Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([CH:22]=[CH2:23])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CCO.CCOC(C)=O.[Pd]>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([CH2:22][CH3:23])[C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C=Cc1c(OCc2ccccc2)ccn(Cc2ccccc2)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1c(OCc2ccccc2)ccn(Cc2ccccc2)c1=O
Yield: 62.6 %

Procedure:
To a solution of 1-benzyl-4-(benzyloxy)-3-vinylpyridin-2(1H)-one (0.5 g, 1.6 mmol) in EtOH (10.0 mL) and EtOAc (10.0 mL) was added Pd/C (10%, 0.25 g) and stirred in an atmosphere of hydrogen gas at 30 psi for 16 h. The catalyst was removed by filtration, the filtrate was concentrated to dryness and the resulting residue was purified by silica gel flash chromatography using EtOAc/hexanes (1:1, v/v) to afford the title compound (0.32 g, 64%) as a pale yellow powder: 1H-NMR (CD3OD) δ: 7.52 (d, 1H, J=7.6 Hz), 7.39-7.2 (m, 10H), 6.41 (d, 1 h, J=7.6 Hz), 5.18 (s, 2H), 5.15 (s, 2H), 2.58 (q, 2H, J=7.2 Hz), 1.03 (t, 3H, J=7.2 Hz), ER-MS m/z=320 (MH+) HR-MS m/z calcd C21H22NO2 320.1651, found 320.1648.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C@H:7]([CH2:17][CH:18]=[CH2:19])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.C(O)C.S(O)(O)(=O)=O.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>C(O)=O.O>[CH2:10]([O:9][CH2:8][C@H:7]([O:6][CH2:5][CH:4]=[N:31][OH:32])[CH2:17][CH:18]=[CH2:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NO
Reactant: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=CO
Solvent: CCO
Solvent: O
Product: C=CC[C@H](COCc1ccccc1)OCC=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.9 %

Procedure:
[(R)-2-(2,2-Diethoxyethoxy)-4-pentenyloxymethyl]benzene (20.0 g) was dissolved in formic acid (160 ml) and water (40 ml), and the mixture was stirred at room temperature for 30 minutes. Next, water (161 ml) and ethanol (400 ml) were added, and then hydroxylamine sulfate (6.38 g) and sodium acetate (8.82 g) were added, followed by stirring at room temperature overnight. Water was added to the reaction solution, and the insoluble matter was dissolved. Then, the excess of ethanol was evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (13.7 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]([C:18]#[N:19])=[CH:10][C:9]=2[CH:20]=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]([C:18]#[N:19])=[CH:10][C:9]=2[CH:20]([OH:21])[CH3:22])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: N#Cc1cc(C=O)c(-c2cccc(F)c2)c2ncccc12
Solvent: C1CCOC1
Product: CC(O)c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 8-(3-fluorophenyl)-7-formylquinoline-5-carbonitrile (20 mg, 0.07 mmol) in tetrahydrofuran (1 mL) was added 1.4 M methylmagnesium bromide in tetrahydrofuran (0.12 mL, 0.17 mmol) at −78° C. The reaction was stirred at −78° C. for 30 minutes, quenched with water at −78° C. The mixture was neutralized with 1 N HCl, and then extracted with ethyl acetate. The combined orgagnic layers were washed with brine, dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step (20 mg, 90%). LCMS calculated for C18H14FN2O (M+H)+: m/z=293.1; Found: 293.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH:3]=1.[F-:22].[Cs+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CS(C)=O>[F:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: [F-]
Reactant: COc1ccc2nc(-c3ccc(C#N)cc3)cc(Cl)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1ccc2nc(-c3ccc(C#N)cc3)cc(F)c2c1
Temperature: 150 °C
Yield: 31.7 %

Procedure:
A mixture of 4-(4-chloro-6-methoxyquinolin-2-yl)benzonitrile (See Example 11, step 1) (1 g, 3.4 mmol), CsF (5.2 g, 34 mmol), and n-Bu4NBr (109 mg, 0.34 mmol) in DMSO (10 mL) was heated to 150° C. for 2 h. An aqueous/EtOAC workup was followed by purification by column chromatography (PE/EA=10/1) to afford desired product (300 mg, 31.7%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([NH:15][C:16]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]([C@H:28]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]2)[C:21]3=[O:27])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(Cl)Cl.Cl>CCOCC>[F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([NH:15][C:16]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]([C@H:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[C:21]3=[O:27])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9]
Reactant: Cc1ccc2c(=O)n([C@H]3CCN(C(=O)OC(C)(C)C)C3)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc2c(=O)n([C@H]3CCNC3)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
A round bottom flask was charged with (S)-tert-butyl 3-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)pyrrolidine-1-carboxylate (100.0 mg, 0.0001826 mol), methylene chloride (3 mL, 0.05 mol) and 2M hydrochloric acid in ether (4 mL) was added and the reaction was stirred at 45° C. for 3 hours. The solvent was removed under reduced pressure under reduced pressure and the residue was purified by reverse phase preparative HPLC to afford the product as white solid.
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1.C(OCC)C>C1COCC1.O.C(Cl)Cl>[CH3:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([O:32][CH3:31])[CH:34]=3)(=[O:41])=[O:40])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)c4cccc(OC)c4)c23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.9 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (Description 4) (120 mg, 0.422 mmol) in THF (2 mL), cooled in an ice bath, was added LiHMDS (1M solution in THF) (0.928 mL, 0.928 mmol). The reaction mixture was stirred at RT for 45 min before the addition of 3-(methyloxy)benzenesulfonyl chloride (218 mg, 1.055 mmol) and the reaction mixture was then stirred at RT for a further 12 h. The reaction mixture was then diluted with water (15 mL) and the aqueous layer extracted with DCM (3×30 mL) and the combined organic extracts dried over a phase separating column and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-20% ethyl acetate in cyclohexane, afforded a solid which was dissolved in the minimum amount of DCM. Upon addition of diethyl ether, a solid precipitated out which was collected by filtration, washed with diethyl ether and dried, to afford the title compound (134 mg). LCMS (A) m/z: 455 [M+1]+, Rt 1.12 min (basic).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc(C[C@@H]2CNCCN2Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(Cc2ccccc2)[C@H](Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a stirred solution of (2R)-1,2-dibenzylpiperazine (2.0 g; 7.5 mmol) in dichloromethane (30 ml), methanesulfonyl chloride (0.86 g; 7.5 mmol) was added and the mixture was stirred at ambient temperature for 1 h. Potassium carbonate (1.1 g) was added and stirring was continued for another hour. Dichloromethane (20 ml) and water (10 ml) were added and the phases were separated. The organic phase was washed with water (10 ml) and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 2.2 g of (2R)-1,2-dibenzyl-4-methanesulfonylpiperazine.
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14](Cl)[N:13]=[C:12]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][C@H:30]1[O:35][C@@H:34]([CH3:36])[CH2:33][NH:32][CH2:31]1.ClCCl>CN(C=O)C.O>[N:1]1([C:10]2[N:15]=[C:14]([N:32]3[CH2:31][C@@H:30]([CH3:29])[O:35][C@@H:34]([CH3:36])[CH2:33]3)[N:13]=[C:12]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Clc1nc(N2CCOCC2)nc(-n2cnc3ccccc32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CN(c2nc(N3CCOCC3)nc(-n3cnc4ccccc43)n2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91 %

Procedure:
The obtained 2-(benzimidazol-1-yl)-4-chloro-6-morpholino-1,3,5-triazine (320 mg, 1.0 mmol) dissolved in DMF (20 ml) was added with potassium carbonate (430 mg, 3.2 mmol) and cis-2,6-dimethylmorpholine (140 mg, 1.2 mmol) and stirred at room temperature for 45 minutes. The reaction mixture was condensed under reduced pressure and the obtained residue was added with dichloromethane and water and shaken for mixing. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 360 mg (yield: 90%) of the titled compound as colorless crystals.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][O:24][CH2:25][CH2:26][NH:27][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[O:29])[CH2:6]1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO.O1CCCC1.C(OCC)(=O)C>[SH:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([CH2:23][O:24][CH2:25][CH2:26][NH:27][C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=2)=[O:29])[CH2:6]1
Reactant: CC(=O)S[C@H]1C[C@@H](COCCNC(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCOC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-[2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl]pyrrolidine (0.59 g) in a mixture of methanol (12 ml) and tetrahydrofuran (12 ml) was added sodium methoxide (28% solution in methanol) (0.25 ml) at -20°~-10° C. in a nitrogen stream and the mixture was stirred at the same condition for 1 hour. To the mixture was added glacial acetic acid (0.1 ml) at -10°~0° C. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (20 ml). The solution was washed with water (20 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on a silica gel (10 g) and eluted with a mixture of acetone and chloroform (5:95 V/V) to give (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl] pyrrolidine (0.46 g).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27](O)(=O)[CH3:28]>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:27]([CH3:28])[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CC(=O)O
Product: CON=C1C[C@@H](c2noc(C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and acetic acid, the title compound was obtained in 76% purity by HPLC. MS(ESI+): m/z=377.0.
Reaction SMILES: [C:1]([CH:3]1[CH:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:5]([C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4]1)#[N:2].[CH2:19]([CH2:21]N)[OH:20]>C1C=CC=CC=1.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[O:20]1[CH2:19][CH2:21][N:2]=[C:1]1[CH:3]1[CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH:5]([C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:4]1
Reactant: N#CC1CC2c3ccccc3C1c1ccccc12
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: c1ccc2c(c1)C1CC(C3=NCCO3)C2c2ccccc21
Temperature: 130 °C
Reaction time: 5 h
Yield: 60.3 %

Procedure:
A mixture of 11-cyano-9,10-dihydro-9,10-ethanoanthracene (4.6 g), ethanolamine (1.8 g) and zinc acetate (250 mg) is stirred at 130° C for 5 hours. The reaction mixture is dissolved in benzene and passed through a column of 10% hydrated alumina. The eluate is evaporated to remove the solvent, and the residue is recrystallized from ether to give 11-(2-oxazolin-2-yl)-9,10-dihydro-9,10-ethanoanthracene (3.3 g) as crystals melting at 155° to 156° C. IR (KRr), 1655 cm-1 (O--C=N).
Reaction SMILES: [C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].O.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27](S(O)(=O)=O)=[CH:26][CH:25]=1.C(O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:34]([O:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:22])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)CCCCCCCCCCCCCCCCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)CCCCCCCCCCCCCCCCC(=O)OCc1ccccc1
Temperature: 40 °C

Procedure:
A solution of 1,18-octadecanedioic acid (75 g, 0.24 mol), p-toluene sulfonic acid mono hydrate (2.27 g, 11.9 mmol) and benzyl alcohol (20.7 g, 0.19 mol) in toluene (2.75 L) was heated to reflux for 3 hr. Water was removed by azeotropic distillation during reflux. Celite (25 g) was added and the mixture was cooled to 40° C. and stirred for an additional hour. The mixture was purified by plug filtration through silica using toluene as mobile phase. Fractions containing 1,18-octadecanedioic acid mono benzyl ester was collected and the volume was reduced by vacuum distillation at 75° C. The solution was cooled to 50° C., heptane was added, and the mixture was cooled to 35° C. Upon crystallisation additional heptane was added over a period of 15 min. and finally the mixture was cooled to 10° C. for an additional hour. The product was collected by filtration, washed with heptane and dried in vacuum. Yield of 1,18-octadecanedioic acid mono benzyl ester was 34 g (35%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](C2C=CC=CC=2)(C2C=CC=CC=2)[O:12][SiH2]C(C)(C)C)[N:6]=1)=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].[Cl-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][OH:12])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cccc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(CO)n1
Reaction time: 2 h
Yield: 63.4 %

Procedure:
A solution of 3.52 g of 6-(diphenyl-tert-butylsilyloxymethyl)-2-pyridinecarboxylic acid methyl ester in 87 ml of tetrahydrofuran is mixed at 24° C. under nitrogen with 13.6 g of tetrabutylammonium fluoride-trihydrate and stirred for 2 hours. Then, it is mixed with 32 ml of concentrated sodium chloride solution and extracted four times with ethyl acetate. The combined organic phases are dried on sodium sulfate and after filtration, concentrated by evaporation in a vacuum. The thus obtained residue is purified by chromatography on silica gel. With hexane/50-100% ethyl acetate, 0.92 g of the title compound is obtained as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]2[CH2:23][OH:24])[CH:5]=[CH:6][C:7]=1[F:8].Cl.C(O)C>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[CH2:23][OH:24])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(F)c(Cl)c2)C(CO)C1
Agent: Cl
Solvent: CCO
Product: OCC1CNCCOC1c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 144 %

Procedure:
To a solution of tert-butyl (6RS,7SR)-7-(3-chloro-4-fluorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (81 mg) in ethanol (1 mL) was added 14.7 N hydrogen chloride-ethanol solution (2.0 mL), and the mixture was stirred at room temperature for 1 hr. The crystals obtained by concentration under reduced pressure were recrystallized from ethyl acetate-ethanol to give the title compound (48 mg).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[C:11]1([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCCl>[N:17]1([C:11]2[CH:16]=[CH:15][C:14]([CH:3]=[O:4])=[CH:13][CH:12]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN(C)C=O
Reactant: c1ccc(N2CCCCC2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=Cc1ccc(N2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39.6 %

Procedure:
To a solution of 2.3 mL (30 mmoles) of N,N-dimethylformamide in 10 mL of 1,2-dichloroethane was added dropwise 2.8 mL (30 mmoles) of phosphorus oxychloride at 0° C. The ice-bath was removed and the reaction mixture was stirred for 15 min. 1-Phenylpiperidine (3.2 mL, 20 mmoles) was added to the above solution portionwise and the reaction mixture was refluxed overnight. The reaction mixture was poured into ice-cold 2N sodium hydroxide solution and stirred at room temperature for 1 h. The organic layer was separated and the aqueous layer was extracted with 2×20 mL of ethyl acetate. The combined organic layer was washed with brine until pH=7, dried over anhydrous sodium sulfate and evaporated. The residue was separated on a silica gel column eluting with ethyl acetate and hexane to afford 1.5 g (40%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([CH2:15][CH2:16][CH2:17][NH:18][CH:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Br:29])[CH:26]=3)[O:21][CH2:20]2)[CH2:10][C@@H:9]1[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[C:34]([N:39]=[C:40]=[O:41])[CH:35]=[CH:36][C:37]=1[F:38]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([CH2:15][CH2:16][CH2:17][N:18]([CH:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Br:29])[CH:26]=3)[O:21][CH2:20]2)[C:40]([NH:39][C:34]2[CH:35]=[CH:36][C:37]([F:38])=[C:32]([Cl:31])[CH:33]=2)=[O:41])[CH2:10][C@@H:9]1[CH3:30])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1CCCNC1COc2ccc(Br)cc2C1
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1CCCN(C(=O)Nc1ccc(F)c(Cl)c1)C1COc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
To a solution of (2S,5R)-4-[3-(6-bromo-chroman-3-ylamino)-propyl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.12 g, 0.25 mmol) in CH2Cl2 (0.5 mL) was added 3-chloro-4-fluoro-phenylisocyanate (0.043 g, 0.25 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated in vacuo and the residue was purified on reverse-phase HPLC to give 0.047 g (29%) of (2S,5R)-4-{3-[1-(6-bromo-chroman-3-yl)-3-(3-chloro-4-fluoro-phenyl)-ureido]-propyl}-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.85 (d, J=17.4 Hz, 1H), 7.62 (d, J=6.3 Hz, 1H), 7.23 (m, 2H), 7.02 (t, J=9.0 Hz, 1H), 6.71 (d, J=9.0 Hz, 1H), 6.14 (br.s, 1H), 4.55 (m, 2H), 4.26 (m, 2H), 3.92 (m, 1H), 3.60-2.70 (m, 10H), 2.05 (m, 2H), 1.46 (s, 9H), 1.37 (d, J=7.2 Hz, 3H), 1.20 (m, 3H). MS-ESI: 653.1 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[NH:5][C:4](=[O:19])[CH:3]1[NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22].[H-].[Na+].Br[CH2:33][C:34]([N:36]([CH:43]([CH3:45])[CH3:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>CN(C)C=O>[O:19]=[C:4]1[N:5]([CH2:33][C:34]([N:36]([CH:43]([CH3:45])[CH3:44])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:35])[C:6]2[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=2[N:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:2](=[O:1])[CH:3]1[NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]
Reactant: CC(C)N(C(=O)CBr)c1ccccc1
Reactant: O=C(Nc1ccccc1)NC1C(=O)Nc2ccccc2N(c2ccccc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CN1C(=O)C(NC(=O)Nc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Yield: 45.4 %

Procedure:
To a solution of 1-(2, 4-dioxo-1-phenyl-2,3,4,5-tetrahydro-1H-benzo [b][1, 4]-diazepin-3-yl)-3-phenyl urea (0.100 g.) in N,N-dimethylformamide (2 ml) cooled to 3° C., was added sodium hydride (0.0104 g; 60% suspension in mineral oil) with stirring. The mixture was stirred 20 minutes, then 2-bromo-N-isopropyl-N-phenyl acetamide (0.0656 g) was added in one portion. The resultant mixture was stirred at ambient temperature overnight. The crude reaction mixture was purified by preparative RP-HPLC with a gradient elution of 60-72% acetonitrile in water with 0.1% trifluoroacetic acid buffer over a 30 minute period at a rate of 100 ml/min. Fractions containing the desired material were combined, frozen and lyophilized to provide the title compound (0.0653 g) as a white powder. 1H NMR (300 MHz, DMSO-d6): d 0.95 (d, J=7.3 Hz, 3H), 0.98 (d, J=7.3 Hz, 3H), 4.19 (d, J=16.6 Hz, 1H), 4.48 (d, J=16.9 Hz, 1H), 4.79 (m, 1H), 5.04 (d, J=7.8 Hz, 1H), 6.87-6.92(m, 1H), 6.95(d, J=7.6 Hz, 1H), 7.18-7.57 (m, 17H), 9.14 (s, 1H); MS (FAB): m/z=562 (MH+); TLC (CH2Cl2 /CH3OH, 19:1): Rf =0.19; RP-HPLC (Vydac C-18, 25 cm×4.6 mm; 60-72% CH3CN in H2O with 0.1% TFA buffer;, 30 minutes; 1 ml/min): tf =17.5 min (t0 =2.5 min); m.p.: 230°-235° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[S:19]([O:12][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc(CCCO)c1
Solvent: c1ccncc1
Product: COc1cccc(CCCOS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A solution of 3-(3-methoxyphenyl)-propanol (69 g, 0.42 mole) and pyridine (400 mL) was stirred at 5° C. as p-toluenesulfonyl chloride (87 g, 0.46 mole) was added portionwise. The reaction mixture was stirred at room temperature for 2 hours, then was poured onto ice/concentrated HCl and was extracted with ether. The extracts were washed with 2N HCl, wawter, saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated to yield 126 g yellow oil, (95%); M+ 320.