Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])[S:6][CH:7]=1.[OH:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:26]=[CH:27][CH:28]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:15][C:14]1[O:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][C:10]=1[CH2:9][CH2:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:26]=[CH:27][CH:28]=2)[N:4]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCc1nc(CCl)cs1
Reactant: COC(=O)Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCc2csc(CCc3nc(-c4ccccc4)oc3C)n2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.3 %

Procedure:
To a mixture of 4-[2-(4-chloromethyl-2-thiazolyl)ethyl]-5-methyl-2-phenyloxazole (0.64 g), methyl 2-(3-hydroxyphenyl)acetate (0.30 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.09 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water, 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetate as a colorless oil (0.31 g, 38%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.[Cl:23][C:24]1[CH:32]=[N:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](O)=[O:27].ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[Cl:23][C:24]1[CH:32]=[N:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1)=[O:27]
Reactant: O=C(O)c1c(Cl)cncc1Cl
Reactant: NCc1ccc(CCO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(CCO)cc1)c1c(Cl)cncc1Cl
Yield: 44.1 %

Procedure:
Using the EDCI coupling general procedure F: Reaction of 2-(4-Aminomethyl-phenyl)-ethanol (306 mg, 2.03 mmol), 3,5-dichloroisonicotinic acid (385 mg, 2.03 mmol), 1-hydroxybenzotriazole (301 mg, 2.22 mmol), 4-methyl morpholine (0.50 mL, 4.45 mmol), and EDCI (426 mg, 2.22 mmol) in anhydrous DMF (5 mL) overnight at room temperature and overnight at 40° C. followed by column chromatography on silica gel (2:2:96 MeOH—NH4OH—CH2Cl2) gave the title compound (291 mg, 44%) as a white foam.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([CH:30]=[O:31])[CH2:26][C:27]([OH:29])=[O:28])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:32])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1(C)[CH:38]=CC(S(O)(=O)=O)=C[CH:34]=1.C([O-])(O)=O.[Na+]>C(O)(C)C>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]3[CH2:26][C:27](=[O:29])[O:28][CH:30]3[O:31][CH:33]([CH3:38])[CH3:34])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:32])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=CC(CC(=O)O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OC1OC(=O)CC1NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Reaction time: 1.25 h
Yield: 198.2 %

Procedure:
A solution of 214e (101 mg, 0.23 mmol) in isopropanol (10 ml) was stirred at room temperature with a catalytic amount of p-toluenesulfonic acid (10 mg). After 75 minutes, the reaction mixture was poured into saturated NaHCO3 and extracted with CH2Cl2. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography (SiO2, CH2CHl2to EtOAc) afforded 56 mg (51%) of 2100a as a white solid: 1H NMR (CDCl3; mixture of diastereomers) δ 7.9-7.8 (2H,m), 7.6-7.5 (1H, m), 7.5-7.4 (2H, m), 7.1 (0.5H, d), 6.9 (0.5H, d), 6.4 (0.5H,d), 5.6 (0.5H, d), 5.3 (0.5H, s), 5.2-5.1 (1H, m), 4.95 (0.5H, m), 4.75-4.5 (1.5H, m), 4.35 (0.5H, t), 4.1 (0.5H, m), 3.98 (0.5H, m), 3.3-2.75 (4H, m), 2.5-2.4 (2H,m), 2.25 (1H, m), 2.1-1.9 (3H,m) 1.75-1.55 (2H,m).
Reaction SMILES: [CH:1]1[C:15]2=[C:16]3[C:8]([C:9]4[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[C:3](B(O)O)[CH:2]=1.I[C:21]1[CH:22]=[C:23]([Br:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:27][C:23]1[CH:22]=[C:21]([C:5]2[CH:6]=[CH:7][C:8]3[C:9]4[C:14]([C:15]5[C:16]=3[C:4]=2[CH:3]=[CH:2][CH:1]=5)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc2c3c(cccc13)-c1ccccc1-2
Reactant: Brc1cccc(I)c1
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: Cc1ccccc1
Product: Brc1cccc(-c2ccc3c4c(cccc24)-c2ccccc2-3)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A flask was charged with 9.1 g of fluoranthene-3-boronic acid, 10.5 g of 3-iodobromobenzene, 2.1 g of tetrakis(triphenylphosphine)palladium(0), 186 mL of toluene, and 74 mL of a 2 M sodium carbonate aqueous solution in an argon atmosphere. The mixture was stirred at 100° C. for 8 hours. After cooling the reaction solution to room temperature, the reaction solution was extracted with toluene. After removing the aqueous phase, the organic phase was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After filtering the organic phase, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 9.2 g of the target 3-(3-bromophenyl)fluoranthene (yield: 70%).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]([CH3:29])=[C:18]([CH3:28])[C:19]4[O:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20]=4[C:26]=3[CH3:27])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[O:3].ClC1C=CC=C(C(OO)=[O:38])C=1>>[CH3:1][S:2]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]([CH3:29])=[C:18]([CH3:28])[C:19]4[O:23][C:22]([CH3:24])([CH3:25])[CH2:21][C:20]=4[C:26]=3[CH3:27])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)(=[O:38])=[O:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(C)c(N2CCN(c3ccc(S(C)=O)cc3)CC2)c(C)c2c1OC(C)(C)C2
Product: Cc1c(C)c(N2CCN(c3ccc(S(C)(=O)=O)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 31.3 %

Procedure:
By using 1-[4-(methylsulfinyl)phenyl]-4-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (200 mg, 0.50 mmol) synthesized in Example 91 and 70% m-chloroperbenzoic acid (272 mg, 1.1 mmol), the reaction was carried out in the same manner as Example 91 to synthesis the title compound 67 mg (yield 31%). Melting point was 256 to 260° C. (hexane-THF).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:22])[N:10]([CH3:21])[C:11](O)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:25].C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:22])[N:10]([CH3:21])[C:11]([Cl:25])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(O)nc(-c2ccncc2)c(-c2cccc(Br)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(Cl)nc(-c2ccncc2)c(-c2cccc(Br)c2)c1=O
Temperature: 85 °C
Reaction time: 15 h

Procedure:
To a 250 mL RBF, was added 5-(3-bromo-phenyl)-2-hydroxy-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (5.76 g, 16.1 mmol), 50 mL POCl3. The mixture was warmed up to 85° C. and stirred for 15 h under nitrogen. The mixture was cooled down to rt and vacuumed down all volatile composites. The black cake obtained was dissolved in dichloromethane, neutralized with sat. NaHCO3. After purified by flash chromatography, the 5-(3-Bromo-phenyl)-2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one was obtained in 4.72 g as white powder. MS (ES+): 376 (M+H)+; (ES−): 374 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH:18]=O)[CH2:13]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:18]([CH:14]1[CH2:15][CH2:16][CH2:17][O:12][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: O=CC1CCCOC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC(C2CCCOC2)Oc2ccc(Br)cc21
Yield: 69.1 %

Procedure:
A solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (18 g, 83.70 mmol), tetrahydro-2H-pyran-3-carbaldehyde (9.55 g, 83.70 mmol) and pyrrolidine (6.95 mL, 83.70 mmol) in MeOH (125 mL) was heated to reflux for 4.5 h. The mixture was allowed to reach r.t. and concentrated. The residue was dissolved in EtOAc (150 mL) and washed with 1M NaOH (80 mL), 1M HCl (80 mL), and brine (80 mL) successively. The organic phase was concentrated, the residue was purified by flash chromatography with a gradient of 10% EtOAc in heptane to 40% EtOAc in heptane to give the title compound (18 g, 69% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.50 (m, 3H), 1.79 (m, 0.5H), 1.94 (m, 1.5H), 2.67 (m, 1H), 2.86 (m, 1H), 3.30 (m, 2H), 3.78 (m, 1H), 3.84 (m, 0.5H), 4.04 (dd, 0.5H), 4.44 (m, 1H), 7.05 (dd, 1H), 7.71 (m, 1H), 7.79 (d, 1H); MS (ES+) m/z 311 [M+H]+.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([OH:16])[C:13]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[Cl:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=C(S(O[CH2:40][C@:41]2(C)[CH2:43][O:42]2)(=O)=O)C=CC=1)([O-])=O.CN(C=O)C>O>[C:1]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:40][C@@H:41]2[CH2:43][O:42]2)[C:13]([NH:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][C:11]=1[Cl:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Reactant: O=C(Nc1cc(Cl)c(OC(=O)c2ccccc2)cc1O)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Cl)c(OC(=O)c2ccccc2)cc1OC[C@@H]1CO1)c1ccccc1
Yield: 98.6 %

Procedure:
To a stirred solution of 4-(benzoylamino)-2-chloro-5-hydroxyphenyl benzoate (103 mg, 0.28 mmol) and [(2S)-2-methyloxiran-2-yl]methyl 3-nitrobenzenesulfonate (73 mg, 0.28 mmol) in DMF (3 mL) cesium carbonate (98 mg, 0.3 mmol) was added. The stirring was continued at ambient temperature over night. The mixture was poured into water and partitioned between water and ethylacetate. The organic phase was washed with water, dried and concentrated in vacuo to give a white solid (117 mg, 98%). The solid was used without further purification.
Reaction SMILES: [Mg].[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.OS(O)(=O)=O>CCOCC>[Br:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([Br:2])[CH:4]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: BrCc1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: Brc1cccc(CCc2cccc(Br)c2)c1

Procedure:
1,2-Bis(m-bromophenyl)ethane was prepared by the method of Lindsay et al (JACS, 1961, 83, 943) as follows. Magnesium (0.05 g, 2.0 mmol) was added to a solution of 3-bromobenzylbromide (1.0 g, 4.0 mmol) in Et2O (10 mL) at rt. After 20 min at room temperature all the magnesium had dissolved and anhydrous ferric chloride (5 mg) was added. The reaction was heated to reflux for 1 hour, cooled, acidified to about pH 1 with 1 M aqueous H2SO4 and extracted with Et2O (3×50 mL). The combined organic extracts were washed with water (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give a yellow solid. Recrystallization from petroleum ether gave 1,2-bis(m-bromophenyl)ethane as a colorless solid. MS (APCI) m/z 338 (50%), 340 (100), 342 (50). 1H NMR (200 MHz, CDCl3): δ2.85, s, 2H; 7.02-7.25, m, 2H; 7.30-7.39, m, 2H.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[CH3:34]>C1(C)C=CC=CC=1>[Br:25][C:26]1[CH:33]=[CH:32][C:29](/[CH:30]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:28][C:27]=1[CH3:34]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C=O)ccc1Br
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(Br)c(C)c1
Temperature: 90 °C
Yield: 52.9 %

Procedure:
2.1 g (6.45 mmol, 1.5 eq) of methyl triphenylphosphoranylideneacetate are added to a solution of 900 mg of 4-bromo-3-methylbenzaldehyde in 5 ml of toluene. The reaction mixture is heated at 90° C. for 1 hour. The solvent is evaporated off and the residual oil is chromatographed on silica gel (8/2 heptane/ethyl acetate). 610 mg of methyl (E)-3-(4-bromo-3-methylphenyl)acrylate are obtained in oil form. Yield=55% over steps a, b and c.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:11]=1
Reactant: CSc1nc(Cc2cccc(F)c2)[nH]c(=O)c1C#N
Reactant: C1CCNCC1
Product: N#Cc1c(N2CCCCC2)nc(Cc2cccc(F)c2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.36 mmol) of 2-(3-fluorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 309 mg (3.63 mmol) of piperidine to give 40 mg (35% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([F:25])=[CH:17][CH:16]=2)=[C:5]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:6]=1.[CH3:26][C:27]1[NH:28][CH:29]=[CH:30][N:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:25][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([C:4]2[O:3][C:2]([N:28]3[CH:29]=[CH:30][N:31]=[C:27]3[CH3:26])=[N:6][C:5]=2[CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:16][CH:17]=1
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)CCCc1nc(Cl)oc1-c1ccc(F)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCc1nc(-n2ccnc2C)oc1-c1ccc(F)c2ccccc12
Temperature: 125 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 2-chloro-5-(4-fluoro-1-naphthyl)-4-oxazolebutanoate (700 mg), 2-methylimidazole (821 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 2 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (150 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 5-(4-fluoro-1-naphthyl)-2-(2-methyl-1-imidazolyl)-4-oxazolebutanoate was obtained as an oil (675 mg, 77%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]2=[O:17].[CH2:18](O)[CH2:19][OH:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16][CH2:18][CH2:19][OH:20])=[O:15])[C:5]2=[O:17]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Br)cnc21
Reactant: OCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCn1cc(C(=O)OCCO)c(=O)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
6-Bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (Intermediate 22, 1.7 g, 5.72 mmol), ethane-1,2-diol (1.91 g, 34.34 mmol) and triphenylphosphine (9.0 g, 34.34 mmol) were dissolved in tetrahydrofuran (100 mL). Diethyl azodicarboxylate (DEAD) (4.97 g, 28.61 mol) was added drop wise and the mixture was stirred for 16 h at room temperature. The mixture was concentrated under reduced pressure, and water (100 mL) was added. The aqueous mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude compound. The crude compound was purified by flash column chromatography over silica gel (100-200 mesh) using eluent gradient of ethyl acetate/petroleum ether: 1:1 to 100:0 to afford 1.6 g (82%) of 2-hydroxyethyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12>C1COCC1>[CH2:35]([O:34][C:32]([N:42]1[CH2:47][CH2:46][CH:45]([N:52]2[C:51](=[O:53])[C:50]3=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]3[C:48]2=[O:58])[CH2:44][CH2:43]1)=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(OCc1ccccc1)N1CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 10.5 h
Yield: 50 %

Procedure:
A solution of DEAD (1.61 mL, 10.2 mmol) in 20 mL of THF was added to a solution of triphenylphosphine (2.69 g, 10.3 mmol), the N-Cbz-piperidine prepared in Example 16A (2.36 g, 100 mmol) and phthalimide (1.50 g, 10.2 mmol) in 80 mL of THF. After stirring 10.5 h at R.T. the mixture was quenched with water, extracted with EtOAc (3×) and the combined extracts washed with brine solution, dried over Na2SO4 and concentrated to give the crude product. Purification of this material by chromatography (hexanes/EtOAc; 2:1) gave 1.81 g, (50%) of 1-benzyloxycarbonyl-4-phthalimidylpiperidine. [1H]-NMR(CDCl3) consistent with structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][C:20]=2[CH:21]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.[OH-:38].[Na+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:38])=[CH:22][C:20]=2[CH:21]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: C=Cc1ccc2oc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2c1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(CCO)ccc2o1
Reaction time: 2 h
Yield: 6.3 %

Procedure:
A solution of 114 mg (o.30 mmol) {2-[(5-Vinyl-benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (57), 5 ml THF and 1.4 ml of a 0.5M solution of 9-BBN in THF was stirred at rt for 4 h. A solution of 86 mg NaOH in 0.6 ml water was added and stirring was continued for further 2 h. The reaction mixture was washed with brine and the organic phase dried over sodium sulfate, the solvent was evaporated and the residue subjected to silica gel chromatography (petrolether/ethylacetate 1:1) to give 54 mg (0.136 mmol) (2-{[5-(2-Hydroxy-ethyl)-benzofuran-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (58).
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[CH:34][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:13]([CH3:33])([CH3:32])[O:14][Si:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)([CH3:17])[CH3:16])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd]>[NH2:1][C:4]1[CH:35]=[CH:34][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:13]([CH3:33])([CH3:32])[O:14][Si:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=2)([CH3:16])[CH3:17])=[CH:6][CH:5]=1
Reactant: C[Si](C)(CCCCOc1ccc([N+](=O)[O-])cc1)O[Si](C)(C)CCCCOc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Product: C[Si](C)(CCCCOc1ccc(N)cc1)O[Si](C)(C)CCCCOc1ccc(N)cc1

Procedure:
1,3-bis[4-(4-nitrophenoxy)butyl]-1,1,3,3-tetramethyldisiloxane (2a) (1.35 g; 3.38 mmol) and 10 mL of a 10 wt % Pd/C (0.0393 g) ethyl acetate solution were mixed, and stirred for 2 days in a hydrogen atmosphere at room temperature. The solution was filtrated by Celite and then concentrated to obtain a colorless oily material (1.18 g, 98% of yield).
Reaction SMILES: C([N:8]1[C@@H:13]2[C@@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1.C(OCC)(=O)C>[Pd].C(O)C>[F:37][C:35]([F:36])([F:38])[C:27]1[CH:26]=[C:25]([CH2:24][O:23][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:15][C@@H:14]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70997.1 %

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Description 22; 826 mg, 1.33 mmol), 10% palladium on charcoal (470 mg, 0.44 mmol), ethyl acetate (10 ml) and ethanol (10 ml) was stirred under hydrogen atmosphere (1 atm) at +60° C. for 1 hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound (500 g, 71%).
Reaction SMILES: [NH2:1][C@@H:2]([CH:25]([CH3:27])[CH3:26])[C:3]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][C@H:6]1[C:14]([NH:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24])=[O:15])=[O:4].[CH2:28]([O:35][C:36]([N:38]([CH2:44][CH2:45][S:46]([CH3:49])(=[O:48])=[O:47])[C@@H:39]([CH3:43])[C:40](O)=[O:41])=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[NH:16][C:14]([C@H:6]1[N:5]([C:3](=[O:4])[C@@H:2]([NH:1][C:40](=[O:41])[C@@H:39]([N:38]([CH2:44][CH2:45][S:46]([CH3:49])(=[O:48])=[O:47])[C:36](=[O:37])[O:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:43])[CH:25]([CH3:27])[CH3:26])[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:15]
Reactant: C[C@@H](C(=O)O)N(CCS(C)(=O)=O)C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](N)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](C)N(CCS(C)(=O)=O)C(=O)OCc1ccccc1)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
In a 50 mL round-bottomed flask, (S)-1-((S)-2-amino-3-methylbutanoyl)-N-(2,6-difluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carb ox amide (Intermediate 6) (29 mg, 77.5 μmol, Eq: 1.00), (S)-2-((benzyloxycarbonyl)(2-(methylsulfonyl)ethyl)amino)propanoic acid (Intermediate 9) (30.6 mg, 93.0 μmol, Eq: 1.2), HATU (35.3 mg, 93.0 μmol, Eq: 1.2) and diisopropylethylamine (16 μL, 93.0 μmol, Eq: 1.2) were combined with DMF (2 mL) to give a colorless solution. The reaction mixture was stirred at rt overnight and then partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 50% EtOAc in hexanes) to give benzyl (S)-1-((S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(2-(methylsulfonyl)ethyl)carbamate (33 mg).