Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]1([CH2:23][N:24]([CH2:37][CH2:38][OH:39])[C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=2)[CH2:22][CH2:21]1.[C:40]([C:44]1[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=1)([CH3:43])([CH3:42])[CH3:41].C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.C(=O)([O-])[O-]>C(Cl)Cl>[CH:20]1([CH2:23][N:24]([CH2:37][CH2:38][O:39][C:47]2[CH:48]=[CH:49][C:44]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:45][CH:46]=2)[C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:35])([F:36])[F:34])[CH:26]=2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCO)CC2CC2)cc1C(F)(F)F
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(OCCN(CC2CC2)c2ccc(C#N)c(C(F)(F)F)c2)cc1
Reaction time: 0.17 h
Yield: 58.1 %

Procedure:
To a slurry of polymer-supported triphenylphosphine (0.23 g, ca. 3 mmol/g, ca. 0.70 mmol) in CH2Cl2 was added 4-[(cyclopropylmethyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile (0.100 g, 0.35 mmol) and 4-tert-butylphenol (0.105 g, 0.70 mmol). The mixture was shaken for 10 min, a solution of DBAD (0.121 g, 0.525 mmol) in CH2Cl2 (0.5 mL) was added, and shaking was continued overnight. Solids were removed by filtration and the filtrate was shaken with polymer-supported carbonate (0.50 g, ca. 2.9 mmol/g, ca. 1.5 mmol CO32−) for 4 h. Solids were removed by filtration, the filtrate was treated with TFA (1 mL) for 1 h and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.0847 g of the title compound as a colorless gum: 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=8.8 Hz, 1H), 7.29 (app. d, J=8.8 Hz, 2H), 7.11 (d, J=2.4 Hz, 1H), 6.90 (dd, J=8.8, 2.5 Hz, 1H), 6.78 (app. d, J=8.7 Hz, 2H), 4.14 (t, J=5.8 Hz, 2H), 3.89 (t, J=5.6 Hz, 2H), 3.39 (d, J=6.2 Hz, 2H), 1.29 (s, 9H), 1.14-0.99 (m, 1H), 0.69-0.59 (m, 2H), 0.36-0.27 (m, 2H); MS (APCI) m/z 417 (M+1).
Reaction SMILES: [N:1]([CH:4]1[C:11](=[O:12])[N:10]2[CH:5]1[CH2:6][CH2:7]OC2(C)C)=[N+:2]=[N-:3].O=C1N2C(CCOC2(C)C)C1.[Si:26](N1C(C=C)CC1=O)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>>[Si:26]([N:10]1[CH:5]([CH:6]=[CH2:7])[CH:4]([N:1]=[N+:2]=[N-:3])[C:11]1=[O:12])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC1(C)OCCC2C(N=[N+]=[N-])C(=O)N21
Reactant: C=CC1CC(=O)N1[Si](C)(C)C(C)(C)C
Agent: CC1(C)OCCC2CC(=O)N21
Product: C=CC1C(N=[N+]=[N-])C(=O)N1[Si](C)(C)C(C)(C)C

Procedure:
Following the procedure described for the preparation of 7-azido-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]-octane from 8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]-octane (Example 5, Step A) and using 1-(t-butyldimethylsilyl)-4-vinyl-2-azetidinone there is obtained 1-(t-butyldimethylsilyl)-3-azido-4-vinyl-2-azetidinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]([NH2:25])=O)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncc(C(N)=O)c(Nc3cccc(Br)c3)c2cc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 3.02 g of 4-[(3-bromophenyl)amino]-6,7-dimethoxy-3-quinolinecarboxamide, 2.43 ml of pyridine, and 22.5 ml of dichloromethane at 0° C. was added 3.18 ml of trifluoroacetic anhydride during 3 min. The reaction mixture was warmed to 25° C., stirred for 60 min, and concentrated. The residue was dissolved in 38 ml of methanol. The resulting solution was treated with 15 ml of 5 N NaOH at 25° C. After 5 m the solution was acidified with carbon dioxide and evaporated free of methanol. The residue was partitioned with dichloromethane-water. The organic layer was washed with water, dried, and evaporated to give a white solid. Recrystallization from ethyl acetate-hexane gave mp 224-228° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5](=[N:20][NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:6](=[CH:13]N1CCOCC1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].Cl>O1CCOCC1>[CH2:1]([O:3][C:4]([C:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:13][N:21]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:20]=1)=[O:29])[CH3:2]
Reactant: CCOC(=O)C(=NNc1ccc(C)cc1)C(=CN1CCOCC1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(-c2ccc(C)cc2)cc1-c1ccccc1

Procedure:
27.6 g. of 2-(4-methylphenylhydrazono)-3-morpholinomethylene-3-phenylpropionic acid ethyl ester are treated with 260 ml. of dioxane and 80 ml. of 2N hydrochloric acid and are heated under reflux for 45 minutes. The reaction is allowed to cool and then is concentrated in vacuum, the residue being taken up in chloroform. The chloroform phase is washed with water and concentrated in vacuum. The residue is treated with petroleum ether. 17.1 g. of 4-phenyl-1-(4-tolyl)-3-pyrazolecarboxylic acid ethyl ester, melting point 115°-117° C., is obtained.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:9]=3[N:8]=[C:7]2[C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>O1CCCC1.C(O)C.[C].[Pd]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:7]2[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:9]=3[N:8]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc([N+](=O)[O-])cc1)n2C1CCCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)cc1)n2C1CCCC1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
Ethyl 1-cyclopentyl-2-(4-nitrophenyl)benzimidazole-5-carboxylate (12 g) obtained in Example 21 was dissolved in tetrahydrofuran (200 ml) and ethyl alcohol (50 ml), 7.5% palladium carbon (50% wet, 1 g) was added. The mixtures was hydrogenated for 1 hr at atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. Tetrahydrofuran was added to the residue to allow crystallization and the crystals were collected by filtration to give the title compound (11 g, yield 98%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[O:13]=[C:9]([CH3:8])[CH2:10][C:11]([NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])=[O:12]
Reactant: C=C1CC(=O)O1
Reactant: COC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CNC(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
29.87 g (0.24 mol) of glycine methyl ester hydrochloride were added to a solution of 20.00 g (0.24 mol) of diketene in 250 ml toluene at 0° C. Then, 40.00 g (0.48 mol) NaHCO3 were added and the reaction mixture was stirred overnight at room temperature. Since thin-layer chromatography detected no more starting material, the reaction mixture was filtered, evaporated and the residue purified by column chromatography. This gave 33.4 g (0.19 mol, 81% yield) oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:16][CH3:17])=[C:11]([CH2:13][CH2:14][Cl:15])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[CH3:19][C:20]1[CH:34]=[CH:33][C:23]2[O:24][CH:25]=[C:26]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:22]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C1(C)C=CC=CC=1.CN(C)C=O>[ClH:15].[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:16][CH3:17])=[C:11]([CH2:13][CH2:14][N:30]3[CH2:31][CH2:32][CH:27]([C:26]4[C:22]5[CH:21]=[C:20]([CH3:19])[CH:34]=[CH:33][C:23]=5[O:24][CH:25]=4)[CH2:28][CH2:29]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1ccc2occ(C3CCNCC3)c2c1
Reactant: CCc1c(CCCl)sc2c1CCN(C(C)=O)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1c(CCN2CCC(c3coc4ccc(C)cc34)CC2)sc2c1CCN(C(C)=O)C2
Temperature: 70 °C
Reaction time: 7 h

Procedure:
A mixture of 5.0 g of 6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 4.9 g of 4-(5-methylbenzo(b)furan-3-yl) piperidine hydrochloride, 2.5 g of potassium carbonate, 3.0 g of potassium iodide, 30 ml of dimethylformamide and 30 ml of toluene was stirred at 70° C. for 7 hours and then poured into water. The toluene layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel and then dissolved into ethanol to make a hydrochloride. The resulting crystals were recrystallized from isopropyl alcohol to give 6-acetyl-3-ethyl-2-(2-(4-(5-methylbenzo(b)-furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride, m.p. 222°-225° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C@H:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:6]=2[CH:22]=1.[Br:23]Br>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C@H:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:6]=2[C:22]=1[Br:23]
Reactant: BrBr
Reactant: C[C@@H]1N=C(c2ccccc2Cl)c2cc(N)ccc2N(C)C1=O
Solvent: CC(=O)O
Product: C[C@@H]1N=C(c2ccccc2Cl)c2c(ccc(N)c2Br)N(C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 75 g (0.239 mol) of (S)-7-amino-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one in 1500 ml of glacial acetic acid is cooled to 0°, treated rapidly with a solution of 12.5 ml of bromine in 350 ml of glacial acetic acid and then the mixture is stirred at 0° for a further 30 minutes. The mixture is treated with ice/water and extracted with methylene chloride. The organic extract is dried over sodium sulphate and evaporated. The residue obtained is recrystallized from methylene chloride/ether and there is obtained (S)-7-amino-6-bromo-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one of melting point 243°; [α]25D =41.7° (1 percent solution in methylene chloride).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:11]1[O:12]C2C=CC=CC=2N=1.C[O-].[Na+]>CN(C=O)C.[Cu]Br>[CH3:11][O:12][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: c1ccc2ocnc2c1
Reactant: Brc1nc2ccccc2o1
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc2ccccc2o1

Procedure:
In Scheme VIII, bromo-benzoxazole 35 (R═CH3) was first treated with copper(I) cyanide in DMF to produce the corresponding aryl-nitrile, which upon treatment with boron tribromide afforded benzoxazole 36. Benzoxazole 36 was also prepared from a second synthetic Route, where the bromo-benzoxazole 35 was treated with zinc cyanide in the presence of a palladium catalyst [i.e. tetrakis(triphenylphosphine)palladium(0)] to afford the corresponding aryl-nitrile, which upon demethylation with boron tribromide produced benzoxazole 36. Benzoxazole 35 (R═H) was treated with copper (I) bromide, and freshly prepared sodium methoxide in DMF to produce methoxy-benzoxazole 37. Bromination of 37 with N-bromosuccinimide in acetonitrile afforded the monobromo benzoxazole 38 (major product) and the dibromobenzoxazole 39 (minor product).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[CH3:16].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][C:10]1[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:9]=1[N:6]1[CH2:5][CH2:4][NH:3][CH:2]([CH3:1])[CH2:7]1
Reactant: CC1CNCCN1
Reactant: Cc1cccc(Br)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1cccc(N2CCNC(C)C2)c1C

Procedure:
650 mg (6.48 mmol) of 2-methylpiperazine, 800 mg (4.32 mmol) of 3-bromo-o-xylene, 50 mg (0.22 mmol) of palladium acetate, 110 mg (0.17 mmol) of BINAP and 830 mg (8.65 mmol) of sodium tert-butoxide in dry toluene (8.6 mL) were heated at 110° C. for 14 hours. After cooling, the resulting reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate phase was concentrated. The residue was purified by chromatography to give the title compound as a yellow semi solid.
Reaction SMILES: Cl.[NH2:2][OH:3].O.C([O-])(O)=O.[Na+].[Br:10][C:11]1[C:12]([CH2:17][C:18]#[N:19])=[N:13][CH:14]=[CH:15][CH:16]=1>C(O)C>[Br:10][C:11]1[C:12]([CH2:17][C:18]([NH:2][OH:3])=[NH:19])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#CCc1ncccc1Br
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(Cc1ncccc1Br)NO
Temperature: 25 °C

Procedure:
A vigorously stirred mixture of hydroxylamine hydrochloride (924 mg, 13.3 mmol), water (4 mL), NaHCO3 (1.12 g, 13.3 mmol), 3-bromo-2-cyanomethylpyridine (Intermediate 1) (1.31 g, 6.65 mmol) and ethanol (14 mL) was heated to reflux for 5 h. The reaction mixture was allowed to cool to room temperature, the ethanol was removed in vacuo and the white solid collected by filtration, washing with water (3×10 mL). The wet solid was dried in vacuo at 40° C. for 1 h to yield 2-(3-Bromo-pyridin-2-yl)-N-hydroxy-acetamidine as a white solid.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([CH2:19][CH3:20])=[CH:13][CH:14]=2)[C:9]1=[O:21])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([CH2:19][CH3:20])=[CH:13][CH:14]=2)[C:9]1=[O:21]
Reactant: CC=CCC1C(=O)c2cc(CC)ccc2C1(C)C
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc2c(c1)C(=O)C(CC=O)C2(C)C
Reaction time: 0.67 h
Yield: 97 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 40 minutes while stirring through a solution, cooled to -70°, of 8.2 g of (RS)-2-(2-buten-1-yl)-6-ethyl-3,3-dimethyl-1-indanone in 120 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 3.72 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 100 ml of dichoromethane and, after the addition of 15 ml of water and 15 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 7.55 g (97%) of (RS)-2-(2-oxoethyl)-6-ethyl-3,3-dimethyl1-indanone were obtained as a light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[C:6](=O)[N:5]2[CH2:18][CH2:19][CH2:20][CH:4]2[C:3]1=[O:21].B>O1CCCC1>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:14])[F:15])=[CH:12][C:7]=2[CH2:6][N:5]2[CH2:18][CH2:19][CH2:20][CH:4]2[C:3]1=[O:21]
Reactant: CN1C(=O)C2CCCN2C(=O)c2cc(C(F)(F)F)ccc21
Agent: B
Solvent: C1CCOC1
Product: CN1C(=O)C2CCCN2Cc2cc(C(F)(F)F)ccc21

Procedure:
If 1,2,3,11a-tetrahydro-10-methyl-7 -trifluoromethyl-5 H-pyrrolo[2,1-c] [1,4] benzodiazepin-5,11(10H)-dione (prepared from proline and 5-trifluoromethyl N-methylisatoic anhydride as described in Example 1) is treated with 1M borane in tetrahydrofuran as described in Example 1, the above compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=1.CN1CCCC1=O.[CH2:26]([Mg]Br)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>O.C1COCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Reactant: Br[Mg]CCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cccc(CCc2ccccc2)c1

Procedure:
75A (1.14 g, 4 mmol), N-methylpyrrolidinone (2.2 mL), Fe(acac)3 (70 mg, 0.2 mmol) and dry THF (25 mL) were stirred under nitrogen at room temperature. Phenethylmagnesium bromide (1.0 M in THF, 5 mL) was added by syringe. After stirring for fifteen minutes, HCl (1 M, 10 mL) was slowly added. The mixture was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with water and then brine, were dried over MgSO4 and were concentrated. Purification was achieved using flash chromatography on SiO2 with hexanes/toluene 50:50. A colourless oil was obtained (660 mg, 69%). NMR 1H (ppm, CDCl3): 7.96-7.85 (m, 2H), 7.33-7.15 (m, 7H), 3.91 (s, 3H), 2.97-2.93 (m, 4H).
Reaction SMILES: CN(C)C=O.[C:6]([O:25][CH2:26][CH:27]([CH2:29][O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[OH:28])(=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH2:50]([N:52]([CH2:58][CH3:59])[CH2:53][CH2:54][C:55](O)=[O:56])[CH3:51]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:50]([N:52]([CH2:58][CH3:59])[CH2:53][CH2:54][C:55]([O:28][CH:27]([CH2:29][O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:26][O:25][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:56])[CH3:51]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)COC(=O)CCCCCCC/C=C\CCCCCCCC
Reactant: CCN(CC)CCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)CCN(CC)CC
Reaction time: 8 h
Yield: 62.2 %

Procedure:
In a solvent mixture of 3 ml N,N-dimethylformamide and 6 ml methylene chloride was dissolved 172 mg (0.277 mmol) of 1,3-dioleoylglycerol followed by addition of 101 mg (0.556 mmol) of N,N-diethyl-β-alanine (hydrochloride), 114 mg (0.553 mmol) of N,N-dicyclohexylcarbodiimide, and 7 mg (0.057 mmol) of 4-dimethylaminopyridine and the mixture was stirred overnight. This reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed with water. The washed solution was dried and concentrated and the residue was subjected to column chromatography (silica gel/methylene chloride-methanol) to provide 129 mg (62%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:6][CH:7]=1.[F:20][CH:21]([F:48])[C:22]([N:24]1[C@H:28]([CH2:29][F:30])[C@@H:27]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[O:26][C:25]1([CH3:47])[CH3:46])=[O:23].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(O)(C)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:48][CH:21]([F:20])[C:22]([N:24]1[C@H:28]([CH2:29][F:30])[C@@H:27]([C:31]2[CH:36]=[CH:35][C:34]([C:2]3[CH:3]=[CH:4][C:5]([C:8](=[O:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:6][CH:7]=3)=[CH:33][CH:32]=2)[O:26][C:25]1([CH3:46])[CH3:47])=[O:23]
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: CC(C)(C)OC(=O)NCCC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCC(=O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 75 °C
Yield: 34.5 %

Procedure:
A solution of the product of step 2, Example 28 (1 g, 3 mmol) and the product of step 4, Example 8 (1.26 g, 3 mmol) in toluene 20 ml and isopropyl alcohol (20 mL) is treated with sodium hydrogen carbonate saturate solution (10 ml). The mixture is deoxygenated and PdCl2(dppf) (111 mg, 0.15 mmol) is added and the reaction mixture deoxygenated again. The mixture is heated at 75° C. overnight. The reaction mixture is partitioned between ethyl acetate (100 ml) and water (50 ml). The phases were separated, the aqueous extracted with ethylacetate and the combined organic layers evaporated. Column chromatography (0-50% ethyl acetate in heptane) gave the title compound (554 mg). MS (ESI+) m/z 536.0 [M+H].
Reaction SMILES: N[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:20][CH:19]=2)[N:3]=1.N([O-])=[O:32].[Na+].C(=O)([O-])O.[Na+]>Cl.O1CCOCC1.O>[CH2:11]([O:10][C:8]([C:7]1[C:2](=[O:32])[NH:3][C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:20][CH:19]=2)=[CH:5][C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cc(-c2ccc(OCOCCOC)cc2)nc(N)c1C(=O)OCC
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(OCOCCOC)cc2)[nH]c(=O)c1C(=O)OCC
Reaction time: 1 h

Procedure:
In 250 ml of 1N hydrochloric acid and 100 ml of dioxane was dissolved 32.2 g of 2-amino-3,4-diethoxycarbonyl-6-(4-methoxyethoxymethoxyphenyl)pyridine, whereto a solution of 6.9 g (1.3 eq.) of sodium nitrite dissolved in 30 ml of water was added dropwise under ice-cooling. The mixture was stirred for 1 hour and left standing in a refrigerator overnight. The mixture was neutralized with sodium hydrogencarbonate, and dioxane was distilled off, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried. Then, the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent:dichloromethane→ethyl acetate).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].I[CH2:13][CH3:14]>CN(C=O)C>[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH2:13][CH3:14]
Reactant: CCI
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
60% Sodium hydride in mineral oil (1.6 g, 39.2 mmol) is added to a solution of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (2.0 mL, 15.7 mmol) in 30.0 mL of DMF, followed by the addition of iodoethane (3.1 mL, 39.2 mmol) and the reaction mixture is stirred at room temperature for 1 hour. After this time, the reaction mixture is quenched with saturated NH4Cl aqueous solution and then extracted with dichloromethane twice. The organics are combined and washed with water twice then brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield 2.512 g of the title compound. Yield: quantitative; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (3H, t, J=8.0 Hz), 1.20 (6H, s), 3.41 (2H, s), 3.48 (2H, q, J=8.0 Hz), 3.70 (3H, s).