Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[N:21]3)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.[SH:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>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].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH3:14][C:12]1[N:13]=[C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2]([S:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:3]([O:15][C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][CH:20]=[N:21]4)[CH:4]=2)[S:10][CH:11]=1
Reactant: Cc1csc(Nc2cc(Oc3cccc4ncccc34)c(Br)cn2)n1
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CCSc1cnc(Nc2nc(C)cs2)cc1Oc1cccc2ncccc12
Temperature: 93 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A flask was charged with tris(dibenzylideneacetone)dipalladium (0) (0.05539 g, 0.06049 mmol), 5-bromo-N-(4-methylthiazol-2-yl)-4-(quinolin-5-yloxy)pyridin-2-amine (0.500 g, 1.210 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.05250 g, 0.09074 mmol), methyl 3-mercaptopropanoate (0.5360 ml, 4.839 mmol), and N-ethyl-N-isopropylpropan-2-anine (0.4215 ml, 2.420 mmol), and degassed dioxane (40 mL) was added. The reaction was stirred at 93° C. overnight. Water was added and the reaction was extracted with ethyl acetate. The organic layer was dried, filtered and concentrated. The residue was purified using silica gel column chromatography with 20-30-40-60-80% ethyl acetate in hexanes and then with ethyl acetate to give the desired product (0.469 g, 85% yield) as yellow solid. 1H NMR (CDCl3) δ 8.93 (m, 1H), 8.37 (d, 1H), 8.19 (m, 1H), 8.02 (dd, 1H), 7.66 (t, 1H), 7.36 (dd, 1H), 7.19 (d, 2H), 6.11 (s, 1H), 3.60 (s, 3H), 2.60 (t, 2H), 1.71 (s, 3H), 1.22 (t, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[C:11]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:7][C:8](O)=[O:9])=[O:5])[CH3:2].CO>O1CCCC1>[F:28][C:24]1[CH:23]=[C:22]([C:11]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=2)=[C:6]([CH2:7][CH2:8][OH:9])[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(CC(=O)O)=C(c1ccc(S(C)(=O)=O)cc1)c1cccc(F)c1
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C(CCO)=C(c1ccc(S(C)(=O)=O)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
15.5 ml (0.155 mol) of borane/methyl sulfide complex are added dropwise to a solution of 31.5 g (0.0775 mol) of 3-ethoxycarbonyl-4-(3-fluorophenyl)-4-(4-methanesulfonylphenyl)-3-butenoic acid, prepared in Example 11, in 90 ml of anhydrous tetrahydrofuran. The mixture is stirred at room temperature for 8 hours and 23.5 ml of methanol are added dropwise. The mixture is evaporated to dryness under vacuum and the residue is taken up with ethyl acetate and then treated with an aqueous solution of 7.6 g of potassium carbonate. The organic phase is decanted and then dried over magnesium sulfate and evaporated to dryness under vacuum to give 29.3 g of ethyl 3-(3-fluorophenyl)-3-(4-methanesulfonylphenyl)-2-(2-hydroxyethyl)-2-propenoate in the form of a viscous oil, which is used as such in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:31])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[Cl:30][C:26]1[CH:25]=[C:24]2[C:29]([C:21]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)([CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)[C:22](=[O:31])[NH:23]2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifloroacetic Acid (5 mL) was added to a solution of rac-4-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.24 g, 0.5 mmol) (from Example 12c supra) in dichloromethane (5 mL). The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo. To the residue was added saturated aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic layers were combined, washed with water and brine, dried over Na2SO4 and concentrated to give rac-6-chloro-3-(3-chlorobenzyl)-3-piperidin-4-yl-1,3-dihydro-indol-2-one as a white solid. (Yield 0.18 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:18][O:19][C:20]([C:22]1[CH:40]=[CH:39][CH:38]=[CH:37][C:23]=1[CH2:24][S:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([OH:36])=O)=[CH:28][CH:27]=1)=[O:21].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:34](=[O:36])[CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([S:25][CH2:24][C:23]2[CH:37]=[CH:38][CH:39]=[CH:40][C:22]=2[C:20]([O:19][CH3:18])=[O:21])=[CH:31][CH:30]=1
Reactant: CCCCCCCNCc1ccc(F)cc1F
Reactant: COC(=O)c1ccccc1CSc1ccc(CCC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(SCc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
N-(2,4-difluorobenzyl)-N-heptylamine (0.64 g, 2.65 mmol) was dissolved in DMF (10 ml), 3-(4-{[2-(methoxycarbonyl)benzyl]thio}phenyl)propanoic acid (0.80 g, 2.41 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)-(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.85 g, 2.65 mmol) and diisopropylethylamine (0.65 g, 5.05 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. EtOAc (15 ml) was added and the organic phase was washed with two portions of sodium hydrogencarbonate (aq, 10 ml). EtOAc was removed by evaporation and the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). The solvent was removed by evaporation and gave 1.10 gram of methyl 2-{[(4-{3-[(2,4-difluorobenzyl)(heptyl)amino]-3-oxopropyl}phenyl)thio]methyl}benzoate (yield 82.2%).
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH3:15])[C:8]([OH:10])=O)=[CH:5][S:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH2:21][CH:22]1[C:40](=[O:41])[N:24]2[C:25]([C:37]([OH:39])=[O:38])=[C:26]([CH2:29][S:30][C:31]3[N:35]([CH3:36])[N:34]=[N:33][N:32]=3)[CH2:27][S:28][C@H:23]12.C[Si](CC(N)=O)(C)C>O.C(OCC)(=O)C.CN(C)C=O>[O:1]1[C:6]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH3:15])[C:8]([NH:21][CH:22]2[C:40](=[O:41])[N:24]3[C:25]([C:37]([OH:39])=[O:38])=[C:26]([CH2:29][S:30][C:31]4[N:35]([CH3:36])[N:34]=[N:33][N:32]=4)[CH2:27][S:28][C@H:23]23)=[O:10])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CCCON=C(C(=O)O)C1=CSCCO1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)C1=CSCCO1
Temperature: 40 °C
Yield: 83.4 %

Procedure:
2-(2,3-Dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetic acid (syn isomer, 1.55 g.), dry N,N-dimethylformamide (0.56 ml.), dry ethyl acetate (2.1 ml.) and phosphoryl chloride (0.66 ml.) were treated in a conventional manner to give an activated acid solution. On the other hand, 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2 g.) and trimethylsilylacetamide (5.6 g.) were added to dry ethyl acetate (40 ml.) and stirred at 40° C. for an hour. To the solution was added the activated acid solution at -15° C. and stirred at -10° to -20° C. for 2 hours. Water (50 ml.) was added to the resultant solution and the ethyl acetate layer was separated. Water (30 ml.) was added to the ethyl acetate layer and adjusted to pH 7.5 with sodium bicarbonate. The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 2.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.75 g.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([NH2:38])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1>C1COCC1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2([NH:38][C:2]3[N:7]=[C:6]([O:8][CH2:9][C:10]([F:11])([F:12])[F:13])[N:5]=[C:4]([NH:14][C:15]4[CH:16]=[CH:17][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])=[CH:26][CH:27]=4)[N:3]=3)[CH2:36][CH2:37]2)=[CH:33][CH:34]=1
Reactant: NC1(c2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Yield: 37.8 %

Procedure:
To a slurry of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (3.6 g) and 1-(4-chlorophenyl)cyclopropanamine (1.49 g) in THF (50 mL) was stirred for 5 hours at 80° C. The precipitate was filtrated through a plug washing with THF to give acrude product that was purified by Biotage eluting with 4/1-hexane/ethyl acetate to give 1.8 g of tert-butyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate as a solid.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:15]([O:18][C:19]3[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:34])[C:8]1=[O:35])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:35])[N:9]([CH3:34])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[CH:32][CH:31]=1
Reactant: Cc1ccc(Oc2cnc3c(c2Cc2ccc(Cl)cc2)c(=O)n(CCCOC=O)c(=O)n3C)cn1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(Oc2cnc3c(c2Cc2ccc(Cl)cc2)c(=O)n(CCCO)c(=O)n3C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-6-((6-methylpyridin-3-yl)oxy)-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (10 mg, 0.020 mmol) in THF (5 mL) and water (5 mL) was added LiOH.H2O (1.70 mg, 0.040 mmol). The reaction was stirred at RT for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4, and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-((6-methylpyridin-3-yl)oxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 mg, 21.2% yield) as a white solid. 1H NMR (CDCl3) δ: 8.29 (s, 1H), 8.20 (d, J=2.4 Hz, 1H), 7.16-7.18 (m, 4H), 7.10 (d, J=8.6 Hz, 1H), 7.03 (s, 1H), 4.76 (s, 2H), 4.24 (t, J=6.2 Hz, 2H), 3.70 (s, 3H), 3.53-3.57 (m, 2H), 3.04 (t, J=7.0 Hz, 1H), 2.54 (s, 3H), 1.92-1.96 (m, 2H). LCMS: MH+ 467 and TR=1.903 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13]([Cl:15])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:9])=[O:8].[CH:17]([CH:20]1[O:25][CH2:24][CH:23]([C:26](Cl)=[O:27])[CH2:22][O:21]1)([CH3:19])[CH3:18]>CC(N(C)C)=O>[CH:17]([CH:20]1[O:25][CH2:24][CH:23]([C:26]([NH:1][C:2]2[C:10]([I:11])=[C:6]([C:7]([Cl:9])=[O:8])[C:5]([I:12])=[C:4]([C:3]=2[I:16])[C:13]([Cl:15])=[O:14])=[O:27])[CH2:22][O:21]1)([CH3:19])[CH3:18]
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: CC(C)C1OCC(C(=O)Cl)CO1
Solvent: CC(=O)N(C)C
Product: CC(C)C1OCC(C(=O)Nc2c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c2I)CO1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
137 g of 5-amino-2,4,6-triiodoisophthaloyl chloride (0.23 mole) are dissolved in 460 ml of DMAC to which are added 110 g (0.57 mole) of 2-isopropyl-1,3-dioxane-5-carboxylic acid chloride. The reaction mixture is stirred under argon at ambient temperature for 4 days. The DMAC is removed in a vacuum. The oil obtained is extracted with 3 l of ethyl acetate and washed twice with 1 l of ice-cold water. The organic phase is dried and concentrated to dryness. The product is crystallized from 200 ml of CH2Cl2. After filtration, 110 g of solid are obtained:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH:10]([F:17])([F:16])[C:11]([CH:13]([F:15])[F:14])=[O:12]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([OH:12])([CH:10]([F:17])[F:16])[CH:13]([F:15])[F:14])=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1N
Reactant: O=C(C(F)F)C(F)F
Product: COc1cc(C(O)(C(F)F)C(F)F)ccc1N

Procedure:
The procedure of Example 4 is used with 2-amino-methoxybenzene and sym-tetrafluoroacetone to give 4-amino[2,2-difluoro-1-hydroxy-1-(difluoromethyl)ethyl]-3-methoxybenzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.[O:25]=[C:26]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:27][C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:28](=[O:29])[CH2:27][C:26]([NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: O=C(O)CC(=O)Nc1ccccc1
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccccc4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.3 %

Procedure:
To a solution of the amine 9 (80 mg, 0.235 mmol), 3-oxo-3-(phenylamino)propanoic acid (1) (42 mg, 0.235 mmol) and BOP (114.6 mg, 0.259 mmol) in DMF (2.4 mL), DIPEA (0.164 mL, 0.941 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between EtOAc and water. Organic phase was collected, washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (EtOAc/MeOH 95:5) followed by crystallization (MeOH) to afford the title compound 5b (11 mg, 9% yield). 1H NMR (DMSO-d6) δ (ppm): 10.55 (s, 1H), 10.19 (s, 1H), 8.5 (d, J=5.4 Hz, 1H), 7.86 (m, 2H), 7.59 (m, 2H), 7.49 (t, J=8.8 Hz, 1H), 7.41 (m, 2H), 7.30 (m, 2H), 7.05 (m, 2H), 6.69 (d, J=5.4 Hz, 1H), 3.99 (s, 3H), 3.52 (s, 2H). MS (m/z): 502.2 (M+H).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8])[CH:2]=[CH2:3].[OH-].[Na+].[C:13](Cl)(=[O:15])[CH3:14]>C1(C)C=CC=CC=1>[CH2:1]([N:4]([CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8])[C:13](=[O:15])[CH3:14])[CH:2]=[CH2:3]
Reactant: CC(=O)Cl
Reactant: C=CCNCC(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=CCN(CC(OC)OC)C(C)=O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
N-allyl-N-dimethoxyethyl amine (30% aqueous, 48.3 grams, 0.10 mole) was added to a glass reaction vessel fitted with a mechanical agitator. The agitator was started and sodium hydroxide (4.44 grams, 0.11 mole) was dissolved in the aqueous amine. Toluene (50 grams) was added and the mixture cooled to 0° to 5° C. Acetyl chloride (8.24 grams, 0.105 mole) was added over 10 minutes while maintaining the temperature below 5° C. The reaction mixture was stirred for 30 minutes at 5° C., agitation was stopped, and the mixture allowed to phase separate. The aqueous layer was discarded. Toluene was removed from the organic layer by rotary evaporation and 14.8 grams (0.08 mole) of N-allyl-N-dimethoxyethyl acetamide was isolated as confirmed by NMR.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Li])CCC.C[O:16][B:17](OC)[O:18]C.Cl>C1COCC1.C(Cl)Cl>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([B:17]([OH:18])[OH:16])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1ccc(B(O)O)cc1
Temperature: -100 °C
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
A solution of 4-bromobenzonitrile (91 g, 0.50 mole) in THF (1.1 L) was dried in the presence of activated 3 Å molecular sieves at room temp. This solution was filtered and cooled to −100° C. A 1.6 M solution of n-butyllithium in hexanes (355 mL. 0.567 mol) was added to the cold solution over 15 min while maintaining the internal temperature between −105 and −93° C. To the resulting orange reaction mixture was added trimethylborate (81 g, 0.78 mol) over 3 min, briefly increasing the reaction temperature to −72° C. The reaction mixture was recooled to −100° C. over 5 minutes and then was allowed to warm slowly to room temperature over 2.3 h. The reaction mixture was acidified with 4N HCl to pH 2.2, and was diluted with CH2Cl2 (200 mL). The aqueous layer was separated and the organic layer was washed with brine (2×200 mL), dried over anhydrous MgSO4, filtered, and the solvent removed under reduced pressure to a pale yellow solid. This solid was additionally purified by dissolution in 1N NaOH and extraction into CH2Cl2/THF (1:1, 2×200 mL). The aqueous phase was acidified with 4N HCl to pH 2.2 and was extracted into CH2Cl2/THF (1:1, 500 mL). The combined organic extracts were concentrated to a crude solid (64.6 g) that was triturated with diethyl ether (160 mL) and dried under vacuum to afford the intermediate title compound (44.0 g, 59.9%) as a white powder. 1H NMR (d6-acetone, 300 MHz): δ 8.03 (d, 2H, J=8.1), 7.75 (d, 2H, J=8.4), 7.54 (s, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:20]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:4]1[CH3:3])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1[nH]c2ccccc2c1C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.5 %

Procedure:
To a suspension of sodium hydride (73 mg, w/w=60%, 1.8 mmol) tert-butyl 2-methyl-1H-indole-3-carboxylate (350 mg, 1.5 mmol) in tetrahydrofuran (30 mL) was added benzoyl chloride (250 mg, 1.8 mmol). The reaction solution was stirred at room temperature for 12 hours. The mixture was concentrated to give a residue, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to give tert-butyl 1-benzoyl-2-methyl-1H-indole-3-carboxylate (440 mg, 88%).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]#[CH:8])[CH2:3][CH2:4][OH:5].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C.Cl>O1CCCC1>[CH3:9][S:10]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][C:7]#[CH:8])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCC(C)CCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCC(C)CCOS(C)(=O)=O
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 2.9 g of 3-methyl-5-hexyn-1-ol and 3.0 g of methanesulfonyl chloride in 50 ml of tetrahydrofuran was added dropwise 4 ml of triethylamine at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture was 10% hydrochloric acid and the extracted with ethyl acetate. The organic layer was washed sequentially with 10% hydrochloric acid and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.88 g of 3-methyl-5-hexynyl methanesulfonate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][CH2:7][C:8]([C@@H:10]([C@H:12]([C@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[O:13][CH2:14][C:15]([OH:17])=[O:16])[OH:11])=[O:9].[C:24](ON1C(=O)CCC1=O)(=[O:27])[CH:25]=[CH2:26]>O.CO.C(N(CC)CC)C>[C:24]([NH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][CH2:7][C:8]([C@@H:10]([C@H:12]([C@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[O:13][CH2:14][C:15]([OH:17])=[O:16])[OH:11])=[O:9])(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)ON1C(=O)CCC1=O
Reactant: NCCSCCCC(=O)[C@H](O)[C@@H](OCC(=O)O)[C@@H](O)[C@H](O)CO
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: C=CC(=O)NCCSCCCC(=O)[C@H](O)[C@@H](OCC(=O)O)[C@@H](O)[C@H](O)CO
Reaction time: 2 h
Yield: 63.7 %

Procedure:
Compound 9 (1.5 g) was dissolved in water/methanol (1:1, 10 mL) to which triethylamine was added to obtain pH 10. N-acryloyloxy succinimide (2.0 g) was added and the mixture was stirred for 2 hr. After TLC analysis indicated the complete disappearance of starting material 9, the volatiles were removed from the reaction mixture. The residue was chromatographed on a silica gel column using 20% methanol in dichloromethane. The appropriate fractions were pooled and solvent was removed to give the derivative 10 as a white foam (1.1g). 1H NMR (D2O) : δ, 1.62-1.95, mm, 6H; 2.64-2.80, m, 2H; 3.05-3.14, m, 2H; 3.28-3.35, m, 1H; 3.68-3.72, dd, 1H; 4.11-4.15, m, 2H; 4.24-4.29, m, 1H; 4.38-4.41, m, 2H; 5.82-5.86,dd, 2H, acryloyl CH2; 6.26-6.36,m, 1H, acryloyl CH: 13C NMR (D2O): 176.92, 175.14, 168.12, 129.42, 78.76, 74.44, 71.47, 66.38, 66.41, 65.70, 60.72, 38.21, 30.11, 27.62, 24.49, 22.31.
Reaction SMILES: [C-]#N.[K+].[N+](C1C=CC(C([C@H:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)=CC=1)([O-])=O.C([OH:31])C>>[OH:31][C@@H:13]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCO
Agent: [C-]#N
Agent: [K+]
Product: CCOC(=O)[C@@H](O)CCc1ccccc1
Reaction time: 2.25 h
Yield: 74 %

Procedure:
To a suspension of potassium cyanide (0. 176 g, 2.70 mmole) in absolute ethanol (43 mL) was added a solution of (S)-2-[4-nitrobenzoyl]-4-phenylbutyric acid, ethyl ester (3.86 g, 10.8 mmole) in absolute ethanol (38 mL) dropwise over a period of 0.5 hours. After stirring 2.25 hours the solvent was removed and the reside was diluted with water and acidified with dilute hydrochloric acid. The organics were extracted with ether. The extracts were combined, silica gel (60 mL) was added and the solvent was removed. The adsorbate was flash chromatographed, eluent (gradient 90/10-80/20 petroleum ether/ethyl acetate) and the solvents were chased with benzene to give the title compound as a yellow oil (1.67 g, 74%): NMR (CDCl3); δ7.38-7.16 (m, 5H), 4.30-4.10(m, 3H), 2.9-2.6 (m, 3H,), 2.2-1.9(m, 2H), 1.15(t, 4 Hz, 3H); [a]25D +178.23 at 10.98 mg/mL CHCl3.