Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[Cl:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:53][O:54][C:55]1[CH:62]=[CH:61][C:58]([CH2:59]O)=[CH:57][CH:56]=1>C1COCC1>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH2:59][C:58]2[CH:61]=[CH:62][C:55]([O:54][CH3:53])=[CH:56][CH:57]=2)=[O:19])[C:3]=1[Cl:21]
Reactant: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)O)n2)c1F
Reactant: COc1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)c2nc(-c3ccc(Cl)c(OC)c3F)cc(N)c2Cl)cc1
Reaction time: 48 h
Yield: 20.8 %

Procedure:
To a solution of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid (600 mg, 1.81 mmol) in THF (10 mL) was added triphenylphosphine (475 mg, 1.81 mmol), diethyl azodicarboxylate (0.29 mL, 1.81 mmol), and 4-methoxybenzyl alcohol (0.34 mL, 2.72 mmol). The reaction mixture was stirred for 48 h. Additional triphenylphosphine (475 mg, 1.81 mmol) was added to the reaction, and the reaction mixture was stirred for 24 h. The reaction mixture was concentrated to dryness and was purified by silica gel chromatography (eluting with a 0-100% EtOAc/hexane gradient) to provide an off-white solid (170 mg, 26%): mp 73-83° C.; 1H NMR (400 MHz, CDCl3) δ 7.66 (dd, J=8.6, 7.8 Hz, 1H), 7.45-7.38 (m, 2H), 7.22 (dd, J=8.7, 1.8 Hz, 1H), 7.16 (d, J=1.7 Hz, 1H), 6.94-6.87 (m, 2H), 5.38 (s, 2H), 4.80 (s, 2H), 3.96 (d, J=0.8 Hz, 3H), 3.81 (s, 3H); ESIMS m/z 451 ([M+H]+), 449 ([M−H]−).
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11](Cl)[C:12]2[C:21]([N:22]=1)=[CH:20][C:19]([O:23][CH3:24])=[C:18]1[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]1)=[O:8].O>CN(C)C=O>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([O:3][CH2:2][CH3:1])[C:12]2[C:21]([N:22]=1)=[CH:20][C:19]([O:23][CH3:24])=[C:18]1[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]1)=[O:8]
Reactant: COC(=O)c1cc(Cl)c2c(cc(OC)c3ncccc32)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C(=O)OC)nc2cc(OC)c3ncccc3c12

Procedure:
2 g of sodium ethylate are added to a solution of 6.2 g of 1-chloro-6-methoxy-4,7-phenanthroline-3-carboxylic acid methyl ester in 100 ml of anhydrous N,N-dimethylformamide and the mixture is heated, whilst stirring and with the exclusion of water, for 10 hours at 100°. The solution is then evaporated to dryness in vacuo, the residue is divided between three times 200 ml of chloroform and 200 ml of water, the organic phases are dried over sodium sulphate and evaporated to dryness in vacuo. By fractionated crystallisation from ethanol, the 1-ethoxy-6-methoxy-4,7-phenanthroline-3-carboxylic acid methyl ester having a melting point of 188°-190° is obtained from the residue.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=O)[NH:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=2)=O)[CH2:7][CH2:6]1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCCC1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[S:33][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=3)=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)NCC(=O)c2cccc(Br)n2)CC1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](c2ncc(-c3cccc(Br)n3)s2)CC1

Procedure:
A solution of trans-4-[2-(6-bromopyridin-2-yl)-2-oxoethylcarbamoyl]cyclohexanecarboxylic acid methyl ester (7.38 g, 19.3 mmol) obtained in Step 2 and a Lawesson reagent (8.20 g, 20.3 mmol) in tetrahydrofuran (120 ml) was heated at reflux for 2 hours in an Ar stream. After the reaction solution was concentrated, a saturated aqueous sodium bicarbonate was added and extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and dried over magnesium sulfate, and after concentrated, the residue was purified by flash chromatography on silica gel (n-hexane:ethyl acetate=1:1) and the title compound (6.1 g) was obtained.
Reaction SMILES: [C:1]([CH:5]1[C:11](=[O:12])[CH2:10][C@H:9]2[N:13]([CH3:14])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].[BH4-].[Na+].[ClH:17]>CO.C(O)C>[ClH:17].[C:1]([CH:5]1[CH:11]([OH:12])[CH2:10][C@H:9]2[N:13]([CH3:14])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1C(=O)C[C@@H]2CC[C@H]1N2C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: COC(=O)C1C(O)C[C@@H]2CC[C@H]1N2C
Reaction time: 4 h

Procedure:
To a solution of the 2-carbomethoxy-3-tropanone obtained in example 4 (17 g, 85 mmol) in 750 ml methanol cooled to −35° C. was added sodium borohydride (17 g, 450 mmol) and the mixture was stirred for 4 hours. The cooled solution was quenched by slow addition of concentrated hydrochloric acid (40 ml) and the mixture was concentrated in vacuo. Water (400 ml) was added and the pH was adjusted to 3 by addition of concentrated hydrochloric acid. After having washed the water phase three times with diethyl ether pH was adjusted to 11 by addition of concentrated ammonium hydroxide and the water phase was extracted three times with methylene chloride. Concentration in vacuo yielded oil which was dissolved in ethanol and added concentrated hydrochloric acid followed by concentration in vacuo. Freeze drying of the residue yielded the title compound as an amorphous product.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:48])([CH2:46][CH3:47])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][N:40]=3)=[CH:35][CH:34]=2)[NH:31][CH3:32])[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1>CO>[CH3:2][C:3]([CH3:48])([CH2:46][CH3:47])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][N:40]=3)=[CH:35][CH:34]=2)[NH:31][CH3:32])[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(NC)c2ccc(-c3ccc(F)cn3)cc2)n1
Agent: Cl
Solvent: CO
Product: CCC(C)(C)Cc1c[nH]c(CC(NC)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in dioxane) (2.6 mL, 10.5 mmol) was added to a solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]-N-methylethanamine (1.3 g, 2.1 mmol) in methanol (20 mL). After stirring at 60° C. for 1 h, volatiles were removed. The residue was partitioned between 1 N hydrochloric acid and hexane/diethyl:ether (3:1). The aqueous phase was washed with hexane/diethyl ether (3:1), basified with saturated aqueous sodium carbonate and extracted with ethyl acetate. Combined extracts were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound. Purification by HPLC (Gilson; Chiralcel AD column; 50% isopropanol/heptane) afforded the pure enantiomers. (M+H) found 381.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Cl.[N-:11]=[N+:12]=[N-:13].[Na+].O.C1CCCCC1>CS(C)=O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][N:11]=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cccc(F)c1CCl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCCCC1
Product: [N-]=[N+]=NCc1c(F)cccc1F
Temperature: 22.5 °C
Reaction time: 4 h
Yield: 100.9 %

Procedure:
A solution of 0.200 g (1.23 mmol) of 2,6-difluorobenzyl chloride in 0.5 mL of DMSO was added dropwise to a mixture of 0.090 g (1.23 mmol) of NaN3 in 2 mL of DMSO at 20-25° C. The reaction was left stirring at 20-25° C. during 4 h. until showing completion by TLC. The crude was treated with 1.6 mL of water and 1.6 mL of cyclohexane and the organic phase was vacuum distilled to obtain 0.210 g (97%) of 2,6-difluorobenzyl azide as yellowish oil
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Mg].[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C:17](=[O:23])[CH2:16]2.[Cl-].[NH4+]>O1CCCC1.BrBr>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([C:17]2([OH:23])[CH:18]3[CH2:21][CH2:22][N:15]([CH2:20][CH2:19]3)[CH2:16]2)=[CH:3][CH:4]=1
Reactant: O=C1CN2CCC1CC2
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: BrBr
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(-c3ccccc3)cc2)CN2CCC1CC2
Yield: 17.2 %

Procedure:
A solution of 4-bromobiphenyl (11.8 g) in dry tetrahydrofuran (60 ml) and bromine (3 drops) were added to stirred magnesium turnings (1.18 g) and the mixture heated under reflux for 70 minutes. A solution of quinuclidin-3-one (3.65 g) in dry tetrahydrofuran (25 ml) was added dropwise to the mixture at 10° C. and the reaction mixture heated under reflux for 90 minutes. Aqueous ammonium chloride (14 g in 56 ml of water) was added dropwise to the mixture and the mixture extracted with diethyl ether. The ether extract was dried (Na2SO4) and evaporated to give a residue which was crystallised from ethyl acetate to give 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (1.4 g) as a colourless solid, m.p. 180°-182° C., microanalysis, found: C, 81.7; H, 7.5; N, 5.0%; C19H21NO requires: C, 81.8; H, 7.5; N, 5.0%. This material was identical to that in Example 1 except that it was a higher melting polymorphic form.
Reaction SMILES: [N+:1]1([O-:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3](N)[N:2]=1.S(=O)(=O)(O)[OH:14].N([O-])=O.[Na+].CCOCC>O>[N+:1]1([O-:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]([OH:14])[N:2]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1nc2ccccc2[n+]([O-])n1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: [O-][n+]1nc(O)nc2ccccc21
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 7.5 g (46 mmol) 1,2,4-benzotriazine-3-amine 1-oxide (Chem. Ber. 46, 3522 (1913) in 75 ml water and 27 ml conc. sulphuric acid one adds dropwise at room temp. a solution of 13.3 g sodium nitrite in 25 ml water. One leaves to stand overnight, filters, takes up in soda solution, washes with ether, acidifies the aqueous phase, filters and recrystallises from glacial acetic acid. One isolates 4.7 g of title compound (63% of theory) of the m.p. 238-239° C.
Reaction SMILES: [C:1]1([C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][C:9]([CH2:17][C:18]([OH:20])=[O:19])([CH2:10]4)[CH2:8]2)[CH2:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:22]12CC3CC(CC(CC(OC)=O)(C3)C1)C2.[Cl-].[Cl-].[Cl-].[Al+3]>C1C=CC=CC=1>[C:1]1([C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][C:9]([CH2:17][C:18]([O:20][CH3:22])=[O:19])([CH2:10]4)[CH2:8]2)[CH2:14]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC12CC3CC(C1)CC(c1ccccc1)(C3)C2
Reactant: COC(=O)CC12CC3CC(CC(Br)(C3)C1)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COC(=O)CC12CC3CC(C1)CC(c1ccccc1)(C3)C2

Procedure:
Preparation of 3-Phenyl-l-adamantaneacetic acid, a hapten. Methyl 3-bromoadamantaneacetate (80 g) (Aldrich Chemical Co. Milwaukee Wis.) was dissolved in benzene (1.6 L) under nitrogen. Aluminum trichloride (37.12 g) was added portionwise over 75 min. at ambient temperature. The reaction mixture was then quenched by the addition of 0.5M phosphoric acid (1.6 L). The layers were separated and the organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to give methyl 3-phenyl-1-adamantaneacetate (80 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:11]([CH:12]=[C:13]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][CH:21]=3)[C:14]=2[CH2:18][CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][C:35](=[O:38])[C:36]#[CH:37].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[C:35]([C:36]1[CH:37]=[C:12]2[N:11]3[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:10]=13)[C:14]([CH2:18][CH3:19])=[C:13]2[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:25]=1)(=[O:38])[CH3:34]
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cc(OCc3ccccc3)ccc12
Reactant: C#CC(C)=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(C)=O)c3c(OCc4ccccc4)ccc1n23
Yield: 38 %

Procedure:
6-Benzyloxy-2-(4-benzyloxyphenyl)-1-ehtylindolizine, prepared in example 23, step 5, (2.17 g, 5.0 mmol) was dissolved in 100 ml of dry toluene under a nitrogen atmosphere, and the mixture was stirred in an ice bath, while 3-butyn-2-one (0.34 ml, 5.75 mmol) was added dropwise. The cooling source was removed and stirring was continued for twenty hours. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (0.57 g, 0.25 mmol) was added in portions and stirring was continued for 11/2 hour. The solvent was evaporated and the crude product was purified by column chromatography over silica gel 60, using 20% of ethyl acetate in petroleum ether as the eluent. Fractions containing the product were colleted and the solvent was evaporated. The crude product was and crystallized from diethyl ether to afford 0.955 g (38%) of 4-acetyl-5-benzyloxy-2-(4-benzyloxyphenyl)-1-ethylpyrrolo[2,1,5-cd]indolizine as crystals. MS(SP): m/z 499 (M+). 1H-NMR (CDCl3, 400 MHz) δ: 1.44 (t, 3H); 2.79 (s, 3H); 3.15 (q, 2H); 5.15 (s, 2H); 5.44 (s, 2H); 7.15 (d, 2H); 7.32-7.46 (m, 7H); 7.50 (d, 2H); 7.60 (d, 2H); 7.67-7.74 (m, 3H); 7.94 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:37])[C:22]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=1)([OH:27])[C:23]([F:26])([F:25])[F:24])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[C:14]([F:17])([F:16])[F:15].Cl([O-])=[O:39].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:37])[C:22]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=1)([OH:27])[C:23]([F:26])([F:24])[F:25])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:39])=[O:11])=[CH:8][C:7]=1[C:14]([F:17])([F:15])[F:16]
Reactant: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C=O)cc3C(F)(F)F)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C(=O)O)cc3C(F)(F)F)cc2Cl)C(F)(F)F)cn(C)c1=O

Procedure:
In analogy to Example 214, step 2, 4-{3-chloro-4-[2-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-3-trifluoromethyl-benzaldehyde was oxidized with sodium chlorite to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=562.0 [M−H+].
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42](C(O)=O)([CH3:44])[CH3:43])=[CH:33][C:32]=2[CH3:49])=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=1)(=O)C.C(O[C:61]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)=[O:62])C1C=CC=CC=1.C(N1CCNCC1)C1C=CC=CC=1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:61]([N:63]4[CH2:64][CH2:65][NH:66][CH2:67][CH2:68]4)=[O:62])([CH3:43])[CH3:44])=[CH:33][C:32]=3[CH3:49])=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: c1ccc(CN2CCNCC2)cc1
Product: Cc1cc(CCCC(=O)NC(C)(C)C(=O)N2CCNCC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 99 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(benzyloxycarbonyl)piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-benzyl-piperazine, respectively.
Reaction SMILES: C(OC([N:8]([CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:9]1[CH:21]=[CH:20][C:12]([C:13](C2NC=CN=2)=[O:14])=[CH:11][CH:10]=1)=O)(C)(C)C.[OH-].[Na+].[NH2:39][CH2:40][CH:41]([OH:44])[CH2:42][OH:43]>C(Cl)(Cl)Cl>[CH2:22]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:39][CH2:40][CH:41]([OH:44])[CH2:42][OH:43])=[O:14])=[CH:20][CH:21]=1)[CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCC=CCCCN(C(=O)OC(C)(C)C)c1ccc(C(=O)c2ncc[nH]2)cc1
Reactant: NCC(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCC=CCCCNc1ccc(C(=O)NCC(O)CO)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of [N-(t-butyloxycarbonyl)-4-(4-pentadecenylamino)benzoyl]imidazole, 50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The mixture is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the resulting oil is crystallized from acetone to yield the product as light yellow crystals.
Reaction SMILES: [OH:1][N:2]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:23][C:24]1[CH:50]=[CH:49][CH:48]=[CH:47][C:25]=1[CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=2)[C:29]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])=[C:28]1[CH2:44][CH2:45][CH3:46].Cl.NO.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:23][C:24]1[CH:50]=[CH:49][CH:48]=[CH:47][C:25]=1[CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]([NH:2][OH:1])=[O:37])[CH:34]=2)[C:29]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])=[C:28]1[CH2:44][CH2:45][CH3:46]
Reactant: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)NO)cc2n1Cc1ccccc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
1-Hydroxybenzotriazole (68 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg) were added to a solution of 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carboxylic acid (100 mg) in dimethylformamide (3 ml), and the mixture was stirred at 20° C. overnight, then hydroxylamine hydrochloride (35 mg) and diisopropylethylamine (0.088 ml) were added. After stirred at 20° C. for 2 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with 1N hydrochloric acid and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography with 10% methanol in chloroform and recrystallization from ethyl acetate to give 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carbohydroxamic acid (67 mg) as pale red crystals.
Reaction SMILES: CS([CH2:5][CH2:6][CH:7]1[CH:13]=[CH:12][N:11]([C:14](=[O:36])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:35])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:17][CH:16]=2)[C:10]2[CH:37]=[CH:38][CH:39]=[CH:40][C:9]=2[S:8]1)(=O)=O.[C-:41]#[N:42].[Na+]>CN(C)C=O>[C:41]([CH2:5][CH2:6][CH:7]1[CH:13]=[CH:12][N:11]([C:14](=[O:36])[C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:35])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:20]=2)[C:10]2[CH:37]=[CH:38][CH:39]=[CH:40][C:9]=2[S:8]1)#[N:42]
Reactant: [C-]#N
Reactant: CS(=O)(=O)CCC1C=CN(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)c2ccccc2S1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCC1C=CN(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)c2ccccc2S1
Temperature: 70 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A mixture of Compound 16 as prepared in Example 11 (0.115 g, 0.197 mM) and sodium cyanide (20 mg) in dimethylformamide was stirred in a 70° C. oil bath for 4 hours. The reaction mixture was then cooled to RT and the DMF was removed under reduced pressure. The residual semi-solid was diluted with water (30 ml) and extracted with ethyl acetate (2×30 ml). The combined ethyl acetate extracts were dried (MgSO4) , filtered and evaporated in vacuo. The crude mixture was purified by chromatography to give pure product as a white solid (71 mg, 70%). m/z (MH+)518
Reaction SMILES: [CH:1]([C:4]1[CH2:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([CH3:3])[CH3:2].C([Li])CCC.[CH3:18][Si:19](Cl)([CH3:34])[CH:20]1[C:28]2[C:23](=[C:24]([CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][C:27]=2[CH3:29])[CH:22]=[C:21]1[CH3:33].[Cl-].[NH4+]>[Cu](C#N)C#N.CCCCCC.C(OCC)C>[CH3:18][Si:19]([CH3:34])([CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:4]1[CH:1]([CH3:3])[CH3:2])[CH:20]1[C:28]2[C:23](=[C:24]([CH:30]([CH3:31])[CH3:32])[CH:25]=[CH:26][C:27]=2[CH3:29])[CH:22]=[C:21]1[CH3:33]
Reactant: CC(C)C1=Cc2ccccc2C1
Reactant: CC1=Cc2c(C(C)C)ccc(C)c2C1[Si](C)(C)Cl
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=Cc2c(C(C)C)ccc(C)c2C1[Si](C)(C)C1C(C(C)C)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.7 %

Procedure:
In a 500-ml two-necked flask were charged 3.20 g (20.2 mmol) of 2-i-propylindene, 48.6 mg (0.54 mmol) of copper cyanide, and 100 ml of diethyl ether. To the mixture was added at -78° C. 14.0 ml of 1.62 M hexane solution of n-butyllithium (22.7 mmol) and the mixture was stirred at room temperature for 4 hours. Subsequently, 6.57 g (23.6 mmol) of dimethyl(2,7-dimethyl-4-isopropylindenyl)silyl chloride was added at -78° C. and the mixture was stirred at room temperature for 12 hours. After addition of aqueous ammonium chloride solution to the reaction mixture, the organic layer was washed with saturated saline and dried over sodium sulfate. The sodium sulfate was removed by filtration and the organic solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel, development solvent: n-hexane:methylene chloride=9:1) to obtain 6.85 g (17.1 mmol, yield: 84.7%) of a pale yellow oil as the target. The product was confirmed to be a mixture of isomers by 1H-NMR.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5]([NH2:6])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:12]([C:4]1[CH:3]=[C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5]=1[NH2:6])([CH3:14])[CH3:13]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cc(-c2ccccc2)cc(C(C)C)c1N
Yield: 56.8 %

Procedure:
4-bromo-2,6-diisopropylaniline (16 g, 62.5 mmol), (PPh3)4Pd (2.2 g, 1.9 mmol), phenylboronic acid (11 g, 87.5 mmol), K3PO4 (26 g, 187 mmol), 400 mL of toluene and 40 mL of water were charged and heated up to reflux for overnight. The reaction mixture was purified by column and distillation method to give 9 g liquid (57% yield).