Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH:15]([C:17]([O:19]C)=[O:18])[CH2:14][CH2:13][N:12]2[C:21]([O:23][CH3:24])=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br-].[Li+].C(N(CC)CC)C.O>CC#N>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH:15]([C:17]([OH:19])=[O:18])[CH2:14][CH2:13][N:12]2[C:21]([O:23][CH3:24])=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(C)(C)C)cc2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
To a solution of dimethyl 2-(4-tert-butylphenyl)piperidine-1,4-dicarboxylate (10.937 g, 32.80 mmol) in MeCN (100 mL) was added lithium bromide (6.58 mL, 262.42 mmol), triethylamine (18.19 mL, 131.21 mmol) and water (2 mL). The resulting mixture was heated under reflux for 3 h, then cooled to room temperature. The solvents were evaporated and the residue dissolved in water. The aqueous layer was washed with MTBE, then acidified by the addition of 3.8 N HCl. The aqueous layer was extracted three times with DCM. The combined organic layers were dried over MgSO4 and evaporated. 2-(4-tert-Butylphenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (9.5 g, 91%) was isolated as a light brown foam. MS m/z 320 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2=[O:18].O1CCCC1>C(N(CC)CC)C>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:12](=[O:17])[C:11]2=[O:18]
Reactant: CCOC(=O)Cl
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N1C(=O)C(=O)c2cc(Cl)ccc21

Procedure:
Ethoxycarbonyl chloride (10.5 ml) is added dropwise to a mixture of 5-chloroisatin (18.16 g), tetrahydrofuran (180 ml) and triethylamine (15.3 ml) with stirring, and the mixture is stirred at room temperature for 5 minutes. The mixture is concentrated under reduced pressure to remove solvent, and water is added to the residue. Crystalline precipitates are collected by filtration, washed with isopropanol and isopropyl ether and then dried, whereby 5-chloro-1-ethoxycarbonylisatin (23.3 g) is obtained.
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[CH:11]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH3:28][O:29]C(OC)(OC)OC>C(O)(=O)C>[CH2:1]([S:5]([NH:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:28]([OH:29])[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[C:12]=2[CH:11]=1)=[O:27])(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: COC(OC)(OC)OC
Reactant: CCCCS(=O)(=O)NC(=O)c1ccc(N)c(NCc2ccc(Cl)cc2Cl)c1
Solvent: CC(=O)O
Product: CCCCS(=O)(=O)NC(=O)c1ccc2nc(O)n(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 0.220 mg of N-1-butanesulfonyl-4-amino-3-(2,4-dichlorobenzylamino)benzamide, 0.3 ml of tetramethoxymethane and 2.0 ml of acetic acid was stirred at 60° C. for 4 hours. Acetic acid was distilled off under reduced pressure, and the residue was extracted with chloroform and with water. The chloroform layer was concentrated, and 4.0 ml of methanol and 36% hydrochloric acid (4 drops) were added to the residue. The mixture was stirred at 60° C. for 2 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The crystals precipitated were washed with water, and were dried to give 0.207 g of 6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-hydroxybenzimidazole (379).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(O)(=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:11](=[O:13])[CH3:12]
Reactant: COc1ccc(N)c(C)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(NC(C)=O)c(C)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
2-methyl-4-(methyloxy)aniline (5 ml, 39 mmol) was dissolved in acetic acid (40 ml) and acetic anhydride (3.7 ml, 39 mmol) was added dropwise. Reaction was heated to 60° C. After 30 min, most of the solvent was removed under reduced pressure and the residue diluted with EtOAc. A saturated solution of sodium bicarbonate was added until solution was pH 8. Organics were then washed with water and a saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure to afford N-[2-methyl-4-(methyloxy)phenyl]acetamide (6.37 g, 35.5 mmol) as a pink fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.95-2.06 (m, 3 H) 2.14 (s, 3 H) 3.71 (s, 3 H) 6.70 (dd, J=8.71, 2.84 Hz, 1 H) 6.77 (d, J=2.75 Hz, 1 H) 7.18 (d, J=8.61 Hz, 1 H) 9.16 (s, 1 H)
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Cl:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]([CH3:32])[C:19]([C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27](=[O:29])[N:26]([CH3:30])[C:25]=2[CH:31]=1)=[O:20].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]([CH3:32])[C:19]([C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27](=[O:29])[N:26]([CH3:30])[C:25]=2[CH:31]=1)([OH:20])[C:2]([F:4])([F:3])[F:1]
Reactant: COc1ccc(C(C)C(=O)c2ccc3oc(=O)n(C)c3c2)c(Cl)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(C)C(O)(c2ccc3oc(=O)n(C)c3c2)C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
Trifluoromethyltrimethylsilane (2M in THF, 6.33 mL) was added at 0° C. to a solution of 5-[2-(2-chloro-4-methoxy-phenyl)-propionyl]-3-methyl-3H-benzooxazol-2-one (1.99 g) in THF (30 mL) followed by the addition of tetrabutylammonium fluoride trihydrate (363 mg). Stirring was continued for 2.5 hours at 0° C. More tetrabutylammonium fluoride (1M in THF, 4.60 mL) was added to the reaction mixture and stirring was continued for 30 minutes at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH=100:0 to 99:1) to give the title compound as a colorless foam (2.0 g, 80%). MS (m/e)=416.3 [M+H+].
Reaction SMILES: I.[C:2]1([C:13]2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8]C(=N)SC.[OH:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][NH2:25].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[CH2:34](O)[CH3:35]>CO>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[OH:19][CH2:20][CH2:21][N:22]1[CH2:23][CH2:24][NH:25][C:13]1=[C:2]1[CH:3]([NH2:8])[CH:4]=[CH:5][CH:6]=[C:7]1[C:35]1[CH:34]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CSC(=N)Nc1ccccc1-c1ccccc1
Reactant: CCO
Reactant: NCCNCCO
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: NC1C=CC=C(c2ccccc2)C1=C1NCCN1CCO

Procedure:
A mixture of 1-(2-biphenylyl)-2-methyl-2-thiopseudourea hydriodide (12 g prepared as described in Example 5) and N-(2-hydroxyethyl)ethylenediamine (10 g) in ethanol (145 ml) was heated under reflux for 165 hours. Removal of the solvent gave an oil which was dissolved in methanol and treated with fumaric acid to give 2-[1-(2-hydroxyethyl)-2-imidazolidinyl-idene]-aminobiphenyl fumarate (m.p. 165°-166° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:46][C:47]([F:52])([F:51])[CH2:48][CH2:49][NH2:50]>C(#N)C>[F:46][C:47]([F:52])([F:51])[CH2:48][CH2:49][NH:50][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: NCCC(F)(F)F
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NCCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25 %

Procedure:
5-(methoxycarbonyl)pyridine-2-carboxylic acid (100 mg, 0.55 mmol) was dissolved in acetonitrile (1 mL). Triethylamine (0.230 mL, 1.66 mmol) and O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (314 mg, 0.83 mmol) were added. The reaction mixture was stirred at rt for 5 min. 3,3,3-trifluoropropylamine hydrochloride (83 mg, 0.55 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and the crude was pardoned between ethyl acetate and 1M sodium hydroxide. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude was purified by column chromatography using a gradient of ethyl acetate in heptane yielded 38 mg (25%) of the title compound as a white solid; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (t, 1 H), 9.11 (d, 1 H), 8.48 (dd, 1 H), 8.18 (d, 1 H), 3.92 (s, 3 H), 3.53-3.60 (m, 2 H), 2.54-2.66 (m, 2 H); MS (ESI) m/z 277[M+H+], m/z 275[M−H+];
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([F:13])=[CH:5][C:3]=1[NH2:4].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:36]([O:40][CH2:41][CH3:42])(=[O:39])[CH:37]=[CH2:38]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:4][C:3]1[CH:5]=[C:6]([F:13])[C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]=1/[CH:38]=[CH:37]/[C:36]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: Nc1cc(F)c(C(F)(F)F)cc1Br
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(C(F)(F)F)c(F)cc1N
Temperature: 85 °C

Procedure:
2-Bromo-5-fluoro-4-(trifluoromethyl)aniline (0.97 mmol) and P(o-tol)3 (0.40 mmol) were dissolved in triethylamine (2.0 mL) in a glass pressure tube and nitrogen gas was bubbled through the solution via a gas dispersion tube for 10 minutes. Ethyl acrylate (1.0 mmol) and palladium acetate (0.20 mmol) were added to the reaction mixture and the tube was sealed and placed into an oil bath pre-heated to 85° C. for 18 h. The resulting solution was concentrated under vacuum and purified via an isco column. Retention time (min)=2.504, method [1], MS(ESI) 278.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CON(C)[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CON(C)C(=O)c1ccc(C)cc1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(C)cc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-N-methyl-4-methylbenzamide. It is used in crude form in the following reaction.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C([C:13]1[CH:18]=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[CH:24][N:25]3[C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:14]=1[OH:34])(C)(C)C.N1C=CC=CC=1.O>C1COCC1>[Br:1][C:23]1[C:22]2[C:26](=[CH:27][C:19]([C:17]3[CH:18]=[CH:13][C:14]([OH:34])=[CH:15][CH:16]=3)=[CH:20][CH:21]=2)[N:25]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:24]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1cc(-c2ccc3ccn(-c4ccncc4)c3c2)ccc1O
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(-c2ccc3c(Br)cn(-c4ccncc4)c3c2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
N-Bromosuccinimide (8.1 mg, 0.046 mmol) was added to a mixture solution of tert-butyl 4-(1-(pyridin-4-yl)-1H-indol-6-yl)phenol (10 mg, 0.035 mmol) in THF (0.5 mL) mixture solution at −78° C. After stirring at −78° C. for 2 hours, the mixture was further stirred at 0° C. for 1 hour and then pyridine (8.5 μL, 0.105 mmol) was added. After stirring at room temperature for 30 minutes, water was added and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated sodium bicarbonate solution and brine, and then concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The target compound was obtained as white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24].C(N(CC)CC)C.C(Cl)(Cl)Cl>C(Cl)Cl>[C:16]1([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][C:6]3[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:22](=[O:25])[CH2:23][CH3:24])=[CH:8][CH:7]=3)[CH2:15][CH2:14]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccc(CN2CCN(c3ccccc3)CC2)cc1
Reactant: CCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCc1ccc(CN2CCN(c3ccccc3)CC2)cc1

Procedure:
A solution of 4-((4-(aminomethyl)phenyl)methyl)-1-phenylpiperazine (0.62 g), propionyl chloride (0.23 ml) and triethylamine (0.37 ml) in methylene chloride (20 ml) was stirred at room temperature for 4 hr. To this reaction mixture was added chloroform (100 ml), and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-brown solid (0.9 g). The obtained solid was crystallized from ethyl acetate (50 ml) to give the title compound (0.5 g) as pale-yellow white crystals, m.p.=140-141° C.
Reaction SMILES: [CH3:1][S:2][CH:3]1[NH:6][C:5](=[O:7])[CH2:4]1.[H-].[Na+].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH3:1][S:2][CH:3]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5](=[O:7])[CH2:4]1
Reactant: BrCc1ccccc1
Reactant: CSC1CC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC1CC(=O)N1Cc1ccccc1
Yield: 55.4 %

Procedure:
A solution of 4-methylthioazetidin-2-one (1.0 g, 8.53 mmol) in dry THF (10 ml) was added dropwise to a suspension of NaH (0.35 g, 8.63 mmol) in dry THF (5 ml) at -20° C. under an inert atmosphere. Benzyl bromide (1.46 g, 8.53 mmol) in dry THF (10 ml) was added dropwise over 15 minutes at -55° C. The resultant mixture was stirred for 2 hours at room temperature, poured onto ice/water (50 g) and filtered, washed with brine and water, dried (MgSO4), and evaporated under reduced pressure to a yellow oil (1.62 g). This was purified by flash chromatography on silica gel eluted with petroleum ether/ethyl acetate to give a yellow solid (0.98 g, 55%), m.p. 26-28° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:14](=[O:26])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:37]Br>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:11]([Br:37])[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[C:14](=[O:26])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1Br)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 8-(benzyloxy)-2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (8.0 g, 18.9 mmol) and sodium bicarbonate (4.8 g, 56.8 mmol) in dichloromethane (100 mL) at room temperature, a solution of bromine (3.5 g, 21.7 mmol) in dichloromethane (30 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with a hexanes and ethyl acetate gradient to provide the titled product.
Reaction SMILES: [CH2:1]([CH:18]([CH:38]([OH:57])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:19]([OH:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(O[CH:61](OCC)[CH2:62][CH2:63]Cl)C.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=[CH:83][NH+:82]=[CH:81]C=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:20]([CH:19]1[CH:18]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:38]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[O:57][CH:61]([CH2:62][CH2:63][N:82]([CH3:83])[CH3:81])[O:37]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: c1cc[nH+]cc1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)C(CCCCCCC/C=C\C/C=C\CCCCC)C(O)CCCCCCC/C=C\C/C=C\CCCCC
Reactant: CCOC(CCCl)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1OC(CCN(C)C)OC(CCCCCCC/C=C\C/C=C\CCCCC)C1CCCCCCC/C=C\C/C=C\CCCCC
Temperature: 80 °C
Yield: 58.2 %

Procedure:
A solution of the diol (6Z,9Z,29Z,32Z)-19-((8Z,11Z)-heptadeca-8,11-dien-1-yl)octatriaconta-6,9,29,32-tetraene-18,20-diol (11) (832 mg, 1.05 mmol) and 3-chloropropionaldehyde diethylacetal (351 μL, 2.10 mmol) in toluene (10 mL) was treated with PPTS (100 mg) and heated (80° C., 2 h). After cooling (rt) the reaction mixture was poured into sat. aq. NaHCO3, extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in a solution of (CH3)2NH (15 mL, 5.6M in EtOH), treated with tetrabutylammonium iodide (25 mg), transferred to a sealed reaction vessel and heated (80° C., 20 h). Once complete the yellow solution was concentrated and the residue was subjected to chromatography (100% EtOAc) to yield 2-(4,5-di((8Z,11Z)-heptadeca-8,11-dien-1-yl)-6-((9Z,12Z)-octadeca-9,12-dien-1-yl)-1,3-dioxan-2-yl)-N,N-dimethylethanamine (12) (203 mg, 22% over 2 steps) as a pale yellow oil. Rf 0.41 (8% CH3OH—CHCl3); 1H NMR (400 MHz, CDCl3) 5.43-5.29 (m, 12H), 4.88-4.83 (m, 0.5H), 4.64-4.58 (m, 0.5H), 3.89-3.82 (m, 0.5H), 3.56-3.50 (m, 1H), 3.35-3.27 (m, 0.5H), 2.78 (app. t, 6H), 2.65-2.50 (m, 2H), 2.46-2.31 (m, 6H), 2.11-2.03 (m, 12H), 1.92-1.78 (m, 2H), 1.65-1.11 (m, 57H), 0.90 (t, 9H). FW 876.51, C60H109NO2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:11].[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([NH:39][CH3:40])[CH3:38])[C:28]([O:30][CH3:31])=[O:29].C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([N:39]([CH3:40])[C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:38])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Reactant: CN[C@@H](C)COc1ccc(C(=O)OC)cc1Cl
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC[C@H](C)N(C)C(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetic acid (296 mg, 0.93 mmol), methyl (S)-3-chloro-4-(2-methylamino-1-propoxy)benzoate (240 mg, 0.93 mmol), EDC(hydrochloride) (268 mg, 1.40 mmol), HOBt (189 mg, 1.40 mmol), and DMAP (23 mg, 0.19 mmol) in DMF (8 mL) was stirred at room temp for 1.5 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with 5% MeOH in CHCl3 as eluent to give 520 mg (100%) methyl (S)-3-chloro-4-[2-[N-methyl-N-[3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetyl]amino]-1-propoxy]benzoate as a red-brown amorphous solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:20][CH2:19][CH2:18][CH:14]([C:15]([NH2:17])=[O:16])[CH2:13]1.CN1C(=O)CCC1>O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:20][CH2:19][CH2:18][CH:14]([C:15]([NH2:17])=[O:16])[CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: NC(=O)C1CCCNC1
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)C1CCCN(c2ccc(F)cc2[N+](=O)[O-])C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The mixture consisting of 1.62 g of 2,5-difluoronitrobenzene, 1.9 g of nipecotamide and 10 ml of NMP was heated with stirring to 80° C. for 2 hours. After the mixture had been allowed to cool, 30 ml of water were added and the mixture was stirred at RT for 30 minutes. The precipitated solid was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:27])[C:12]([OH:26])=[C:13]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:16])[N:14]=[C:3]21.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36].CNC.CO>C(Cl)Cl.CO>[C:35]([NH:1][C:2]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH2:5][N:4]1[C:11](=[O:27])[C:12]([OH:26])=[C:13]([C:15]([NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[O:16])[N:14]=[C:3]21)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Agent: CNC
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
To a stirred solution of 10-amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (25 mg, 0.067 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.05 mL) followed by acetyl chloride (0.05 mL). After 16 h at room temperature the reaction mixture was concentrated to give crude product which was dissolved in methanol (2 mL) and treated with 2M dimethylamine/methanol (0.5 mL). The resulting reaction mixture stirred at 60° C. for 2 h, cooled and purified by preparative HPLC to afford the title compound as a white solid (3 mg, 11% yield). 1H NMR (500 MHz, CDCl3) δ: 12.00 (s, 1H), 7.32-7.35 (m, 3H), 7.04-7.09 (m, 2H), 6.69 (s, 1H), 4.57 (d, 2H, J=5.8 Hz), 4.14 (d, 2H, J=3.66 Hz), 2.63-2.66 (m, 2H), 2.44-2.47 (m, 1H), 1.91-1.97 (m, 4H), 1.86 (s, 3H), 1.63-1.67 (m, 2H). LCMS (M+H)=415.29. HPLC purity: >95%.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:24])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C:8]([C:25]([O:27]C)=[O:26])=[CH:7][C@H:6]1[OH:29])(=[O:3])[CH3:2].C(N(CC)CC)C>C(N(CC)CC)C.O>[C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:24])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C:8]([C:25]([OH:27])=[O:26])=[CH:7][C@H:6]1[OH:29])(=[O:3])[CH3:2]
Reactant: COC(=O)C1=C[C@@H](O)[C@@H](NC(C)=O)[C@H](C(=O)NCCCCCc2ccccc2)O1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1[C@H](O)C=C(C(=O)O)O[C@H]1C(=O)NCCCCCc1ccccc1
Yield: 53.5 %

Procedure:
(4R,5R,6R)-5-Acetylamino-4-hydroxy-6-(phenethylpropylcarbamoyl)-5,6-dihydro-4-H-pyran-2-carboxylic acid, methyl ester (300 mg) in triethylamine/water (1:2, 1.5 ml) was heated at 50° C. for 2 hours. Further triethylamine (1 ml) was added and the reaction heated for 2 hours. The reaction mixture was evaporated to dryness and co-evaporated with toluene (5 ml, ×3) and ether and dried to give the title compound (155 mg). 1H NMR (250MHz, D6 -DMSO, rotamers) 7.7 (1H, 2×d, J=9Hz), 7.2--7.4 (5H, m), 5.8 (1H, 2×d, J=5Hz), 4.8 (1H, 2×d, J=8Hz)), 4.2 (1H, m), 4.1 (1H, m), 3.0-3.8 (5H, m), 2.7--2.9 (2H, m) 1.8 (3H, two s) 1.4-1.6 (2H, m) 0.8 (3H, m). Mass Spec. (Low resolution): MH+ =391. Mass Analysis: C20H26N2O6.0.8 C6H5N, 1.0 H2O Requires: C, 60.9; H,8.2; N, 8.0. Found: C, 60.9; H, 8.0; N, 8.1.