Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:40](C=O)=[C:39]([F:45])[CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].Cl.[NH2:47][OH:48]>CN1CCCC1=O.C(OCC)(=O)C.O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:40](=[N:47][OH:48])[CH:39]([F:45])[CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C=O)c(F)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C4=CC(F)C(=NO)C=C4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 117 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-fluoro-4-formylphenyl)-2-thienylmethyl)benzene (272 mg) obtained in Example 180-(1) was dissolved in N-methyl-2-pyrrolidone (10 ml) and added thereto was hydroxylamine hydrochloride (34 mg). The mixture was heated under stirring at 117° C. overnight. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was washed with water and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-2:1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-hydroxyimino-3-fluorophenyl)-2-thienylmethyl)benzene (177 mg) as colorless caramel. APCI-Mass m/Z 693/695 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-hydroxyimino-3-fluorophenyl)-2-thienylmethyl)benzene (175 mg) was dissolved in chloroform (5 ml) and added thereto was 1,1′-carbonyldiimidazole (46 mg). The mixture was stirred at room temperature overnight. 1,1′-Carbonyldiimidazole (92 mg) was further added thereto, and the mixture was stirred at 40° C. for 6 hours. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was separated and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)benzene (158 mg) as colorless caramel. APCI-Mass m/Z 675/677 (M+NH4). (3) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)benzene was treated in a manner similar to Example 106-(3) to give desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)benzene as pale yellow powder. APCI-Mass m/Z 507/509 (M+NH4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.O1CCOCC1.Cl>[Zn].O>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(CCC(=O)CCc2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Zn]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CCCCCc2ccc(OC)cc2)cc1
Yield: 111 %

Procedure:
A mixture of 1,5-bis(4-methoxyphenyl)pentan-3-one of Example 7 (57 g, 0.19 mole), amalgamated zinc (200 g), dioxane (250 ml), concentrated hydrochloric acid (250 ml) and 150 ml of water was refluxed overnight. A further 50 ml of concentrated hydrochloric acid was added after the first 6 hours. The organic layer was separated, diluted with ether, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 60 g of a thick oil. NMR and mass spectra confirmed the structure.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18].[N:20]([O-])=O.[Na+]>O>[S:1](=[O:3])(=[O:2])([OH:5])[O-:4].[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([N+:6]#[N:20])=[C:8]([N+:17]([O-:19])=[O:18])[CH:9]=1
Reactant: O=S(=O)(O)O
Reactant: O=N[O-]
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Product: O=S(=O)([O-])O
Temperature: 75 °C

Procedure:
To a 500 mL three-necked flask equipped with a mechanical stirrer is added 99.5 g of concentrated sulfuric acid and 62.5 g of 4-trifluoro-2-nitroaniline (or 4-amino-3-nitro-benzotrifluoride). After heating to 75° C., 200 g of water is added at which time the temperature is reduced to 0° C. Sodium nitrite solution (52.9 g, 40% by weight in water) is added over two hours while maintaining the temperature at 0-5° C. The title diazonium salt solution (351 g) is filtered and stored at −15° C. for later use.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6](F)[C:3]=1[CH:4]=[O:5].[CH2:13](N)[CH2:14]CC.[C:18]1(C)C=CC(S(O)(=O)=O)=C[CH:19]=1.C([Mg]Br)C>C1(C)C=CC=CC=1.O1CCCC1.CCOCC.[Cl-].[Mn+2].[Cl-]>[CH2:13]([C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([CH2:18][CH3:19])[C:3]=1[CH:4]=[O:5])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc(F)c(C=O)c(F)c1
Reactant: CCCCN
Agent: [Mn+2]
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1cc(OC)cc(CC)c1C=O

Procedure:
Prepared in analogy to Example 57(a)-(b) from 2,6-difluoro-4-methoxybenzaldehyde, N-butylamine and p-toluenesulphonic acid in toluene, then treatment with 3 equivalents of ethylmagnesium bromide and manganese(II) chloride in tetrahydrofuran and ether followed by chromatography on silical gel. MS (ISP): 193.3 ([M+H]+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([S:10][C:11]2[N:15]([CH3:16])[C:14]([CH2:17][O:18][CH:19]3OCCO3)=[N:13][C:12]=2[CH:24]([CH3:26])[CH3:25])[CH:6]=[C:7]([Cl:9])[CH:8]=1.[C:27](=O)([O-])[OH:28].[Na+]>CO>[Cl:9][C:7]1[CH:6]=[C:5]([S:10][C:11]2[N:15]([CH3:16])[C:14]([CH2:17][O:18][CH2:19][CH:27]=[O:28])=[N:13][C:12]=2[CH:24]([CH3:25])[CH3:26])[CH:4]=[C:3]([Cl:2])[CH:8]=1
Reactant: CC(C)c1nc(COC2OCCO2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nc(COCC=O)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a mixture of methanol (1 ml)and 6N-hydrochloric acid (1 ml)was dissolved 156 mg (0.37 mmol)of 5-(3,5-dichlorophenylthio)-2-(1,3-dioxolan-2-yloxymethyl)-4-isopropyl-1-methylimidazole (23a), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution to neutralize, and extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was fractionated by silica gel chromatography (ethyl acetate)to obtain 39 mg of {[5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methoxy}acetaldehyde (24a)as oil (yield 28%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[C:10](OC(=O)C)(=[O:12])C.O>C(O)=O.CO>[CH:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8])=[O:12]
Reactant: O=C(O)C1CCCCN1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Solvent: CO
Product: O=CN1CCCCC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 40 g of a racemic mixture of 2-piperidinecarboxylic acid (0.310 mmol) in 300 mL of formic acid at 0° C. there are added dropwise 200 mL (2.15 mmol) of acetic anhydride. The whole is then stirred at ambient temperature overnight. The reaction mixture is then cooled to 0° C., hydrolysed by the addition of 250 mL of water and stirred for half an hour at 0° C. before being concentrated to dryness. The oil so obtained is taken up in 200 mL of methanol and then concentrated to dryness. The title product is obtained in the form of an oil with a yield of 98%. It is used directly, without further purification, for the following step.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)[C:9]2=[O:12])=[CH:4][CH:3]=1.CN(C(ON1N=[N:38][C:33]2[CH:34]=[CH:35][CH:36]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCC1.O>CN(C=O)C>[CH:33]1([NH:38][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:13]([N:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9]3=[O:12])[CH:14]=2)[CH2:34][CH2:35][CH2:36]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(O)cc2c1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CCC2)cc1-n1ccc2ccc(O)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
3-(7-Hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoic acid (295 mg), HATU (406 mg) and cyclobutylamine (0.43 ml) were dissolved in DMF (25 ml) and stirred at room temperature for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (magnesium sulfate) and concentrated. The residue was purified by column chromatography with ethyl acetate to give N-cyclobutyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide as a white solid (150 mg); NMR Spectrum: (DMSOd6) 1.35 (m, 2H), 2.03 (m, 2H), 2.10 (s, 3H), 2.20 (m, 2H), 4.40 (m, 1H), 6.65 (d, 1H), 7.12 (d, 1H), 7.22 (m, 1H), 7.46 (d, 1H), 7.60 (m, 2H), 7.76 (s, 1H), 7.85 (d, 1H) 8.60 (d, 1H), 10.00 (s, 1H); Mass Spectrum: M+H+ 349.
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[C:16]([F:28])[CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[C:16]([F:28])[CH:15]=3)[C:8](=[O:12])[N:9]([CH2:31][C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[O:33])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)c(F)c3)c2s1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)c(F)c3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-2′-fluorobiphenyl-2-carbonitrile (1.6 g), 2-bromo-1-(4-methoxyphenyl)ethanone (1.1 g) and N,N-dimethylformamide (19 mL) was added 60% sodium hydride (0.23 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.8 g, 86%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][N:13]=2)[CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:27]=1.C(N(CC)CC)C>CS(C)=O.O>[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([O:11][C:10]3[CH:9]=[C:8]([CH:25]=[CH:24][CH:23]=3)[CH:7]=[C:4]3[CH2:5][CH2:6][N:1]([C:33]([NH:32][C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[O:34])[CH2:2][CH2:3]3)=[N:13][CH:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C(=C1CCNCC1)c1cccc(Oc2ccc(N3CCCC3)cn2)c1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cccc(Oc3ccc(N4CCCC4)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.2 %

Procedure:
To a solution of 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-(pyrrolidin-1-yl)pyridine (0.119 g, 0.354 mmol) in DMSO (2 mL) was added phenyl pyridin-3-ylcarbamate (0.076 g, 0.354 mmol) followed by triethylamine (0.049 mL, 0.354 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The residue was purified by silica gel column chromatography (32% acetone/hexane) to give the title compound (0.11 g, 68.8% yield). 1H NMR (500 MHz, CDCl3): δ 8.56 (s, 1H), 8.24 (s, 1H), 8.12 (d, J=7.3 Hz, 1H), 7.58 (s, 1H), 7.28 (m, 1H), 6.83 (m, 6H), 6.37 (s, 1H), 3.62 (m, 2H), 3.51 (m, 2H), 3.27 (m, 4H), 2.58 (m, 2H), 2.44 (m, 2H), 2.02 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 156.57, 154.53, 153.74, 143.38, 141.54, 140.80, 138.66, 137.47, 136.49, 130.41, 129.30, 127.70, 124.96, 123.66, 122.73, 119.38, 117.18, 113.11, 47.83, 45.70, 44.75, 41.01, 35.74, 29.71, 29.15, 25.39; m/z (456.2, MH+); HPLC: 97.0%.
Reaction SMILES: [CH2:1]1[CH2:11][CH2:10]N2[C:4](=NCCC2)[CH2:3][CH2:2]1.[CH3:12][C:13](=[O:17])[O:14][CH2:15][CH3:16]>C(#N)C>[C:1]1([C:12]2[C:13](=[O:17])[O:14][CH2:15][C:16]=2[C:4]2[CH:3]=[CH:2][CH:1]=[CH:11][CH:10]=2)[CH:11]=[CH:10][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1OCC(c2ccccc2)=C1c1ccccc1
Reaction time: 0.5 h

Procedure:
After dissolving compound 2 (5.00 g, 36.7 mmol) in ACN (30 ml), compound 10 (7.31 g, 36.7 mmol) and TEA (5.63 ml) were sequentially added thereto. After the agitation for 30 minutes at room temperature, the temperature was reduced to 0° C., DBU (16.5 ml) was dropped and the agitation for 1 hour was carried out. After the termination of the reaction, EA and 1N HCL aqueous solution were added thereto and the organic layer was washed three times with brine. Water was removed by using anhydrous Na2SO4 and the distillation under the reduced pressure was carried out to obtain compound 18.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[SH:10].[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18]2[S:10][C:3]3[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: COc1ccc(N)c(S)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
A mixture of 2-amino-5-methoxybenzenethiol (5.0 g, 32.2 mmol) and 4-nitrobenzoyl chloride (6.0 g, 32.2 mmol) in toluene (250 ml) was heated under reflux with a catalytic amount of 4-toluenesulphonic acid in a Dean-Stark trap for 6 h. On cooling to room temperature the precipitate was collected by filtration, washed with toluene and recrystallised from AcOH to give the title compound (7.0 g, 76%) as a pale yellow solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([O:12][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:11][CH:10]=2)=[CH:31][CH:32]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Oc1ccc(-n2cncn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(I)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-n3cncn3)cc2)cc1
Yield: 69.3 %

Procedure:
The title compound (130 mg, 80%) was prepared from 4-[1,2,4]triazol-1-yl-phenol (0.7 g, 0.43 mmol) and (R)-2-(4-Iodo-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.23 g, 0.56 mmol) using the procedure of Example 146, step 3.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[CH2:13](O)[CH2:14][CH:15]=[CH2:16]>>[C:1]([O:12][CH2:16][CH2:15][CH:14]=[CH2:13])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCC(=O)O
Reactant: C=CCCO
Product: C=CCCCCCCCC(=O)OCCC=C

Procedure:
Following the aforementioned procedure, diene was prepared from dec-9-enoic acid and but-3-en-1-ol. The resulting yellow oil was purified by silica gel chromatography (30:1 hexanes:diethyl ether) to afford the desired product as a colorless oil. IR (neat): 3077 (m), 2927 (s), 2855 (s), 1737 (s), 1641 (m), 1458 (m), 1418 (m), 1353 (m), 1243 (s), 1170 (s), 1115 (m), 992 (s), 912 (s), 725 (m), 635 (m); 1H NMR (400 MHz, CDCl3): δ 5.86-5.74 (2H, m), 5.14-4.91 (4H, m), 4.12 (211, t, J=6.8 Hz), 2.38 (2H, ddt, J=13.6, 6.8, 1.4 Hz), 2.29 (2H, t, J=7.6 Hz), 2.06-2.01 (2H, m), 1.63-1.59 (2H, m), 1.39-1.26 (8H, m); 13C NMR (100 MHz, CDCl3): δ 174.0, 139.3, 134.2, 117.3, 114.3, 63.4, 34.5, 33.9, 33.3, 29.2, 29.2, 29.1, 29.0, 25.1; HRMS (ESI+) [M+H]+ calcd for C14H25O2: 225.1855. found: 225.1855.
Reaction SMILES: Br[CH:2]1[CH2:4][C:3]1([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Mg].II.Cl[P:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:34]CCCCC>[Cu](I)I.C1COCC1>[C:5]1([C:3]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][C:2]2([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:34])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrC1CC1(c1ccccc1)c1ccccc1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CCCCCC
Agent: I[Cu]I
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(P(c2ccccc2)c2ccccc2)CC1(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Under a nitrogen atmosphere, 1-bromo-2,2-diphenylcyclopropane (1.44 g, 5.0 mmol) and magnesium (0.134 g, 5.5 mmol) and THF (10 ml) were placed in a reaction flask. Then, a trace amount of iodine was added and the mixture was stirred at 40° C. for 2 hours. After cooling, copper iodide (0.961 g, 5.0 mmol) and chlorodiphenylphosphine (0.90 ml, 5.0 mmol) were added and the resulting mixture was stirred at 40° C. for 20 hours. After cooling to room temperature, hexane (10 ml) was added to the reaction mixture, and crystal separated was then collected by filtration. The crystal was dissolved in toluene, washed with an aqueous 28% ammonia solution and a brine, and dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure and the concentrate was recrystallized from a mixture of methanol and toluene to give the title compound (0.98 g, 50%) as white crystal.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:22]3[C:21](=[O:23])[NH:20][CH:19]=[N:18][C:17]=3[N:16]([CH3:24])[C:15](=[O:25])[C:14]=2[CH3:26])=[C:8]([F:27])[CH:7]=1>>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:22]3[C:21](=[O:23])[N:20]([CH2:2][CH2:3][OH:4])[CH:19]=[N:18][C:17]=3[N:16]([CH3:24])[C:15](=[O:25])[C:14]=2[CH3:26])=[C:8]([F:27])[CH:7]=1
Reactant: OCCBr
Reactant: Cc1c(Nc2ccc(Br)cc2F)c2c(=O)[nH]cnc2n(C)c1=O
Product: Cc1c(Nc2ccc(Br)cc2F)c2c(=O)n(CCO)cnc2n(C)c1=O

Procedure:
The title compound was prepared according to the procedure used for Example 9 by reaction of 2-bromoethanol with compound 9F. 1H NMR (400 MHz, MeOD) δ ppm 1.70 (s, 3H) 3.74 (s, 3H) 3.82 (t, J=5.05 Hz, 2H) 4.13 (t, J=5.05 Hz, 2H) 4.53 (s, 1H) 6.78 (t, J=8.72 Hz, 1H) 7.26 (dd, J=8.21, 1.39 Hz, 1H) 7.37 (dd, J=10.48, 2.15 Hz, 1H) 10.27 (s, 1H) [M+H] calc'd for C17H16BrFN4O3, 424. found, 424.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:9](=O)[CH2:10][O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C[OH:38]>>[C:1]([O:5][C:6](=[O:34])[CH:7]([OH:38])[CH:8]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:9][CH2:10][O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)OCc1ccccc1)C(=O)COc1c(F)c(F)cc(F)c1F
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)C(O)C(CCOc1c(F)c(F)cc(F)c1F)NC(=O)OCc1ccccc1
Yield: 81 %

Procedure:
To a dry round bottom flask equipped with a magnetic stir bar was added composition 12 (189 mg, 0.38 mM, 1 equiv) and MeOH (20 mL). With constant stirring was added NaBH4 (8 mg, 0.228 mmol, 0.6 equiv). Upon addition gas bubbles were produced and the resulting clear colorless solution was stirred at 0° C. for 30 minutes. Solvent was removed in vacuo and the resulting solid was purified via column chromatography (silica gel, 2:1, hexanes/EtOAc) to give 13 as a sticky white solid. (165 mg, 0.34 mmol, 81% yield) ESMS: 488.2 (M+H+), 510.8 (M+Na+).
Reaction SMILES: [Al+3].[Cl-:2].[Cl-:3].[Cl-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][C:6]1=[CH2:7].[CH3:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1C(Cl)=CC=C(Cl)C=1>[CH2:7]=[C:6]([CH2:8][C:9](=[O:10])[C:15]1[CH:14]=[CH:13][C:18]([Cl:2])=[C:17]([Cl:3])[CH:16]=1)[C:5]([OH:11])=[O:12]
Reactant: CCCCCC
Reactant: C=C1CC(=O)OC1=O
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccc(Cl)cc1
Product: C=C(CC(=O)c1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Aluminium chloride anhydrous (53 g, 0.13 mol.) was added to a solution of itaconic anhydride (15 g, 0.13 mol.) in dichlorobenzene (100 mL) at room temperature. The reaction mixture was heated to 50° C. for 3 hours. and then inverse quenched with cold water/37% hydrochloric acid (100 mL/100 mL) maintaining the temperature below 30° C. After stirring the quenched reaction for 15 min., hexane (80 mL) was added and stirring continued for 0.5 hours. The product was filtered and dried in a vacuum oven to give the crude unsaturated-ketoacid as a colourless solid, 36 g, recrystallization from diethyl ether provided the pure acid (22 g, 67%) as colourless prisms melting at 156-57° C.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=34)=[N:8][CH:9]=2)[N:4]1[C@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.Cl[C:30]([O:32][CH3:33])=[O:31].CCN(C(C)C)C(C)C>CN(C=O)C>[C:21]([C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[CH:13][C:12]([C:7]3[N:6]=[C:5]4[C:10]([NH:11][C:3](=[O:2])[N:4]4[C@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:30]([O:32][CH3:33])=[O:31])[CH2:24]4)=[CH:9][N:8]=3)=[C:16]2[CH:17]=1)#[N:22]
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n([C@H]5CCCNC5)c4n3)c2c1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC[C@H](n2c(=O)[nH]c3cnc(-c4cnn5ccc(C#N)cc45)nc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a solution of example 6 (200 mg, 0.26 mmol) in DMF (2.6 mL), methyl chloroformate (27 mg, 0.28 mmol) and DIPEA (0.068 mL, 0.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure, dissolved in CH2Cl2, and washed thrice with saturated NaHCO3 aqueous solution. The combined organic phases were dried over MgSO4 and concentrated to dryness. The crude residue was chromatographed on a silica gel flash system (ISCO Combiflash) using CH2Cl2/MeOH mixtures of increasing polarity as eluent to afford 36 mg of the desired product (32% yield).