Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7]([C:9]1[N:10]=[C:11]([C:31]2[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:38])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=3)=[CH:16][C:15]=2[Cl:30])[CH:13]=1)=O)([CH3:5])[CH3:4].C1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:46]>CCOC(C)=O>[Cl:30][C:15]1[CH:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=2)[CH:18]=[CH:19][C:14]=1[N:12]1[CH:13]=[C:9]([C:7]2[S:46][CH2:2][C:3]([CH3:5])([CH3:4])[N:6]=2)[N:10]=[C:11]1[C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:38]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)(CO)NC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)c(-c2c(Cl)cccc2Cl)n1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)CSC(c2cn(-c3ccc(-c4cccc(S(C)(=O)=O)c4)cc3Cl)c(-c3c(Cl)cccc3Cl)n2)=N1
Yield: 17.2 %

Procedure:
To a N2 purged 50 mL round bottom flask attached with condenser was added 1-(3-Chloro-3′-methanesulfonyl-biphenyl-4-yl)-2-(2,6-dichloro-phenyl)-1H-imidazole-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (140 mg, 236 μmol), anhydrous benzene (14 mL) and P2S5 (500 mg, 2.25 mmol). The reaction solution was stirred at reflux for 1 hr. The reaction solution was diluted with EtOAc (100 mL) and filtered through a Buchner funnel to remove excess P2S5. The filtrate was washed with aq. 0.1 N NaOH. The organic phase was partitioned, dried over Na2SO4, filtered, concentrated in vacuo, and chromatographed through a 25 g SiO2 column using a gradient of 100% Hexane to 80% EtOAc to afford 24 mg (17% yield) of title compound. MS (ESI) 590.0, 592.0, 594.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (t, J=2 Hz, 1H), 8.21 (t, J=2 Hz, 1H), 8.17 (d, J=2 Hz, 1H), 8.14 (d, J=8 Hz, 1H), 8.10 (d, J=8 Hz, 1H), 7.99 (d, J=8 Hz, 1H), 7.95 (d, J=8 Hz, 1H), 7.78-7.85 (m, 2H), 7.74 (t, J=8 Hz, 1H), 7.49-7.61 (m, 3H), 7.43 (d, J=8 Hz, 1H), 3.36 (br s, 2H), 3.26 (s, 3H), 1.48 (s, 6H).
Reaction SMILES: P(=O)(O)(O)O.N(CCO)(CCO)CCO.CO[CH:18]([O:24]C)[C:19]([CH3:23])=[CH:20][CH2:21][CH3:22].[CH3:26][C:27]([CH3:31])=[CH:28][CH2:29]O>C(O)(=O)C>[CH3:23][C:19](=[CH:20][CH:21]([CH3:22])[CH2:29][CH:28]=[C:27]([CH3:31])[CH3:26])[CH:18]=[O:24]
Reactant: CCC=C(C)C(OC)OC
Reactant: CC(C)=CCO
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: OCCN(CCO)CCO
Product: CC(C)=CCC(C)C=C(C)C=O
Temperature: 110 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
The amine-H4PO3 catalyst (2.0 g, 1 w/w %) prepared by mixing orthophosphoric acid (85%) with triethanolamine (in 1:1 equivalent) was dissolved in acetic acid (4 ml, 2 ml/w %) and added to a mixture of 1,1-dimethoxy-2-methylpent-2-ene (200 g, 1.52 mol) and 3-methyl-but-2-en-1-ol (131 g, 1.52 mol). The mixture was heated to 110° C. for 2 h, then at 160° C. for further 4 h. During this period, volatile materials were collected through a 10 cm Vigreux column. The remaining oil was distilled in vacuo to give 2,4,7-trimethylocta-2,6-dienal (66%).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[H-].[Na+].[Cl:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:13](F)=[CH:12][CH:11]=1>CS(C)=O>[Cl:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:13]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])=[CH:12][CH:11]=1
Reactant: Fc1ccc(Cl)nc1-c1ccc(Cl)cc1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: FC(F)(F)COc1ccc(Cl)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
To a solution of 1.273 g trifluoroethanol in 20 ml dimethylsulfoxide was added 0.463 g sodiumhydride 55% in oil and the mixture was stirred at room temperature for 15 min. To the resulting solution was added a solution of 3.2 g 6-chloro-2-(4-chloro-phenyl)-3-fluoro-pyridine in 10 ml dimethylsulfoxide and the mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel with a gradient of heptane to dichloromethane to yield 3.30 g of the title compound as slightly yellow solid. MS (EI): 322.1 and 324.2 (M+H). The product was obtained as 85:15 mixture of F vs Cl substitution products (6-chloro-2-(4-chloro-phenyl)-3-(2,2,2-trifluoro-ethoxy)-pyridine vs. 2-(4-chloro-phenyl)-3-fluoro-6-(2,2,2-trifluoro-ethoxy)-pyridine) that were better separable at the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[F:20][C:21]1[CH:22]=[C:23]([C@H:28]([NH2:30])[CH3:29])[CH:24]=[C:25]([F:27])[CH:26]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:20][C:21]1[CH:22]=[C:23]([C@H:28]([NH:30][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:29])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: O=C(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1
Reactant: C[C@@H](N)c1cc(F)cc(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: C[C@@H](NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1cc(F)cc(F)c1
Yield: 94.8 %

Procedure:
Following a similar procedure to that described in Example (1a), 3.0 g of 4-fluorophenyl 3-nitrophenyl ketone, 3.55 g of (R)-1-(3,5-difluorophenyl)ethylamine hydrochloride, 9.38 ml of triethylamine, 1.61 ml of titanium tetrachloride, 3.08 g of sodium cyanoborohydride and 1.05 ml of acetic acid were reacted, to obtain 4.48 g of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:20]([O:22]C)=O)[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:6]([N+:10]([O-:12])=[O:11])[C:7]=1[C:8]#N.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.Cl.[OH2:41]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:22])[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:6]([N+:10]([O-:12])=[O:11])[C:7]=1[CH:8]=[O:41]
Reactant: O
Reactant: COC(=O)c1cc(Cl)c(C#N)c([N+](=O)[O-])c1-c1cccc(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: O=Cc1c(Cl)cc(CO)c(-c2cccc(F)c2)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 52.9 %

Procedure:
To a mixture of methyl 4-chloro-5-cyano-3′-fluoro-6-nitrobiphenyl-2-carboxylate (1.02 g, 3.05 mmol) in methylene chloride (20 mL) was added 1.0 M diisobutylaluminum hydride in hexane (7.6 mL, 7.6 mmol) at −78° C. The reaction was warmed to room temperature over 2 hours with stirring. 5.0 M Hydrogen chloride in water (30 mL, 100 mmol) was slowly added with stirring for 1 hour. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and then concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the desired product (0.50 g, 53%). LCMS calculated for C14H10ClFNO4 (M+H)+: m/z=310.0; Found: 310.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]2[O:11][CH2:12][CH2:13][O:14][C:3]=12.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH2:12]1[CH2:13][O:14][C:3]2[C:4](=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=2[NH:1][C:15]([CH3:16])=[O:17])[O:11]1
Reactant: CC(=O)c1ccc(N)c2c1OCCO2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C(C)=O)c2c1OCCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4'-amino-2',3'-ethylenedioxyacetophenone (310 mg, 1.60 mmol) in 2.3 mL of pyridine under nitrogen was cooled in an ice/water bath and 6.9 mL of acetic anhydride was added drop-wise. The mixture was allowed to warm to room temperature and then stirred for 16 hours. The mixture was concentrated by rotary evaporation and the residue was stirred into water. The residue was isolated by filtration and washed with water. Drying gave 2',3'-ethylenedioxy-4'-(methylcarbonylamino)acetophenone (289 mg, 1.23 mmol), m.p. 142°-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](S(C1C=CC=CC=1)(=O)=O)[N:7]=[C:6]2[N:21]1[CH2:26][CH2:25][N:24](C#N)[CH2:23][CH2:22]1.[Al].[Li].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: COc1ccc2c(c1)c(N1CCN(C#N)CC1)nn2S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Al]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc2[nH]nc(N3CCNCC3)c2c1
Reaction time: 3 h
Yield: 81.1 %

Procedure:
To a stirred mixture of 4-[5-methoxy-1-phenylsulfonyl-1H-indazol-3-yl]-1-piperazinecarbonitrile (9.5 g, 0.0239 mol) in THF (150 ml) under N2 was added, dropwise, lithium aluminum [50 ml (2.1 eq) of a 1M LiAlH4 solution in THF]. After complete addition the reaction was warmed to reflux and stirred for 3 hours. To the cooled reaction was added carefully, H2O (15 ml) to destroy the excess LiAlH4. The mixture was allowed to stand overnight. The reaction mixture was filtered through a coarse sintered glass funnel. The resultant cake was washed well with THF and the THF filtrate was concentrated to afford 6.0 g, of a residue. The residue was triturated with ether and H2O and the resultant solid was collected and dried to afford 4.5 g of 5-methoxy-3-(1-piperazinyl)-1H-indazole, m.p. 163°-169° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].CS(O[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])(=O)=O>CN(C=O)C>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CS(=O)(=O)OCCc1ccccc1F
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCc1ccccc1F)C(=O)OC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (8.24 g) in DMF (200 ml) was added dropwise dimethyl malonate (24.9 g) under ice-cooling, and the suspension was stirred at 50° C. for 30 min. After cooling to room temperature, a solution of 2-(2-fluorophenyl)ethyl methanesulfonate in DMF (30 ml) was added dropwise, and the mixture was stirred at 150° C. for 1 hr. After cooling to room temperature, the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give dimethyl 2-[2-(2-fluorophenyl)ethyl]malonate.
Reaction SMILES: C([O:5][C:6](=[O:27])/[C:7](=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]2)=[C:15]([O:25][CH3:26])[CH:14]=1)/[CH2:8][CH2:9][CH2:10][Cl:11])(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C(Cl)Cl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[Cl:11][CH2:10][CH2:9][CH2:8]/[C:7](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]2)=[C:15]([O:25][CH3:26])[CH:14]=1)/[C:6]([OH:27])=[O:5]
Reactant: COc1cc(/C=C(\CCCCl)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a methylene chloride (20 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid tert-butyl ester (5 g), trifluoroacetic acid (10 mL) was added and the reaction solution was agitated at room temperature for 2 hours. After confirming disappearance of the starting materials, the reaction solution was concentrated under reduced pressure. The resulted solids were separated by filtering and 5.7 g of the title compound was obtained by washing with ethyl acetate further. The physical properties of the compound are as follows.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([NH:7][C:8](=[O:15])[CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH2:3]1>C(O)C.[Pd]>[F:1][C@@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[NH:7][C:8](=[O:15])[CH2:9][CH2:10][S:11]([CH3:14])(=[O:12])=[O:13]
Reactant: CS(=O)(=O)CCC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)CCC(=O)N[C@@H]1CNC[C@H]1F
Reaction time: 16 h
Yield: 97.7 %

Procedure:
A nitrogen sparged suspension of (3R,4R)-benzyl 3-fluoro-4-(3-(methylsulfonyl)propanamido)pyrrolidine-1-carboxylate (2.80 g, 7.52 mmol, 1.00 eq) and 10% Pd/C (300 mg) in ethanol (250 mL) was stirred under a hydrogen atmosphere (1 atm) for 16 hr. The reaction mixture was then sparged with nitrogen and filtered through a pad of Celite®. The Celite® was washed with additional ethanol (50 mL). The combined filtrates were concentrated under reduced pressure to give the title compound (1.75 g, 98% yield, 95% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.13 (d, J=6.7 Hz, 1 H) 4.73-5.02 (m, 1 H) 3.99-4.20 (m, 1 H) 3.32 (t, J=7.6 Hz, 2 H) 3.14 (dd, J=11.7, 6.8 Hz, 2 H) 2.94-3.01 (m, 4 H) 2.87-2.91 (m, 1 H) 2.52-2.59 (m, 3 H). m/z (APCI+) for C8H16FN2O3S 239.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:13][C:12]=1[F:21].[Li+].[OH-]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:21]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(OC)cc2F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of methyl 6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinate (1.0 equiv.) in THF/MeOH (2:1, 0.09 M) was added LiOH (1.5 equiv.) and the reaction was stirred at room temperature for 1 hour. The solution was quenched with 1N HCl, extracted with ethyl acetate, washed with brine, dried with sodium sulfate, filtered and concentrated to give 6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinic acid in 84% yield. LC/MS=284.1 (M+H), Rt=0.76 min.
Reaction SMILES: [Mg].[CH2:2]([Br:4])[CH3:3].[CH3:5][O:6][N:7]=[C:8]1[C:17]2[C:12](=[CH:13]C=[C:15](C3C=NN(CC)C=3OS(CCC)(=O)=O)[C:16]=2C)[S:11](=O)(=O)[C:10](=C=O)[CH2:9]1>C1COCC1>[CH3:5][O:6][N:7]=[C:8]1[C:17]2[C:12](=[CH:13][CH:3]=[C:2]([Br:4])[C:16]=2[CH3:15])[S:11][CH2:10][CH2:9]1
Reactant: CCCS(=O)(=O)Oc1c(-c2ccc3c(c2C)C(=NOC)CC(=C=O)S3(=O)=O)cnn1CC
Reactant: CCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CON=C1CCSc2ccc(Br)c(C)c21

Procedure:
1.1 Grams (46 mmol) of magnesium was dispersed in 10 ml of THF, and 2.2 g (20 mmol) of ethyl bromide was dropwise added under nitrogen current. The mixture was allowed to react for 10 minutes, and then a THF solution of 2.9 g (10 mmol) of the 4-methoxyimino-5-methyl-6-bromothiochroman obtained in the above (1) was gradually added at room temperature. The mixture was refluxed for 3 hours and then cooled to room temperature, and carbon dioxide gas was bubbled in for 1 hour. To the reaction mixture was added 5% hydrochloric acid, and the mixture was extracted with ether. An ether layer was extracted with a 5% potassium carbonate aqueous solution, and an aqueous layer was neutralized with concentrated hydrochloric acid. The neutralization product was extracted with ethyl acetate, and the extract was washed with a saturated sodium chloride aqueous solution. The washed extract was dried over sodium sulfate, and then the solvent was distilled off to give 1.6 g (yield 63%) of 4-methoxyimino-5-methylthiochroman-6-carboxylic acid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([CH2:33][CH2:34][NH2:35])[CH2:29]1)[CH3:27]>>[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([CH2:33][CH2:34][NH:35][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: CCN1CC[C@H](CCN)C1
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Product: CCN1CC[C@H](CCNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1

Procedure:
Prepared by proceeding in a similar manner to Example 58, starting from (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67) and 2-((S)-1-ethylpyrrolidin-3-yl)ethylamine (Intermediate 208).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:4][CH:3]=1.[CH2:26]=[O:27]>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11]([CH2:26][OH:27])=[N:10][N:9]=[C:8]2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nncn1Cc1ccc(Cl)cc1
Reactant: C=O
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nnc(CO)n1Cc1ccc(Cl)cc1
Temperature: 125 °C
Yield: 101.4 %

Procedure:
A mixture of Boc-protected triazole from example 3 (7.7 g, 21.221 mmol) and paraformaldehyde (3.23 g, 5 eq.) in 50 mL of o-xylene was heated at 125° C. for 3 h. After cooling, the mixture was filtered over a Celite-fritted funnel and washed with 10 mL of o-xylene. The filtrate was concentrated in vacuo to provide the desired intermediate as a foam (8.45 g, 100%+)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:28][CH3:29].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:28][CH3:29])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A solution of (R)-benzyl 3-(tert-butoxycarbonylamino)piperidine-1-carboxylate (5.00 g, 14.95 mmol, Example E) in dry DMF (50 mL) was added dropwise to a suspension of sodium hydride 60% in mineral oil (0.7176 g, 17.94 mmol) in dry DMF (10 mL). The mixture was stirred at 0° C. for 1 hour and allowed to stir at room temperature for 2 hours. The mixture was then cooled to 0° C. and treated dropwise with iodoethane (1.315 mL, 16.45 mmol). The reaction mixture was stirred at 0° C. for 2 hours and allowed to warm to room temperature over 18 hours. Water (50 mL) was added, and the mixture was extracted into EtOAc (3×70 mL). The organic layers were combined, washed with water (3×20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Biotage Flash 40M+) eluting with 20% EtOAc/hexane to provide (R)-benzyl 3-(tert-butoxycarbonyl(ethyl)amino)piperidine-1-carboxylate (5.01 g, 92% yield) as an oil. LCMS (APCI+) m/z 363 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28][CH2:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[C:7]([CH3:18])([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1.[OH:39]OS([O-])=O.[K+]>O1CCCC1.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28]([CH2:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:34])[F:35])=[O:39])[C:7]([CH3:18])([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: O=S([O-])OO
Reactant: CC1(c2ccncc2)COc2cc(O)ccc2C1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2ccncc2)COc2cc(O)ccc2C1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Reaction time: 5 h
Yield: 81 %

Procedure:
To a solution of (3RS,4RS)-7-hydroxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]-3-(4-pyridyl)chroman (6.1 mg, 0.011 mmol) in tetrahydrofuran (0.5 ml) was added under ice-cooling a solution of Oxone® (monopersulfate compound; DuPont product) (3.4 mg, 0.0055 mmol) in water (0.5 ml), which was then stirred for 5 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and washed with saturated saline solution. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate) to give (3RS,4RS)-7-hydroxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-3-(4-pyridyl)chroman (5.1 mg, yield 81%).
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:30][O:31][C:32](=[O:37])[CH:33]([NH2:36])[CH2:34][CH3:35]>>[CH:1]1([N:7]([CH2:25][CH:26]2[CH2:27][CH2:28]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][NH:36][CH:33]([CH2:34][CH3:35])[C:32]([O:31][CH3:30])=[O:37])=[CH:21][CH:22]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(N)C(=O)OC
Reactant: O=Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Agent: Cl
Product: CCC(NCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1)C(=O)OC

Procedure:
Following the general method as outlined in Example 73, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(4-formylphenyl)pyrimidine-4-carboxamide (Intermediate 24; 80.00 mg; 0.18 mmol) and 2-amino-butyric acid methyl ester hydrochloride (Sigma, 55 mg; 0.36 mmol), the title compound was obtained as a colorless oil after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:9]=1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[N:39][CH:40]=1.CC([O-])(C)C.[Na+].O1CCOCC1>[NH4+].[Cl-]>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:9]=[C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:34][C:35]3[CH:40]=[N:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[N:13]=[C:12]([CH3:14])[N:11]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccncc3Cl)n2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccncc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 100 °C
Yield: 23.2 %

Procedure:
A glass microwave reaction vessel was charged with 4-(3-chloropyridin-4-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (32 mg, 0.069 mmol), 5-amino-2-methoxypyridine (0.017 mL, 0.139 mmol), Brett precatalyst ((SP-4-4)-[2-[2-(amino-κN)ethyl]phenyl-κC]chloro[dicyclohexyl[3,6-dimethoxy-2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]phosphine-κP]palladium) (2 mg) and sodium 2-methylpropan-2-olate (16.64 mg, 0.173 mmol) and dioxane (1 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 16 h. The reaction mixture was diluted with saturated NH4Cl (10 mL) and extracted with EtOAc (2×20 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as orange oil. The crude product was purified by silica gel chromatography eluting with 20% THF/CH2Cl2 to give N,N-bis(4-methoxybenzyl)-4-(3-(6-methoxypyridin-3-ylamino)pyridin-4-yl)-6-methyl-1,3,5-triazin-2-amine (9 mg, 0.016 mmol, 24% yield). 1H NMR (300 MHz, CDCl3) δ 10.32 (s, 1H); 8.49-8.68 (m, 1H); 8.33 (s, 1H); 8.24 (d, J=5.12 Hz, 2H); 8.03 (d, J=5.12 Hz, 2H); 7.95 (d, J=1.61 Hz, 1H); 7.38 (dd, J=8.70, 2.41 Hz, 2H); 7.21 (d, J=8.33 Hz, 2H); 7.14 (d, J=8.33 Hz, 2H); 6.98 (s, 1H); 6.87 (d, J=8.33 Hz, 2H); 6.79 (d, J=8.33 Hz, 2H); 6.72 (d, J=8.77 Hz, 1H); 4.86 (s, 2H); 4.79 (s, 2H); 3.81 (s, 3H); 3.76 (s, 3H); 2.56 (s, 3H). m/z (ESI, +ve ion) 550.0 (M+H)+.