Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.CC(O)=O>CN(C=O)C.CC(O)(C)C>[O:5]1[CH2:6][CH2:7][CH:2]([O:1][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:3][CH2:4]1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: N#Cc1ccc(OC2CCOCC2)cc1
Temperature: 60 °C

Procedure:
Step-1: To a stirred solution of 4-hydroxytetrahydropyran (3.80 g, 0.0373 mol) in dry DMF (50 mL) was added 95% NaH solid (1.12 g, 0.0466 mol) in small portions over 5-10 min. After the evolution of gas had subsided, 4-chlorobenzonitrile (5.18 g, 0.038 mol) was added in one portion, and the mixture heated to 60° C. overnite. The mixture was diluted with tBuOH (about 5 mL) and neutralized to pH 7 using glacial AcOH. The DMF was concentrated in vacuo, and the crude product chromatographed over a 120 g Isco column using 30% DCM/hexanes to DCM as an eluent to get step-1 product, 4-(tetrahydropyran-4-yloxy)benzonitrile), as a white solid. (5.7 g, 76%): LC Rt=2.72; 1H NMR (300 MHz, (CD3)2CO-d6) δ 1.63-1.75 (m, 2H), 2.02-2.10 (m, 2H), 3.55 (ddd, J=11.8, 9.1, 3.3 Hz, 2H), 3.90 (dt, J=12.0, 4.5 Hz, 2H), 4.76 (septet, J=4.5 Hz, 1H), 7.16 (d, J=9 Hz, 2H), 7.69 (d, J=9 Hz, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Br[CH2:21][C:22](=[O:25])[CH2:23][CH3:24]>>[CH2:21]([N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18])[C:22](=[O:25])[CH2:23][CH3:24]
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: CCC(=O)CBr
Product: CCC(=O)Cn1c(Oc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Yield: 56 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 1-bromo-2-butanone were reacted by the same way with the example 1 to obtain the titled compound (185 mg, yield: 56%).
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]([C:20]1[NH:21][C:22]([O:26][Si](C(C)(C)C)(C)C)=[CH:23][C:24]=1[CH3:25])=[O:19].[CH:34]1([CH:40]=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH3:16][O:17][C:18]([C:20]1([CH:40]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C:24]([CH3:25])=[CH:23][C:22](=[O:26])[NH:21]1)=[O:19]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)c1[nH]c(O[Si](C)(C)C(C)(C)C)cc1C
Reactant: O=CC1CCCCC1
Solvent: ClCCl
Product: COC(=O)C1(C(O[Si](C)(C)C(C)(C)C)C2CCCCC2)NC(=O)C=C1C
Yield: 85.2 %

Procedure:
tert-Butyldimethylsilyltrifluoromethanesulfonate (2.40 ml, 2.75 g, 10.4 mmol, 2.0 equiv) was added dropwise over 8 min to a stirring solution of 5-(tert-butyl-dimethyl-silanyloxy)-3-methyl-1H-pyrrole-2-carboxylic acid methyl ester (1.4 g, 5.2 mmol, 1.0 equiv) and cyclohexanecarbaldehyde (0.94 ml, 0.87 g, 7.8 mmol, 1.5 equiv) in dichloromethane (100 ml) at −78° C. The resultant solution was stirred at −78° C. for 2 h, then pH=7 buffer solution (50 ml) was added. The organic layer was washed with brine solution (50 ml), and dried over sodium sulfate. The solids were filtered and the filtrate was concentrated. The residue obtained was purified by flash column chromatography (5% ethyl acetate-dichloromethane initially, grading to 8% ethyl acetate-dichloromethane, then to 10% ethyl acetate-dichloromethane) to give 2-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (1.69 g, 85%) as a colorless oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:24][C@@:25]1([CH2:32][S:33](Cl)(=[O:35])=[O:34])[C:29](=[O:30])[NH:28][C:27](=[O:31])[NH:26]1>C1COCC1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([S:33]([CH2:32][C@@:25]3([CH3:24])[NH:26][C:27](=[O:31])[NH:28][C:29]3=[O:30])(=[O:34])=[O:35])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@]1(CS(=O)(=O)N2CCC(c3ccc(F)cc3)CC2)NC(=O)NC1=O
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
4-(4-Fluorophenyl)piperidine hydrochloride (63 mg, 0.29 mmol) was taken up in 3 mL of dry THF, neutralized with diisopropylethylamine (50 μL, 0.29 mmol) and cooled on an ice-water bath. [(4S)-4-metyl-2,5-dioxo-imidazolodin-4-yl]methanesulfonyl chloride (80 mg, 0.35 mmol) was added and after stirring for 10 min, diisopropylethylamine (50 μL, 0.29 mmol) was added and the reaction mixture was stirred at ambient temperature until LC-MS (APCD) indicated consumption of the amine. The reaction mixture was evaporated and the residue taken up in EtOH and heated to 50° C. and allowed to cool before water was added. The precipitated product was collected and washed with EtOH/water and dried in vacuum to yield 87 mg.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([NH:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:5]2)[O:3]C1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O>[CH2:11]([NH:10][CH:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1)[CH2:12][CH3:13]
Reactant: CCCNC1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCNC1CCC(=O)CC1
Temperature: 5 °C
Reaction time: 24 h

Procedure:
4-N-propylamino-cyclohexanone-ethyleneketal 2 (134 g, 0.673 mol) was taken in tetrahydrofuran (268 ml) and cooled to 4-6° C. Concentrated hydrochloric acid (178 ml, 2.01 mol) was diluted with water (2144 ml) and the mixture was cooled to 4° C. This diluted hydrochloric acid was added to the reaction mixture at 4-6° C. in 15 minutes. The reaction was allowed to come to 24-26° C. and stirring was continued for 24 hours. The reaction mass (2750 ml) was concentrated to 1800 ml at 50° C. and 35 mbar pressure. Sodium carbonate (148 g, 1.4 mol) was added to achieve pH 10. The reaction mixture was extracted with dichloromethane (3670 ml). The dichloromethane layers were combined and dried over sodium sulfate (20 g). The dichloromethane layer was concentrated to dryness at 40° C. and 15 mbar pressure. The product 3 was yellow viscous oil. The weight of the product 3 obtained was 52.5 g (52.84%); GC purity 86.07%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(Nc2ncccn2)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ccc(Br)cc2)c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, N-(4-bromophenyl)pyrimidin-2-amine (75 mg) was added to a suspension of sodium hydride (16 mg) in anhydrous DMF (3 ml), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0° C. and 4-methoxybenzyl chloride (0.045 ml) was added thereto, followed by stirring the resulting mixture at room temperature for 1 hour. Saturated brine was added to the reaction solution and the resulting mixture was extracted 3 times with ethyl acetate. Organic layers were washed 3 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: ethyl acetate/hexane=1/10) to obtain N-(4-bromophenyl)-N-(4-methoxybenzyl)pyrimidin-2-amine (107 mg).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18][OH:19])[CH2:15][O:14]1>N1C=CC=CC=1.CCOCC>[C:7]1([CH3:8])[CH:9]=[CH:10][C:4]([S:1]([O:19][CH2:18][CH:16]2[CH2:15][O:14][C:13]([CH3:20])([CH3:12])[O:17]2)(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OCC(CO)O1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reaction time: 8 h

Procedure:
57.2 g (300 mmol) of tosyl chloride are added to a solution of 39.6 g (300 mmol) of (2,2-dimethyl[1,3]dioxolan-4-yl)methanol in 170 ml of pyridine at 0° C. The mixture is stirred overnight, diluted with ether, washed with a 1N hydrochloric acid solution until the aqueous phase is at acid pH, and then washed with a saturated sodium hydrogen carbonate solution.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]2[NH:15][C:14](=[O:16])[C:13]3[N:17]([CH:20]([F:22])[F:21])[CH:18]=[N:19][C:12]=3[CH:11]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].O[C@H:24]([C@H:26]1[CH2:30][N:29]([C@@H:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[CH3:32])[C:28](=[O:41])[CH2:27]1)[CH3:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(Cl)Cl>[C:1]([N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([O:16][C@@H:24]([C@H:26]3[CH2:30][N:29]([C@@H:31]([C:33]4[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)[CH3:32])[C:28](=[O:41])[CH2:27]3)[CH3:25])[C:13]3[N:17]([CH:20]([F:21])[F:22])[CH:18]=[N:19][C:12]=3[CH:11]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Reactant: CC(C)(C)n1cc(-c2cc3ncn(C(F)F)c3c(=O)[nH]2)cn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4cnn(C(C)(C)C)c4)cc4ncn(C(F)F)c34)CC2=O)cc1
Temperature: 40 °C
Reaction time: 1.25 h

Procedure:
6-(1-tert-butyl-1H-pyrazol-4-yl)-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridin-4(5H)-one 2.33 (33 mg, 0.107 mmol), lactam alcohol 1.05 (42 mg, 0.16 mmol), and PPh3 (44 mg, 0.17 mmol) were taken up in THF (1 mL). To the resulting suspension was added DEAD (26 μL, 0.17 mmol) dropwise. The resulting cloudy solution was heated to 40° C. and stirred 1.25 h. The solution was then diluted with DCM and concentrated directly onto silica gel. Purification by silica gel chromatography (15% to 60% acetone in hexanes) afforded (R)-4-((R)-1-(6-(1-tert-butyl-1H-pyrazol-4-yl)-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.34 that was used without further purification.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[SH:10].Cl[C:12]1[C:17]([CH2:18][CH:19]([CH3:21])[CH3:20])=[N:16][CH:15]=[CH:14][N:13]=1.Cl>CO.CCCCCC.O>[CH2:18]([C:17]1[C:12]([S:10][C:9]2[CH:8]=[CH:7][O:6][C:5]=2[CH3:4])=[N:13][CH:14]=[CH:15][N:16]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)Cc1nccnc1Cl
Reactant: Cc1occc1S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCCCCC
Product: Cc1occc1Sc1nccnc1CC(C)C
Temperature: 65 °C

Procedure:
Into a 25 ml round bottom 3 neck flask equipped with magnetic stirrer, Y tube, nitrogen inlet, and reflux condenser with calcium chloride drying tube is placed a solution of 0.15 g (0.0028 moles) of sodium methoxide in 2 ml absolute methyl alcohol. To the sodium methoxide solution, while maintaining the temperature at 22° - 25° C, is added 0.32 g (0.0028 moles) of 2-methyl-3-furan thiol dissolved in 2 ml absolute methanol. The reaction mass is stirred for a period of 10 minutes at 22° - 25° C at which time a solution of 0.43 g (0.0025 moles) of 2-chloro-3-isobutyl-pyrazine in 2 ml absolute methanol is added dropwise over a period of 2 minutes. The reaction mass is then heated to reflux at 65° C under nitrogen and maintained at reflux for a period of 4 hours. At the end of the 4 hour reflux period, the reaction mass is cooled to room temperature. 10 ml of water is added to the reaction mass which is then neutralized to a pH of 5 with dilute hydrochloric acid. Two 7 ml portions of n-hexane are then used to extract the reaction mass. The hexane layers are separated, combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to a red amber oil weighing 0.51 g. The major material is isolated using GLC techniques (conditions: 8 feet × 1/4inche SE-30 column) and is confirmed by NMR, IR and Mass Spectral Analysis to be a material having the structure: ##SPC15##
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][C:12]([CH3:18])=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[N:27]=1>CN(C)C=O>[Br:25][C:26]1[N:27]=[C:28]([CH2:32][N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([CH3:18])[N:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:19]=[CH:20][C:21]([CH3:22])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH:29]=[CH:30][CH:31]=1
Reactant: BrCc1cccc(Br)n1
Reactant: Cc1ccc2c(=O)c(C(=O)c3ccc(C)c(C)c3)c[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(=O)c(C(=O)c3ccc(C)c(C)c3)cn(Cc3cccc(Br)n3)c2n1
Yield: 18.7 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 0.100 g (0.342 mmol) of 3-(3,4-Dimethyl-benzoyl)-7-methyl-1H-[1,8]naphthyridin-4-one, 16.4 mg (0.410 mmol, 60% dispersion in oil) of sodium hydride, 0.103 g (0.410 mmol) of 2-bromo-6-bromomethyl-pyridine and 3.5 mL of N,N dimethylformamide. The crude brown solid was purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 29.5 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-7-methyl-1H-[1,8]naphthyridin-4-one as an off white solid. LC-MSD, m/z for C24H20BrN3O2 [M+H]: 463.07 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.7 min
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](I)=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)[O:22][B:21](B2OC(C)(C)C(C)(C)O2)[O:20]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([B:21]([OH:22])[OH:20])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Fc1ccc(-n2ncc3c(I)ccnc32)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1
Temperature: 84 °C

Procedure:
To a 16×100 mm reaction vial was added Intermediate 2A (61.8 mg, 0.182 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (85.5 mg, 0.337 mmol), potassium acetate (77 mg, 0.785 mmol), and DMSO (1 mL). Argon was bubbled into the reaction mixture for 5 minutes. Next, PdCl2(dppf).CH2Cl2 (10 mg, 0.012 mmol) was added and the reaction mixture was heated at 84° C. for 18 h. The desired product was confirmed to be present by LC/MS (Condition B): 88.0%; ret. T=3.4 min; (M+H)+ 258.04.
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([C:18](Cl)=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1>ClCCl.C(OCC)(=O)C>[CH3:11][O:10][N:9]([CH3:8])[C:18]([C:13]1[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:19]
Reactant: CNOC
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
The intermediate N-methoxy-N-methyl-p-biphenylcarboxamide was first formed. Pyridine (4 mL, 5 equivalents) and N,O-dimethylhydroxylamine hydrochloride (980 mg, 10 mmol) were added to a solution of p-biphenylcarbonyl chloride (2.16 g, 10 mmol) in dry dichloromethane (10 mL). The solution was stirred for 2 hours at room temperature and then diluted with ethyl acetate (20 mL), washed sequentially with 1N HCl (2×20 mL), saturated sodium bicarbonate (20 mL), and brine (20 mL). It was then dried over magnesium surfate and evaporated under reduced pressure to give N-methoxy-N-methyl-p-biphenylcarboxamide as a solid (1.78 g, 74%). The solid was recrystallized from ethyl acetate/hexane for analysis: mp 77°-78° C. The identity of the solid was confirmed as that of N-methoxy-N-methyl-p-biphenylcarboxamide by IR, proton NMR, 13C NMR and elemental analysis, with mass spectrometric determination of the molecular weight.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1>C(#N)C>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([N:13]3[CH:17]=[CH:16][CH:15]=[N:14]3)=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: c1cn[nH]c1
Reactant: Brc1ccc(-n2ccnc2)cc1
Solvent: CC#N
Product: c1cnn(-c2ccc(-n3ccnc3)cc2)c1

Procedure:
Operating protocol B (82° C., 48 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 535 mg of 1-(4′-bromophenyl)-1H-imidazole (2.4 mmoles), 136 mg of pyrazole (2 mmoles) and 1.2 ml of acetonitrile.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].[NH2:37][CH2:38][C:39]([CH3:42])([OH:41])[CH3:40].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:35])([F:36])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:37][CH2:38][C:39]([OH:41])([CH3:42])[CH3:40])=[O:9])=[O:4]
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)(O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(O)CNC(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 6.8 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 22, 22 mg, 0.044 mmol), 1-amino-2-methylpropan-2-ol (5.85 mg, 0.066 mmol), 4-methylmorpholine (17.72 mg, 0.175 mmol), and HATU (21.65 mg, 0.057 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=13.2 min) to provide (R/S)-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N-(2-hydroxy-2-methylpropyl)propanamide (2 mg, 2.99 μmol, 6.83% yield): LCMS=574.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.36 Hz), 7.50-7.79 (7 H, m), 5.11 (1 H, s), 3.48-3.58 (2 H, m), 3.14-3.22 (2 H, m), 2.48 (2 H, t, J=6.71 Hz), 1.16 (3 H, s), 1.16 (3 H, s); HPLC peak RT=8.2 min (Method A).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(O)cc(OC)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OC)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.2 %

Procedure:
To a solution of methyl 3-hydroxy-5-methoxybenzoate (6.00 g) in DMF (50 mL) were added benzyl bromide (6.20 g) and potassium carbonate (5.50 g), and the mixture was stirred at room temperature for 15 hr. 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 (ethyl acetate/hexane) to give the title compound (8.90 g) as a white solid.
Reaction SMILES: COC[O:4][C@H:5]1[C@:18]23[CH2:19][CH2:20][C@@H:7]([CH2:8][C@H:9]2[C@@:10]2([CH3:25])[C@H:15]([CH2:16][CH2:17]3)[C@:14]([CH3:24])([C:21]([OH:23])=[O:22])[CH2:13][CH2:12][CH2:11]2)[C@@H:6]1[S:26]([CH3:28])=[O:27].FC(F)(F)C(O)=O>O1CCCC1>[OH:4][C@H:5]1[C@:18]23[CH2:19][CH2:20][C@@H:7]([CH2:8][C@H:9]2[C@@:10]2([CH3:25])[C@H:15]([CH2:16][CH2:17]3)[C@:14]([CH3:24])([C:21]([OH:23])=[O:22])[CH2:13][CH2:12][CH2:11]2)[C@@H:6]1[S:26]([CH3:28])=[O:27]
Reactant: COCO[C@@H]1[C@@H](S(C)=O)[C@H]2CC[C@@]13CC[C@H]1[C@@](C)(CCC[C@@]1(C)C(=O)O)[C@@H]3C2
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CS(=O)[C@H]1[C@H]2CC[C@@]3(CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O)[C@@H]3C2)[C@@H]1O

Procedure:
To a solution of (1R,4S,5R,9S,10S,12S,13S,14S)-14-(methoxymethoxy)-5,9-dimethyl-13-(methylsulfinyl)tetracyclo[10.2.2.01,10.04,9]hexadecane-5-carboxylic acid (4.1 mg, 0.0099 mmol) obtained in Example 115 in tetrahydrofuran (2 mL) was added trifluoroacetic acid (2 mL) under stirring on ice. After stirring at 50° C. for 29 hours, the reaction mixture was evaporated, to give (1R,4S,5R,9S,10S,12S,13S,14S)-14-hydroxy-5,9-dimethyl-13-(methylsulfinyl)tetracyclo[10.2.2.01,10.04,9]hexadecane-5-carboxylic acid. This product was further purified by silica gel column chromatography so as to separate two isomers based on the configuration of sulfoxide, to give isomer 1 (0.71 mg) and isomer 2 (1.01 mg).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:50])[CH2:18][C:17]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[C:33]([F:45])[CH:32]=4)=[C:26]([CH2:46][CH2:47][CH3:48])[N:25]=[C:24]3[CH3:49])[CH:21]=[CH:22][C:16]=2[O:15]1>C(OCC)(=O)C>[CH3:13][C:14]1([CH3:50])[CH2:18][C:17]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:3][C:4](=[O:7])[O:5][N:44]=5)=[C:33]([F:45])[CH:32]=4)=[C:26]([CH2:46][CH2:47][CH3:48])[N:25]=[C:24]3[CH3:49])[CH:21]=[CH:22][C:16]=2[O:15]1
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)c(F)c1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)c(F)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.14 g), sodium hydrogen carbonate (1.6 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile (0.98 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-carbonyldiimidazole (0.4 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.6 g, 55%).