Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][C@H:4]([OH:14])[CH2:3]1.[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH3:21])(=O)=O.O>C1COCC1>[CH3:21][O:14][C@H:4]1[CH2:5][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][N:2]([CH3:1])[CH2:3]1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CN1C[C@@H](O)C[C@@H](c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@H]1C[C@@H](c2ccccc2)CN(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of cis-1-methyl-5-phenyl-3-piperidinol (2.03 g) in THF (20 ml) was treated with 60% sodium hydride dispersion in oil (480 mg) and heated 15 min. at reflux. The mixture was cooled to room temperature and treated with methyl tosylate (1.86 g) in THF (5 ml). The reaction mixture was stirred for 1 hour at ambient temperature, treated with water (5 ml) and the solvents removed under reduced pressure. The residue was partitioned between water (100 ml) and ether (100 ml). The organic phase was dried over magnesium sulphate and the solvent removed under reduced pressure. The resulting oil was triturated with cyclohexane (10 ml) and the resulting crystals (300 mg; unchanged starting material) removed by filtration. The mother liquors were evaporated under reduced pressure and the resulting gum converted to the fumarate which was recrystallised from methanol/ethyl acetate to give the title compound as the sesquifumarate (500 mg) Mpt. 152°-4°
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1)([O-:6])=O.C(=O)([O-])O.[Na+].[C:20](Cl)(=[O:22])[CH3:21]>[Pd].O1CCCC1CCO.O.CN(C)C=O>[C:20]([N:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[OH:6])(=[O:22])[CH3:21]
Reactant: COc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Agent: [Pd]
Agent: NN
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(N(O)C(C)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.7 %

Procedure:
Under ice-cooling, 10% palladium on activated carbon (0.46 g) and hydrazine monohydrate (4.9 mL, 100 mmol) were added to a solution of 3-nitroanisole (7.7 g, 50 mmol) in tetrahydrofuran-ethanol solution (1:1, 100 mL), stirred for 3 hours at room temperature, and let stand overnight at about 5° C. The whole was filtered with celite with ethanol (100 mL), and the filtrate was concentrated under reduced pressure. Sodium hydrogen carbonate (13 g, 150 mmol) and anhydrous N,N-dimethylformamide (50 mL) were added to the obtained residue. Moreover under ice-cooling, acetyl chloride (5.4 mL, 76 mmol) was added thereto and the mixture was stirred for 1 hour. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (300 mL×1, 200 mL×1). The combined organic layer was washed with brine (100 mL×2) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatograpy to give the title reference compound (9.3 g) as an orange oil (quantitative yield)
Reaction SMILES: [C:1]([Si:5]([O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]CC2C=CC=CC=2)=[CH:21][CH:20]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C.C1CCCCC=1>[C:1]([Si:5]([O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](Oc1ccc(OCc2ccccc2)cc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(C)(C)[Si](Oc1ccc(O)cc1)(c1ccccc1)c1ccccc1
Yield: 99.1 %

Procedure:
A mixture of t-butyl-[4-benzyloxyphenoxy]-diphenylsilane (170 g, 388 mmol) and 10 g of 10% palladium on carbon in ethanol-cyclohexene (2:1, v/v) was heated at reflux for 48 hours. The catalyst was filtered and the solvent was removed in vacuo to provide 134 g of product as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[S:19][C:18]([C:20]#[N:21])=[C:17]([CH3:22])[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]([O:34]C)=[O:33].[Li+].[OH-]>>[Cl:24][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[C:26]([F:25])[CH:27]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:23])[C:9]([C:15]1[S:19][C:18]([C:20]#[N:21])=[C:17]([CH3:22])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11]
Reactant: Cc1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)sc1C#N
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(C(O)(C(C)c2ccc(-c3ccc(C(=O)O)c(F)c3)cc2Cl)C(F)(F)F)sc1C#N

Procedure:
The compound was prepared in analogy to Example 60, step 2, from 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-thiophene-2-carbonitrile and 3-fluoro-4-methoxycarbonylphenylboronic acid (CAS Reg. No. 505083-04-5). The resulting ester was hydrolyzed by addition of aqueous LiOH solution (1N) to the reaction mixture. Light yellow solid. MS (m/e, ISP neg. ion)=496.3 [M−H+].
Reaction SMILES: C(Cl)Cl.[F:4][CH:5]1[CH:10]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][CH:7]([OH:20])[CH2:6]1.C(N(CC)C(C)C)(C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(OCC)(=O)C.CCCCCC>[CH3:30][S:31]([O:20][CH:7]1[CH2:8][CH2:9][CH:10]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]([F:4])[CH2:6]1)(=[O:33])=[O:32]
Reactant: OC1CCC(OCCc2ccccc2)C(F)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OC1CCC(OCCc2ccccc2)C(F)C1
Yield: 99.8 %

Procedure:
A methylene chloride (10 mL) solution of 3-Fluoro-4-(2-phenylethoxy)cyclohexanol (0.450 g, 1.89 mmol) in N,N-diisopropylethylamine (0.688 mL, 3.96 mmol) was cooled in an ice bath under nitrogen. Methanesulfonyl chloride (0.154 mL, 1.98 mmol) was added dropwise to the reaction solution. After 0.5 h the contents of the reaction flask were washed with 5% potassium bisulfate. The aqueous layer was extracted (2×) with methylene chloride and the combined organic portions dried with anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. Flash column chromatography (hexane:ethyl acetate, 60:40) gave 3-Fluoro-4-(2-phenylethoxy)cyclohexyl methanesulfonate as a colorless oil (0.597 g, 100% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[C:3]=1[CH3:26].[CH3:27][O:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:33]5[CH:32]=[CH:31][N:30]=[C:29]([O:28][CH3:27])[CH:34]=5)[C:3]([CH3:26])=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C
Reactant: COc1cc(B(O)O)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C)ccn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
A solution of N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (38 mg, 0.1 mmol) in DME (1 mL) was added to a reaction tube containing 2-methoxypyridin-4-ylboronic acid (46 mg, 0.15 mmol) and Pd(PPh3)4 (6 mg, 0.005 mmol). Saturated Na2CO3 solution was added (100 μL) and the reaction was stirred at 80° C. overnight. The reaction was filtered, concentrated and purified by column chromatography (0-50% ethyl acetate in hexanes) to obtain 40 mg (44%) of a clear oil. ESI-MS m/z calc. 453.4. found 454.3 (M+1)+. Retention times: 2.06 minutes. H NMR (400 MHz, DMSO) 8.85 (s, 1H), 8.20 (d, J=5.2 Hz, 1H), 7.86 (s, 1H), 7.54 (d, J=1.5 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.32 (dd, J=1.6, 8.3 Hz, 1H), 6.97 (dd, J=1.2, 5.2 Hz, 1H), 6.77 (s, 1H), 3.87 (s, 3H), 2.31 (s, 3H), 2.09 (s, 3H), 1.51-1.48 (m, 2H), 1.17-1.15 (m, 2H).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1.C(N(CC)CC)C.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH2:48][CH:49]([OH:52])[CH:50]=[CH2:51])[CH:42]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:51][CH2:50][C:49](=[O:52])[CH2:48][CH2:47][C:43]1[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=1
Reactant: C=CC(O)CCc1cccnc1
Reactant: Brc1ccc2ccccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CCc1cccnc1)CCc1ccc2ccccc2c1
Temperature: 100 °C
Yield: 47.8 %

Procedure:
Palladium(II) acetate (0.056 g), tri-o-tolylphosphine (0.148 g), 2-bromonaphthalene (0.49 g) and triethylamine (10 ml) were added to a solution of (±)-5-(3-pyridyl)-1-penten-3-ol (0.40 g) in acetonitrile (30 ml) and the mixture heated at 100° C. for 24 hours. The solvents were removed under reduced pressure and water was added to the residue. The mixture was extracted with dichloromethane, the combined extracts dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:ethyl acetate (2:1) to give the sub-title ketone as a brown oil (0.327 g).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][C:12]=2[NH2:21])[O:6][CH2:5][CH2:4][O:3]1.[C:22](OCC)(OCC)(OCC)[CH3:23]>C1(C)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH3:22][C:23]1[N:10]([CH2:9][CH2:8][CH2:7][C:2]2([CH3:1])[O:3][CH2:4][CH2:5][O:6]2)[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1
Reactant: CC1(CCCNc2c(N)cnc3ccccc23)OCCO1
Reactant: CCOC(C)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: Cc1nc2cnc3ccccc3c2n1CCCC1(C)OCCO1
Yield: 99.6 %

Procedure:
A solution of N4-[3-(2-methyl-[1,3]dioxolan-2-yl)propyl]quinoline-3,4-diamine (6.20 g, 21.6 mmol), triethyl orthoacetate (3.10 g, 25.8 mmol) and pyridinium p-toluenesulfonate (0.18 g, 0.71 mmol) in toluene (250 mL) was heated at reflux under a Dean-Stark trap for 2 hours, periodically draining off the distillate and adding fresh toluene to the reaction mixture. The solution was concentrated under reduced pressure, and the residue was taken up in dichloromethane (150 mL), washed successively with a saturated aqueous sodium bicarbonate solution and water (100 mL each), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 2-methyl-1-[3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-1H-imidazo[4,5-c]quinoline (6.70 g) as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][O:22][CH2:23][C:24](O)=[O:25].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[CH3:21][O:22][CH2:23][C:24]([NH:11][CH2:10][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)=[O:25]
Reactant: COCC(=O)O
Reactant: NCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)NCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A mixture of 8.6 g of 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butylamine (obtained according to PREPARATION (I), step (b)), 2.46 g of methoxyacetic acid, 5.55 g of triethylamine in 50 ml of dichloromethane is cooled to 0° C. and 14.5 g of BOP is added thereto. The reaction mixture is stirred for one hour at room temperature and concentrated under vacuum. The residue is taken up in ethyl acetate and is successively washed with water, dried over Na2SO4 and concentrated under vacuum. The residue is chromatographed on silica gel using CH2Cl2 /CH3OH (100/1 v/v) as the eluent to give 7.5 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[N:4][CH:3]=1.[I:16]N1C(=O)CCC1=O>CS(C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[N:4][C:3]=1[I:16]
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1cncc(NCC2CCOCC2)n1
Solvent: CS(C)=O
Solvent: O
Product: Clc1nc(NCC2CCOCC2)cnc1I
Temperature: 0 °C
Reaction time: 24 h
Yield: 55.2 %

Procedure:
6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (0.250 g, 1.098 mmol) was dissolved in a mixture of DMSO (4.30 ml) and H2O (0.105 ml). It was cooled to 0° C. in an ice bath and was then treated with N-iodosuccinimide (0.247 g, 1.098 mmol) by portion-wise addition. Once the addition was complete the reaction mixture was stirred at ambient temperature for 24 hr. Additional NIS (0.025 g, 0.111 mmol) was added. Stirring at ambient temperature was continued for 24 hr. The reaction mixture was diluted with H2O (50 ml). This was extracted with EtOAc (3×50 ml). The organic layers were combined and washed with brine (1×50 ml). The organic layer was dried (Na2SO4), filtered, and the solvent removed in vacuo to give 0.410 g of crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 30 EtOAc/70 heptane to 100 EtOAc gave 0.2144 g (55%) of 6-chloro-5-iodo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine. LCMS (m/z): 353.9 (MH+), retention time=0.92 min. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.37 (qd, 2H) 1.59 (s, 2H) 1.67 (d, J=12.91 Hz, 2H) 1.77-1.94 (m, J=14.87, 7.63, 7.63, 3.52 Hz, 1H) 3.25 (t, J=6.46 Hz, 2H) 3.39 (td, J=11.74, 1.96 Hz, 2H) 4.00 (dd, J=11.15, 3.72 Hz, 2H) 4.80 (br. s., 1H) 7.62 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:23]([CH2:29][CH2:30][CH:31]([F:33])[F:32])[C:24]([O:26]CC)=[O:25])[CH:8]=2)[N:3]=1.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:23]([CH2:29][CH2:30][CH:31]([F:33])[F:32])[C:24]([OH:26])=[O:25])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)C(CCC(F)F)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(C(CCC(F)F)C(=O)O)ccc2n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
1.2 g of ethyl 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-5,5-difluoropentanoate are dissolved in 15 ml of tetrahydrofuran, and 10 ml of 2N sodium hydroxide solution are added. The mixture is stirred at 50° C. for 4 h and subsequently evaporated in vacuo. The mixture is then adjusted to pH2 using 25% hydrochloric acid with ice-cooling, with yellow crystals precipitating. The precipitate obtained is filtered off and dried in vacuo. Yield: 800 mg (71%) of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-5,5-difluoropentanoic acid; LC-MS retention time: 1.35 min (“nonpolar” gradient).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][C:41]#[CH:42]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([NH:39][CH2:40][C:41]#[CH:42])=[O:35])=[CH:37][CH:38]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C#CCN
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: C#CCNC(=O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 77.5 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropyne (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 44 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 568 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([CH:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH:23]1[CH2:27][CH2:26][N:25]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: c1ccc(CC2CCNC2)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(Cc3ccccc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-benzylpyrrolidine (9.7 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (5.8 mg). Calcd for C22H22N2O2: 346.1681, found 346.1693.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C@@H:5]([CH:13]([CH3:15])[CH3:14])[N:6]=[C:7]([O:10][CH2:11][CH3:12])[CH2:8][N:9]=1)[CH3:2].[Li]CCCC.Br[CH2:22][C@@H:23]([CH:33]([CH3:35])[CH3:34])[CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH2:26]([O:25][CH2:24][C@H:23]([CH:33]([CH3:35])[CH3:34])[CH2:22][C@H:8]1[C:7]([O:10][CH2:11][CH3:12])=[N:6][C@H:5]([CH:13]([CH3:15])[CH3:14])[C:4]([O:3][CH2:1][CH3:2])=[N:9]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)[C@H](CBr)COCc1ccccc1
Reactant: CCOC1=N[C@H](C(C)C)C(OCC)=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC1=N[C@H](C(C)C)C(OCC)=N[C@H]1C[C@H](COCc1ccccc1)C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of (R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine (15.4 g, 0.084 mol) in anhydrous THF (250 mL) at −78° C. was added dropwise 2.5 M n-BuLi in hexanes (34 mL, 0.085 mol) over 45 min. After stirring for 30 min at −78° C., a solution of (S)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene (15.6 g, 0.056 mol) in THF (100 L) was added dropwise over 30 min. The mixture was stirred for 2 h at −78° C. and then at −20° C. for 18 h. After evaporation, the residue was partitioned between H2O (200 mL) and EtOAc (3×200 mL). The combined organic layers were washed with brine (0.5 L), dried over MgSO4, evaporated, and purified by flash chromatography on silica gel eluting with 1:25 EtOAc/hexane to give (2S,5R)-2-((S)-2-(benzyloxymethyl)-3-methylbutyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine (18.5 g, 80%). 1H NMR (400 MHz, CDCl3): δ8.00 (s, 1H), 7.34-7.24 (m, 5H), 4.50 (s, 2H), 4.03 (m, 1H), 3.93 (m, 1H), 3.72 (s, 3H), 3.62 (s, 3H), 3.54-3.42 (m, 2H), 2.27 (m, 1H), 1.94-1.88 (m, 1H), 1.80-1.61 (m, 1H), 1.47-1.42 (m, 1H), 1.05 (d, J=6.4 Hz, 3H), 0.88 (d, J=6.4 Hz, 3H), 0.80 (d, J=6.4 Hz, 3H), 0.68 (d, J=6.4 Hz, 3H); MS: 403 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH2:9][CH2:10][CH2:11][OH:12])[CH:3]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CN(C)C1C=CN=CC=1.ClCCl.O>[C:20]([O:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[CH3:8])(=[O:22])[CH3:21]
Reactant: Cc1ccc(Cl)cc1CCCO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCCc1cc(Cl)ccc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-2-(3-hydroxypropyl)toluene (3.7 g, 20 mmol), triethylamine (40 mmol) and 4-dimethylaminopyridine (4 mmol) in dichloromethane (20 mL) was added acetic anhydride (15 mmol) at 0° C. The mixture was stirred for ca. 1 h at 0° C., diluted with water, and extracted with AcOEt. The extract was washed with diluted aqueous HCl and brine, dried over MgSO4, and concentrated to give quantitatively the title compound: 1H NMR (CDCl3) δ7.11 (bs, 1H), 7.07 (bs, 2H), 4.07 (t, 2H, J=7.2 Hz), 2.65 (dd, 2H, J=7.2, 8.1 Hz), 2.28 (s, 3H), 2.05 (s, 3H), 1.84~1.96 (m, 2H). 5) 2-(3-Acethoxypropyl)-4-chloro-6-nitrotoluene
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:44][CH:45]1[CH2:50][NH:49][CH2:48][CH2:47][N:46]1[C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=1)=[O:52]>>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:15])[C@H:11]([C:27]([N:49]3[CH2:48][CH2:47][N:46]([C:51]([O:53][CH2:54][C:55]4[CH:56]=[CH:57][C:58]([N+:61]([O-:63])=[O:62])=[CH:59][CH:60]=4)=[O:52])[CH:45]([CH3:44])[CH2:50]3)=[O:29])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CC1CNCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C(C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 83.9 %

Procedure:
Following a procedure similar to that described in Preparation 1(i), but using 3.06 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 1.34 g of N,N-carbonyldiimidazole and 2.30 g of 2-methyl-1-(4-nitrobenzyloxycarbonyl)piperazine, 4.07 g of the title compound were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][CH:18]([OH:20])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C1(C=CC(O)=CC=1)O.[C:29](OC)(=[O:33])[C:30]([CH3:32])=[CH2:31]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:29]([O:20][CH:18]([CH2:17][CH2:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=1)[CH3:19])(=[O:33])[C:30]([CH3:32])=[CH2:31]
Reactant: CC(O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=C(C)C(=O)OC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Oc1ccc(O)cc1
Product: C=C(C)C(=O)OC(C)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
A 1 liter flask was charged with a mixture of 69.5 grams (0.25 mole) of 4-(3,5-di-t-butyl-4-hydroxyphenyl) butane-2-ol, 350 milliliters of methyl methacrylate, 0.5 gram of hydroquinone and 5 grams of tetraisopropyl titanate as the catalyst. The mixture was heated to reflux and a methanolmethylmethacrylate azeotrope slowly distilled off over a 3.5 hour period. The reaction flask was cooled slightly and 25 milliliters of water was added dropwise to hydrolyze the catalyst. The reaction mixture was allowed to cool to room temperature. The mixture was stirred 15 minutes longer and then filtered through diatomaceous earth. One hundred milliliters of hexane was added to the filtrate which separated into organic and inorganic phases. The organic phase containing the product in hexane was separated and dried over magnesium sulfate. The hexane was evaporated to obtain 82 grams (95 percent) of 4-(3,5-di-t-butyl-4-hydroxyphenyl)-2-butyl methacrylate. The boiling point of this compound was 150° to 155° C at 0.15 milliliters of mercury pressure.