Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:10]1[C:11](Cl)=[N:12][C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)=[N:14][C:15]=1Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Cl.C(C1C=CC(C(N)=N)=CC=1)(OC)=O.C(C(C([O-])=O)C(OCC)=O)CCCCCCCC.P(Cl)(Cl)(Cl)=O.[H][H]>CO.[C].[Pd].C(N(CC)CC)C>[CH2:1]([C:10]1[CH:11]=[N:12][C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [H][H]
Reactant: CCCCCCCCCc1c(Cl)nc(-c2ccc(C(=O)OC)cc2)nc1Cl
Agent: [Pd]
Agent: CCCCCCCCCC(C(=O)[O-])C(=O)OCC
Agent: COC(=O)c1ccc(C(=N)N)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCc1cnc(-c2ccc(C(=O)OC)cc2)nc1

Procedure:
A mixture of 40 g of 5-n-nonyl-2-(4-carbomethoxy-phenyl)-4,6-dichloropyrimidine (obtainable by condensing 4-carbomethoxybenzamidine hydrochloride with ethyl n-nonylmalonate and subsequently reacting the 4,6-dihydroxy compound with phosphorus oxychloride) and 40 ml of triethylamine is dissolved in 400 ml of methanol and, after addition of 20 g of 5 percent palladium carbon, hydrogenated under atmospheric pressure at 50° until the calculated amount of hydrogen has been taken up. Working up gives methyl p-(5-nonylpyrimidyl)-benzoate, m.p. 61.7°, c.p. 65°.
Reaction SMILES: N(C([O-])=O)=NC([O-])=O.[OH:9][C:10]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].[CH:21](O)([CH3:23])[CH3:22].C1COCC1>C(OCC)(=O)C.O>[CH3:15][O:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:10]=1[O:9][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)O
Reactant: COC(=O)c1ccc(C)cc1O
Agent: O=C([O-])N=NC(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)cc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
Disopropyl azodicarboxylate (8.7 mL, 44 mmol) is added to a stirred solution of methyl 2-hydroxy-4-methylbenzoate (4.85 g, 29.2 mmol), isopropanol (3.3 mL, 44 mmol), triphenylphosphene (11.5 g, 43.8 mmol) and THF (50 mL) at room temperature. The exothermic reaction is cooled in an ice bath and is allowed to stir overnight at room temperature. The mixture is diluted with ethyl acetate and water, and the organic phase is washed with brine and dried over MgSO4. The crude residue is purified by flash chromatography (20 to 40% EtOAc/heptane) to afford the title compound (4.95 g, 81%) as an oil. ES/MS m/e 209.3 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:13])(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[C:5]([Cl:3])(=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccccc1
Reaction time: 8 h

Procedure:
Benzoyl chloride was synthesized by refluxing 5 ml of 2 M thionyl chloride in 10 ml of toluene with benzoic acid for 30 minutes. The residual thionyl chloride and toluene were removed by distillation. 2 gm of the 3-amino-propyl resin was then incubated at room temperature overnight with the fresh benzoyl chloride in pyridine. The next day, the resin was washed with methanol and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16].C[O-].[Na+].Cl>COCCOC.O.CCOC(C)=O>[F:13][C:14]([F:21])([F:20])[C:15](=[O:16])[CH2:11][C:10]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([CH3:1])[CH:3]=1)=[O:12]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc(C(C)=O)cc1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To stirred solution of 1-(3-methyl-4-methoxyphenyl)ethanone (3.29 g, 20 mmol) in DME was added ethyl trifluoroacetate (5.68 g, 40 mmol) and sodium methoxide (4.32 g, 80 mmol), and the resulting reaction mixture was stirred at room temperature overnight. EtOAc (200 ml) and water (50 ml) were added, and the pH of the aqueous layer was adjusted to 6 by addition of 1 N HCl solution. The organic layer was washed with brine (50 ml), dried over Na2SO4, and concentrated in vacuo to give the crude product which was recrystallized from isooctane to give the title compound (3.2 g, 62%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21]Br)[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: BrCC1CCC(CBr)CC1
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCc2ccc(OCC3CCC(CBr)CC3)cc2N1
Yield: 30.8 %

Procedure:
A mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (196 mg, 1.2 mmol), 1,4-bis(bromomethyl)cyclohexane (972 mg, 3.6 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) was dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column to give 7-((4-(bromomethyl)cyclohexyl)methoxy)-3,4-dihydroquinolin-2(1H)-one (intermediate 49) (130 mg, 30%) as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[OH:17])[C:5]1=[O:28])(=[O:3])[CH3:2].F[B-](F)(F)F.[CH3:34][O+](C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[O:17][CH3:34])[C:5]1=[O:28])(=[O:3])[CH3:2]
Reactant: C[O+](C)C
Reactant: COc1ccc(C(O)=C2C(=O)N(C(C)=O)c3ccc(C(C)=O)cc32)cc1OC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21)c1ccc(OC)c(OC)c1
Reaction time: 3 h

Procedure:
4.0 g (10.5 mmol) 1,5-diacetyl-3-[(3,4-dimethoxy-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V) are suspended in 100 ml methylene chloride and combined with 3.1 g (21 mmol) trimethyloxonium tetrafluoroborate as well as 7.2 ml Hünig base (ethyldiisopropylamine) at ambient temperature. The solution is stirred for 3 h, then a further 1.55 g trimethyloxonium tetrafluoroborate and 3.5 ml Hünig base are added and the mixture is stirred overnight. After the same amount of reagent has been added again and the mixture has been stirred for a further 5 h, the reaction is washed three times with water, the organic phase is dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue is chromatographed through a silica gel column with methylene chloride/methanol 9:1, the corresponding fractions are combined and concentrated by rotary evaporation.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([Cl:33])=[C:30](O)[CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:33])=[C:28]([CH:27]=1)[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[CH:10][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=3)=[CH:12][N:13]=2)[CH2:6][CH2:7]1
Reactant: Oc1cc(Br)ccc1Cl
Reactant: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(O)CC3)nc2)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(Br)ccc4Cl)CC3)nc2)n1
Temperature: 50 °C

Procedure:
To a solution of ethyl {5-[2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl]-2H-tetrazol-2-yl}acetate (44 mg, 0.132 mmol), 5-bromo-2-chlorophenol (32.9 mg, 0.158 mmol) and triphenylphosphine (45 mg, 0.172 mmol) in THF (660 μL) was added diethyl azodicarboxylate (27.2 μL, 0.172 mmol). The mixture was heated at 50° C. for 4 h. The solvent was evaporated and the crude product was purified by Combiflash chromatography (SiO2-12 g, gradient elution of 10-50% EtOAc/hexanes over 30 min) to afford the title product as a solid. MS: m/z 422, 424 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH2:10]O)[CH:7]=[C:6]([F:12])[CH:5]=1>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([F:12])[CH:5]=1
Reactant: COC(=O)c1cc(F)cc(CO)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(C)cc(F)c1
Reaction time: 2 h
Yield: 85.9 %

Procedure:
Ethanol (2 ml) was added to round bottom flask containing 3-fluoro-5-hydroxymethyl-benzoic acid methyl ester (667 mg, 3.6 mmol) and palladium (10 wt. % on activated carbon, 300 mg) under argon. The flask was evacuated using a water aspirator and then filled with hydrogen from a balloon. After stirring for 2 h, the palladium on carbon was removed by filtration through celite. The filtrate was then concentrated to afford 520 mg (87%) of 3-fluoro-5-methyl-benzoic acid methyl ester.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[CH:19][C:18]=2[C:22]([OH:24])=O)=[CH:13][CH:12]=1.[CH3:25][CH:26]1[NH:30][CH2:29][C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([OH:31])[CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:21][N:20]=[CH:19][C:18]=2[C:22]([N:30]2[CH:26]([CH3:25])[CH2:27][C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([OH:31])[CH2:29]2)=[O:24])=[CH:15][CH:16]=1
Reactant: O=C(O)c1cn[nH]c1-c1ccc(Cl)cc1
Reactant: CC1CC(O)(c2ccccc2)CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(O)(c2ccccc2)CN1C(=O)c1cn[nH]c1-c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 26.2 %

Procedure:
N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.04 mmol) was added to a solution of 5-(4-chlorophenyl)-1H-pyrazole-4-carboxylic acid (11 mg, 0.048 mmol, 1.2 equ.), 5-methyl-3-phenylpyrrolidin-3-ol (7 mg, 0.04 mmol) and TBTU (15 mg, 0.048 mmol, 1.2 equ.) in DMF (0.3 mL) at rt. The reaction mixture was left at rt for 2 h. The crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (4 mg). MS (ESI, pos. ion) m/z: calcd for C21H20ClN3O2: 381.1244, found 381.1243.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]2.[C:17]1([O:23][C:24](=O)[O:25]C2C=CC=CC=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:13][CH3:14])[O:15][CH3:16])[N:8]([C:24]([O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 12, 2.28 g, 7.94 mmol) and diphenylcarbonate (2.13 g, 9.93 mmol) in THF (40 ml) at −17° C. was treated drop wise over 5 min with LHMDS (1M in THF, 8.34 ml, 8.34 mmol). The yellow reaction mixture was stirred for 30 min, quenched with sat. aq. NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by normal phase chromatography (80 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H) 7.37-7.45 (m, 2H) 7.19-7.28 (m, 3H) 5.46 (s, 1H) 3.80-3.87 (m, 2H) 3.29 (s, 6H) 2.84 (t, 2H) 1.90-2.00 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([C:36]2([CH:42]=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH2:37]2)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:29]=[C:30]([C:36]5([CH:42]=[O:43])[CH:37]=[CH:38][CH:39]=[CH:40][CH2:41]5)[CH:31]=[CH:32][C:33]=4[O:34][CH3:35])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(C2(C=O)C=CC=CC2)cc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2(C=O)C=CC=CC2)cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole (2.01 g; 9.13 mmol), K2CO3 (2.0 g), and 1-[3-(3-chloropropoxy)-4-methoxy-phenyl]phenylmethanone (3.93 g; 11.3 mmol) and acetonitrile (50 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was evaporated and the residue was partitioned between water (150 ml) and dichloromethane (400 ml). The dichloromethane solution was washed with water and brine (100 ml), dried over MgSO4, then concentrated to an oil. The purification was done by flash chromatography over a silica gel column (SiO2, 40 g; eluted with dichloromethane, 300 ml; 1% methanol in dichloromethane, 850 ml). The material thus obtained as a colorless oil solidified on standing. Recrystallization from ethanol (150 ml) gave 1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]phenylmethanone as white crystals, 3.07 g (63%), m.p.=140°-141° C.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[H-].[Na+].[CH2:12]([O:19][C:20](=[O:26])[CH:21](Br)[C:22](=[O:24])[CH3:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.O>[CH2:12]([O:19][C:20](=[O:26])[CH:21]([N:5]1[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]1)[C:22](=[O:24])[CH3:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: CC(=O)C(Br)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C(C(=O)OCc1ccccc1)n1ccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 3-trifluoromethylpyrazole (0.703 g, 5.16 mmol) in THF (36.9 ml) is added NaH (0.199 g, 4.98 mmol). The reaction mixture is stirred at RT for 10 mins and then treated with 2-bromo-3-oxo-butyric acid benzyl ester (1.0 g, 3.69 mmol). After stirring at 40° C. for 30 mins, the mixture is diluted with water (50 ml) and extracted with EtOAc (2×50 ml). The combined organics are washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by ISCO combiflash chromatography, eluting with 0 to 100% (iso-hexane/EtOAc) on a 24 g SiO2-column to afford the title compound; MS: m/z 327.22 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])=[C:4]([F:15])[CH:3]=1.[C:16]([C:18]1[N:22]([CH3:23])[C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]([C:18]1[N:22]([CH3:23])[C:21]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])=[C:4]([F:15])[CH:3]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CC(C)NS(=O)(=O)c1ccc(Br)cc1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)NS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1F
Reaction time: 16 h
Yield: 12.7 %

Procedure:
According to general procedure B, 4-bromo-2-fluoro-N-isopropylbenzenesulfonamide (177 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-fluoro-N-isopropylbenzenesulfonamide (24 mg, 13%) was provided after purification. MS (ESI) m/z 321. HPLC purity 100.0% at 210-370 nm, 9.0 min.; the Xterrag RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].C(Cl)Cl.[Cl-].[NH2:18][C:19]1[N:23](C(OC(C)(C)C)=O)[N:22]=[C:21]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=2)[CH:20]=1>CN(C=O)C.C(#N)C.C(O)=O.N1C=CC=CC=1>[CH3:40][O:39][C:35]1[CH:34]=[C:33]([CH2:32][CH2:31][C:21]2[CH:20]=[C:19]([NH:18][C:11]([C:8]3[N:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)=[O:13])[NH:23][N:22]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: COc1cccc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)c1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: O=CO
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Nc2cc(CCc3cccc(OC)c3)n[nH]2)nc1
Reaction time: 8 h

Procedure:
5-Methoxycarbonylpyridine-2-carboxylic acid (0.285 g, 1.58 mmol) was added to DCM (40 ml), to this was added oxayl chloride (0.165 ml, 1.90 mmol) and a few drops of anhydrous DMF. The reaction mixture was stirred for 30 mins before the addition of tert-butyl 5-amino-3-[2-(3-methoxyphenyl)ethyl]pyrazole-1-carboxylate (0.50 g, 1.58 mmol) and pyridine (2.0 ml). The reaction was stirred overnight. The reaction was evaporated to dryness to give yield to a gum. To this gum was added formic acid. The reaction mixture was stirred for 1 h before being evaporated to dryness. The resulting gum was quenched with saturated potassium carbonate (30 ml), extracted with DCM (3×50 ml), dried (MgSO4) and the solvent removed in vacuo to yield a viscous gum. Trituration with acetonitrile gave the desired product as a slightly yellow solid (24 mg, 4%); 1H NMR (400.132 MHz, DMSO) δ 2.92 (s, 4H), 3.74 (s, 3H), 3.95 (s, 3H), 6.50 (s, 1H), 6.76 (d, 1H), 6.83-6.82 (m, 2H), 7.20 (t, 1H), 8.26 (d, 1H), 8.53 (d, 1H), 9.17 (s, 1H), 10.38 (s, 1H), 12.31 (s, 1H); MH+381.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([OH:14])[CH:10]([CH3:22])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[CH3:22])=[CH:16][CH:17]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1(O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CNCCC1(O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-(4-Chloro-phenyl)-4-hydroxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 4.6 mmol) in dichloromethane (40 mL) at about 0° C. was added trifluoroacetic acid (10 mL). The solution was stirred for about 2 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was neutralized with saturated sodium bicarbonate, and washed with brine and dried over magnesium sulfate. The solvent was removed to give a yellow solid. No purification was needed.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1.Cl.[O:51]1[CH:55]=[C:54]([CH2:56][NH2:57])[N:53]=[CH:52]1>>[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([NH:57][CH2:56][C:54]4[N:53]=[CH:52][O:51][CH:55]=4)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: NCc1cocn1
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Agent: Cl
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cocn1
Yield: 51 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with oxazol-4-ylmethanamine hydrochloride, the title compound was obtained as a white solid in 51% yield: mp 183-184° C. (ethyl acetate/hexane): 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.41-7.32 (m, 2H), 7.08-6.97 (m, 2H), 6.31 (t, J=5.3 Hz, 1H), 4.97 (s, 2H), 4.52 (d, J=5.3 Hz, 2H), 2.63 (s, 3H); MS (ES+) m/z 415.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[F:18][C:19]([F:26])([F:25])[C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>>[F:18][C:19]([F:26])([F:25])[C:20]1[CH:24]=[CH:23][N:22]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[N:21]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: FC(F)(F)c1cc[nH]n1
Product: FC(F)(F)c1cc(-n2ccc(C(F)(F)F)n2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (74 mg, 0.285 mmol) and 3-trifluromethyl-pyrazol (48 mg, 0.353 mmol) similar to Example 166 and was isolated as a white solid (mp 139–140° C., 53 mg, 0.148 mmol, 52%). 1H NMR (CDCl3): 9.73 (s, 1H), 8.82 (m, 3H), 8.26 (s, 1H), 7.50 (m, 1H), 6.87 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:17][OH:18]>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12](=[N:17][OH:18])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCOCCCN1CCC(=O)CC1
Agent: Cl
Product: CCCCOCCCN1CCC(=NO)CC1

Procedure:
1-(3-Butoxypropyl)-4-piperidone oxime is prepared from 1-(3-butoxypropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: N1(CO)C2C=CC=C[C:4]=2N=N1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[CH3:27][N:28]1[CH:36]=[N:35][C:34]2[C:29]1=[N:30][C:31]([C:56]#[N:57])=[N:32][C:33]=2[C:37]1[CH:38]=[N:39][C:40]([O:47][CH2:48][CH2:49][CH:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O.CCO.C(N(CC)CC)C>[CH3:27][N:28]1[CH:36]=[N:35][C:34]2[C:29]1=[N:30][C:31]([C:56]#[N:57])=[N:32][C:33]=2[C:37]1[CH:38]=[N:39][C:40]([O:47][CH2:48][CH2:49][CH:50]2[CH2:55][CH2:54][N:53]([CH3:4])[CH2:52][CH2:51]2)=[C:41]([C:43]([F:46])([F:44])[F:45])[CH:42]=1
Reactant: OCn1nnc2ccccc21
Reactant: Cn1cnc2c(-c3cnc(OCCC4CCNCC4)c(C(F)(F)F)c3)nc(C#N)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCC(CCOc2ncc(-c3nc(C#N)nc4c3ncn4C)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
Triethylamine (30 μL), 1H-benzotriazole-1-methanol (48 mg), and sodium triacetoxyborohydride (91 mg) were added to a solution of 9-methyl-6-{6-[2-(piperidin-4-yl)ethoxy]-5-(trifluoromethyl)pyridin-3-yl}-9H-purine-2-carbonitrile monohydrochloride (100 mg) in THF (1.5 mL)-EtOH (1.5 mL), and the mixture was stirred at room temperature for 16 hours. After a saturated aqueous NaHCO3 solution and EtOAc were added to the reaction mixture, extraction thereof was performed using EtOAc, and the extract was washed with saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH=100:0 to 80:20), whereby 9-methyl-6-{6-[2-(1-methylpiperidin-4-yl)ethoxy]-5-(trifluoromethyl)pyridin-3-yl}-9H-purine-2-carbonitrile (57 mg) was obtained as a solid.