a reflux condenser, the mixture was stirred in an oil bath at 120° C. while refluxing. After 3 hours of continued heating and stirring, the solution was cooled to 10° C., and the precipitated crystals were collected by filtration. These were suspended in 100 ml of a mixed solution of water and isopropyl alcohol (volumetric ratio=2:5), after which the crystals were again collected by filtration and dried under reduced pressure at 40° C. overnight, to obtain 33.45 g of 5-(3-cyclohexene-1-yl)methylenehydantoin. The yield was 87.0%. The crude crystals were recrystallized from ethanol to obtain a pure product.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:21][CH2:20][C:10]2=[CH:11][C:12](Br)=[C:13]3[C:17]([C:16]([CH3:18])=[CH:15][CH2:14]3)=[C:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2[C:17]3[CH:16]([CH3:18])[CH2:15][CH2:14][C:13]=3[CH:12]=[CH:11][C:10]=2[CH2:20][CH2:21]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2cc(Br)c3c(c2CC1)C(C)=CC3
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(C)CC3

Procedure:
Into a 500 ml Parr hydrogenation bottle, the product from step (b) (80 mg, 0.23 mmol) dissolved in EtOH (50 ml) was placed. To the argon purged bottle, 10% Pd—C (wet, 100 mg) was added. The bottle was shaken over hydrogen (50 psi) for 3 h. The reaction mixture was filtered through celite and solvent evaporated in vacuo to give the sub-titled compound as colorless oil. MS: ESI (positive): 274 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[C:13](=[O:14])[CH2:12][NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([N:11]1[CH2:12][C:13](=[O:14])[N:9]([CH2:8][C:7]2[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:10]1=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1CNC(=O)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN(Cc2ccccc2)C(=O)N1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
A solution of the product from step (a) (5.9 g) in DMF (15 ml) was added under N2 to a stirred suspension of anhy. K2CO3 (3.5 g) in DMF (15 ml), followed by the addition of benzyl bromide (4.3 g, Aldrich). After additions were complete, the mixture was stirred at room temperature for 16 hours, then poured into ice-water and extracted with ethyl acetate (×3). The combined extracts were washed with brine, dried over MgSO4 and evaporated to give a yellow oil which was flash chromatographed through a silica column using ethyl acetate to give the desired product as a yellow oil (7.0 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cn1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cn1
Temperature: 82.5 °C
Yield: 46.5 %

Procedure:
To a mixture of the amidine of Step 1 (9.8 g, 33.9 mmol) and sodium bicarbonate (5.7 g, 67.8 mmol) in isopropanol (700 ml), 3-bromo-1,1,1-trifluoroacetone (5.3 ml, 50.8 mmol) was added. After heating at 80-85° C. for 24 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude material (25.7 g) was purified by chromatography (silica gel, ethyl acetate/acetone, 98/2) to give 2-methyl-5-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine (6.3 g, 46%) as a white solid: Anal. Calc'd. for C17H16N3SO3F3: C, 50.55, H, 4.12, N, 10.40. Found: C, 50.51, H, 3.91, N, 10.25.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[N:9]([C:13]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:15]=2)[N:10]=[CH:11][CH:12]=1)(=O)=O.C1[CH2:46][O:45][CH2:44]C1.C(N(CC)CC)C.C[OH:55]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:30]([O:29][C:27]([NH:26][C:22]1([C:19]2[CH:18]=[CH:17][C:16]([C:14]3[N:15]=[C:8]4[C:7]([C:44]([O:45][CH3:46])=[O:55])=[CH:12][CH:11]=[N:10][N:9]4[C:13]=3[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24][CH2:25]1)=[O:28])([CH3:31])([CH3:32])[CH3:33]
Reactant: CO
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(OS(=O)(=O)C(F)(F)F)ccnn4c3-c3ccccc3)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccnn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazin-8-yl trifluoromethanesulfonate that was prepared in a manner analgous to that described for Intermediate Example Int-15 (0.15 g, 0.25 mmol) in MeOH (0.4 mL) and THF (0.04 mL) in an autoclave was added 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.040 g, 0.050 mmol, 0.20 equiv) and triethylamine (0.040 mL, 0.27 mmol, 1.1 equiv.). The autoclave was flushed with CO (approximately 5 bar) three times, then was pressurized with CO (5.2 bar), stirred at room temperature 30 min., and briefly placed under reduced atmosphere (0.06 bar). The autoclave was then pressurized with CO (5.9 bar at 20° C.), heated to 100° C., and stirred at this temperature for 18 h. The resulting solution was concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 10 g cartridge, 100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 2.5 min, gradient to 70% hexane/30% EtOAc 3.0 min, 70% hexane/30% EtOAc 2.5 min, gradient to 50% hexane/50% EtOAc 3.5 min, 50% hexane/50% EtOAc 4.0 min, gradient to 100% EtOAc 1.0 min, 100% EtOAc 5.8 min) to give methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-8-carboxylate (0.081 g, 63%):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>ClCCl>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][N:30]([C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[O:9])[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)ccn2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.3 %

Procedure:
To a dichloromethane solution (4 ml) of 4-chloropicolinic acid chloride (175 mg, 0.994 mmol), N-ethyldiisopropylamine (346 μl, 1.99 mol) and N-Boc-piperazine (278 mg, 1.49 mmol) were added, followed by stirring at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=60/1), to obtain 4-(4-chloro-pyridine-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (166 mg, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.S(Cl)([Cl:20])(=O)=O>C(Cl)Cl>[Cl:20][CH:10]([C:9](=[O:16])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)Cc1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(Cl)C(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a solution of ethyl 4-(4-chlorophenyl)-3-oxobutanoate (61.0 g, 253 mmol) in DCM (811 mL) in an ice bath was added sulfuryl chloride (34.2 g, 253 mmol) and the resulting solution was allowed to stir at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate solution (200 mL) and the layers separated. The organic layer was washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 70.8 g of title compound. (100% yield). 1H NMR (400 MHz, CDCl3) δ: 7.33-7.30 (m, 2H), 7.17-7.14 (m, 2H), 4.85 (s, 1H), 4.26 (dq, 1H, J=7.2, 1.2 Hz), 4.02 (d, 1H, J=16.8 Hz), 3.97 (d, J=16.8 Hz, 1H), 1.29 (t, 3H, J=7.2 Hz).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:37])=[C:26]([C:28]3[C:29]([C:35]#[N:36])=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH:27]=2)OC1>>[F:34][C:31]1[CH:30]=[C:29]([C:35]#[N:36])[C:28]([C:26]2[CH:27]=[CH:22][CH:23]=[CH:24][C:25]=2[F:37])=[CH:33][C:32]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Product: CC(C)(O)c1ccn2c(-c3cc(-c4ccccc4F)c(C#N)cc3F)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-4,2′-difluorobiphenyl-2-carbonitrile as described in Example 65 to give 4,2′-difluoro-5-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as a white solid: δH (400 MHz, CDCl3) 1.62 (6H, s), 4.47 (1H, s), 7.08 (1H, d, J 7), 7.39-7.46 (2H, m), 7.55 (1H, dd, J 8 and 3), 7.60-7.64 (3H, m), 7.85 (1H, s), 8.81 (1H, d, J 7); m/z (ES+) 391 (M++H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12](OC1C=CC=CC=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[Li+].[OH-:23]>CO.O>[O:23]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:3])=[O:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1cc2c(Oc3ccccc3)cccc2[nH]1
Agent: [Li+]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2ccccc2n1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
132 (160 mg, 0.569 mmol) is dissolved in 5 ml of methanol and treated with a solution of LiOH (27.2 mg, 1.138 mmol) in 3 ml of water. The mixture is stirred at room temperature overnight. Since the reaction is not complete (TLC), additional LiOH (30 mg, 1.25 mmol) is added and the stirring is continued for additional 18 h. After evaporation, the crude product is acidified at 0° C. with 2M HCl and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated.