Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7](Cl)(=[O:9])=[O:8].[C:11]([O:15][C:16](=[O:35])[NH:17][C@H:18]([C:23](=[O:34])[NH:24][C@H:25]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[NH:28][CH2:27][C@@H:26]1[OH:33])[CH2:19][CH:20]([CH3:22])[CH3:21])([CH3:14])([CH3:13])[CH3:12].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.CCOC(C)=O>[C:11]([O:15][C:16](=[O:35])[NH:17][C@H:18]([C:23](=[O:34])[NH:24][C@H:25]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[NH:28][CH:27]([S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:9])=[O:8])[C@H:26]1[OH:33])[CH2:19][CH:20]([CH3:22])[CH3:21])([CH3:13])([CH3:14])[CH3:12]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)NC[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)NC(S(=O)(=O)c2ccccn2)[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
Pyridine-2-sulfonyl chloride (0.71 g, 0.4 mmol) was added to a solution of [(S)-1-((3S,4S,7R)-3-Hydroxy-7-methyl-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert-butyl ester (0.126 g, 0.344 mmol), sodium bicarbonate (0.87 g, 1.03 mmol) in CH2Cl2 (3 ml) and H2O (2 ml) and was stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc (100 ml), washed with H2O, brine, dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 3% MeOH/CH2Cl2) to yield the title compound (0.180 g, 70%): 1H NMR: 8.68 (m, 1H), 8.05 (1H, d), 7.92 (1H, dd), 7.50 (1H, dd), 6.66 (1H, bd), 4.95–4.88 (dd), 4.20–3.87 (m, 3H), 3.65 (1H, bs), 3.40 (1H, d), 1.94–1.57 (m, 4H), 1.45–1.38 (m, 6H), 1.14 (3H, dd), 0.94 (6H, dd); Electrospray mass spec: M+H+=499.0.
Reaction SMILES: O[C:2](C)(C)CC(O)=O.C([C:12]([CH2:19][C:20]([O-])=O)([OH:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)C.[OH-].[Na+].O>CO.C1C=CC=CC=1.[Pt].[OH-].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:18][C@H:12]1[CH2:19][CH2:20][C:16]([CH3:2])([CH3:17])[O:15][C:13]1=[O:14]
Reactant: CCOC(=O)C(O)(CC(=O)[O-])C(C)=O
Reactant: CC(C)(O)CC(=O)O
Agent: [Pt]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CO
Product: CC1(C)CC[C@H](O)C(=O)O1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
In absolute methanol were dissolved 5.2 g of β-hydroxyisovaleric acid and 15.2 g of monoethyl acetylmalate, and 0.14 g of sodium hydroxide was added to the solution. The mixture was subjected to Kolbe electrolysis by applying a voltage of ±20 V for 5 hr through the use of a platinum electrode. After the reaction, 8 g of sodium hydroxide was added to the reaction mixture, and 200 ml of a mixed solution comprising water and methanol (1:1) was added thereto. The mixture was allowed to stand overnight for hydrolysis. A major portion of methanol contained in the solution was removed by distillation, and a neutral component contained in the solution was extracted with diethyl ether, and hydrochloric acid was added to the remaining aqueous alkaline solution to adjust the pH to 1. Thereafter, sodium chloride was added thereto until a saturated solution was prepared, and the reaction product was extracted with chloroform. The resultant chloroform solution was washed with water and dried over magnesium sulfate, and the chloroform was removed by distillation under a reduced pressure. Then 8.3 g of the crude product thus obtained was dissolved in 150 ml of benzene, 0.1 g of p-toluenesulfonic acid was added thereto, and the mixture was refluxed for 5 hr. The refluxed solution was cooled to room temperature and extracted with an ether, and the extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water, and the solvent was removed from the extract by distillation under a reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography to obtain 5.2 g of (S)-2-hydroxy-5,5-dimethyl-δ-valerolactone.
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]([NH:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=2)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[N:28]3[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]3=[N:26][N:25]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)NNc2ccc(F)cn2)CC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2nnc3ccc(F)cn23)CC1
Reaction time: 4 h

Procedure:
Hexachloroethane (893 mg, 3.77 mmol) was added portionwise to a solution of Intermediate 7a (667 mg, 1.89 mmol), triphenylphosphine (990 mg, 3.77 mmol) and triethylamine (1.05 mL, 7.55 mmol) in dry THF (20 mL) at RT and stirred for 4 h. The resulting precipitate was filtered off and the filtrate evaporated. The residue was purified by SCX-2, eluting with MeOH followed by 2M NH3 in MeOH, to give an off-white solid. This was triturated (diethyl ether) to give the title compound as a colourless solid LCMS (Method 1): Rt 2.33 min, m/z 336 [MH+].
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH:12][C:13]([N:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([CH3:21])[CH2:16]3)=[O:14])[CH2:3]1)[CH2:9]2.[C:22](Cl)(=[O:24])[CH3:23].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:21][C@H:17]1[CH2:18][CH2:19][CH2:20][N:15]([C:13]([NH:12][CH:5]2[CH:4]3[CH2:3][C:2]4([O:1][C:22](=[O:24])[CH3:23])[CH2:9][CH:8]([CH2:7][CH:6]2[CH2:11]4)[CH2:10]3)=[O:14])[CH2:16]1
Reactant: C[C@H]1CCCN(C(=O)NC2C3CC4CC2CC(O)(C4)C3)C1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC12CC3CC(C1)C(NC(=O)N1CCC[C@H](C)C1)C(C3)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-3-Methyl-piperidine-1-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide 0.15 g (0.51 mmol), 0.109 ml of acetyl chloride, 0.3 ml of pyridine in 1.5 ml of methylene chloride was stirred at room temperature overnight. A saturated NaHCO3 solution was added, the organic phase extracted with methylene chloride, washed with HCl 1 N solution and dried over sodium sulphate. Flash chromatography on silica gel (eluant CH2Cl2/MeOH: 95/05) yielded 75 mg of the title compound
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH3:21][C@@H:22]1[CH2:27][C:26](=O)[CH2:25][C@H:24]([CH3:29])[O:23]1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:26]3[CH2:25][C@H:24]([CH3:29])[O:23][C@H:22]([CH3:21])[CH2:27]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: C[C@@H]1CC(=O)C[C@H](C)O1
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: C[C@@H]1CC(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)C[C@H](C)O1

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and (2R,6S)-2,6-dimethyl-tetrahydro-pyran-4-one using decaborane yielded the title compound as a white solid. MS (ESI): m/z=391.1 [M+H]+.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=[O:17])[CH:12]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)[CH3:20]>N1C=CC=CC=1>[CH2:1]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([O:18][C:25]3[CH:26]=[CH:27][C:22]([O:21][CH2:19][CH3:20])=[CH:23][CH:24]=3)=[O:17])[CH:12]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CCc2cc(C(=O)O)ccc2C1
Reactant: CCOc1ccc(O)cc1
Solvent: c1ccncc1
Product: CCCCCC1CCc2cc(C(=O)Oc3ccc(OCC)cc3)ccc2C1
Yield: 97.3 %

Procedure:
Analogously to Example 1, 6.16 g of 2-pentyl-1,2,3,4-tetrahydronaphthalene-6-carboxylic acid are converted into the acid chloride and this is reacted with 3.45 g of p-ethoxyphenol in 15 ml of absolute pyridine. There are obtained 8.9 g of crude p-ethoxyphenyl 2-pentyl-1,2,3,4-tetrahydro-6-naphthoate which, for purification, is chromatographed on 230 g of silica gel. Elution with toluene/hexane (1:1) and toluene/hexane (7:3) yields 8.8 g of substance which are recrystallized from acetone/hexane up to constant melting point and clearing point and dried in a high vacuum (0.01 mbar). There are obtained colorless crystals of p-ethoxy-phenyl 2-pentyl-1,2,3,4-tetrahydro-6-naphthalene; m.p. 95.4°-96.2° C., cl.p. 119.0°-119.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)[CH:10]([OH:12])[CH3:11])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[CH3:33][N:34](C)C=O.O>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:33]#[N:34])[CH:14]=2)[CH:10]([OH:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(O)C(Cc1ccc(Cl)cc1)c1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: CCCCP(CCCC)CCCC
Solvent: O
Product: CC(O)C(Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Temperature: 115 °C

Procedure:
To a solution of 4-(4-chlorophenyl)-3-(3-bromophenyl)-2-butanol (1.5 kg, 4.6 mol) in dimethylformamide/water (volume ratio 99:1, 15 L total) was added zinc cyanide (0.39 kg, 3.3 mol), 1,1′-bis(diphenylphosphino)ferrocene (115 g, 0.21 mol) and tris(dibenzylideneacetone)dipalladium (76 g, 0.08 mol). The reaction mixture was stirred and degassed at room temperature for 1 h, and heated at 115° C. for 6 h before cooling to room temperature. Tributylphosphine (46 mL, 0.17 mol) was then added. After stirring for 1 h, the reaction was quenched with aqueous ammonia (1.56 L). After stirring for 1 h, the mixture was filtered through solka floc, and the cake was washed with isopropyl acetate. The filtrate was washed with water (5 L), and the aqueous layer was extracted with isopropyl acetate (4 L). The organic layers were combined, washed with water (10 L×2) and concentrated to give the title compound, which was used for the ensuing reaction after azeotroping with toluene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[C:12]([O:16][C:17](=[O:28])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:12]([O:16][C:17](=[O:28])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)=[CH:23][CH:22]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2-Bromo-5-(trifluoromethyl) pyridine (3000 mg, 13.274 mmol), [2-(4-hydroxy-phenyl)ethyl]-carbamic acid tert-butyl ester (3150 mg, 13.274 mmol) and potassium carbonate anhydrous (2752 mg, 19.911 mmol) were dissolved in DMF (150 ml) and reaction was stirred at 60° C. overnight. The reaction mixture was washed with EtOAc and water (3×). Organic layers were combined and dried over phase separator filter tube affording the crude product which was purified on Biotage SP-1 system using 50 g Si SNAP column. The column containing sample was eluted with EtOAc/CyHex gradient (0-30% of EtOAc/30 CV). Fractions with desired product were gathered and solvent was evaporated to give the required product {2-[4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester as a white solid (2200 mg, yield=42.9%, purity 99%). [M+H]+=383.39
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:29])=[C:7]([C:21]([NH:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26])=[O:22])[C:8]([I:20])=[C:9]([C:18]=1[I:19])[C:10]([NH:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[O:11])(=[O:3])[CH3:2].[OH-].[Na+].[OH:32][CH:33]([CH2:36][O:37][CH3:38])[CH2:34]Cl>C(O)C(O)C.CO>[OH:26][CH2:25][CH:24]([NH:23][C:21](=[O:22])[C:7]1[C:6]([I:29])=[C:5]([N:4]([CH2:34][CH:33]([OH:32])[CH2:36][O:37][CH3:38])[C:1](=[O:3])[CH3:2])[C:18]([I:19])=[C:9]([C:10]([NH:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[O:11])[C:8]=1[I:20])[CH2:27][OH:28]
Reactant: COCC(O)CCl
Reactant: CC(=O)Nc1c(I)c(C(=O)NC(CO)CO)c(I)c(C(=O)NC(CO)CO)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(O)CO
Product: COCC(O)CN(C(C)=O)c1c(I)c(C(=O)NC(CO)CO)c(I)c(C(=O)NC(CO)CO)c1I
Reaction time: 44 h

Procedure:
5-Acetamido-N,N'-bis(1,3-dihydroxy-2-propyl)-2,4,6-triiodoisophthalamide (1036 g, 1.39 mol) was slurried in a mixture of propylene glycol (4170 ml) and methanol (4170 ml). After adding 18.25 M sodium hydroxide (114 ml, 2.08 mol), the mixture was heated at about 50°. When all or nearly all of the starting material was dissolved, the excess of methanol was evaporated in vacuo. Thereafter 2-hydroxy-3-methoxypropyl chloride (259 g, 2.08 mol) was added. The reaction mixture was heated at 50° for 44 hours and then stored at room temperature for 44 hours. Ater neutralization with concentrated hydrochloric acid, the reaction mixture was evaporated in vacuo. The residue was dissolved in methanol (3500 ml) and treated with a mixture of Dowex anion exchange resin 1×4 (2.87 kg) and Amberlite cation exchange resin (1.2 kg). The ion exchange resin was filtered off and washed with 80% aqueous methanol. The filtrate was evaporated in vacuo to dryness and the residue dissolved in isopropyl alcohol (5 1) at 80°. The product was precipitated by cooling to 13.5° and collected on a filter. Further purification was performed by recrystallization from isopropyl alcohol (4 1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([C:11]([OH:13])=[O:12])=[C:4]([CH3:14])[C:3]=1[OH:15].Br[CH2:17][CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([C:11]([OH:13])=[O:12])=[C:4]([CH3:14])[C:3]=1[O:15][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: Cc1c(C(=O)O)cc(C(=O)O)c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1c(C)c(C(=O)O)cc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.4 %

Procedure:
2.400 g (11.42 mmol) of dimethyl 5-hydroxyisophthalic acid, 1.4 g (11.6 mmol) of 3-bromopropene and 1.6 g (11.6 mmol) of potassium carbonate were dispersed in 40 ml of acetone and stirred for 15 hours at reflux temperature. The mixture was cooled to room temperature and filtered off insoluble salts after the addition of 150 ml of diethylether. The filtrate was concentrated and purified through the silicagelcolumn chromatography (developing solvent: diethylether/hexane=½), 2.612 g of dimethyl 5-allyloxyisophthalic acid in water-white solid powder was obtained (yield: 94.1%).
Reaction SMILES: Br[C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].C([Li])(C)(C)C.CN(C)[CH:22]=[O:23]>O1CCCC1>[CH:22]([C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)=[O:23]
Reactant: CN(C)C=O
Reactant: Oc1ncc(C(F)(F)F)cc1Br
Agent: [H-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cc(C(F)(F)F)cnc1O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Under nitrogen, the compound from Step A above (48.8 g, 202 mmol) was added in small portions to a suspension of sodium hydride (8.9 g, 220 mmol) in anhydrous tetrahydrofuran (500 mL). After complete addition of the intermediate, the reaction mixture was cooled to −78° C. and treated with tert-butyllithium (260 mL, 444 mmol) added dropwise via syringe. After stirring for 5 min, N,N-dimethylformamide (50 mL, 707 mmol) was added slowly, maintaining the temperature below −50° C. The resultant mixture was allowed to slowly warm to room temperature over 10 h. The mixture was quenched with 2N hydrochloric acid and then diluted with ethyl acetate (1000 mL). The organic layer was separated, washed with saturated brine, dried over magnesium sulfate and evaporated in vacuo. The desired product was precipitated out of a mixture of ethyl acetate and hexanes and filtered to yield a light brown solid.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:2]1>C(O)(=O)C.[Pd]>[O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[CH:3]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:2]1
Reactant: O=c1c(-c2ccccc2)coc2ccccc12
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1c2ccccc2OCC1c1ccccc1

Procedure:
Isoflavone (3.00 g) was dissolved in acetic acid (100 ml), and the solution hydrogenated at 50°-60° and 10.4-13.8 atm using 10% w/v palladium or carbon catalyst. The solution was filtered and evaporated, and the residue chromatographed on alumina, eluting with toluene. The product thus obtained gave, on recrystallisation from petroleum ether, (60°-80°) isoflavanone, 0.90 g., m.pt 73°-76°.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3ccccc3OC)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)O)c2)c1

Procedure:
This compound is prepared by hydrolysis of 9c using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[CH3:28])[NH2:24]>CN(C=O)C.C(O)(C)C>[ClH:2].[OH:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[CH3:28])[NH:24][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(N)cc1O
Reactant: COCCOc1cc2nccc(Cl)c2cc1OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: COCCOc1cc2nccc(Nc3ccc(C)c(O)c3)c2cc1OC
Temperature: 150 °C
Yield: 52.4 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (250 mg, 0.82 mmol) and 3-hydroxy-4-methylaniline (123 mg, 1 mmol) in DMF (5 ml) was heated at 150° C. for 30 minutes. The mixture was diluted with isopropanol and the resulting solid collected by filtration and washed with isopropanol to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (168 mg, 58%).
Reaction SMILES: CC(C)([O-])C.[K+].[K].[CH3:8][C@@:9]12[C:25](=[O:26])[CH2:24][CH2:23][C@H:22]1[C@H:21]1[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:27])=[CH:17][C:18]=3[CH2:19][CH2:20]1)[CH2:11][CH2:10]2.[N:28](OCCC(C)C)=[O:29]>C(O)(C)(C)C.O>[CH3:8][C@@:9]12[C:25](=[O:26])/[C:24](=[N:28]/[OH:29])/[CH2:23][C@H:22]1[C@@H:21]1[CH2:20][CH2:19][C:18]3[CH:17]=[C:16]([OH:27])[CH:15]=[CH:14][C:13]=3[C@H:12]1[CH2:11][CH2:10]2
Reactant: CC(C)CCON=O
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C/C(=N\O)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of potassium tert-butoxide under an atmosphere of N2, freshly prepared by dissolving potassium metal (80 mg, 2.05 mmol) in 2 mL tert-butanol, oestrone (200 mg, 740 mmol) was added. The reaction mixture was then stirred for 1 hour at room temperature under N2 and isoamyl nitrite (180 μmol, 1.34 mmol) was added dropwise. The deep red mixture obtained was stirred overnight and then poured into water (20 mL). The resulting solution was extracted with ether (2×20 mL) and the aqueous layer was acidified with glacial acetic acid (10 mL) to give a light yellow precipitate. This was left separating for two hours after which the solid was filtered (140 mg, 63%): mp 223-225° C. (lit. 226-227° C.);43 TLC (chloroform/acetone, 9:1) Rf 0.27 cf. Rf 0.69 (E1); IR (KBr) 3385 (NOH), 2920-2860 (aliph CH), 1735 (C═O), 1605-1500 (arom C═C) cm−1; δH (DMSO-d6, 400 MHz) 0.89 (3H, s, C-18-H3), 1.30-2.85 (11H, m), 2.70-2.81 (2H, m, C-6-H2), 6.46 (1H, d, JC-2-H,C-4-H=2.3 Hz, C-4-H), 6.52 (1H, dd, JC-1-H,C-2-H=8.4 Hz and JC-4-H,C-2-H=2.3 Hz, C-2-H), 7.05 (1H, d, JC-2-H,C-1-H=8.2 Hz, C-1-H), 9.05 (1H, s, exchanged with D2O, OH) and 12.39 (1H, s, exchanged with D2O, NOH); δC (DMSO-d6, 100.4 MHz) 14.09 (q, C-18), 25.09 (t), 25.46 (t), 26.18 (t), 29.02 (t), 30.92 (t), 37.20 (d), 43.20 (d), 44.59 (d), 48.50 (s, C-13), 112.70 (d), 114.83 (d), 125.82 (d), 129.59 (s), 136.88 (s), 154.84 (s, C-3 or C-16), 155.23 (s, C-3 or C-16) and 204.64 (s, C═O); MS m/z (FAB+) 453.2 [30, (M+H+NBA)+], 300.1 [100, (M+H)+]; MS m/z (FAB−) 451.3 [38, (M−H+NBA)−], 298.2 [100, (M−H)−]; Acc MS m/z (FAB+) 300.15963, C18H22NO3 requires 300.15997. CHN,
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13]I)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrCCBr.Cl[Si](C)(C)C.[C:28](Cl)(=[O:30])[CH3:29]>C1C=CC=CC=1.CN(C)C(=O)C.[Cu].[Zn].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][C:28](=[O:30])[CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CI)NC(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]
Agent: C[Si](C)(C)Cl
Solvent: c1ccccc1
Solvent: BrCCBr
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H](CC(C)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of methyl N-((benzyloxy)carbonyl)-3-iodo-L-alaninate (10 g, 27.5 mmol), from Step 1, zinc-copper couple (3.3 g) in benzene (110 mL) and N,N-dimethylacetamide (7.4 mL) was sonicated in an ultra-sound bath for 2 hours. Over this period, 3 portions of 1,2-dibromoethane (0.24 mL) and chlorotrimethylsilane (0.17 mL) were added. To this mixture was then added bis(triphenylphosphine)palladium chloride (0.958 g, 1.4 mmol) and acetyl chloride (2.5 mL, 35.2 mmol) and the mixture was heated at 70° C. for 2 hours. After cooling to room temperature, the mixture was filtered on celite with ethyl acetate, the organic layer was then washed with a saturated solution of ammonium chloride, brine (2×), dried over magnesium sulfate, filtered and the solvent evaporated under vacuum. The residue was purified by silica gel chromatography using ethyl acetate and hexanes to afford methyl N-((benzyloxy)carbonyl)-4-oxo-L-norvalinate.