Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][S:22]([NH:25][CH3:26])(=[O:24])=[O:23])[CH:19]=2)[NH:14][C:13]=1[Si:27]([CH3:30])([CH3:29])[CH3:28])(C(C)(C)C)(C)C.F>N1C=CC=CC=1.C(OCC)(=O)C>[OH:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][S:22]([NH:25][CH3:26])(=[O:24])=[O:23])[CH:19]=2)[NH:14][C:13]=1[Si:27]([CH3:30])([CH3:28])[CH3:29]
Reactant: CNS(=O)(=O)Cc1ccc2[nH]c([Si](C)(C)C)c(CCCO[Si](C)(C)C(C)(C)C)c2c1
Agent: F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)Cc1ccc2[nH]c([Si](C)(C)C)c(CCCO)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a solution of 0.0738 g (0.157 mmol, 1.0 equiv.) of 3-(3-t-butyldimethysilyloxypropyl)-2-trimethylsilyl-N-methyl-1H-indole-5-methanesulfonamide in 2 mL of pyridine at 0° C. was added 1 mL of 48% aqueous hydrofluoric acid. The solution was stirred for 20 minutes at 0° C. The solution was diluted with 25 mL of ethyl acetate and washed with 10 mL of 10% aqueous sodium carbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield 0.0551 g (99%) of 3-(3-hydroxypropyl)-2-trimethylsilyl-N-methyl-1H-indole-5-methanesulfonamide, homogeneous by 1H NMR and TLC.
Reaction SMILES: [C-]#N.[K+].[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C>O>[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:21])=[O:11])=[CH:8][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)C(O)c2ccccc2)cc1
Yield: 41.5 %

Procedure:
To a solution of KCN (5 g) in water (35 mL) is added 4-methoxybenzaldehyde (27.2 g, 0.2 mole), benzaldehyde (21.2 g, 0.2 mole) and 95% ethanol (70 mL). The mixture is refluxed under nitrogen for 4.5 hours and the ethanol removed in vacuo. Water (200 mL) is added to the residue and then distilled off at reduced pressure (to remove remaining unreacted bezaldehyde). The procedure is repeated twice and the residual water azeotroped with ethanol. The crude product (56.3 g, orange semi-solid) is purified by flashchromatography (on silica Merck-60, preabsorbed in dichloromethane-ethyl acetate and eluted with hexane-ethyl acetate 8:2) to yield a light yellow solid (20.1 g, 41.5%), m.p. 99°-101° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:9][C:5]1[CH:4]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[C:2]([C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)=[CH:7][C:6]=1[F:8]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Product: Cc1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 96.5 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 2.56 g (7.37 mmol) of 1-bromo-4,5-difluoro-2-[(4-methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 1.35 g (9.93 mmol) of 4-methylphenylboronic acid. Purification by silica gel chromatography (MPLC) with ethyl acetate/hexane (3:7) gave 2.55 g (97%) of 1,2-difluoro-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 147.0-148.0° C.; NMR (CDCl3) δ 2.32 (s, 3H), 3.05 (s, 3H), 6.92 (d, J=8 Hz, 2H), 7.03 (d, J=8 Hz, 2H), 7.17-7.32 (m, 4H), 7.79 (d, J=8 Hz, 2H). MS (FAB): m/e 365 (M+Li). Anal. Calc'd for C20H16F2O2S: C, 67.03; H, 4.50. Found: C, 67.18; H, 4.48.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)=O)=[CH:4][CH:3]=1.[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(O)c(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
Titanium tetrachloride (1.70 mL, 15.5 mmol) was added dropwise to a suspension of zinc powder (2.12 g, 32.4 mmol) in anhydrous THF (60 mL) at RT. After refluxing for 1 h, a mixture of 82 (1.18 g, 4.00 mmol) and cyclohexanone (1.18 g, 12.0 mmol) dissolved in THF (20 mL) was added dropwise. Refluxing was continued for 30 min. The reaction mixture was cooled to RT and filtered through Celite. Water (250 mL) was added and the mixture was extracted with ether (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 1.15 g (80%) of compound 83 as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ1.58 (br s, 6H), 2.20 (m, 4H), 5.10 (br s, 1H), 6.77 (m, 2H), 6.89 (t, J=8.6 Hz, 1H), 6.96 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20](/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:28]=2)=[N:7][C:6]([CH3:29])=[N:5]1)([CH3:3])[CH3:2]>C1COCC1.C(O)C.[Pd]>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:28]=2)=[N:7][C:6]([CH3:29])=[N:5]1)([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C/c1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)CCc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2

Procedure:
A solution of 0.11 g (0.28 mmol) of (E)-methyl 3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acrylate in 5 ml of THF/ethanol mixture was subjected to hydrogenation over 100 mg of 10% Pd—C for 4 hours. The mixture was filtered through celite; the filtrate was concentrated in vacuum to give Methyl 3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoate. Yield 96 mg. M/z 396.2, calc. 395.20
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:8]=2[S:9][CH:10]=1)(=[O:5])=[O:4].O1CC[CH2:19]OO1>CS(O)(=O)=O.FC(F)(F)C(O)=O>[Cl:15][C:11]1[C:8]2=[C:7]3[C:14]([CH2:1][N:2]([CH3:19])[S:3](=[O:4])(=[O:5])[C:6]3=[CH:10][S:9]2)=[CH:13][CH:12]=1
Reactant: C1COOOC1
Reactant: CNS(=O)(=O)c1csc2c(Cl)cccc12
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2ccc(Cl)c3scc(c23)S1(=O)=O
Temperature: 35 °C
Reaction time: 2 h

Procedure:
0.2 g of 7-chloro-benzo[b]thiophene-3-sulphonic acid-methylamide are dissolved in 3 ml of methanesulphonic acid at 35° C. and combined with a solution of 0.03 g of trioxane in 0.9 ml trifluoroacetic acid. After 2 h stirring at 35° C. the reaction mixture is poured onto 100 ml of ice water and the aqueous phase is extracted with ethyl acetate. The combined organic extracts are dried with Na2SO4, evaporated down in vacuo and then purified by chromatography. Yield: 0.06 g. M.p.: 146° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:20]=[CH:19][C:11]([O:12]C2CCCCO2)=[CH:10][CH:9]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(C=CC(O)=CC=1)O>C(Cl)Cl>[C:8]1([CH:20]=[CH:19][C:11]([OH:12])=[CH:10][CH:9]=1)[OH:7].[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1=COCCC1
Reactant: c1cc(OC2CCCCO2)ccc1OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Oc1ccc(O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C1CCOCC1
Reaction time: 12 h

Procedure:
Another functionalization substance may be 2-[2-(undec-10-enyl)-4-(tetrahydro-2H-pyran-2-yloxy) phenoxy]tetrahydro-H-pyran. This molecule may be synthesized from 2-[4-(tetrahydro-2H-pyran-2-yloxy) phenoxy]tetrahydro-2H-pyran using any prior art process. The intermediate may be synthesized by first adding dihydropyran (0.83 mL, 9.1 mmol) and pyridinium p-toluenesulfonate (0.11 g, 0.45 mmol) to a solution of hydroquinone (0.25 g, 2.3 mmol) in CH2Cl2 (3 mL). This reaction mixture is then stirred for about 12 hours and diluted with 10 mL of CH2Cl2. The mixture is subsequently washed by 3×5 mL of NaHCO3 and 1×5 mL brine, dried over MgSO4, and concentrated to a white solid. Silica gel chromatography (4:1 hexane/ethyl acetate) provides the di-tetrahydropyran hydroquinone as a white solid (0.48 mg, 75%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[Mg].CN([CH:14]=[O:15])C>C1COCC1.C(Cl)Cl>[Br:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([Br:8])[CH:5]=1)[CH:14]=[O:15]
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1cc(Br)cc(Br)c1
Reaction time: 5 h

Procedure:
A mixture of 15.7 g (50 mmoles) of 1,3,5-tribromobenzene and 1.344 g (56 mmoles) of magnesium in 200 mL of THF was stirred 5 hrs. At room temperature 7.5 mL (100 mmoles) of DMF was then added at 0° and the reaction mixture was stirred overnight. Solvent was removed in vacuo at room temperature the residue was taken up in 200 mL of ethyl acetate and washed with 6×50 mL of satd. sodium chloride soln. The organic phase was dried over anhyd. MgSO4. Solvent was removed to give a crude solid, which was dissolved in minimum amount of methylene chloride, and applied on silica gel. Elution with 1:9 mixture of ether:hexane mixture containing 3% methylene chloride gave the desired 3,5-dibromobenzaldehyde as white solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:12]([C:15]1[C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH:20]=1)[CH2:13][CH3:14].Cl>C(O)C.[Na]>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH:18]1[CH2:19][CH2:20][CH:15]([CH2:12][CH2:13][CH3:14])[C:16](=[O:21])[CH2:17]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCC1=CCCCC1=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCC1CCC(C(C(=O)OCC)C(=O)OCC)CC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.3 %

Procedure:
A solution of sodium metal (30 mg, 1.30 mmol) in absolute ethanol (4.0 mL) was stirred at −10° C. for 0.5 h. Diethyl malonate (3.5 mL, 23 mmol) was added at −10° C. followed by addition of a solution of 2-propylcyclohexenone (3.0 g, 21.7 mmol) in absolute ethanol (3.0 mL). The reaction mixture was stirred an additional 12 h at room temperature. The reaction mixture was acidified to pH 3 with 10% hydrochloric acid and then extracted several times with diethyl ether. The combined ether extracts were washed with water, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield a yellow oil. Purification by flash column chromatography (silica, 83:17 hexanes/ethyl acetate) gave 2-(3-oxo-4-propyl-cyclohexyl)-malonic acid diethyl ester (5.07 g): 1H NMR (300 MHz, CDCl3) δ 4.21 (q, J=7 Hz, 2H), 4.20 (q, J=7 Hz, 2H), 3.30 (s, 0.5H), 3.28 (s, 0.5H), 2.67–1.55 (m, 8H), 1.43–1.11 (m, 10H), 0.90 (t, J=7 Hz, 1.5H), 0.90 (t, J=7.0 Hz, 1.5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH:20]=3)[CH:15]=[C:10]2[N:9]=[CH:8]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:20]=3)[CH:15]=[C:10]2[N:9]=[CH:8]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(-c5cnn(C6CCN(C(=O)OC(C)(C)C)CC6)c5)cnc43)cc2OC)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(COc2ccc(Cn3cnc4cc(-c5cnn(C6CCNCC6)c5)cnc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To a stirred solution of tert-butyl 4-(4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.15 g, 0.24 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (0.5 mL). The resulting mixture was stirred at room temperature. After 1 h, the reaction mixture was concentrated, and the residue was diluted with 1M potassium carbonate solution (20 mL) and extracted with dichloromethane (3×10 mL). The combined organic phases were washed with brine (3×20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to afford 0.065 g (52%) of the product as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.59 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 6.93 (s, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 5.40 (s, 2H), 5.03 (s, 2H), 4.30 (m, 1H), 3.94 (s, 3H), 3.82 (s, 3H), 3.31-3.28 (m, 2H), 2.84-2.80 (m, 2H), 2.24-2.22 (m, 2H), 2.04-1.97 (m, 2H) ppm; (M+1)=526.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[C:13]([O:17][C:18](=[O:30])[CH2:19][O:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:30])[CH2:19][O:20][N:21]([C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)CONCc1ccc(F)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CC(C)(C)OC(=O)CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 85 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with [N-(4-fluorobenzyl)aminooxy]-acetic acid tert-butyl ester as described in the preparation of compound 1-A gave the title amide as white crystals (85% yield): mp 119-120° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.48 (9H, s, t-Bu), 1.74 (6H, s, CH3), 4.30 (2H, s, CH2), 4.88 (2H, s, CH2), 6.48 (1H, s, CH), 7.0 (2H, m, aromatics), 7.38 (2H, m, aromatics). Anal. calcd for C20H24FNO7: C, 58.67; H, 5.91; N, 3.42. Found: C, 58.83; H, 5.92; N, 3.31.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH3:20])=[O:18]>C(#N)C>[CH3:20][O:19][C:17]([N:2]1[CH2:3][CH:4]2[CH2:8][C:7](=[O:9])[CH2:6][CH:5]2[CH2:1]1)=[O:18]
Reactant: O=C1CC2CNCC2C1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)N1CC2CC(=O)CC2C1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (0.559 g, 2.34 mmol) was dissolved in 20 mL of acetonitrile, and potassium carbonate (0.646 g, 4.68 mmol) and methyl chloroformate (0.22 mL, 2.8 mmol) were then added to the solution in an ice-water bath successively. Upon completion of the addition, the reaction mixture was allowed to increase to room temperature, and stilled overnight. The solvent was evaporated, and 50 mL of water was then added to the residue. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine and 50 mL of water successively, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid methyl ester 2a (0.25 g, yield 58.4%) as a colorless oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH:22][C@@H:23]([CH2:36][NH2:37])[CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>>[OH:22][C@H:23]([CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1)[CH2:36][NH:37][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 228) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 255 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.2 Hz, 3H), 1.20-1.70 (m, 6H), 1.95-2.10 (m, 2H), 2.67 (brt, J=11.7 Hz, 2H), 2.70-3.20 (m, 7H), 3.62-3.75 (m, 2H), 3.95-4.10 (m, 3H), 6.59 (d, J=7.5 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.80-7.00 (m, 3H), 7.06 (d, J=9.0 Hz, 2H), 9.32 (brs, 1H), 10.61 (brs, 1H), 10.73 (brs, 1H); MS (ES) m/z: 518.1 (MH+); HRMS Calcd. for C25H36N5O5S(MH+): 518.2437. Found: 518.2452.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][Cl:11])[C:3]([OH:5])=[O:4].[C:12](ON1C(=O)CCC1=O)([O:14][CH2:15][CH:16]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13]>O1CCOCC1.C([O-])(O)=O.[Na+]>[CH:27]1[C:28]2[CH:16]([CH2:15][O:14][C:12]([NH:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][Cl:11])[C:3]([OH:5])=[O:4])=[O:13])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: N[C@@H](CCCCCCl)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(N[C@@H](CCCCCCl)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 113.8 %

Procedure:
The amine, (S)-2-amino-7-chloroheptanoic acid (-)-pseudoephedrinyl amide (1.8 mmol, 0.59 g) (for reference, Myers, A. G. et al. J. Am. Chem. Soc. 1995, 117, 8488), was dissolved in 7.2 mL of a heterogeneous mixture (1:1 v/v) of dioxane and saturated aqueous NaHCO3. The mixture was degassed under reduced pressure, placed under nitrogen and chilled to 0° C. To the mixture was added Fmoc-OSu (2.2 mmol, 0.73 g) in four equivalent portions over 15 min. Another 1 mL of dioxane was added to improve solubility of the Fmoc-OSu. The mixture was allowed to stir 20 min at 0° C. and 4 h at 20° C. After the mixture was concentrated under reduced pressure, it was extracted into AcOEt (250 mL). The organic layer was washed with saturated aqueous NaHCO3 (3×5 mL), saturated NaCl (3×5 mL) and dried (MgSO4). After the solvent was removed under reduced pressure, the residue obtained was purified by silica gel chromatography (AcOEt/hexanes:40/60%). The protected compound was obtained as a white foam (0.823 g, 83%) after removal of solvents under reduced pressure: [α]D25 -503.7° (c 0.01, CHCl3), Rf 0.25 (AcOEt/hexanes:1/1).
Reaction SMILES: [CH2:1]([C@@:4]1([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:33][CH3:34])[CH2:25][NH:26][S:27]([CH:30]2[CH2:32][CH2:31]2)(=[O:29])=[O:28])[C:5]1=[O:35])[CH:2]=[CH2:3].[H-].[Na+].I[CH3:47]>C1COCC1>[CH2:1]([C@@:4]1([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:33][CH3:34])[CH2:25][N:26]([CH3:47])[S:27]([CH:30]2[CH2:31][CH2:32]2)(=[O:28])=[O:29])[C:5]1=[O:35])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C2CC2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O

Procedure:
A solution of N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-1-yl)butyl)cyclopropanesulfonamide (Example 414, Step C, 1.5 g, 2.253 mmol) in THF was treated with sodium hydride (60% dispersion in mineral oil, 6.76 mmol) and iodomethane (0.280 ml, 4.51 mmol) at room temperature for 3 hours. The reaction mixture was quenched with HCl (1N) and diluted with DCM. The organic extract was washed with satd NaCl and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an oil. The product was purified by chromatography through a RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (4 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][N:32]1[CH2:33][CH2:34][CH:29]([C:25]2[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=2)[CH2:30][CH2:31]1
Reactant: O=Cc1cccc(Oc2ccc(Cl)c(Cl)c2)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc(Oc4ccc(Cl)c(Cl)c4)c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-(3,4-dichlorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 497.15 (M+H)+.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1>CN1C(=O)CCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:2]3=[N:9][CH:8]=[CH:7][C:6]([I:10])=[C:3]3[CH:4]=[N:19]2)=[CH:14][CH:13]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=Cc1c(I)ccnc1F
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncc3c(I)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.2 %

Procedure:
To a dry 16×100 mm Chem-Glass reaction tube under N2 was added 2-fluoro-4-iodonicotinaldehyde (600 mg, 2.390 mmol), (4-fluorophenyl)hydrazine (332 mg, 2.63 mmol) and anhydrous NMP (3.2 mL). The reaction mixture was flushed with argon, securely capped, stirred for 20 min at room temperature, and then placed in a 185° C. oil bath for 2 h. The reaction mixture was then allowed to stir at room temperature for 16 h. The reaction mixture was diluted with EtOAc (200 mL) and the organic layer was extracted with water (5×50 mL), brine (1×50 mL), dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by Biotage Silica gel chromatography on a 90 g Thompson Single Step™ silica cartridge using a linear gradient from 100% hexanes to 100% dichloromethane over 12 column volumes to give 480 mg (59.2%) of the title compound, Intermediate 2A, as an off white solid. 1H NMR (500 MHz, methanol-d4) δ ppm 8.22-8.28 (3 H, m), 8.15 (1 H, s), 7.78 (1 H, d, J=4.88 Hz), 7.25-7.37 (2 H, m). LC/MS (Condition A): 100% purity; ret. T=2.9 min, (M+H)+ 339.97.
Reaction SMILES: O1CCCC1.[OH-].[Na+].C([N:10]1[CH2:15][CH2:14][N:13]([CH:16]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=O>CO>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[N:13]2[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]2)=[CH:30][CH:29]=1
Reactant: COc1ccc(C(c2ccc(OC)cc2)N2CCN(C=O)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(c2ccc(OC)cc2)N2CCNCC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
6 ml of tetrahydrofuran, 9 ml of methanol and 9 ml of 10% aqueous sodium hydroxide were added to 1.68 g of the above-mentioned compound (2) followed by stirring for 2 hours at 60° C. After concentrating the reaction solution to roughly 10 ml and saturating it with sodium chloride, the concentrate was extracted with dichloromethane (20 ml×4). After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.48 g of the target compound. Yield: 95%