Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[N:6][CH:7]=1.[CH2:29](I)[CH3:30].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.O>[CH2:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH2:14]2)=[N:6][CH:7]=1)[CH3:30]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(O)cn3)c2)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOc1ccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a stirred solution of tert-butyl 4-(3-(5-hydroxypyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.6 g, 1.56 mmol) in acetone (5 mL) was added ethyl iodide (0.304 g, 1.96 mmol), K2CO3 (0.431 g, 3.12 mmol) and 18-crown-6 (0.824 g, 3.12 mmol) at 0° C. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate three times. The organic layer was washed with fresh water and brine solution, dried over Na2SO4 and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (1:19 acetone:hexanes) to give the title compound (610 mg, 95%). 1H NMR (500 MHz, CDCl3): δ 7.86 (d, J=2.5 Hz, 1H), 7.27 (m, 2H), 6.96 (d, J=7.5 Hz, 1H), 6.90 (m, 2H), 6.85 (d, J=9 Hz, 1H), 6.32 (s, 1H), 4.02 (q, 2H, J=6.8), 3.49 (s, 2H), 3.38 (s, 2H), 2.45 (s, 2H), 2.30 (s, 2H), 1.47 (s 9H) 1.40 (t, J=6.92 Hz, 3H); m/z (411.51, M+ H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[C:10](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:10])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a suspension of 4-bromo-3-fluorophenol (2.87 g) and cesium carbonate (12.2 g) in N,N-dimethylformamide (30 mL) was added methyliodide (1.87 mL) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 1-bromo-2-fluoro-4-methoxybenzene (3.02 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([C:21]2[CH:26]=[N:25][CH:24]=[C:23](Cl)[N:22]=2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[CH2:30].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[C:21]2[N:22]=[C:23](/[CH:30]=[CH:29]/[C:28]([O:32][CH2:33][CH3:34])=[O:31])[CH:24]=[N:25][CH:26]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(c1cncc(Cl)n1)[C@@H]1CCN(Cc2ccccc2)C1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)/C=C/c1cncc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccccc3)C2)n1
Temperature: 150 °C
Reaction time: 72 h

Procedure:
To a stirred solution of tert-butyl [(3R)-1-benzyl-3-pyrrolidinyl](6-chloro-2-pyrazinyl)carbamate (910 mg) in DMF (15 mL) was added ethyl acrylate (1.27 mL), palladium(II) acetate (26 mg), tris(2-methylphenyl)phosphine (107 mg), and N,N-diisopropylethylamine (1.22 mL). The mixture was stirred in the sealed tube at 150° C. for 3 days. The resulting mixture was allowed to cool to ambient temperature, poured into water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (96:4 v/v) to give ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino}-2-pyrazinyl)acrylate (755 mg) as a pale yellow foam.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C.FC(F)(F)C(O)=O.[F:41][C:42]([F:70])([F:69])[CH2:43][N:44]1[C:48]([C:49]2[N:58]=[C:57]3[N:51]([CH2:52][CH2:53][O:54][C:55]4[CH:62]=[C:61]([NH:63][CH:64]([CH3:68])[C:65]([OH:67])=O)[CH:60]=[CH:59][C:56]=43)[CH:50]=2)=[N:47][CH:46]=[N:45]1>CN(C=O)C>[F:41][C:42]([F:69])([F:70])[CH2:43][N:44]1[C:48]([C:49]2[N:58]=[C:57]3[C:56]4[CH:59]=[CH:60][C:61]([NH:63][C@@H:64]([CH3:68])[C:65]([NH2:2])=[O:67])=[CH:62][C:55]=4[O:54][CH2:53][CH2:52][N:51]3[CH:50]=2)=[N:47][CH:46]=[N:45]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(Nc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Nc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(N)=O
Reaction time: 18 h
Yield: 29.5 %

Procedure:
HATU (179 mg, 0.47 mmol), ammonium chloride (50 mg, 0.942 mmol) and triethylamine (0.22 mL, 1.57 mmol) were added to a solution of (S)-2-{2-[2-(2,2,2-trifluoro-ethyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino}-propionic acid trifluoroacetate salt (168 mg, 0.314 mmol) in DMF (3 mL) and stirred for 18 hours. The reaction mixture was concentrated in vacuo and the residue treated with ethyl acetate and water, the organics layer separated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM), then trituration in water to give 529 (39 mg, 30%). LCMS: RT=3.23 min, [M+H]+=422. 1H NMR 400 MHz (DMSO-d6): δ 8.05 (1 H, s), 7.91 (1 H, s), 7.40 (1 H, br, s), 7.01 (1 H, br, s), 6.46 (1 H, dd, J=8.86, 2.33 Hz), 6.25 (1 H, d, J=7.11 Hz), 6.13 (1 H, d, J=2.29 Hz), 5.92 (2 H, q, J=8.89 Hz), 4.46-4.39 (4 H, m), 3.81 (1 H, t, J=6.96 Hz), 1.32 (3 H, d, J=6.87 Hz)
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:10][C:11]([C@@H:13]1[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([N:44]2[CH2:48][CH2:47][C@@H:46]([NH2:49])[CH2:45]2)=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:14]1)=[O:12])[CH3:9].[CH3:50][O:51][C:52]1[C:53](=O)[C:54](=[O:58])[C:55]=1[O:56]C>CCO.CN(C1C=CN=CC=1)C>[CH2:8]([NH:10][C:11]([C@@H:13]1[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([N:44]2[CH2:48][CH2:47][C@@H:46]([NH:49][C:53]4[C:54](=[O:58])[C:55](=[O:56])[C:52]=4[O:51][CH3:50])[CH2:45]2)=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:14]1)=[O:12])[CH3:9]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: COc1c(OC)c(=O)c1=O
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](Nc5c(OC)c(=O)c5=O)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A mixture comprising (2S,3S,4R,5R)-5-[2-((R)-3-Amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid ethylamide trifluoroacetate (Intermediate E) and 3,4-dimethoxy-3-cyclobutene-1,2-dione in absolute EtOH and cat.DMAP is heated using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 120° C. for 1 hour. The solvent is removed in vacuo and the resulting crude product partitioned between ethyl acetate and water. The organic portion is separated, dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography on silica gel eluting with EtOAc/iso-hexane (30-100% EtOAc) affords the titled compound.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3]>C(Cl)Cl>[CH3:8][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:9][CH2:10][OH:11]
Reactant: CC(C)=CCC/C(C)=C/CO
Solvent: ClCCl
Product: CC(C)CCCC(C)CCO
Reaction time: 24 h
Yield: 102.4 %

Procedure:
According to the general procedure, a solution of geraniol (52 μL, 0.29 mmol) and rac-32 (9.0 mg, 0.0057 mmol, 2.0 mol %) in CH2Cl2 (3 mL) was pressurized with H2 to 62 bar and stirred for 24 h. Filtration of the reaction mixture and evaporation of the solvent gave 44 as a clear liquid (47 mg, 98%). 1H NMR30 (300 MHz, CDCl3): δ 3.68 (m, 2H), 1.61-1.17 (m, 10H), 0.90 (s, 9H); 13C NMR (75.5 MHz, CDCl3): δ 61.4, 30.1, 39.4, 37.5, 29.7, 28.1, 24.8, 22.8, 22.7, 19.8.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.C1C=CC2OC(=O)CCC=2C=1.O1C2C(=CC=CC=2)C=CC1=O.[Cl:35][S:36](O)(=[O:38])=[O:37].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl.CCCCCC>[CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:36]([Cl:35])(=[O:38])=[O:37])[CH:8]=2)[O:3]1
Reactant: CC1(C)C=Cc2ccccc2O1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C1CCc2ccccc2O1
Agent: O=c1ccc2ccccc2o1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC1(C)CCc2cc(S(=O)(=O)Cl)ccc2O1
Temperature: 5 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A solution of 2,2-dimethylchroman [obtained by an analogous procedure to that described in Chem. Ber., 1904, 37, 494, for the preparation of 2,2-dimethyl-2H-chromene, but using dihydrocoumarin as starting material in place of coumarin] (50 g, 308 mM) in dichloromethane (250 ml) was added dropwise to a solution of chlorosulphonic acid (40 ml, 602 mM) and phosphorus pentachloride (50 g, 204 mM) in dichloromethane (250 ml), cooled to 5° C. under an atmosphere of argon. The colour of the solution changed from pale yellow to orange. When the addition was complete, the mixture was slowly allowed to attain ambient temperature and stirred for 2 hours. The reaction mixture was poured onto ice-water and the organic phase was separated. The aqueous layer was extracted with dichloromethane (3×20 ml), and the combined organic extracts were washed with water and dried (MgSO4). The solvent was removed by evaporation to give 2,2-dimethylchroman-6-sulphonyl chloride as a pale purple solid (42.6 g, 53% yield), m.p. 89°-92° C. (after recrystallisation from hexane).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10].[CH3:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)=[O:17]>CC(C)=O>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])=[CH:20][CH:19]=1)(=[O:17])[CH3:15]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCC(=O)OC(C)C)cc1

Procedure:
Potassium carbonate (17.0g.) was added to a solution of isopropyl bromoacetate (24.0g.) and 4-hydroxyacetophenone (17.7g.) in acetone (200ml.). The mixture was heated under reflux for 24 hours, cooled and filtered. The filtrate was evaporated to an oil which was dissolved in ether (150ml.). The solution was washed with sodium bicarbonate solution (2 × 30ml.), water (2 × 30ml.), dried and evaporated. The residual oil was distilled to give isopropyl 4-acetylphenoxyacetate, I.R. peaks at 1750 and 1670 cm-1.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([Cl:35])=[O:34])=[CH:31][CH:30]=1.Cl>O1CCCC1>[ClH:35].[NH2:8][CH:9]([C:33]([C:32]1[CH:36]=[CH:37][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1)=[O:34])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(N)C(=O)c1ccc(OC)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 108 %

Procedure:
5 g (18.6 mmol) of ethyl N-(diphenylmethylene)glycinate in solution in 20 ml of tetrahydrofuran are added to a solution of 18.7 ml (18.6 mmol) of 1N potassium tert-butoxide in 20 ml of tetrahydrofuran cooled to −70° C. After stirring for 30 minutes, this mixture is added to a solution containing 3.2 g (18.6 mmol) of 4-methoxybenzoyl chloride in 20 ml of tetrahydrofuran at −70° C. One hour after the addition, the reaction medium is hydrolysed with a 1N aqueous solution of hydrochloric acid and concentrated. The residue is taken up in water and extracted with diethyl ether. The organic phase is dried over magnesium sulphate and the solvent is then evaporated off. 5.5 g of ethyl 2-amino-3-(4-methoxyphenyl)-3-oxopropanoate hydrochloride are obtained with a quantitative yield.
Reaction SMILES: COC(C1(CN)CC1)=O.[CH3:10][O:11][C:12](=[O:23])[C:13]([CH3:22])([CH3:21])[CH2:14][NH:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH3:10][O:11][C:12]([C:13]1([CH2:14][NH:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:21][CH2:22]1)=[O:23]
Reactant: COC(=O)C(C)(C)CNC1CCCC1
Agent: COC(=O)C1(CN)CC1
Product: COC(=O)C1(CNC2CCCC2)CC1

Procedure:
Cyclopentylaminomethyl-cyclopropanecarboxylic acid methyl ester was prepared from 1-aminomethyl-cyclopropanecarboxylic acid methyl ester following the method similar to the preparation of 3-cyclopentylamino-2,2-dimethyl-propanoic acid methyl ester above.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]([O:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26])(=[O:22])[CH3:21]>>[C:20]([O:23][C:24]([CH3:29])([CH3:28])[C:25]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:26])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Product: CC(=O)OC(C)(C)C(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and 2-acetoxyisobutyryl chloride. m.p.: 162-165° C. 1H-NMR (CDCl3) δ: 10.78 (1H, br s), 8.36 (1H, d, J=9.2 Hz), 8.28 (1H, br s), 7.85-7.76 (2H, m), 7.68-7.53 (3H, m), 7.26 (1H, d, J=1.8 Hz), 7.08 (1H, dd, J=1.8, 9.2 Hz), 2.21 (3H, s), 1.75 (6H, s)
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1.[C:13]([N:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>BrC(Br)C.O1CCCC1>[Cl:12][C:7]1[CH:6]=[C:5]([C:22]2([OH:25])[CH2:23][CH2:24][N:20]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:21]2)[CH:10]=[C:9]([F:11])[CH:8]=1
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: CC(Br)Br
Agent: II
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)cc(Cl)c2)C1
Yield: 35.2 %

Procedure:
To a slurry of magnesium turnings (0.38 g, 14.4 mmol), a small crystal of iodine and a few drops of dibromoethane in dry tetrahydrofuran (30 mL) under nitrogen was added a solution of 1-bromo-3-chloro-5-fluorobenzene (3 g, 14.4 mmol) in dry tetrahydrofuran (30 mL). The mixture was refluxed for 30 min and then cooled to ambient temperature after which a solution of 1-N-boc-3-pyrrolidone (2.9 g, 15.8 mmol) in a small amount of dry tetrahydrofuran was added. The resulting mixture was stirred at ambient temperature for 2 h after which Aqueous sodium carbonate (10%) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phase was dried (Na2SO4), filtered and evaporated. Purification by flash column chromatography on silica gel (isooctane/ethyl acetate, 1:0 to 1:1) gave the title compound (1.6 g). MS m/z (relative intensity, 70 eV) 315 (M+, 1), 259 (99), 214 (99), 143 (65), 57 (bp).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1B(O)O.C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:16]1[S:15][CH:19]=[CH:18][CH:17]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: OB(O)c1cccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1cccc2cc(C=O)c(-c3cccs3)nc12
Temperature: 115 °C
Yield: 75.8 %

Procedure:
A mixture of 2-chloro-8-methylquinoline-3-carboxaldehyde (234 mg, 1.14 mmol), 2-thiopheneboronic acid (248 mg, 1.94 mmol), K2CO3 (315 mg, 2.28 mmol), palladium(II) acetate (10 mg, 0.045 mmol) and triphenylphosphine (48 mg, 0.182 mmol) in water (2 mL) was degassed. 1,4-Dioxane (6 mL) was added and the mixture further degassed, then heated at 115° C. for 2 h under microwave irradiation. The reaction mixture was filtered through Celite, washed with DCM and water and the filtrate was concentrated in vacuo. The residue was partitioned between DCM (100 mL) and H2O (50 mL). The aqueous layer was re-extracted with DCM (50 mL) and the combined organic layers were dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (SiO2, DCM) gave 8-methyl-2-(thien-2-yl)quinoline-3-carboxaldehyde (219 mg) as a yellow solid. This was dissolved in MeOH/DCM (6 mL/3 mL) and to it was added sodium borohydride (59 mg, 1.56 mmol). The reaction mixture was stirred at room temperature, quenched by the addition of glacial AcOH (0.1 mL) and the solvent removed in vacuo. The residue was partitioned between DCM (200 mL) and 5% aqueous Na2CO3 solution (40 mL). The aqueous layer was re-extracted with DCM (60 mL) and the combined organic layers were dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 3% EtOAc in DCM) gave the title compound as a yellow solid (110 mg, 38%). δH (CDCl3) 8.27 (s, 1H), 7.70 (d, J 6 Hz, 1H), 7.65 (d, J 12 Hz, 1H), 7.55 (d, J 12 Hz, 1H), 7.48 (d, J 9 Hz, 1H), 7.36-7.45 (m, 1H), 7.15-7.20 (m, 1H), 5.10 (d, J 5.8 Hz, 2H), 2.85 (s, 3H), 1.94 (t, J 12 Hz, 1H). LCMS (ES+) 256.2 (M+H)+, RT 4.06 minutes (Method 4).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:34])[N:9]([C@@H:16]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:10]2=[O:15])=[O:4].[CH3:35][NH:36][CH3:37].O1CCCC1>C(#N)C.C(OCC)(=O)C>[CH3:35][N:36]([CH3:37])[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:34])[N:9]([C@@H:16]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:10]2=[O:15])=[O:4]
Reactant: CCOc1cc([C@@H](CC(=O)N(C)C)N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)ccc1OC
Reactant: CNC
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(=O)N(C)C)N2C(=O)c3cccc(NC(=O)CN(C)C)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of (3R)-3-[4-(2-chloroacetylamino)-1,3-dioxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide (8.10 g, 16.6 mmol) and dimethylamine in tetrahydrofuran (27 mL, 2N, 54 mmol) in acetonitrile (150 mL) was stirred at room temperature overnight. The solvent was removed in vacuo to give an oil. The oil was dissolved in ethyl acetate (150 mL), washed with sodium hydrogen carbonate (2×50 mL, sat), brine (50 mL), and dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. The solid was purified by column chromatography (Silica Gel, 1.5% methanol in methylene chloride) to give (3R)-3-{4-[2-(dimethylamino)acetylamino]-1,3-dioxoisoindolin-2-yl}-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide as a white solid (6.3 g, 76% yield). To the solid in ethyl acetate (40 mL) was added hydrogen chloride in ether (20 mL, 1N). The suspension was filtered and washed with ether to give (3R)-3-{4-[2-(dimethylamino)acetylamino]-1,3-dioxoisoindolin-2-yl}-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide hydrogen chloride as a yellow solid (6.4 g, 72% yield); mp, 122-124° C.; 1H NMR (DMSO-d6) δ 1.33 (t, J=7 Hz, 3H, CH3), 2.75 (s, 3H, CH3), 2.89 (s, 6H, 2CH3), 2.98 (s, 3H, CH3), 3.22 (dd, J=5.4, 16.5 Hz, 1H, CHH), 3.60 (dd, J=9.2, 16.5 Hz, 1H, CHH), 3.71 (s, 3H, CH3), 3.97 (q, J=7 Hz, 2H, CH2), 4.30 (s, 2H, CH2), 5.62 (dd, J=5.6, 8.7 Hz, 1H, NCH), 6.86-6.93 (m, 2H, Ar), 7.00 (s, 1H, Ar), 7.65 (t, J=7.1 Hz, 1H, Ar), 7.84 (t, J=7.5 Hz, 1H, Ar), 8.17 (d, J=7.9 Hz, 1H, Ar), 10.49 (s, 1H, ClH), 10.64 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.72, 34.41, 34.81, 36.59, 43.21, 50.43, 55.53, 57.77, 63.78, 111.79, 112.38, 119.32, 119.45, 119.58, 127.97, 131.90, 131.95, 134.12, 135.77, 147.76, 148.47, 164.28, 167.24, 167.33, 169.15; Anal Calcd for C26H32N4O6+HCl+1.1H2O: C, 56.49; H, 6.42; N, 10.13; Cl, 6.41; H2O, 3.58. Found: C, 56.33; H, 6.61; N, 9.95; H2O, 3.51.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH2:16][CH:17]2[S:21]C(=S)N[C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[OH-:24].[Na+].Cl>C(OCC)(=O)C>[CH3:3][C:2]([C:5]1[CH:6]=[C:7]([CH2:16][CH:17]([SH:21])[C:18]([OH:23])=[O:24])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:1]
Reactant: CC(C)(C)c1cc(CC2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(CC(S)C(=O)O)cc(C(C)(C)C)c1O
Temperature: 15 °C

Procedure:
To 114.5 g of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-2-thioxo-4-thiazolidinone, 815 ml of 2M sodium hydroxide was added. The resultant mixture was heated to reflux temperature over the course of one hour and maintained at reflux for 2 hours. The mixture was cooled in an ice/water bath to 15° C. and 290 ml of 6M hydrochloric acid was added dropwise under a nitrogen atmosphere over 15 minutes, keeping the temperature of the mixture below 16° C. The resultant solid was dissolved by adding 600 ml of ethyl acetate to the mixture. The organic layer was separated, washed 3 times with 100 ml of saturated sodium chloride solution, dried over sodium sulfate and then the solvent was removed in vacuo to yield 100.3 g (100% of yield) of the subtitled intermediate. mp 137°-140° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1Cl)[C:5]([NH:7][CH2:8][C:9]1([N:19]([CH3:21])[CH3:20])[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH2:10]1)=[O:6].C(N(CC)CC)C.[F:33][C:34]([F:45])([F:44])C1C=CC(C(Cl)=O)=CC=1>C1COCC1>[F:33][C:34]([F:45])([F:44])[C:24]1[CH:23]=[CH:22][C:4]([C:5]([NH:7][CH2:8][C:9]2([N:19]([CH3:21])[CH3:20])[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)=[O:6])=[CH:3][CH:2]=1
Reactant: CN(C)C1(CNC(=O)c2ccc(Cl)c(Cl)c2)CCC2(CC1)OCCO2
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C1(CNC(=O)c2ccc(C(F)(F)F)cc2)CCC2(CC1)OCCO2

Procedure:
A solution of 1.0 g (0.00465 mole) of the ketal from Example 1, part A and 0.47 g (0.65 ml) of triethylamine in 15 ml of THF was cooled in an ice bath. To this cooled solution there was added a solution of 0.97 g (0.00465 mole) of p-trifluoromethylbenzoyl chloride in 10 ml of THF over 10 minutes while stirring. The mixture was placed in a refrigerator overnight. Upon removal from the refrigerator, the bulk of the solvent was removed on a rotary evaporator. The residue was taken up in diethyl ether and aqueous sodium bicarbonate solution. The separated aqueous layer was extracted with diethyl ether. The diethyl ether liquid fractions were pooled and dried to yield the crude, named product, 2.07 g, m.p. 128°-130° C. Recrystallization from a mixture of methylene chloride and Skellysolve® B gave product weighing 1.56 g, m.p. 129°-130.5° C. The elemental analysis was as follows: