Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[F:59][C:60]1[CH:61]=[CH:62][CH:63]=[C:64]2[C:69]=1[NH:68][C:67](=[O:70])[C:66]([CH:71]1[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1)=[CH:65]2>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:24])([F:23])[F:25])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([N:74]4[CH2:75][CH2:76][CH:71]([C:66]5[C:67](=[O:70])[NH:68][C:69]6[C:64]([CH:65]=5)=[CH:63][CH:62]=[CH:61][C:60]=6[F:59])[CH2:72][CH2:73]4)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O
Reactant: O=c1[nH]c2c(F)cccc2cc1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O)N1CCC(c2cc3cccc(F)c3[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 59 %

Procedure:
(S)-2-(1,4-Dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (49 mg, 0.098 mmol) was dissolved in N,N-dimethylformamide (1.5 mL). N,N-Diisopropylethylamine (70 μl, 0.402 mmol) was added to the mixture followed by TBTU (34.5 mg, 0.107 mmol). 8-Fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (33.0 mg, 0.117 mmol) was added to the mixture. Reaction stirred at room temperature for 3.5 hours. Reaction was quenched with 50% acetonitrile-water. Material was purified by reverse phase prep HPLC (acetonitrile-water-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 59% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.91 (s, 1H) 11.81 (s, 1H) 7.77 (s, 1H) 7.48 (s, 2H) 7.26-7.41 (m, 1H) 7.06-7.18 (m, 1H) 5.58 (d, J=16.79 Hz, 1H) 5.40 (d, J=17.09 Hz, 1H) 4.55 (d, J=12.51 Hz, 1H) 4.28-4.44 (m, 1H) 4.06-4.22 (m, 2H) 3.86-4.07 (m, 1H) 3.13-3.24 (m, 2H) 3.06 (t, J=10.83 Hz, 1H) 2.98 (dd, J=16.48, 8.24 Hz, 1H) 2.84-2.95 (m, 1H) 2.65 (t, J=12.05 Hz, 1H) 2.33-2.48 (m, 1H) 1.93 (d, J=10.07 Hz, 1H) 1.78-1.89 (m, 1H) 1.47-1.62 (m, 1H) 1.32-1.46 (m, 1H). High resolution MS m/e (M+H)+=726.0337.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[O:9]([C:16]1[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH:22]=O)=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.C(O)C>[O:9]([C:16]1[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH:22]=[N:2][OH:3])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=CCOc1ccc(Oc2ccccc2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=CCOc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 25 g of hydroxylamine hydrochloride and 29.4 g of anhydrous sodium acetate in 100 ml of water is added dropwise at room temperature to a solution of 68.5 g of 4-phenoxyphenoxyacetaldehyde in 300 ml ethanol. After the slightly exothermic reaction has subsided, the mixture is stirred for 2 hours at reflux temperature. The mixture is then cooled to 0° C. and stirred for 3 hours at this temperature, whereupon the resultant oxime crystallises. The crystallised 4-phenoxyphenoxyacetaldehyde oxime is isolated by suction filtration, repeatedly washed thoroughly with water and dried in a vacuum cabinet at 40° C. Melting point: 102°-105° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[F:32][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:13])=[O:14])[CH:7]=2)[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][CH3:33])=[N:3][CH:4]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Reactant: COc1ccccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate PPP) (58.34 mg, 0.118 mmol), (2-methoxyphenyl)boronic acid (35.9 mg, 0.236 mmol), Pd(AmPhos)2Cl2 (8.36 mg, 0.012 mmol), potassium phosphate (75 mg, 0.354 mmol), 1,4-dioxane (443 μl), and water (148 μl). The vial was flushed with Ar (g), then sealed and heated in a microwave reactor for 30 min h at 90° C. LC/MS showed conversion to the protected product. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 2 h, the mixture was diluted with MeOH and concentrated, and the crude product was purified by chromatography on silica gel (12-g column, 3% MeOH/DCM) to give 4-fluoro-1-(2-methoxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (49 mg, 0.118 mmol, 100% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.99 (br. s., 1H), 8.70 (d, J=1.7 Hz, 1H), 8.49 (d, J=1.8 Hz, 1H), 7.99 (dd, J=1.8, 8.9 Hz, 1H), 7.78 (dd, J=1.8, 8.8 Hz, 1H), 7.58-7.50 (m, 1H), 7.38-7.27 (m, 2H), 7.23 (d, J=8.3 Hz, 1H), 7.16-7.10 (m, 1H), 6.89 (d, J=4.6 Hz, 1H), 3.65 (s, 3H); m/z (ESI) 416.2 (M+H)+.
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]([NH:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([NH2:41])[CH:37]=3)[N:32]=2)[CH2:22]1>>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]([NH:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([NH:41][C:1]([NH:20][CH:17]4[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]4)=[O:2])[CH:37]=3)[N:32]=2)[CH2:22]1
Reactant: Nc1ccc2nc(NC3COc4ccccc43)ccc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)Nc2ccc3nc(NC4COc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-methyl-piperidin-4-ylamine and rac-N2-(2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine; MS: m/e=418.6 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[C:10](Cl)([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11].N1C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[CH:25]1[C:26]2[CH:14]([CH2:13][O:12][C:10](=[O:11])[NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=3)[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(CO)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(CO)cc1)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
A mixture of (4-amino-phenyl)-methanol (500 mg), Fmoc-Cl (1.2 g) and pyridine (1 ml) in THF (15 ml) was stirred for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was recrystallized from dichloromethane. Yield: 470 mg. MS-ESI: [M+H]+=346.
Reaction SMILES: [CH3:1][N:2](/[CH:4]=[C:5]1\[C:6](=[O:14])[NH:7][C:8]2[C:13]\1=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:3].[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)/[C:5](=[CH:4]/[N:2]([CH3:1])[CH3:3])/[C:6]1=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)/C=C1\C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)/C=C1\C(=O)N(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (3Z)-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one (iii-a, 626 mg, 3.33 mmol) in DMF (10 mL) was added NaH (151 mg, 6.29 mmol) and the reaction was stirred at RT. After 10 min, benzyl bromide (500 μL, 4.20 mmol) was added and the mixture was stirred under an atmosphere of Ar for 22 h. The reaction was quenched with a few drops of water and poured into a separatory funnel containing EtOAc (150 mL) and washed with water (2×100 mL), followed by brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (EtOAc/Hexane) to yield (3Z)-1-benzyl-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one as a yellow solid (iv-a, 660 mg, 71%). NH4OAc QC conditions. DAD Retention Time =1.71 min. M+H=279.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C@H:8]([CH2:24][NH:25][C:26]([C:28]1[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=1)=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].N#N.[H][H]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:37])[NH:7][C@H:8]([CH2:24][NH:25][C:26]([C:28]1[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=1)=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)CNC(=O)c1nc(Cl)c(N)nc1N
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN)CNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of ((S)-5-benzyloxycarbonylamino-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-pentyl)-carbamic acid tert-butyl ester (0.68 g, 1.27 mmol) in EtOH (20 mL) under an inert atmosphere of N2 is treated with activated palladium on charcoal (10%). The reaction mixture is then placed under a positive pressure of hydrogen and stirred at RT. After 3 h, the catalyst is removed by filtration through Celite® (filter material). The filtrate is concentrated in vacuo and the resulting colourless oil is dissolved in MeOH (10 mL) and allowed to stand at RT overnight. A cream precipitate forms which is removed by filtration and the solution is concentrated in vacuo. Purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water with 0.1% NH3) affords the title compound. [M+H]+ 402.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](O)=[O:19])=[C:12]([C:21]([F:24])([F:23])[F:22])[C:11]=1[Cl:25].[NH:26]1[CH2:36][CH2:35][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:26]2[CH2:27][CH2:28][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:35][CH2:36]2)=[O:19])=[C:12]([C:21]([F:23])([F:22])[F:24])[C:11]=1[Cl:25]
Reactant: COc1ccccc1Sc1ccc(/C=C/C(=O)O)c(C(F)(F)F)c1Cl
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)/C=C/c2ccc(Sc3ccccc3OC)c(Cl)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
To the acyl chloride (37 mg, 0.1 mmol) prepared from the compound of Example 351B, as a solution in CH2Cl2 was added 1.2 eq. of ethyl isonipecotate and 1.2 eq. of Hunig's base. The mixture was stirred at room temperature for 20 min., ˜90% of the solvent was removed in vacuo, and the resultant solution was loaded on a silica column to elute with hexane and EtOAc (3:2) to give 51 mg (98%) of the title compound. 1H-NMR (CDCl3, 300 MHz) δ 1.25 (t, J=7.5 Hz, 3H), 1.65-1.78 (m, 2H), 1.92-2.02 (br, 2H), 2.51-2.60 (m, 1H), 2.93-3.24 (br, 2H), 3.82 (s, 3H), 3.88-3.96 (m, 1H), 4.15 (q, J=7.5 Hz, 2H), 4.40-4.50 (br, 1H), 6.48 (d, J=15 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 7.02 (d, J=7.5 Hz, 2H), 7.12 (d, J=9 Hz, 1H), 7.49 (t, J=9 Hz, 2H), 7.86 (qq, J=4.5 Hz, 1H). MS (DCI/NH3) m/e 528 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18].Cl>ClCCl.C1(C)C=CC=CC=1>[C:17]([C:6]1[CH:5]=[CH:4][C:3]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:2]([CH3:1])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Cc1ccccc1NS(C)(=O)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2-methylphenyl)methanesulfonamide (1.84 g, 10 mmol) in dichloromethane (2 mL) was added aluminum chloride (3.3 g, 25 mmol) carefully at 0° C. Then acetyl chloride (1.07 ml, 15 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 0.5 hours, the reaction was monitored by using TLC and 1H-NMR, and after completion of the reaction, the reaction mixture was diluted with toluene and poured into 2N HCl aqueous solution with stirring at 0° C. The precipitate solid was filtered, washed with H2O, and dried to give a mixture of the title compound and by-product (N-acetylated product) (2.31 g, ratio; title compound: by-product=81:19 (ratio was determined by 1H-NMR)) as a flesh color powder.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:26]=[C:25]([N:27]5[CH:31]=[CH:30][CH:29]=[CH:28]5)[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:11]=2)[O:8][CH:9]=1)=[O:4].[NH3:33]>CO>[O:32]=[C:18]1[CH2:17][C:16]([C:12]2[CH:11]=[C:10]([C:7]3[O:8][CH:9]=[C:5]([C:3]([NH2:33])=[O:4])[N:6]=3)[CH:15]=[CH:14][CH:13]=2)=[N:22][C:21]2[CH:23]=[CH:24][C:25]([N:27]3[CH:28]=[CH:29][CH:30]=[CH:31]3)=[CH:26][C:20]=2[NH:19]1
Reactant: COC(=O)c1coc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1coc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A suspension of 2-[3-(4-oxo-7-pyrrol-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-phenyl]-oxazole-4-carboxylic acid methyl ester (Example 25) (44mg) in a 5N solution (3 mL) of NH3 in MeOH was stirred at 20° C. for 3 d. Insoluble material was filtered off and the solution was evaporated in vacuum. The residue was triturated with EtOAc to give the title compound (22 mg) as light-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:16])[NH:13]C(=O)N[C:10]2=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[OH-:18].[Na+]>>[ClH:1].[NH2:13][C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([CH3:16])[C:10]([OH:18])=[O:15]
Reactant: CC1(c2ccc(Cl)c(Cl)c2)NC(=O)NC1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC(N)(C(=O)O)c1ccc(Cl)c(Cl)c1
Yield: 27 %

Procedure:
A solution of 5-(3,4-dichloro-phenyl)-5-methyl-imidazolidine-2,4-dione (3.0 g; CAS 52715-57-8) in 3N NaOH (30 ml) was refluxed overnight. The reaction mixture was cooled to 0°, then brought to pH 1 by dropwise addition of concentrated HCl. The resulting white slurry was filtered. The solid was washed extensively with H2O, dried in the vacuum, resuspended in EtOH (25 ml), collected by filtration, washed with EtOH and diethylether and dried in the vacuum to give (RS)-2-amino-2-(3,4-dichloro-phenyl)-propionic acid hydrochloride (1.35 g, 27%) as off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][CH2:13][C:12](=[O:23])[N:11]3[CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:5]2=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:9](=[O:28])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][CH2:13][C:12](=[O:23])[N:11]3[CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:5]2=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@]2(C(=O)Nc3cc(Cl)ccc32)N1CC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)[C@@]2(c3ccc(Cl)cc31)[C@@H](c1cccc(Cl)c1)CCC(=O)N2CC1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (rac) (2′S,3′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)spiro[indoline-3,2′-piperidine]-2,6′-dione (Example 62, Step H) (114 mg, 0.274 mmol) in DMF (2 mL) at 0° C. was added a dispersion of 60% sodium hydride in mineral oil (10.98 mg, 0.274 mmol) followed by (2-(chloromethoxy)ethyl)trimethylsilane (48.4 μL, 0.274 mmol). The reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature and stirred at room temperature for 24 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with 1M LiCl, sat. aq. NaCl solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[CH3:25][S:26][CH2:27][C:28]#[CH:29]>C(NCC)C.[Cu](I)I.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:29]#[C:28][CH2:27][S:26][CH3:25])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: C#CCSC
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CSCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 5 h

Procedure:
A mixture of N-[(4-Chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example No. 5 (1.57 g), propargyl methyl sulfide (0.355 g, 4.12 mmol), copper iodide (0.125 g), and dichlorobis(triphenylphosphine)palladium (II) (0.462 g) in diethylamine (38 mL) are stirred at room temperature overnight. An additional 0.092 g of propargyl methyl sulfide is added, and the mixture is stirred another 5 h. The reaction mixture was then concentrated in vacuo, and the residue is suspended in water (100 mL) and extracted with three portions of EtOAc. The combined organic layers are then dried over MgSO4, filtered, and concentrated in vacuo. Column chromatography (elution with 5-10%MeOH/CH2Cl2) yielded the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1CC(O)=S.BrC1[S:13]C=CC=1Br.C([Li])CCC.[S].Cl[CH2:25][C:26]([O:28]C)=[O:27]>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:13][CH2:25][C:26]([OH:28])=[O:27]
Reactant: OC(=S)Cc1sccc1Br
Reactant: COC(=O)CCl
Reactant: Brc1ccsc1Br
Agent: [Li]CCCC
Agent: [S]
Product: O=C(O)CSc1sccc1Br
Yield: 76 %

Procedure:
The compound is prepared analogously to Example 10 by saponification of the crude methyl ester of (3-bromo-2-thienylthio-acetic acid prepared with a 76% yield from 2,3-dibromothiophene, butyllithium, sulfur, and methyl chloroacetate. After chromatography on silica gel (eluent: hexane/acetone/acetic acid = 93:5:2), the product is obtained as a non-crystallizing oil. The compound shows the physiochemical data to be expected (IR, NMR spectrum) and yields correct elementary analyses for C, H, S, and Br.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=[CH:6][CH:5]=2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.O.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>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=[CH:6][CH:5]=2
Reactant: Cc1ccccc1B(O)O
Reactant: CCOC(=O)Cc1c(Br)[nH]c2cccc([N+](=O)[O-])c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1c(-c2ccccc2C)[nH]c2cccc([N+](=O)[O-])c12

Procedure:
To a deoxygenated solution of ethyl (2-bromo-4-nitro-1H-indol-3-yl)acetate from Step B (250 mg, 0.76 mmol), 2-methylphenylboronic acid (156 mg, 1.15 mmol), and Na2CO3 (202 mg, 1.91 mmol) in EtOH (10 mL), toluene (10 mL) and H2O (0.5 mL) was added tetrakis(triphenylphosphine)palladium (44 mg, 0.038 mmol) and the resulting mixture was heated at reflux for 18 h. The cooled mixture was diluted with H2O (20 mL) and extracted with EtOAc (2×50 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CHCl3:EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=339 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[CH:7]([C:9]([CH3:11])=[O:10])=[CH2:8]>>[C:9]([CH:7]1[CH2:8][CH2:5][C:4]([CH3:6])=[C:2]([CH3:1])[CH2:3]1)(=[O:10])[CH3:11]
Reactant: C=C(C)C(=C)C
Reactant: C=CC(C)=O
Product: CC(=O)C1CCC(C)=C(C)C1

Procedure:
The reaction between 2,3-dimethylbutadiene and methyl vinyl ketone was performed in substantially the same manner as in Example 45, except that each of the compounds synthesized in Examples 42 to 44 was individually used as the Lewis acid catalyst. The yields of the reaction product (i.e., 4-acetyl-1,2-dimethylcyclohexene) are shown in Table 1.
Reaction SMILES: [C:1]1([NH:7][N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:29]([O:31][CH2:32][CH2:33]Cl)=[CH2:30].[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH:29]([O:31][CH2:32][CH2:33][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[N:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)=[CH2:30]
Reactant: C(=NNc1ccccc1)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: C=COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: C=COCCN(N=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 4-(diphenylamino)benzaldehyde N-phenylhydrazone (10 g, 0.027 mol) and methyl ethyl ketone (50 ml) was added to 100 ml 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The mixture was stirred at room temperature until all solid entered into solution. Then, 2-chloroethyl vinyl ether (5.5 ml, 0.054 mol, from Aldrich) was added to the mixture, followed by the addition of potassium hydroxide (3.02 g, 0.054 mol) and potassium carbonate (3.73 g, 0.027 mol) in two portions. The mixture was refluxed for 15 hours. The solvent was evaporated off and the crude product was purified by column chromatography using a mixture of hexane-acetone in a volume ratio of 7:1 as the eluant. Fractions containing the product were collected and the solvents were evaporated. The product was dried at 50° C. in a vacuum oven for 5 hours to yield 3.5 g (38%). The melting point was found to be 107–108° C. The 1H-NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 3.52–4.47 (m, 6H, N—CH2—CH2—O, CH2═); 6.43 (q, 1H, O—CH═); 6.70–8.03 (m, 20H, Ar, CH═N). The IR spectrum of the product was characterized by the following absorption frequencies (KBr, cm−1): ν(C—H) 2983; 2926; 2878, ν(arene C—H) 3033, ν(C═C, in Ar) 1618; 1591; 1494, ν(C—N) 1315; 1276, γ(Ar) 751; 693. The mass spectrum of the product was characterized by the following mass peaks (m/z): 434.4 (100%, M+1), 148.2.