Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.B1C2CCCC1CCC2.[CH3:24][O:25][C:26]1[CH:51]=[CH:50][C:29]([CH2:30][N:31]2[C:35]3=[N:36][CH:37]=[CH:38][C:39]([O:40][C:41]4[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][C:42]=4[F:48])=[C:34]3[C:33](I)=[N:32]2)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C=O)C.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].O>[NH2:47][C:44]1[CH:45]=[CH:46][C:41]([O:40][C:39]2[CH:38]=[CH:37][N:36]=[C:35]3[N:31]([CH2:30][C:29]4[CH:50]=[CH:51][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)[N:32]=[C:33]([CH2:1][CH:2]4[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]4)[C:34]=23)=[C:42]([F:48])[CH:43]=1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(CC3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 72 °C
Reaction time: 6 h

Procedure:
To a 10 mL reaction flask was added tert-butyl 4-methylenepiperidine-1-carboxylate (81 mg, 0.411 mmol) and was purged with N2(g) three times. 9-BBN (0.821 ml, 0.411 mmol) was added and the clear solution refluxed (72° C.) for 1 hour. The reaction was cooled to ambient temperature and then added directly to a mixture of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (181 mg, 0.370 mmol; prepared as in Example 7, Step B), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (10.1 mg, 0.0123 mmol) and potassium carbonate (68.1 mg, 0.493 mmol) in DMF:H2O (1 mL:0.1 mL). The dark orange mixture was stirred at 60° C. for 6 hours, then cooled to ambient temperature and poured into water. The pH was adjusted to 11 with 1N NaOH, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (Biotage 25M) eluting with 3% MeOH/CH2Cl2 to afford the desired product. Yield: 25 mg, 11%. LRMS (APCI pos) m/e 562.1 (M+H).
Reaction SMILES: O[C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[S:4][C:3]=1[C:11]([O:13]C)=O.FC(F)(F)C1SC(C(OC)=O)=C(OS(C(F)(F)F)(=O)=O)C=1.[CH2:36]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)[CH3:37].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:36]([C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:6]=[C:5]([C:7]([F:8])([F:9])[F:10])[S:4][C:3]=2[CH2:11][OH:13])=[CH:40][CH:39]=1)[CH3:37]
Reactant: COC(=O)c1sc(C(F)(F)F)cc1O
Reactant: CCc1ccc(B(O)O)cc1
Agent: COC(=O)c1sc(C(F)(F)F)cc1OS(=O)(=O)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Product: CCc1ccc(-c2cc(C(F)(F)F)sc2CO)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 208 starting from methyl 3-hydroxy-5-(trifluoromethyl)thiophene-2-carboxylate and by coupling of methyl 5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)thiophene-2-carboxylate and 4-ethylphenyl boronic acid followed by LAH reduction to afford the desired product as an off-white oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH2:11])[C:9]=1[Cl:10])[C:5]#[N:6].CCN(C(C)C)C(C)C.Br[CH2:22][CH2:23][OH:24]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:11][CH2:22][CH2:23][OH:24])[C:9]=1[Cl:10])[C:5]#[N:6]
Reactant: N#Cc1cc(N)c(Cl)c(N)c1
Reactant: OCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(N)c(Cl)c(NCCO)c1
Temperature: 100 °C
Yield: 29.7 %

Procedure:
To a solution of 3,5-diamino-4-chlorobenzonitrile (200 mg, 1.193 mmol) in DMF (2 mL) was added Hunig's base (2.501 mL, 14.32 mmol) followed by 2-bromoethanol (0.506 mL, 7.16 mmol). The resulting solution was heated at 100° C. for 10 h. LC-MS indicated ca. 30% conversion. It was passed through a pad of celite, rinsed with EtOAc. After concentration, purification via silica gel chromatography (0-70% EtOAc in Hexanes, 24 g) gave 3-amino-4-chloro-5-((2-hydroxyethyl)amino)benzonitrile (75 mg) as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[O:12][CH2:13][O:14][CH3:15].N1C=CC=CC=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.[Pd].O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:6]=[CH:5][C:4]=1[O:12][CH2:13][O:14][CH3:15]
Reactant: COCOc1ccc([N+](=O)[O-])cc1OC
Reactant: CC(C)(C)C(=O)Cl
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1ccc(NC(=O)C(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
To a solution of 2-methoxy-1-(methoxymethoxy)-4-nitrobenzene (1.2 g, 5.63 mmol) in ethyl acetate (30 ml) was added 10%-Pd/C (120 mg) at room temperature, and reaction was carried out under a hydrogen atmosphere. After 30 minutes, the mixture thus obtained was filtered by the use of Celite and the filtrate was concentrated under reduced pressure. To a solution of the resulting residue in ethyl acetate (30 ml) were added pyridine (0.546 ml, 6.75 mmol) and pivaloyl chloride (0.763 ml, 6.19 mmol) at 0° C., and the resulting mixture was warmed up to room temperature. After 15 hours, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution and the resulting mixture was poured into water (100 ml) and extracted with ethyl acetate (50 ml×2), and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain N-[3-methoxy-4-(methoxymethoxy)phenyl]-2,2-dimethylpropanamide (1.48 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.[CH3:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][NH:19][CH3:18])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: CN
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Solvent: CCO
Product: CNCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
A solution containing 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (5.5 g, 20.4 mmol), obtained as explained in EP 106515, a 40% solution of methylamine in ethanol (60 mL) and ethanol is stirred at 100° C. for 16 h in a closed vessel. The product is isolated by flash chromatography as a white solid. mp 98°-101° C.; 1H NMR (80 MHz, CDCl3)δ(TMS) 8.12 (s, 1H, N=CH), 7.81 (s, 1H, N=CH), 7.73 (d, J=8.5 Hz, 1H, arom), 7.5-7.1 (m, 2H, arom), 4.78 (s, 2H, CH2 -Tr), 3.28 (AB system, Δv=0.49, J=12.3 Hz, 2H, NCH2), 2.29 (s, 3H, NMe).
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:4]=1[Cl:13].[OH-].[Na+]>O>[Cl:13][C:4]1[CH:5]=[C:6]([F:12])[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[OH:2]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Yield: 97.9 %

Procedure:
2-Chloro-4-fluoro-5-nitrophenyl methyl carbonate (120 g 0.48 mol) was combined with a solution of sodium hydroxide (22.7 g, 0.57 mol) in water (300 mL) and the resultant mixture was refluxed for 4 h. The insoluble solids were removed by filtration and the filtrate was acidified with dilute HCl. The precipitated solid was collected by filtration and washed with water to give 2-chloro-4-fluoro-5-nitrophenol (90 g, 98% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.18 (s, 1H), 8.10 (d, J=10.4 Hz, 1H), 7.62 (d, J=7.2 Hz, 1H); MS (ESI) m/z: 192.1 (M+H+).
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])([O-:17])=[O:16].O>C(Cl)Cl>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([CH:7]=[CH:8][C:1]=1[O:9][CH3:10])[C:21]([C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=1)=[O:22]
Reactant: COc1ccccc1OC
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.5 %

Procedure:
To a stirred ice bath cooled solution of veratrole (2.55 mL, 20 mmol) in methylene chloride (30 mL) under nitrogen was added aluminum chloride (2.93 g, 22 mmol). A slight exotherm resulted. To the resulting mixture was added 3-nitrobenzoyl chloride (3.8 g, 20 mmol) in 30 mL of methylene chloride., The reaction was then allowed to warm to room temperature and followed by heating to refluxed. After 5 hours at reflux the reaction mixture was allowed to cool to room temperature and stirred for 72 hours. The reaction mixture was then poured into 100 mL of iced water and stirred for 20 minutes. This mixture was extracted with CH2Cl2 (3×60 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the crude product as a green solid. The crude product was purified by flash column chromatography (silica gel, CH2Cl2) to afford 2.21 g (39%) of the product as a yellow solid: mp 133–135° C.; 1H NMR (CDCl3) δ 8.64–8.56 (m, 1H), 8.49–8.39 (m, 1H), 8.10–8.05 (m, 1H), 7.76–7.65 (m, 3H), 7.55–7.47 (m, 1H), 7.36–7.29 (m, 1H), 7.00–6.87 (m, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 13C NMR (CDCl3) δ 192.8, 153.8, 149.4, 147.9, 139.7, 135.2, 129.5, 128.9, 126.2, 125.6, 124.4, 11.8, 110.0, 56.2, 56.1; Anal. Calcd for C15H13NO5. Theoretical: C, 62.72; H, 4.56; N, 4.88. Found: C, 62.74; H, 4.59; N, 4.89.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]#[C:6][C:7]1[S:11][C:10]([NH:12]C(OC(C)(C)C)=O)=[N:9][CH:8]=1)[CH3:2].FC(F)(F)C(O)=O.C(=O)(O)[O-]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[C:5]#[C:6][C:7]1[S:11][C:10]([NH2:12])=[N:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C#Cc1cnc(NC(=O)OC(C)(C)C)s1
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C#Cc1cnc(N)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-tert-Butoxycarbonylamino-thiazol-5-yl)-propynoic acid ethyl ester (1.2 g, 4.049 mmol) was dissolved in DCM (20 ml), trifluoroacetic acid (4.617 g, 40.93 mmol) was added in drop wise fashion at 0° C. After complete addition the reaction was allowed to stir for overnight at room temperature. Additional 3 ml of TFA was charged to the reaction and stirred for 2 hr. TLC showed complete reaction. Reaction was basified with sat. bicarbonate. The aqueous layer was extracted with ethyl acetate (30 ml×3). The combined organic layer was washed with water followed by brine and dried over anhydrous sodium sulfate and the solvent was removed on vacuo. The sticky solid product was obtained (0.700 g)
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[S:20][C:19]([C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([O:29]C)=[O:28])[CH2:23][CH2:22]4)=[N:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1.[Li+].[OH-].Cl.CCOCC>O1CCCC1.CO>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[S:20][C:19]([C@H:21]4[CH2:22][CH2:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]4)=[N:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@H](c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: 25 °C

Procedure:
To a solution of methyl trans-4-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate (Example 21-11, 91 mg, 0.197 mmol) in tetrahydrofuran (2.00 mL) and methanol (0.75 mL) was added aqueous 1N LiOH (0.590 mL, 0.590 mmol). The resultant solution was stirred 20 minutes at room temperature and then 30 minutes at 50° C. The solution cooled to room temperature and was quenched with HCl (0.571 mL, 0.571 mmol) and then aqueous 25% NH4OAc solution (to pH=7). The mixture was extracted with 2-Me-THF. The combined organic fractions were washed with brine, dried (Na2SO4), and were filtered before concentration to dryness. The residue was triturated in hot ethyl acetate. The product was collected by filtration (wash with ethyl acetate, then ether and then hexanes) to yield trans-4-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (37.6 mg 0.084 mmol, 43%) as a yellowish solid. MS APCI [M+H]+ m/z 449.1. 1H NMR (400 MHz, DMSO) δ 12.12 (s, 1H), 10.34 (s, 1H), 8.86 (d, J=4.9, 1H), 8.15 (s, 1H), 7.99 (s, 1H), 7.66 (d, J=8.0, 1H), 7.39 (t, J=7.9, 1H), 7.35-7.29 (m, 2H), 3.07-2.89 (m, 1H), 2.30 (ddd, J=11.5, 6.8, 2.5, 1H), 2.16 (d, J=10.4, 2H), 2.09-1.96 (m, 2H), 1.66-1.41 (m, 4H). rhSYK Activity: +++
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.[CH:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]C.N1CCCCC1.Cl>N1C=CC=CC=1>[C:1]([OH:7])(=[O:6])/[CH:2]=[CH:3]/[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CCCCCCCCCCCC=O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCCCCCCCCCC/C=C/C(=O)O
Temperature: 35 °C
Yield: 65.6 %

Procedure:
To a dry flask containing malonic acid (56.5 g) and pyridine (132 ml) was added dodecanal (100 g) dropwise to maintain the internal temperature under 35° C. under nitrogen atmosphere while stirring. After the addition, piperidine (4 ml) was added. The reaction mixture was then heated to 55° C. for 1 hr and 90° C. for 3 hrs. The mixture was cooled to room temperature and poured into ice-water (˜1 L). After the addition of 400 ml 6M HCl, the mixture was extracted with ethyl acetate (2 L). The ethyl acetate phase was washed with DI water twice. The solvent was removed under vacuum. The crude product was crystallized from hexane. The pure product was obtained as a white solid (80.5 g, 65.6% yield). Proton NMR(CDCl3) δ 0.88 (t, 3H), 1.26 (m, 16H), 1.45 (m, 2H), 2.22 (m, 2H), 5.82 (td, 1H), 7.09 (td, 1H).
Reaction SMILES: Cl.N1CCC(OC2C=CC(C(N3CCC([N:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][C:22]4=[O:31])CC3)=O)=C(OC)C=2)CC1.CN(C=O)C.ClCC#N>C(=O)([O-])[O-].[K+].[K+]>[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][C:22]1=[O:31]
Reactant: COc1cc(OC2CCNCC2)ccc1C(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: Cl
Agent: N#CCCl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc2N1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1-(1-(4-(4-Piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-3,4-dihydro-2(1H)-quinolinone hydrochloride from Example 190 (500 mg, 1.00 mmole) was dissolved in 7 ml of dry DMF containing 303 mg (2.19 mmole) of potassium carbonate. The suspension was cooled to 0° C. and 90 gL (1.42 mmole) of chloroacetonitrile was added neat with stirring. The cooling bath was removed after 10 minutes and the reaction was continued at room temperature for 4 hr. All volatiles were rotoevaporated and the residue was partitioned between ethyl acetate and brine. The combined organic extracts were dried and concentrated to yield 430 mg of 1-(1-(4-(N-cyanomethyl)piperidin-4-yloxy)-2-methoxybenzoyl) piperidin-4-yl)-3,4-dihydro-2(1H)-quinolinone as an oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([CH:16]=[N:17][OH:18])[N:13]=[C:12]([CH3:19])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:22][CH3:23].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([O:34][CH2:35][C@@H:36]2[CH2:41][O:40][C@@H:39]([CH:42]=[CH2:43])[CH2:38][O:37]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([O:34][CH2:35][C@@H:36]2[CH2:41][O:40][C@@H:39]([C@H:42]3[O:18][N:17]=[C:16]([C:14]4[CH:15]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]5[CH:20]=[CH:21][C:2]([F:1])=[C:3]([O:22][CH3:23])[CH:4]=5)[N:11]=[C:12]([CH3:19])[N:13]=4)[CH2:43]3)[CH2:38][O:37]2)(=[O:32])=[O:33])=[CH:27][CH:26]=1
Reactant: COc1cc(CNC(=O)c2cc(C=NO)nc(C)n2)ccc1F
Reactant: C=C[C@H]1CO[C@H](COS(=O)(=O)c2ccc(C)cc2)CO1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: COc1cc(CNC(=O)c2cc(C3=NO[C@H]([C@H]4CO[C@H](COS(=O)(=O)c5ccc(C)cc5)CO4)C3)nc(C)n2)ccc1F
Reaction time: 5 h
Yield: 24.3 %

Procedure:
To a stirred solution of N-(4-fluoro-3-methoxybenzyl)-6-((hydroxyimino)methyl)-2-methyl pyrimidine-4-carboxamide (3.84 g, 12.08 mmol, Preparation #9) and ((2S,5S)-5-vinyl-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (3.0 g, 10.06 mmol, Preparation#11) in CHC3 (30 mL), was added iodobenzene diacetate (6.48 g, 20.13 mmol, Aldrich) portion wise (divided in to 4 equal portions and added over a period of 4 hrs). After the addition is completed, the reaction mixture was stirred for another 5 h and quenched with water (100 mL). The product was extracted with DCM (2×100 mL). Combined organic layers were washed with brine solution (100 mL), dried over sodiumsulphate and evaporated to dryness. The residue obtained containing two diastereomers and other impurities was purified by flash column chromatography using silica gel (230-400 mesh) eluting with 40% EtOAc in n-hexane. First eluting compound fractions were combined and evaporated to dryness under reduced pressure, triturated with 40% EtOAc in hexane to afford ((2S,5R)-5-((S)-3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate 1.5 g (24%). 1H NMR (400 MHz, CDCl3): δ 8.48 (s, 1H), 8.28 (t, J=6.4 Hz, 1H), 7.79 (d, J=8 Hz, 2H), 7.36 (d, J=8 Hz, 2H), 7.08-6.96 (m, 2H), 6.90-6.86 (m, 1H), 4.68-4.60 (m, 3H), 4.02-3.93 (m, 2H), 3.88 (s, 3H), 3.85-3.72 (m, 5H), 3.59-3.38 (m, 5H), 2.75 (s, 3H), 2.42 (s, 3H); MS m/z: 615 (m+H)+.
Reaction SMILES: N1(C2NC=CN=2)CCCCC1.N1([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:27][CH2:26]3)=[O:24])=[CH:19][CH:18]=2)C=CN=C1.[F:39]C1C=CC(C(C2CCNCC2)=O)=CC=1>>[F:39][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:27][CH2:26]2)=[O:24])=[CH:19][CH:18]=1
Reactant: O=C(c1ccc(-n2ccnc2)cc1)C1CCN(CCc2ccccc2)CC1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: c1c[nH]c(N2CCCCC2)n1
Product: O=C(c1ccc(F)cc1)C1CCN(CCc2ccccc2)CC1

Procedure:
For example if the desired piperidinyl imidazole derivative of Formula I is [4-(1H-imidazol-1-yl)phenyl][1-(2-phenylethyl)-4-piperidinyl]methanone; then 4-fluorophenyl-4-piperidinyl methanone is reacted with 1-halo-2-phenylethane thereby producing the intermediate of Formula IV, 4-fluorophenyl[1-(2-phenylethyl)-4-piperidinyl]methanone.
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[O:3][CH:2]=1.O[N:9]=[C:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1CCCCC1.C1(C)C=CC=CC=1>[O:3]1[CH:2]=[CH:1][CH:5]=[C:4]1[CH:6]1[O:7][N:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:17]1
Reactant: O=Cc1ccco1
Reactant: NC(=NO)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: c1ccc(C2=NOC(c3ccco3)N2)cc1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A mixture of 2-furfural (1.0 mL, 1.17 g, 12.2 mmol, 1.5 equivalents), N′-hydroxybenzimidamide (1.11 g, 8.1 mmol) and one drop of piperidine in toluene (100 mL) was heated to reflux for 18 hours in a SOXHLETT apparatus that was charged with SILCARBON 3 Angstrom molecular sieve (8 g). The reaction mixture was allowed to cool to room temperature, and the solvent was removed in vacuo. After purification by automated column chromatography on an ISCO COMPANION apparatus (SiO2, gradient heptane/ethyl acetate), the 5-(furan-2-yl)-3-phenyl-4,5-dihydro-1,2,4-oxadiazole product (745 mg, 3.5 mmol) was obtained as a brown oil that solidified to a tan solid upon standing. The overall reaction yield was approximately 43%. LC-MS [M+H] 215 (C12H10N2O2+H, expected 215.07].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:28])[CH:3]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([SH:37])[CH:34]=[CH:35][CH:36]=1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1.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.C(Cl)(Cl)Cl.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[F:28][C:4]1[CH:3]=[C:2]([S:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: COc1cccc(S)c1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Sc2ccc(-c3ccc(CCC4(NC(C)=O)COC(C)(C)OC4)cc3)c(F)c2)c1
Yield: 102.2 %

Procedure:
A solution of N-{5-[2-(4′-bromo-2′-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (225 mg) of Reference Example 10, 3-methoxybenzenethiol (70 mg), diisopropylethylamine (129 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (12.9 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (14.9 mg) in 1,4-dioxane (2 mL) was heated under reflux for 1 hr under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.26 g) as yellow crystals.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[CH2:29]([NH2:34])[CH2:30][CH:31]([CH3:33])[CH3:32].ClCCl>O.C([O-])(O)=O.[Na+]>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:34][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)CCNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Sodium triacetoxyborohydride (24.9 g, 117.48 mmol) is added to a stirred solution of 1-Boc-4-piperidone (15.6 g, 78.3 mmol), iso-amyl amine (10.0 ml, 86.15 mmol), and dichloromethane (400 ml). The reaction is stirred overnight at room temperature under nitrogen. The reaction is diluted with water and aqueous saturated NaHCO3, and extracted with dichloromethane (150 ml×3). The dichloromethane is concentrated under vacuum, diluted with ethyl acetate and washed with aqueous saturated NaHCO3, dried over Na2SO4, filtered, and concentrated to yield (19.99 g) of 4-(3-methyl-butylamino)-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=271 (M+1); 1H NMR (CDCl3): δ=4.05 (2H, brs), 2.84-2.73 (2H, brm), 2.67-2.55 (2H, m), 1.84 (2H, brd), 1.67-1.58 (1H, m), 1.51-1.44 (10H, m), 1.41-1.33 (2H, m), 1.30-1.18 (2H, m), 0.90 (6H, d).