Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1Br.[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC>CN(P(N(C)C)(N(C)C)=O)C.O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[CH:17]=[CH2:18]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1nc2c(cc1Br)N(C)C(=O)C2(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=Cc1cc2c(nc1OC)C(C)(C)C(=O)N2C
Temperature: 65 °C
Yield: 735.5 %

Procedure:
A mixture of 138 mg (0.048 mmol) 5-methoxy-6-bromo-1,3,3-trimethyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one, 138 mg (0.48 mmol) of tri-n-butyl-vinyltin and 15 mg of bis(triphenylphosphine-palladium(II) chloride in 1 ml of HMPA was heated under nitrogen to 65° C. for 14 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The ethyl acetate solution was washed with water several times. To this ethyl acetate solution was added 1 ml of saturated KF, and the mixture filtered. The filtrate was dried (Na2SO4), evaporated, and the residue chromatographed on silica using 1:1 ethyl acetate/hexanes as the elutant. Appropriate fractions were combined and evaporated to afford 82 mg of 5-methoxy-1,3,3-trimethyl-6-vinyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one. 1H NMR (CDCl3) δ 6.90 (d,d 1H), 5.75 (d, 1H), 5.30 (d, 1H), 3.95 (s, 3H), 3.20 (s, 3H), 1.40 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]([CH2:8][NH:9][C:10]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])=[N:6][CH:7]=1.[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[CH2:31]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[CH2:31][N:9]([CH2:8][C:5]1[C:4]([CH3:19])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[C:10]([CH3:11])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:18]
Reactant: Cc1cc(Cl)cnc1CNC(C)(C)c1ccccn1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncc(Cl)cc1C)C(C)(C)c1ccccn1

Procedure:
Using General Procedure A: Reaction of (5-chloro-3-methyl-pyridin-2-ylmethyl)-(1-methyl-1-pyridin-2-yl-ethyl)-amine in CH3CN with 2-bromomethyl-5-cyano-benzoic acid methyl ester, KI, and DIPEA gave 2-{[(5-chloro-3-methyl-pyridin-2-ylmethyl)-(1-methyl-1-pyridin-2-yl-ethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester as a pale yellow solid. 1H NMR (CDCl3) δ 1.60 (s, 6H), 2.17 (s, 3H), 3.80 (s, 2H), 3.91 (s, 3H), 4.24 (s, 2H), 7.10-7.12 (m, 2H), 7.47 (d, 1H, J=6.0 Hz), 7.63-7.65 (m, 1H), 7.77 (d, 2H, J=9.0 Hz), 7.88 (s, 1H), 8.03-8.09 (m, 2H), 8.56-8.57 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH3:10][O-:11].[Na+]>O1CCCC1>[Br:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C)ccc1Br
Temperature: 25 °C
Yield: 46.1 %

Procedure:
To a cooled (0° C.) solution of 3-bromo-2-chloro-6-methylpyridine (300 mg, 1.45 mmol) in tetrahydrofuran (20 mL), add sodium methoxide (1.57 g, 29 mmol), slowly with stirring. Allow the mixture to warm to ambient temperature and stir overnight. Add additional sodium methoxide (500 mg) and stir at 100° C. overnight. Quench with water (20 mL), extract three times with ethyl acetate (30 mL). Combine the organics and wash with water then brine, and dry over sodium sulphate. Filter and concentrate to give the title product as a yellow solid (135 mg, 46%). 1HNMR (MeOH-d4): δ 7.72 (d, 1H), 6.70 (d, 1H), 3.93 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7]([C:8](=O)[CH:9]=[CH:10][C:11]=3[S:17]([CH3:20])(=[O:19])=[O:18])=[N:6][C:5]=2[CH:4]=1>CN(C)C=O.C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[S:17]([CH3:20])(=[O:19])=[O:18])[NH:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2sc3c(S(C)(=O)=O)ccc(=O)c-3nc2c1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)Nc1cccc(S(C)(=O)=O)c1S2
Yield: 35.7 %

Procedure:
2-Methoxy-6-methylsulphonylphenothiazine (m.p. 204°-206°C.; 16.05 g.) is prepared by reduction of 2-methoxy-6-methylsulphonyl-9-oxophenothiazine (47 g.) by means of zinc powder (28 g.) in dimethylformamide (175 cc.), acetic acid (73 cc.) and distilled water (73 cc.).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[N:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][C:9]3=[O:18])=[N:4][C:3]1=2.[CH3:20][O:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][CH:25]=1)=[O:23].[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:19])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[N:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH:8]([CH:30]([OH:31])[C:27]4[CH:26]=[CH:25][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:29][CH:28]=4)[C:9]3=[O:18])=[N:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2nc3c(nc21)CCCC3=O
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(C(O)C2CCc3nc4c(nc3C2=O)C(C)(C)CCC4(C)C)cc1
Reaction time: 8 h
Yield: 64.8 %

Procedure:
0.5 g of 1,2,3,4,6,7,8,9-octahydro-6,6,9,9-tetramethylphenazin-1-one and 0.38 g of methyl terephthalaldehydate were dissolved in 15 ml of methanol, followed by the addition of a small amount of sodium hydroxide. The obtained mixture was stirred overnight to precipitate crystals. The crystals were recovered by filtration, washed with a small amount of methanol and dried in a vacuum to give 0.53 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5](=[O:7])[CH3:6].[OH:11][CH2:12][C:13]([CH3:17])([CH2:15]O)[CH3:14].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[CH3:1][O:2]/[N:3]=[C:4](/[C:8]1([CH3:9])[O:11][CH2:12][C:13]([CH3:17])([CH3:15])[CH2:14][O:10]1)\[C:5](=[O:7])[CH3:6]
Reactant: CC(C)(CO)CO
Reactant: CON=C(C(C)=O)C(C)=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CO/N=C(\C(C)=O)C1(C)OCC(C)(C)CO1
Reaction time: 2 h
Yield: 79 %

Procedure:
20 g (0.14 mol) of pentane-2,3,4-trione 3-(O-methyloxime), 43.4 g (0.42 mol) of neopentyl glycol and 0.1 g of conc. sulfuric acid in 80 ml of toluene were heated at the boil on a water separator at a pressure of 800 mbar for 2 hours. The mixture was extracted with water and toluene and then worked up as in Example 4b). This gave 30 g of an oil of a purity of 84% (yield 79%).
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][C:13]2[C:12]([OH:15])=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH2:2]C.N1(C2CC3C(O)=CC=CC=3CC2)CCC[CH2:21][CH2:20]1>>[N:4]1([CH:5]2[CH2:14][C:13]3[C:12]4[O:15][CH:20]=[CH:21][C:11]=4[CH:10]=[CH:9][C:8]=3[CH2:7][CH2:6]2)[CH2:1][CH2:2][CH2:18][CH2:17][CH2:16]1
Reactant: CCCN(CCC)C1CCc2cccc(O)c2C1
Reactant: Oc1cccc2c1CC(N1CCCCC1)CC2
Product: c1cc2ccc3c(c2o1)CC(N1CCCCC1)CC3

Procedure:
In the same manner but replacing 5,6,7,8-tetrahydro-7-(dipropylamino)-1-naphthalenol with an equivalent amount of 5,6,7,8-tetrahydro-7-(1-piperidinyl)-1-naphthalenol, 6,7,8,9-tetrahydro-8-(1-piperidinyl)-naphtho[1,2-b]furan is obtained.
Reaction SMILES: CO[C:3]([C:5]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:15]2[C:7](=[CH:8][C:9]3[C:14]2=[CH:13][CH:12]=[C:11]([F:27])[CH:10]=3)[C:6]=1[OH:28])=[O:4].[NH2:29][CH2:30][C:31]([O-:33])=[O:32].[Na+]>>[F:27][C:11]1[CH:10]=[C:9]2[C:14]([N:15]3[C:7](=[CH:8]2)[C:6]([OH:28])=[C:5]([C:3]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:4])[C:17](=[O:18])[N:16]3[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1c(O)c2cc3cc(F)ccc3n2n(Cc2ccc(F)cc2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc3cc(F)ccc3n2n(Cc2ccc(F)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 7-fluoro-4-(4-fluoro-benzyl)-1-hydroxy-3-oxo-3,4-dihydro-4,4a-diaza-fluorene-2-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 428 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH3:23][C:24]1[C:28]([CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[C:27]([CH3:36])[NH:26][C:25]=1[CH:37]=O>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:37]\[C:25]1[NH:26][C:27]([CH3:36])=[C:28]([CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[C:24]=1[CH3:23])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1C1CCN(C)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C1CCN(C)CC1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one was condensed with 3,5-dimethyl-4-(1-methyl-piperidin-4-yl)-1H-pyrrole-2-carbaldehyde to give the titled compound.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Cl[C:13]1[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[C:15]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:14]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C1COCC1>[C:1]1([C:13]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[C:15]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(Cl)nc(OCc2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2ccccc2)nc(-c2ccccc2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Phenylboronic acid (3.4 g), Pd(OAc)2 (528 mg), tBu2-P-Ph-Ph (1.4 g) and potassium fluoride (4.1 g) were added in that order to a THF (200 mL) solution of methyl 2-chloro-6-benzyloxypyridine-4-carboxylate (6.5 g), and stirred overnight at 50° C. The reaction liquid was filtered through Celite, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a yellow oil.
Reaction SMILES: O[C@@H:2]1[CH2:7][N:6](C(=O)C(F)(F)F)[C@H:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C.C(O)(=O)C>[CH2:44]([O:51][NH:52][C@H:2]1[CH2:7][NH:6][C@H:5]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:4][CH2:3]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](O)CN1C(=O)C(F)(F)F
Reactant: NOCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: CC(=O)O
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Temperature: 0 °C
Yield: 74.2 %

Procedure:
A solution of 47.9 g (161 mmol) of (2S,5S)-tert-butyl 5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate in dehydrated acetonitrile (318 mL) was cooled from −30 to −40° C. under argon atmosphere, and 20.5 mL (177 mmol) of 2,6-lutidine was added, and then 28.4 mL (169 mmol) of trifluoromethanesulfonic acid anhydride was added dropwise over 40 minutes, followed by further allowing to react at −30° C. for 15 minutes. To this reaction mixture was added 39.7 g (322 mmol) of benzyloxyamine (washed with acetonitrile (11 mL)) within 8 minutes, followed by raising the temperature to 0° C. within 30 minutes, and further 20.5 mL (177 mmol) of 2,6-lutidine was added, followed by allowing to react at 0 to 5° C. for 2 days. This reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate (960 mL) and washed sequentially with water (960 mL), 10% aqueous citric acid solution (960 mL×3 times), 6.5% aqueous sodium hydrogencarbonate solution (480 mL) and saturated brine (480 mL). Each aqueous layer was back-extracted with ethyl acetate (960 mL), the organic layers were combined, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 1,4-dioxane (320 mL) solution and water (86 mL), and, under ice cooling, 2.5M NaOH (128 mL) was added dropwise, followed by allowing to react at the same temperature for 0.5 hours. Acetic acid (ca. 9.3 mL) was added to the reaction mixture, followed by concentration under reduced pressure, and subsequently the resulting concentrated residue was extracted with ethyl acetate (580 mL, 290 mL). After the organic layers were washed respectively with 50% aqueous potassium carbonate solution (580 mL), they were combined, and the solvent was distilled off under reduced pressure. The resulting residue was applied to silica gel column chromatography (hexane/ethyl acetate=4/1→0/1→ethyl acetate/methanol=100/1→19/1) to afford 36.58 g of the title compound as a colorless oil (yield 74%). Instrumental data were consistent with those of Example 4.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].FC(F)(F)S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:39][C:40]([F:43])([F:42])[F:41])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NC1CCN(CC(F)(F)F)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in THF (5.0 mL) was added TEA (0.06 mL, 0.64 mmol) and stirred for 10 min. Then 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.03, 0.16 mmol) was added and stirred for 16 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a brown solid (0.05 g, 44%).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH2:13]([O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Oc1cccc2ccccc12
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCCCOc1cccc2ccccc12
Temperature: 25 °C
Yield: 98.4 %

Procedure:
1-naphthol (5 g, 34.7 mmol), iodohexane (8.82 g, 41.6 mmol) and K2CO3 (7.2 g, 50 mmol) in acetonitrile (150 ml) were refluxed overnight under N2. After being cooled to room temperature, water (10 ml) was added and acetonitrile was evaporated. Water (150 ml) and Et2O (150 ml) were added. The ethereal layer was extracted and washed with water (2×100 ml), brine (100 ml), dried over MgSO4, filtered and evaporated to dryness to afford 7.8 g (98%) of compound 2 as an orange oil after during at 80° C. under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:9])([O:11][CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[CH3:10])=[N:6][CH:7]=1
Reactant: CC(C)(O)c1ccc(Br)cn1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(OCOCC[Si](C)(C)C)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from Step 1 (14 mmol) in methylene chloride (50 mL) at 0° C. was added N,N-diisopropylethylamine (37.3 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (15.3 mmol). The resulting mixture was stirred at room temperature for 18 hours, then refluxed for 24 hours. After cooling to room temperature the mixture was quenched with saturated aqueous ammonium chloride solution and partitioned between methylene chloride and water. The crude product from the organic phase was chromatographed on silica gel eluting with 6% ethyl acetate in hexane to afford the 5-bromo-2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)pyridine compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]OS(C)(=O)=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc(O)c1
Reactant: CS(=O)(=O)OCCCCCOCc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc(OCCCCCOCc2ccccc2)c1

Procedure:
Alkylation reaction of phenol 24 with methanesulfonic acid 5-benzyloxypentyl ester gave 2-(2-(3-(5-benzyloxypentoxy)phenoxy)ethyl)isoindoline-1,3-dione as yellow oil. Yield (1.0 g, 62%): 1H NMR (400 MHz, CDCl3) δ 7.84-7.87 (m, 2H), 7.70-7.73 (m, 2H), 7.25-7.40 (m, 5H), 7.09-7.14 (m, 1H), 6.42-6.48 (m, 3H), 4.50 (s, 2H), 4.20 (t, J=5.8 Hz, 2H), 4.10 (t, J=5.6 Hz, 2H), 3.90 (t, J=6.4 Hz, 2H), 3.64 (t, J=6.0 Hz, 2H), 3.48 (t, J=6.0 Hz, 2H), 1.40-1.80 (m, 6H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([C@@H:25]3[CH2:29][C@@H:28]([OH:30])[CH2:27][N:26]3[C:31](=[O:52])[CH2:32][C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:24])=[O:17])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([C@@H:25]3[CH2:29][C@@H:28]([O:30][S:54]([CH3:53])(=[O:56])=[O:55])[CH2:27][N:26]3[C:31](=[O:52])[CH2:32][C:33]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:24])=[O:17])[CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC[C@H]1CCCN(CC2CCCCC2)C1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 30 mg of (2R)-N-{((3R)-1-cyclohexylmehyl-3-piperidyl)methyl}-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide in 0.6 ml of chloroform, 0.018 ml of triethylamine and 0.004 ml of methanesulfonyl chloride were added under cooling with ice, followed by 50 minutes' stirring at room temperature. The reaction liquid was diluted with chloroform, washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resultant residue was purified by means of a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=100/10/1) to provide 33 mg of the title compound.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH2:5].[N:8]([CH:11]1[CH2:16][CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[CH2:13][CH2:12]1)=[C:9]=[O:10]>C1COCC1.[Pd]>[NH:14]1[CH2:13][CH2:12][CH:11]([N:8]2[CH:3]=[CH:4][NH:5][C:9]2=[O:10])[CH2:16][CH2:15]1
Reactant: O=C=NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(CN)OC
Agent: [Pd]
Solvent: C1CCOC1
Product: O=c1[nH]ccn1C1CCNCC1
Reaction time: 3 h

Procedure:
Aminoacetaldehyde dimethylacetal (1.2 g) was added to a solution of benzyl 4-isocyanatopiperidine-1-carboxylate (3 g) in THF (100 ml) and the mixture was stirred for 3 hours. 20% Palladium on charcoal (500 mg) was added and the mixture was hydrogenated under a hydrogen filled balloon. The catalyst was filtered through Celite and the residue was evaporated to dryness then dissolved in ethanol and subjected to repeat hydrogenation with fresh palladium on charcoal catalyst (500 mg). The catalyst was filtered through Celite and the residue was evaporated to dryness then dissolved in 2M HCl (50 ml) and allowed to stand for 4 hours. The reaction mixture was basified with 2M NaOH (50 ml) and evaporated to dryness using toluene (100 ml) to azeotrope final traces of solvent. The residue was triturated with methanol (100 ml) and filtered. The filtrate was evaporated to dryness to give the title compound as an off-white solid, yield 2.2 g, NMR DMSO D6 (Part spectrum some peaks obscured by DMSO): 1.3-1.8 (m, 5H) 3 (m, 2H) 3.9 (m, 1H) 6.3 (d, 1H) 6.4 (d, 1H) 9.9 (s broad, 1H).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.[Cl-].[NH4+]>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[CH:34]([C:33]1[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1)[OH:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Fc1ccc(Br)c(OCc2ccccc2)c1
Reactant: COc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(O)c2ccc(F)cc2OCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.59 M, 3.14 mL) was added dropwise to a solution of 2-benzyloxy-1-bromo-4-fluorobenzene (1.4 g, 5.0 mmol) in THF (50 ml) at −78° C. and the mixture was stirred at the same temperature for 15 minutes. To this solution, a solution of 4-methoxybenzaldehyde (680 mg, 4.99 mmol) in THF (15 mL) was added dropwise at −78° C. and the mixture was stirred at the same temperature for 1.5 hours, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=n-hexane:dichloro-methane:acetone (12:3:1)] to obtain the title compound (1.41 g, 83%) as a colorless oil.
Reaction SMILES: C1COCC1.[F:6][C:7]1[CH:8]=[C:9]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]([O:15][CH3:16])=[C:11]([CH2:13]O)[CH:12]=1.S(Cl)([Cl:27])=O.CN(C=O)C>C(OCC)(=O)C>[Cl:27][CH2:13][C:11]1[CH:12]=[C:7]([F:6])[CH:8]=[C:9]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]=1[O:15][CH3:16]
Reactant: O=S(Cl)Cl
Reactant: COc1c(CO)cc(F)cc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1c(CCl)cc(F)cc1OCc1ccccc1
Temperature: 0 °C

Procedure:
A THF (25 mL) solution of {5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}methanol (6.94 g, 26 mmol) was cooled to 0° C. and was then treated with thionyl chloride (2.5 mL, 34 mmol) and DMF (5.0 mL, 65 mmol) for 30 min. Ethyl acetate and ice water were then added. The layers were partitioned, and the aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The product, 1-(chloromethyl)-5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]benzene, was obtained as an orange oil (6.82 g, 24.3 mmol, 93% yield), which solidified upon storage in the freezer. 1H NMR (400 MHz, CDCl3): δ 7.45-7.26 (m, 5H), 6.72-6.66 (m, 2H), 5.09 (s, 2H), 4.61 (s, 2H), 3.91 (s, 3H).