Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:20][N:19]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:39](Cl)(=[O:41])[CH3:40]>C1COCC1>[C:39]([N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:9][CH:10]=3)=[N:19][CH:20]=2)[CH2:25][CH2:26]1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCNCC4)cn3)cc2)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C)c4)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To the solution of 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)acetamide 131-1 (20 mg, 0.05 mmol) in THF (1 mL) was added DIEA (19 mg, 0.15 mmol) and acetyl chloride (3.9 μL, 0.055 mmol). The reaction was stirred at room temperature for 40 min. The solvent was removed by rotary evaporation and the residue was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 131 as off-white solid. MS m/z 430.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.50 (s, 1H), 8.45 (d, 1H), 7.97 (d, 1H), 7.87 (d, 1H), 7.71 (d, 2H), 7.57 (s, 1H), 7.49 (d, 1H), 7.42 (d, 2H), 7.37 (dd, 1H), 3.68 (s, 2H), 3.52 (m, 4H), 3.09 (t, 2H), 3.02 (t, 2H), 2.48 (s, 3H), 1.97 (s, 3H).
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9]C([O-])(C)C.[K+].IC.C(OC(N[C@H](C1(C)CCCCC1)C(O)=O)=O)(C)(C)C>C(Cl)Cl>[CH3:9][C:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[O-]
Reactant: O=CC1CCCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1(C)CCCCC1
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Product: CC1(C=O)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A flame-dried 500-mL round-bottomed flask capped with a rubber septum was charged with anhydrous CH2Cl2 (150 mL) via cannula and cyclohexanecarboxaldehyde (12) (9.09 mL, 75 mmol, 1.0 equiv) via syringe under N2. The flask was cooled in an ice bath for 10 min, the septum was removed, and t-BuOK (10.9 g, 97.5 mmol, 1.3 equiv) was added in one portion with rapid stirring. The septum was replaced, and iodomethane (14.0 mL, 225 mmol, 3.0 equiv) was added in one portion via syringe. The mixture was stirred at 0° C. under N2 for 30 min. The mixture was then allowed to warm to room temperature and stirred an additional 2 h. The resulting pale yellow, heterogeneous mixture was filtered through a 10-cm diameter medium porosity fritted disk funnel, and the cake was washed with CH2Cl2 (3×15 mL). The filtrate was washed with brine (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was distilled under reduced pressure (1 torr) while maintaining the receiving flask between −20 to −40° C. (bp <30° C.). The distillate was a clear, colorless oil that contained (1-methyl)cyclohexanecarboxaldehyde (13) and 1.25 equiv CH2Cl2, as determined by 1H-NMR analysis: 13.2 g total, ˜7.2 g (1-methyl)cyclohexanecarboxaldehyde (57 mmol, 76% yield). The product was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=1)[C:3]([OH:2])=[O:19]
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Reactant: Oc1ccccc1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2ccccc2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C19H22O5 [M+Na]+: 353.3.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([OH:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)C(C)C)C.Cl>C(Cl)Cl.CS(C)=O>[CH2:7]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)C(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
To a solution of 2.3 ml of oxalyl chloride in 40 ml of methylene chloride cooled at -65° C. is added a solution of 4.45 g of dimethylsulfoxide in 20 ml of methylene chloride over a period of 10 minutes, and the mixture is stirred at -60° C. for 10 minutes. To the mixture is added a solution of 5 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate in 50 ml of methylene chloride over a period of 10 minutes, and the resulting mixture is stirred at -60° C. for 20 minutes. To the mixture is added 10.3 g of diethylisopropylamine over a period of 10 minutes, and the temperature is raised from -60° C. up to -30° C. To the mixture is added 80 ml of 1N hydrochloric acid, and the mixture is stirred at room temperature. The methylene chloride layer is separated, washed with water, dried and concentrated under reduced pressure. The residue is purified by silicagel column chromatography (hexane: ethyl acetate=4:1 to 2:1), to give 2.6 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[CH3:23][CH:24]1[O:29][CH:28]([CH3:30])[CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:22][O:21][C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]3[CH2:25][CH:24]([CH3:23])[O:29][CH:28]([CH3:30])[CH2:27]3)[CH:11]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20]
Reactant: CC1CNCC(C)O1
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(NC(=O)CCCCCN2CC(C)OC(C)C2)c2nccc(C)c2c1
Yield: 55.1 %

Procedure:
A mixture of 5.5 g (0.015 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide and 1.85 ml (0.018 mole) of 2,6-dimethylmorpholine in 90 ml of benzene was heated under reflux for 24 hr. Triethylamine (2 ml) was added and the mixture was heated under reflux for an additional 2 hr, allowed to cool, and filtered. The filtrate was washed with water, dried and concentrated. TLC(silica gel--ethyl acetate) demonstrated a mixture of the unchanged bromo compound, Rf(silica--ethyl acetate)=0.63, and the product, Rf=0.08. A solution of the residue, 1.3 ml (0.01 mole) of 2,6-dimethylmorpholine, and 1.5 ml of triethylamine in 80 ml of benzene was heated under reflux for 40 hr, allowed to cool, filtered, washed with water, dried and concentrated. The residue was chromatographed over 200 g of silica gel with 1 liter each of the following solutions of methanol in ethyl acetate: 1.5%, 2%, 3% to afford 3.7 g of crude product. Recrystallization from hexane afforded 3.3 g of the title compound, mp 87°-90°. The NMR spectrum confirmed the presence of hexane.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].CCCCCCC.[S:16](=O)(=[O:19])([OH:18])[OH:17].C(C(CCCC)C([O-])=O)C.[K+:31]>C(OCC)(=O)C>[K+:31].[OH:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[S:16]([O-:19])(=[O:18])=[O:17]
Reactant: Oc1ccc(O)cc1
Reactant: O=S(=O)(O)O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=S(=O)([O-])c1cc(O)ccc1O
Temperature: 12.5 °C
Reaction time: 0.21 h
Yield: 96.6 %

Procedure:
Hydroquinone (20 g, 0.1816 mol) and n-heptane (60 mL) was taken in a round bottom flask, after cooling the flask to about 10-15° C., sulfuric acid (36 N, 17.8 g) was added dropwise at the same temperature and stirring continued further for about 10-15 min. The temperature was slowly raised to 50-60° C. then stirred for 3-8 h. The reaction mass was then cooled to 25-35° C., n-heptane was decanted and ethyl acetate (200 mL) added to dissolve the solid formed. A solution of potassium 2-ethylhexanoate (36.4 g, 0.1996 mol) in ethyl acetate (200 mL) was added slowly. The reaction was further stirred for an hour. The precipitated crude solid was filtered, washed with ethyl acetate to give 40 g of 2,5-dihydroxybenzenesulfonic acid potassium salt.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][C:6](Cl)=[O:7].[NH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OCC2C=CC=CC=2)[CH2:12][CH2:11]1.C(N(CC)CC)C>O1CCCC1>[NH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:2][CH2:3][O:4][CH2:5][C:6]2=[O:7])[CH2:12][CH2:11]1
Reactant: NC1CCC(NC(=O)OCc2ccccc2)CC1
Reactant: O=C(Cl)COCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC1CCC(N2CCOCC2=O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
13-9.1 6.32 g (40.3 mmol) of (2-chloroethoxy)acetyl chloride are added to the solution of 10 g (40.3 mmol) of benzyl (4-aminocyclohexyl)carbamate and 6.2 ml of triethylamine (TEA) in 300 ml of tetrahydrofuran, and the mixture is subsequently stirred at room temperature for 20 hours. The reaction mixture is then evaporated under reduced pressure, the residue is taken up in 20 ml of water, and the aqueous solution is extracted three times with 20 ml of ethyl acetate each time. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off, the residue is taken up in 20 ml of acetonitrile, and 2.3 g of caesium carbonate are added to the resultant solution. The reaction mixture is then left to stir at room temperature for 48 hours and then evaporated under reduced pressure, the residue is taken up in 20 ml of water, and the aqueous solution is extracted four times with 20 ml of ethyl acetate each time. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off, the residue is taken up in 50 ml of tetrahydrofuran, 0.3 g of 5% palladium/carbon is added to the resultant solution, and the mixture is hydrogenated until the take-up of hydrogen ceases. The catalyst is subsequently filtered off, and the filtrate is evaporated to dryness under reduced pressure, giving 1.5 g of 4-(4-aminocyclohexyl)morpholin-3-one as a colourless oil; ESI 199. 13-9.2 Analogously to Example 7.3, reaction of cis-N′-BOC-4-hydroxy-D-proline and 4-chlorophenyl isocyanate gives the compound (2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid; ESI 285; m.p. 132°. 13-9.3 Analogously to Example 7.1, reaction of the amine 13-9.1 and the acid 13-9.2 gives the compound 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)cyclohexan-1-yl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 465; m.p. 245°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:6][N:7]=1.[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[NH:22][N:21]=[N:20][N:15]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(C#N)c2)cnc1N
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(-c2cccc(-c3nnn[nH]3)c2)cnc1N
Temperature: 105 °C
Yield: 22.8 %

Procedure:
To a solution of 3-amino-6-(3-cyanophenyl)-N-methylpyrazine-2-carboxamide (93 mg, 0.37 mmol) in dry N,N-dimethylformamide (1 mL) were added sodium azide (27 mg, 0.41 mmol), and ammonium chloride (22 mg, 0.41 mmol). The reaction was heated to 100-110° C. overnight. Reaction cooled to room temperature and treated with saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was washed with ethyl acetate (2×30 mL). The sodium bicarbonate layer was cooled to 0° C. and neutralized with 2.0 N hydrochloric acid until the pH of the solution became in the 2-3 range. The aqueous layer was extracted with ethyl acetate (100 mL) and washed with water (20 mL) and saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate, filtered, and concentrated at reduced pressure to afford 3-amino-N-methyl-6-[3-(1H-tetrazol-5-yl)phenyl]pyrazine-2-carboxamide (25 mg, 23% yield) as light yellow solid. 1H NMR (400 MHz, d6-DMSO): 8.92 (s, 1H), 8.84 (m, 1H), 8.70 (br s, 1H), 8.40 (br d, 1H), 8.12 (br d, 1H), 7.70 (t, 1H), 2.92 (br s, 3H); MS (EI) for C13H12N8O: 297 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Br:15])[CH:9]=2)=[O:5])C.[Li+].[OH-].[CH3:18]O.O>>[CH3:1][O:3][C:4]([C:6]1[N:7]([CH3:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Br:15])[CH:9]=2)=[O:5]
Reactant: CO
Reactant: CCOC(=O)c1cc2ccc(Br)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc2ccc(Br)cc2n1C

Procedure:
6-Bromo-1-methyl-1H-indole-2-carboxylic acid methyl ester was prepared by N-methylation of 6-bromo-1H-indole-2-carboxylic acid ethyl ester using the procedure described in Example 13 for N-methylation of indole carboxylic acid esters. Ester hydrolysis was performed with LiOH (4 equ.) in methanol-water 4:1, 12 h at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was acidified to pH˜2-3 with 2N HCl and extracted in ethyl acetate. The organic phase was washed with brine, dried (Na2SO4) and evaporated in vacuo to yield 95% of 6-bromo-1-methyl-1H-indole-2-carboxylic acid [(1S,2R)-2-cyanomethyl-carbamoyl)-cyclohexyl]-amide; m/z 253.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][N:13]=[C:12]([C:15]([OH:17])=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:42]1([CH2:48][NH2:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:42]1([CH2:48][NH:49][C:15]([C:12]2[CH:11]=[C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[O:14][N:13]=2)=[O:17])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1cc(-c2ccc3[nH]ncc3c2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCCC1)c1cc(-c2ccc3[nH]ncc3c2)on1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
5-(1H-Indazol-5-yl)isoxazole-3-carboxylic acid (35 mg, 0.15 mmol, Example 71A), was dissolved in N,N-dimethylformamide (0.8 mL) followed by the addition of HATU (60 mg, 0.15 mmol) dissolved in N,N-dimethylformamide (0.8 mL). Then a solution of 1-cyclohexylmethanamine (17 mg, 0.17 mmol), dissolved in N,N-dimethylformamide (0.8 mL) was added, followed by diisopropylethylamine (56 μL, 0.31 mmol) dissolved in N,N-dimethylformamide (0.8 mL). The resulting mixture was shaken for 3 hours at 40° C. The reaction was filtered, checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase HPLC (Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm), 50 mL/min, 10-100% acetonitrile/0.1% trifluoroacetic acid in water) to provide the title product. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.91-0.97 (m, 2H), 1.12-1.27 (m, 4H), 1.61-1.75 (m, 5H), 3.08-3.16 (m, 2H), 7.22-7.24 (m, 1H), 7.71-7.75 (m, 1H), 7.87-7.92 (m, 1H), 8.23-8.27 (m, 1H), 8.38-8.41 (m, 1H). MS (ESI+) m/z 325 (M+H)+; (ESI−) m/z 323 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH:30]=[C:31]1[C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]=2[CH2:35][O:34][C:33]2[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]1=2>C(#N)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[CH:6]1[CH2:11][CH2:10][N:9]([CH2:28][CH2:29][CH:30]=[C:31]2[C:37]3[CH:38]=[CH:39][CH:40]=[N:41][C:36]=3[CH2:35][O:34][C:33]3[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]2=3)[CH2:8][CH2:7]1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 25 °C
Reaction time: 312 h

Procedure:
To a solution of the product of step 3 (0.251 g, 0.680 mmol) in acetonitrile (4 mL) was added potassium carbonate (0.310 g, 2.24 mmol) in water (2 mL), followed by 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (170 mg, 448 mmol). The resulting orange solution was stirred at rt 13 days. The mixture was diluted with ethyl acetate and washed with water and brine. The washed extracts were dried over magnesium sulfate, filtered and concentrated. Pure titled compound was afforded by silica gel chromatography of the crude material (methylene chloride-98/2 methylene chloride/methanol gradient); 107 mg, 41%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[NH:7][C:8]([S:10]([CH2:12][C:13]3[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=3)=[O:11])=[N:9][C:5]=2[CH:4]=1.CC(C)([O-])C.[Na+].Cl[CH2:32][N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[N:34]1.N1(CN2C3C=CC(OC)=CC=3N=C2S(CC2C(C)=C(OC)C(C)=CN=2)=O)C2C=CC=CC=2N=N1>ClCCl.C(Cl)(Cl)Cl.CO>[N:33]1([CH2:32][N:9]2[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:24]=[CH:23][C:6]=3[N:7]=[C:8]2[S:10]([CH2:12][C:13]2[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=2)=[O:11])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[N:34]1
Reactant: ClCn1nnc2ccccc21
Reactant: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: CC(C)(C)[O-]
Agent: COc1ccc2c(c1)nc(S(=O)Cc1ncc(C)c(OC)c1C)n2Cn1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)n(Cn3nnc4ccccc43)c2c1
Temperature: 30 °C
Reaction time: 72 h

Procedure:
5-Methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (172 mg) was dissolved in 20 ml of dichloromethane. Sodium tert-butoxide (55 mg) and 1-(chloromethyl)-1H-benzotriazole (85 mg) was added. The reaction mixture was stirred at 30° C. for 3 days. TLC analysis (developing solvent; chloroform-methanol 15:1) showed major one spot of 1-[(benzotriazol-1-yl)methyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole above 5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole. The titled product was purified by preparative thin layer chromatography. 195 mg of product, a mixture of 1-[(benzotriazol-1-yl)methyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole and 1-[(benzotriazol-1-yl)methyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole was obtained (3:2 ratio).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:26]([NH:28][C@H:29]([C:39]([NH:41][C@H:42]([C:52]([NH:54][C@H:55]([C:57]([NH:59][C@H:60]([C:70]([NH:72][C@H:73]([C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[CH2:74][C:75](=[O:77])[NH2:76])=[O:71])[CH2:61][CH2:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:58])[CH3:56])=[O:53])[CH2:43][CH2:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:40])[CH2:30][CH2:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]>CN(C=O)C.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:26]([NH:28][C@H:29]([C:39]([NH:41][C@H:42]([C:52]([NH:54][C@H:55]([C:57]([NH:59][C@H:60]([C:70]([NH:72][C@H:73]([C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[CH2:74][C:75](=[O:77])[NH2:76])=[O:71])[CH2:61][CH2:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:58])[CH3:56])=[O:53])[CH2:43][CH2:44][C:45](=[O:51])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:40])[CH2:30][CH2:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C)C(C)C
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
A solution of Z-Glu(OtBu)-Val-Val-Glu(OtBu)-Glu(OtBu)-Ala-Glu(OtBu)-Asn-OtBu (Ro 22-4311/001, 42.6 g; 32.0 mmol) in DMF (650 mL) containing 10% Pd-BaSO4 (15.0 g) was hydrogenated in a Vibromixer apparatus for 3 h. The reaction mixture was filtered through a bed of celite which was washed with DMF (5×250 mL). The combined filtrate was evaporated to 600 mL and DMSO (300 mL) added. The resultant solution was used for the next stage of synthesis. A portion was evaporated to dryness, taken up in MeOH and precipitated with Et2O. The resultant gel was filtered, washed with Et2O and dried in vacuo; mp 246°-249° dec; [α]D25 -18.78° (c 1, DMF); Rf 0.78 (n-BuOH:AcOH:Pyr:H2O; 1-1-1-1). Anal. calc. for C57H99N9O18 (1198.46): C, 57.13; H, 8.33; N, 10.52. Found: C, 56.83; H, 8.32; N, 10.39.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH:10]2[CH2:15][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH:12]([CH2:23][OH:24])[O:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:26][C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28].[H-].[Na+].O>CS(C)=O>[C:1]1([CH2:7][O:8][CH2:9][CH:10]2[CH2:15][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH:12]([CH2:23][O:24][CH2:26][C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])[O:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1CN(Cc2ccccc2)CC(COCc2ccccc2)O1
Reactant: CCCN(CCC)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCN(CCC)C(=O)COCC1CN(Cc2ccccc2)CC(COCc2ccccc2)O1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
A mixture of 4.9 g (0.015 mole) of 6-[(phenylmethoxy)methyl]-4-(phenylmethyl)-2-morpholinemethanol and 2.84 g (0.016 mole) of 2-chloro-N,N-dipropylacetamide are dissolved in 100 ml of dry DMSO and the mixture stirred at room temperature under nitrogen. Slowly, 0.88 g of sodium hydride (0.0183 mole, 50% oil dispersion) is added to the DMSO mixture and the reaction allowed to stir at ambient temperature (22°). After stirring for 10 minutes, an exothermic reaction begins to take place and an ice-bath is used to maintain the reaction temperature below 30°. After stirring for 1/2 hour, the ice-bath is removed and the reaction allowed to stir at room temperature for 18 hours. The excess NaH is destroyed by adding 5 ml of methanol and the entire reaction mixture is then poured into 400 ml of water. The product is extracted and washed with 6×300 ml portions of water. The product is then extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined and washed with 6×300 ml portions of water. The CHCl3 layer is separated and dried over anhydrous Na2SO4 overnight. The CHCl3 is removed in vacuo yielding the crude product as a dark oil. The resulting oil is purified on a neutral Alumina III column (200 g), eluting with 2% methanol/chloroform, yielding 4.6 g (69%) of the desired product, 2-[[6-[(phenylmethoxy)methyl]-4-(phenylmethyl)-2-morpholinyl]methoxy]-N,N-dipropylacetamide.