Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.[F:34][C:35]([F:44])([F:43])[C:36]1[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=1>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:42][C:39]2[CH:38]=[CH:37][C:36]([C:35]([F:43])([F:34])[F:44])=[CH:41][N:40]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cn1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared in Example 54, 200 mg, 0.69 mmol) in methylene chloride (10 mL) and one drop of N,N-dimethylformamide was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.42 mL, 0.84 mmol). Gas evolution began immediately. The reaction mixture was allowed to warm slowly to 25° C. where it was stirred for 30 min. After this time, the reaction mixture was treated with a solution of N,N-diisopropylethylamine (0.24 mL, 1.39 mmol) and 5-trifluoromethyl-2-aminopyridine (150 mg, 0.905 mmol) in tetrahydrofuran (4 mL) in one portion. The resulting reaction mixture was stirred for 16 h at 25° C. After such time, the reaction was diluted with water (15 mL) and was extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded the 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide (77 mg, 26%) as a white solid: mp 113.8-117.5° C.; EI-HRMS m/e calcd for C20H19Cl2F3N2O (M+) 430.0826, found 430.0835.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:12]3[C:13]([CH3:33])=[C:14]([N:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)[CH2:21][CH2:20]4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:35])[CH3:34])=[CH:4][CH:3]=1>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:33])=[C:14]([N:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=5)[CH2:21][CH2:20]4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:35])[CH3:34])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(F)cc3)C(C)(C)O4)CC2)cc1
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(c3ccc(F)cc3)C(C)(C)O4)CC2)cc1
Yield: 78 %

Procedure:
Using 3-(4-fluorophenyl)-5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Example 64, the title compound was synthesized in the same manner as in Example 46. Yield 78%. mp. 139–141° C. (ethanol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]4[CH2:32][CH2:33][N:29]([CH3:28])[C:30]4=[O:34])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 78.5 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (452 mg) described in Preparation Example 112 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (370 mg) was obtained.
Reaction SMILES: C([N:4]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[C:25]([NH2:31])[C:21]=3[C:22](=[O:24])[CH:23]=2)=[CH:14][C:13]=1[F:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br)(=O)C.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.O>O1CCCC1>[NH2:31][C:25]1[C:21]2[C:22](=[O:24])[CH:23]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[C:13]([F:32])[CH:14]=3)[O:19][C:20]=2[C:28]([F:29])=[CH:27][C:26]=1[F:30]
Reactant: CC(=O)N(CCCCCCBr)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: C1CCNC1
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCCCCN4CCCC4)c(F)c3)cc(=O)c12

Procedure:
500 mg (1.07 mmol) of 5-amino-2-[4-(6-bromohexylamino)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 52 was dissolved in 15 ml of tetrahydrofuran, 0.891 ml of pyrrolidine was added and the mixture was heated at reflux for 1.5 hours. Water was added to the reaction solution and the mixture was extracted with a mixed solvent of chloroform and methanol. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol:triethylamine=90:10:1) and recrystallized from chloroform/n-hexane to give Compound 54 which was converted into hydrochloride according to the same manner as that in Example 16 to give 88 mg (17%).
Reaction SMILES: [C:1]([OH:19])(=O)[CH2:2][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][CH2:16][CH3:17].S(Cl)([Cl:22])=O>C1CCCCC1>[C:1]([Cl:22])(=[O:19])[CH2:2][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][CH2:16][CH3:17]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCC(=O)O
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 80 °C
Yield: 81.6 %

Procedure:
In a one L (liter) two-necked flask were placed 102.1 g (0.38 mol) of heptadecanoic acid and 200 milliliter (mL) of cyclohexane, and the flask was equipped with a 100 mL dropping funnel containing 67.3 g (0.57 mol) of thionyl chloride and a reflux tube. Then, the heptadecanoic acid was completely dissolved under heating and stirring of the flask in an oil bath at 80° C. Thereafter the thionyl chloride was added dropwise over a period of 2 hours, and further the oil bath was maintained at 80° C. for one hour. From the resultant reaction mixture were removed the cyclohexane and the thionyl chloride under reduced pressure by means of an aspirator. The resultant reaction mixture was subjected to vacuum distillation. Thus 88.5 g (0.31 mol) of heptadecanoyl chloride was obtained in a yield of 81.2% based on the fed heptadecanoic acid.
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=[O:9])[CH:7]=[CH:6][CH:5]([OH:10])[O:4]1)[CH3:2].[CH:11]([O-])([O-])OC.S([O-])([O-])(=O)=O.[Mg+2]>>[CH2:1]([CH:3]1[C:8](=[O:9])[CH:7]=[CH:6][CH:5]([O:10][CH3:11])[O:4]1)[CH3:2]
Reactant: CCC1OC(O)C=CC1=O
Reactant: COC([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CCC1OC(OC)C=CC1=O
Yield: 86 %

Procedure:
A 14.2 g quantity of 2-ethyl-6-hydroxy-3-oxo-3,6-dihydro-2H-pyran and 50 g of methyl orthoformate are reacted in the presence of 10 g of magnesium sulfate under reflux for 24 hours. After the reaction, the mixture is filtered to remove the magnesium sulfate, and the filtrate is concentrated in vacuum to remove the excess methyl orthoformate. The residue is poured into 50 ml of water, the mixture is extracted with ether, and the ethereal layer is washed with a sodium carbonate solution and dried over magnesium sulfate. The dried mass is distilled to remove the ether, and the residue is further distilled at a reduced pressure of 12 mm Hg to give 13.4 g of 2-ethyl-6-methoxy-3-oxo-3,6-dihydro-2H-pyran as a yellow liquid fraction at 85° to 90° C in a yield of 86%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>CCO.CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of tert-butyl 4-(4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (I43) (0.570 g, 1.87 mmol) in EtOH (5 mL) and DMF (5 mL) was added to a solution of 10% Pd/C (200 mg) in DMF (10 mL). The reaction was stirred at room temperature for 24 hours under an atmosphere of hydrogen. The reaction was filtered through a pad of celite and washed through with EtOAc (130 mL). The solvent was removed in vacuo to yield a brown oil which was purified by column chromatography on silica gel (0-50% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I44) (0.46 g, 89%) as a crystalline solid; 1H NMR (400 MHz, CDCl3) δ 7.02-6.96 (m, 2H), 6.67-6.61 (m, 2H), 4.21 (bs, 2H), 3.57 (s, 2H), 2.77 (t, J=12.2 Hz, 2H), 2.53 (tt, J=12.1, 3.5 Hz, 1H), 1.77 (d, J=13.3 Hz, 2H), 1.64-1.50 (m, peak obscured by solvent), 1.48 (s, 9H). LCMS Method C: rt 4.77 min; m/z 221 [M-tButyl+2H]+, 177 [M-Boc+2H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)=[O:2].[CH3:14][Mg]Br>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:4]=[C:5]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)[CH3:14]
Reactant: CS(=O)(=O)Nc1cccc(C=O)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cccc(NS(C)(=O)=O)c1
Reaction time: 2 h

Procedure:
Under argon and at 0° C., 83 mg (0.417 mmol) of N-(3-formylphenyl)methanesulfonamide (Example 86A) were initially charged in 1 ml of abs. tetrahydrofuran. At 0° C., 99 mg (0.833 mmol) of methylmagnesium bromide (3 M in diethyl ether) were added dropwise (resulting in the formulation of a precipitate), and the reaction solution was stirred at this temperature for 2 h. The reaction solution was quenched with water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:22])([F:21])[CH:4]([C:17]([F:20])([F:19])[F:18])[C@H:5]([NH:8][C@@H](C1C=CC=CC=1)C)[CH2:6][OH:7]>CO>[ClH:1].[NH2:8][C@@H:5]([CH:4]([C:3]([F:2])([F:21])[F:22])[C:17]([F:18])([F:19])[F:20])[CH2:6][OH:7]
Reactant: C[C@@H](N[C@H](CO)C(C(F)(F)F)C(F)(F)F)c1ccccc1
Agent: Cl
Solvent: CO
Product: N[C@H](CO)C(C(F)(F)F)C(F)(F)F
Reaction time: 2 h
Yield: 117.4 %

Procedure:
A 2 L Parr bottle was flushed with N2 and 9.374 g (0.10 g/mmol) of 10% Pd/C was carefully added to the flask. Then, 50 mL of anhydrous MeOH was added and the flask was carefully swirled. A solution of 36.136 g (98.3 mmol, 1.0 equiv) of (2S)-4,4,4-trifluoro-2-{[(1R)-1-phenylethyl]amino}-3-(trifluoromethyl)butan-1-ol hydrochloride salt dissolved in 50 mL of MeOH was added to the flask. The Parr bottle was flushed with more N2, and then capped. The heterogeneous reaction mixture was hydrogenated at 45 psi for 2 h. The reaction was checked for completion by 1H NMR. The reaction was worked up by filtering through a 1-inch pad of the Celite® reagent and washing with 1.5-2 L of MeOH. The filtrates were combined and concentrated in vacuo to give 28.56 g (100%) of (2S)-2-amino-4,4,4-trifluoro-3-(trifluoromethyl)butan-1-ol hydrochloride salt as a cream-colored solid. Further purification by triturating with 80 mL of 1:1 hexane:Et2O can also be performed. Mass Spectrum (+ESI): 212.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([NH:14][C:15]3[C:16]4[CH:17]=[N:18][NH:19][C:20]=4[CH:21]=[CH:22][CH:23]=3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH:5]=[C:4]([S:24][CH3:25])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:31]>O1CCOCC1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([NH:14][C:15]3[C:16]4[CH:17]=[N:18][NH:19][C:20]=4[CH:21]=[CH:22][CH:23]=3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH:5]=[C:4]([S:24]([CH3:25])=[O:31])[N:3]=1
Reactant: CSc1cc(-c2nccnc2Nc2cccc3[nH]ncc23)nc(C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Product: Cc1nc(-c2nccnc2Nc2cccc3[nH]ncc23)cc(S(C)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-(3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-yl)-1H-indazol-4-amine (20 mg, 0.057 mmol) and 3-chloroperoxybenzoic acid (14.82 mg, 0.086 mmol, Aldrich, St. Louis, Mo.—77%) in dioxane (1 mL) was stirred at room temperature for 2 h. LCMS showed no starting material left. The reaction mixture was used for the next step of reaction without purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:16])=[N-]>[I-].[Zn+2].[I-]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]2[CH:10]([CH2:16]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCN(Cc2ccccc2)CC1
Reactant: C=[N+]=[N-]
Agent: [I-]
Agent: [Zn+2]
Product: c1ccc(CN2CCC3CC3C2)cc1

Procedure:
Reaction of 1-benzyl-1,2,5,6-tetrahydropyridine with diazomethane and zinc iodide, according to the method of Attia, Ind. J. Chem., 16B, 98 (1978) provides 3-benzyl-3-azabicyclo[4.1.0]heptane. Hydrogenolytic removal of the benzyl group gives 3-azabicyclo[4.1.0]heptane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Li]C(CC)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[Cl:1][C:2]1[C:7]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:9]=[CH:10][C:3]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Reactant: CCOC(=O)Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 101.1 %

Procedure:
To a solution of 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.03 g, 9.81 mmol, Adesis) in THF (49 mL) at about −78° C. was added sec-BuLi (1.4 M in cyclohexane, 15.4 mL, 21.6 mmol) dropwise. The reaction was stirred at about −78° C. for about 1 h before ethyl chloroformate (2.36 mL, 24.5 mmol) was added rapidly. The reaction mixture was allowed to warm to ambient temperature and was stirred for about 40 min. The reaction was quenched with saturated aqueous NH4Cl (25 mL). EtOAc (50 mL) and water (50 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×20 mL) and the combined organic layers were washed with brine (2×20 mL). The organics were dried over anhydrous Na2SO4, filtered, and concd to dryness under reduced pressure to give a yellow oil. The oil was purified by silica gel chromatography eluting with a gradient of 0-10% EtOAc in heptane to give ethyl 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (3.78 g, 98%) as a yellow oil: LC/MS (Table 1, Method b) Rt=3.98 min; MS m/z: 381 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O1CCOCC1.CCOC(C)=O>[CH3:16][O:15][C:13]([NH:1][C@@H:2]([C@@H:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4])=[O:14]
Reactant: COC(=O)Cl
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of (2S,3S)-2-amino-3-methylpentanoic acid (1.0 g, 7.62 mmol) in dioxane (10 mL) at 0° C. was added NaOH (12.58 g, 25.2 mmol) followed by dropwise addition of methyl chloroformate (1.18 mL, 15.25 mmol). The solution was warmed to room temperature with stirring over 2 h, diluted with EtOAc, washed with 1 N HCl, brine, dried (Na2SO4), filtered and solvent removed in vacuo to give the title compound (1.4 g, 7.4 mmol, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 1.27-1.39 (m, 1H) 1.38-1.53 (m, 2H) 1.58-1.72 (m, 3H) 1.82-1.94 (m, 2H) 2.04 (d, J=3.8 Hz, 2H) 3.70 (s, 3H) 4.94 (br s, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=1>CS(C)=O>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccnc1F
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccnc1OC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Potassium tert-butoxide (1.08 g, 8.62 mmol) was added to a solution of 1-benzyl-4-hydroxypiperidine (1.5 g, 7.84 mmol) in dimethylsulfoxide (5 mL) and the mixture was stirred at room temperature for 1 hour. 2-Fluoro-3-methylpyridine (957 mg, 8.62 mmol) was then added and the reaction mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water, and the organic layer was separated and washed with sodium hydrogen carbonate solution and brine. The organic solution was then dried over magnesium sulfate concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 70:30, to afford the title compound as a solid in 85% yield, 1.9 g. 1H NMR (CDCl3, 400 MHz) □: 1.79-1.94 (m, 2H), 1.98-2.09 (m, 2H), 2.17 (s, 3H), 2.37-2.47 (m, 2H), 2.68-2.77 (m, 2H), 3.61-3.51 (bs, 2H), 5.12-5.20 (m, 1H), 6.74 (m, 1H), 7.24-7.37 (m, 6H), 7.95 (m, 1H); LRMS APCI m/z 283 [M+H]+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]([F:22])[F:21])[CH:18]=[N:19][C:4]=2[CH:3]=1.[F:23][CH:24]([F:40])[CH2:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.O.[Cl-].[Na+].O>[F:23][CH:24]([F:40])[CH2:25][N:26]1[CH:30]=[C:29]([C:2]2[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])[C:5]3[N:17]([CH:20]([F:22])[F:21])[CH:18]=[N:19][C:4]=3[CH:3]=2)[CH:28]=[N:27]1
Reactant: CC1(C)OB(c2cnn(CC(F)F)c2)OC1(C)C
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](Oc1nc(-c2cnn(CC(F)F)c2)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
Intermediate 2.64 (25 mg, 0.076 mmol), 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40 mg, 0.16 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (1.6 mg, 0.0023 mmol) and K3PO4 (52 mg, 0.25 mmol) were taken up in 1,4-dioxane (0.9 mL) under Ar. Water (0.1 mL) was added and the resulting stirred mixture was heated to 100° C. After 1.25 h, the reaction mixture was cooled to r.t. and was diluted with EtOAc (2 mL), water (1 mL), and brine (1 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (4×1.5 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (0% to 15% MeOH in DCM) to afford (R)-4-((R)-1-(6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.26. LCMS-ESI+ (m/z): [M+H]+ calcd for C15H19F4N6O2: 427.2; found 426.8. 1H NMR (400 MHz, Chloroform-d) δ 8.26 (s, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.60 (t, J=61.1 Hz, 1H), 7.51 (s, 1H), 6.32-5.97 (m, 2H), 5.72-5.58 (m, 1H), 4.51 (td, J=13.5, 4.3 Hz, 2H), 3.65-3.52 (m, 1H), 3.36 (dd, J=9.7, 6.1 Hz, 1H), 3.00-2.84 (m, 1H), 2.55 (dd, J=17.2, 9.3 Hz, 1H), 2.44 (dd, J=17.2, 7.3 Hz, 1H), 1.48 (d, J=6.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH:17]2[CH2:21][NH:20][C:19](=[O:22])[N:18]2[CH3:23])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].[H-].[Na+].[CH3:28][S:29]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1)(=[O:31])=[O:30].Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:25])[C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH:17]2[CH2:21][N:20]([CH2:36][C:35]3[CH:34]=[CH:33][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:39][CH:38]=3)[C:19](=[O:22])[N:18]2[CH3:23])=[CH:12][CH:13]=1)([CH3:24])[CH3:6])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CNC(=O)N2C)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(S(C)(=O)=O)cc3)C(=O)N2C)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
A solution of 2-methyl-2-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionic acid ethyl ester (0.143 g, 0.408 mmol) in dry DMF (4 mL) was treated a 60% suspension of NaH (0.033 g, 0.825 mmol) and the resultant mixture was stirred at room temperature for 20 minutes under N2. The reaction mixture was cooled to 0° C. and then treated with p-methylsulfonylbenzyl chloride and then warmed to room temperature and stirred for 16 h. The reaction was acidified with aqueous 1 N HCl (4 mL), diluted with water and extracted with Et2O. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by column chromatography using a gradient of 4:1 to 1:1 hexanes:acetone to afford 0.090 g (42%) 2-(4-{2-[1-(4-methanesulfonyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester. Rf=0.40 (1:1 hexanes:acetone) MS (ES+) Calc'd for C26H35N2O7S (M+1) 518. Found m/z 518 (100%). 1H NMR.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19].O>N1C=CC=CC=1>[CH2:12]([O:20][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CCCCCCCO
Solvent: O
Solvent: c1ccncc1
Product: C#CCCCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 7.5 °C
Reaction time: 20 h
Yield: 85.8 %

Procedure:
To an ice-cooled solution of p-toluenesulfonyl chloride (17.4 g, 91.3 mmol) in pyridine (30 ml), 7-octyn-1-ol (9.6 g, 76.1 mmol) was added dropwise, and stirred at 5-10° C. for 20 hours. The reaction mixture was added with water (15 ml), stirred, then poured into water (500 ml), and extracted with ether (500 ml). The ether layer was washed with cold 1N-hydrochloric acid, saturated aqueous sodium hydrogencarbonate and water, dried over magnesium sulfate, and concentrated under reduced pressure to afford 18.3 g of 7-octynyl-p-toluenesulfonate (yield; 85.7%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([CH3:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH3:17][C:12]1[CH:11]=[CH:10][C:15]([O:16][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
In an argon atmosphere, 4-fluorobenzaldehyde (0.53 mL, 5.0 mmol) and p-cresol (648 mg, 6.0 mmol) were dissolved in dimethylacetamide (8 mL), and to the solution were added potassium carbonate (828 mg, 6.0 mmol) and cupric oxide (95 mg, 0.50 mmol) and the mixture was heated under reflux for 1.5 hours. The reaction solution was cooled down to room temperature, and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with a 0.5 N aqueous sodium hydroxide solution, water and brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (6:1 hexane/ethyl acetate) to obtain 4-(4methylphenoxy)benzaldehyde (697 mg, 66%).