Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[N:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]2[CH:7]=[CH:8][N:9]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[C:10]2=[N:11][CH:12]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
Sodium hydride (0.63 g, 25.15 mol) was added in small portion to a stirred solution of 5-bromo-7-azaindole (3.3 g, 16.75 mmol) in THF (50 mL) at room temperature and the resulting suspension was stirred at room temperature for 15 min. Triisopropylsilyl chloride (5.3 mL, 25.15 mmol) was added and the mixture was heated at 80° C. for 3 h. The solvent was evaporated and the residue was dissolved in water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by Biotage HPFC system (10% EtOAc/Hexane) to afford the desired 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine as a white solid (5.2 g, 88%); Mass Spec 355 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:10]3[CH2:25][CH2:26][C:27](=[O:28])[C:9]2=3)=[C:4]([S:29][CH3:30])[CH:3]=1.O.[CH3:32][N:33](C)C=O>[C-]#N.[Zn+2].[C-]#N>[O:14]=[C:12]1[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=2)[C:10]2[CH2:25][CH2:26][C:27](=[O:28])[C:9]=2[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]#[N:33])=[CH:3][C:4]=2[S:29][CH3:30])[NH:13]1
Reactant: CSc1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CSc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Temperature: 110 °C

Procedure:
Under an atmosphere of argon, a mixture of 4-(4-bromo-2-(methylthio)phenyl)-1-(3-(trifluoromethyl)phenyl)-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-2,5-dione (intermediate 25, 1.74 g, 2.8 mmol based on 80% purity), zinc cyanide (430 mg, 3.64 mmol) and tetrakis (triphenylphosphine)palladium(0) (323 mg, 0.28 mmol) in N,N-dimethylformamide (12 mL) is heated at 110° C. over night and then cooled to room temperature. Water is added, and the mixture is extracted with dichloromethane. The organic layer is concentrated under reduced pressure, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 1.09 g. ESI mass spectrum: [M+H]+=444; Retention time HPLC: 0.58 min (X011_S03).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=[CH:4][CH:3]=1.[F:26][C:27]([Si](C)(C)C)([F:29])[F:28].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])([CH3:14])[C:27]([F:29])([F:28])[F:26])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:24])([F:23])[F:25])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(=O)c1cn(-c2ccc(Br)cc2)c(-c2ccccc2C(F)(F)F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(O)(c1cn(-c2ccc(Br)cc2)c(-c2ccccc2C(F)(F)F)n1)C(F)(F)F
Temperature: 50 °C
Reaction time: 48 h
Yield: 38.9 %

Procedure:
To a solution of 1-[1-(4-bromophenyl)-2-(2-trifluoromethyl-phenyl)-1H-imidazol-4-yl]-ethanone (0.24 g, 0.59 mmol) and trifluoromethyl-trimethylsilane (0.10 mL, 0.68 mmol) in toluene (3 mL, anhyd) at 0° C. was added a 1.0M solution of tetrabutylammonium fluoride (TBAF) in THF (0.12 mL, 20 mol %, dried over 4 Å molecular sieves). After 24 h the reaction mixture was charged with additional trifluoromethyl-trimethylsilane (0.10 mL) and 1.0M TBAF (0.12 mL) and then heated at 50° C. After 48 h (total) the reaction mixture was allowed to cool to ambient temperature, quenched with H2O and extracted with DCM (2×30 mL). The combined extracts were dried (Na2SO4), concentrated and purified by chromatography (silica, EtOAc/Hex, 20:80 to 60:40) to yield the title compound (0.11 g, 39%) as a white solid. 1H-NMR (DCM-d2): δ 7.76 (d, 1H), 7.50-7.60 (m, 2H), 7.46 (d, 2H), 7.27 (m, 2H), 7.02 (d, 2H), 4.36 (s, 1H), 1.72 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([CH3:13])([CH3:12])[CH:8]=[CH:7]2.CO.C(=O)([O-])[O-:23].[K+].[K+]>[Pd](Cl)Cl.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([CH3:12])([CH3:13])[CH2:8][C:7]2=[O:23]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(C)c1cc(Cl)c2c(c1)C=CC(C)(C)N2
Agent: Cl[Pd]Cl
Agent: [K+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(C)c1cc(Cl)c2c(c1)C(=O)CC(C)(C)N2
Reaction time: 6 h
Yield: 28.4 %

Procedure:
1.0 g of methyl 2-(8-chloro-1,2-dihydro-2,2-dimethylquinolin-6-yl)propionate was added to 20 ml of methanol. 2.0 g of palladium chloride was further added to the solution, and the mixture was stirred at 55°-60° C. for 6 hours. After cooling, 2 g of potassium carbonate and benzene were added to the mixture, then the mixture was further stirred. The precipitates were filtered off and washed with benzene. The filtrate and the wash were combined and concentrated, followed by addition of dilute aqueous solution of sodium hydrogencarbonate, and extraction with ether. The ethereal solution was washed with water, saturated aqueous solution of sodium sulfate and then the solvent was distilled off. The residue was purified by column chromatography on silica gel (benzene:ether=9:1) to give 0.3 g of methyl 2-(8-chloro-1,2,3,4-tetrahydro-2,2-dimethyl-4-oxoquinolin-6-yl)propionate (Compound 31).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (2.307 g, 5.75 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.230 g, 5.75 mmol) dissolved in water (2 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.352 mL, 5.75 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 20 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (1.682 g, 79%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.83-1.94 (m, 1H), 2.16-2.29 (m, 2H), 2.34-2.43 (m, 1H), 3.06-3.18 (m, 1H), 3.51 (ddd, 1H), 3.64 (s, 3H), 4.12 (ddd, 1H), 5.10-5.22 (m, 1H), 5.57 (s, 1H), 7.40 (d, 2H), 7.58 (d, 2H). MS m/z 371 (M+H)+
Reaction SMILES: C([Si]([O:8][C:9](=O)[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])(C)C)(C)(C)C.C(Cl)(=O)C([Cl:30])=O>CN(C=O)C.C(Cl)Cl>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:11]=[CH:10][C:9]([Cl:30])=[O:8])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OC(=O)C=Cc1ccccc1O[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1C=CC(=O)Cl
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a 0° C. cold solution of 6.3 g of 3-[2-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-acrylic acid tert-butyl-dimethyl-silyl ester and 8 drops of DMF in 15 ml of CH2Cl2 was added dropwise 2.0 ml of oxalyl chloride. After complete addition the reaction mixture was allowed to warm to room temperature and stirring was continued for 60 h. The reaction mixture was filtered, evaporated to dryness and taken up in MTBE. The solution was cooled in the refrigerator overnight, filtered and evaporated to yield 4.4 g of 3-[2-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-acryloyl chloride.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:18]([CH2:19][CH:20]([OH:22])[CH3:21])[N:17]=[CH:16][N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[OH:22][CH:20]([CH3:21])[CH2:19][N:18]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][N:28]([CH2:27][C:26]([CH3:42])([OH:43])[CH3:25])[CH:32]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)=[N:15][CH:16]=[N:17]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(O)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(O)Cn1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CC(C)(C)O)c3)ccc1-2

Procedure:
Following the procedure for 114, 1-[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-propan-2-ol was reacted with 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 459. MS(ESI+) 467.1. 1H NMR (400 MHz, DMSO) δ 8.35 (d, J=8.3, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.43 (dd, J=8.3, 1.8, 1H), 7.30 (d, J=1.7, 1H), 4.95 (d, J=5.3, 1H), 4.82 (dd, J=13.3, 7.5, 1H), 4.76-4.66 (m, 2H), 4.46-4.32 (m, 2H), 4.28-4.14 (m, 1H), 4.03 (s, 2H), 3.44 (t, J=5.0, 2H), 1.16 (d, J=6.3, 3H), 1.10 (s, 6H)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[CH:5]=[CH:6][CH:7]=1>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCCCCCCCCc1cccc(I)c1
Solvent: C1CCOC1
Product: OCCCCCCCCCCCCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.5 %

Procedure:
Anhydrous THF (20 ml) was added to a flame-dried 100 ml two-necked flask containing 12-m-iodophenyldodecanoic acid (3.30 g, 8.21 mmol). The solution was cooled in an ice bath before BH3 -THF (15.0 ml, 1M) was added drop-wise. The reaction mixture was allowed to warm to room temperature and to stir under anhydrous conditions for 20 hours. The reaction mixture was again cooled to 0° C. and quenched with H2O. Ether and additional H2O were then added. The ether layer was extracted with H2O, sat. NaHCO3, and more H2O and dried (MgSO4). The solvent was removed under reduced pressure to yield a yellow oil. The crude compound was purified by column chromatography (90 g silica gel, hexanes-:ethyl acetate 8:1) to yield a white solid, compound 8, 12-m-iodophenyldodecanol (3.14 g, 98.4% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[CH3:9][O-:10].[Na+].C1(C)C=CC=CC=1>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:10][CH3:9])[CH:3]=1
Reactant: C[O-]
Reactant: Clc1cc(Br)ccn1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(Br)ccn1

Procedure:
4-Bromo-2-chloropyridine, sodium methoxide (1.6 equiv.) and toluene (6.1 volumes) were heated to 95° C. for 40 h. Toluene (6.1 volumes) and water (3 volumes) were added and the lower aqueous phase cut away. The organic was washed with water (1.5 volumes) and then the volatiles evaporated to give the title compound as an oil. HRMS (ES, M+H) Calcd 187.9711. Found 187.9711.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:7]=[C:8]([CH2:16]O)[CH:9]=[C:10]([F:15])[C:11]=1[N+:12]([O-:14])=[O:13].CO.C([O-])(O)=O.[Na+]>CCOCC>[Br:2][CH2:16][C:8]1[CH:9]=[C:10]([F:15])[C:11]([N+:12]([O-:14])=[O:13])=[C:6]([F:5])[CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cc(CO)cc1F
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=[N+]([O-])c1c(F)cc(CBr)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of PBr3 (7.04 mL, 73 mmol) in Et2O (200 mL) is added under argon at 0° C. a solution of (3,5-difluoro-4-nitro-phenyl)-methanol (9.3 g, 48.7 mmol) in Et2O (200 mL). The reaction mixture was allowed to warm to 25° C. and stirred for 24 h at 25° C. After the addition of MeOH (5 mL) at 0° C., the reaction mixture was poured onto cold aq. NaHCO3 solution and the product was extracted with EtOAc. Combined organic extracts were washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated to provide the title compound after filtration through a plug of silicagel with hexane-EtOAc 3:1 as a yellow solid: TLC (hexane-EtOAc 3:1) Rf=0.40; HPLC RtA=2.01 min; 1H NMR (400 MHz, CDCl3): δ 7.14 (d, 2H), 4.40 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]2[CH3:14])=[CH:4][C:3]=1[O:15][CH3:16].[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][C:32](O)=[O:33])[N:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:32](=[O:33])[CH2:31][N:24]3[C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:30]4[C:22]([C:18]4[NH:17][CH:21]=[CH:20][N:19]=4)=[N:23]3)[CH2:10][C@@H:9]2[CH3:14])=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(N2CCNC[C@@H]2C)ccc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)C[C@@H]2C)ccc1Cl

Procedure:
The title compound was prepared following protocol A. (S)-1-(4-Chloro-3-methoxyphenyl)-2-methylpiperazine and [3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (1% to 7% MeOH in CH2Cl2) to provide 1-[(S)-4-(4-chloro-3-methoxyphenyl)-3-methylpiperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) 8.77 (d, 0.6H), 8.66 (d, 0.3H), 8.57-8.54 (m, 1H), 7.30-7.19 (m, 4H), 6.48-6.40 (m, 2H), 5.54-5.36 (m, 2H), 4.25 (br. d, 0.6H), 4.00 (br. d, 0.6H), 3.88 (s, 1.3H), 3.86 (s, 1.7H), 3.82-3.48 (m, 3.2H), 3.36-3.29 (m, 0.6H), 3.17-3.13 (m, 2H), 1.51-1.43 (m, 3H); LC/MS m/z (M+H)+ 466.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:47]1([CH3:57])[CH:52]=[CH:51][C:50]([S:53](Cl)(=[O:55])=[O:54])=[CH:49][CH:48]=1>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[N:8]([S:53]([C:50]2[CH:51]=[CH:52][C:47]([CH3:57])=[CH:48][CH:49]=2)(=[O:55])=[O:54])[C:7](=[O:9])[C@H:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:4]
Reactant: COC(=O)[C@@H]1NC(=O)[C@H]1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1S(=O)(=O)c1ccc(C)cc1
Temperature: -20 °C
Reaction time: 48 h
Yield: 48.2 %

Procedure:
To a -78° C. THF (5 mL) solution of compound 7 (4.36 mg, 0.67 mmol) was added 1N THF solution of sodium bis(trimethylsilyl)amide (0.67 mL, 0.67 mmol), and the resultant solution was stirred for 15 min. p-Toluenesulfonyl chloride (134 mg, 0.70 mmol) was added, and the mixture was stirred at -78° C. for 4 h and at -20° C. for 21/2 days. The reaction mixture was partitioned between EtOAc and H2O. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (Et2O:hexane/3:2) to afford 210 mg (48%) of the title product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH:17]([C:19]([CH3:21])=[O:20])=[CH2:18]>>[CH:11]1([C:5]2[CH:6]=[CH:7][C:8]([CH2:18][CH2:17][C:19](=[O:20])[CH3:21])=[CH:9][CH:10]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: c1ccc(C2CCCCC2)cc1
Reactant: C=CC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)CCc1ccc(C2CCCCC2)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of aluminium chloride (0.15 mole) in cyclohexylbenzene (0.5 mole) at 10° - 15° C was added dropwise methyl vinyl ketone. The resulting mixture was left overnight at room temperature and worked up as above The crude ketone was purified by distillation, b.p. 150 - 60 (2 mm), followed by column chromatography using silica as support and petrol/ethyl acetate as eluants.
Reaction SMILES: O[CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:19]2[S:23][C@H:22]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)[CH2:21][S:20]2)[CH:10]=[C:11]([O:17][CH3:18])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(O)C>[O:39]1[CH2:40][CH2:41][N:36]([CH2:2][CH2:3][S:4]([C:7]2[CH:8]=[C:9]([C@H:19]3[S:23][C@H:22]([C:24]4[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=4)[CH2:21][S:20]3)[CH:10]=[C:11]([O:17][CH3:18])[C:12]=2[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5])[CH2:37][CH2:38]1
Reactant: CCCOc1c(OC)cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1S(=O)(=O)CCO
Reactant: C1COCCN1
Solvent: CCO
Product: CCCOc1c(OC)cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1S(=O)(=O)CCN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(3-(vinylsufonyl)-5-methoxy-4-propoxyphenyl)-4-(3,4,5-methoxyphenyl)-1,3-dithiolane (22) (FIG. 25) (0.040 g,0.076 mmole) was dissolved in absolute ethanol (10 ml) and morpholine (13 ml) was into the reaction which was stirred at room temperature for 4 hours. The solvent and excess amine were removed in vacuo, and the remaining oil purified by flash column chromatography with 1:1 hex/ethyl acetate as eluent. The product mixture (oil) contains a 1.0/1.0 cis/trans ratio (0.022.5 g, 49%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.Cl[S:16]([CH2:19][C@H:20]([CH3:31])[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])(=[O:18])=[O:17]>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:16]([CH2:19][C@H:20]([CH3:31])[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])(=[O:18])=[O:17])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: C[C@@H](CS(=O)(=O)Cl)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](CS(=O)(=O)N1CCN(C)CC1)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar was charged with 0.42 mL (1.05 eq) N-methyl-piperazine, 1 mL NEt3 and 20 mL CH2Cl2. The solution was cooled to 0° C. and 1.0 g of benzyl 3-chlorosulfonyl-2(R)-methylpropionate from Example 3 in 5 mL CH2Cl2 was added. After 1 hour reaction was concentrated in vacuo. The residue was partioned between EA/H2O and the organic phase was washed with saturated aqueous bicarb., brine, dried, and concentrated in vacuo to yield benzyl 3-[(4-methylpiperizin-1-yl)sulfonyl]-2(R)-methylpropionate which was used without further purification.
Reaction SMILES: [C:1]1([C@H:7]([CH2:11][CH3:12])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:28]3[C@H:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:30]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:28]3[C@H:24]([CH2:25][N:26]([C:8](=[O:10])[C@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:11][CH3:12])[CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: CC[C@H](C(=O)O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
N,N'-Carbonyldiimidazole (0.49 g) is added to a solution of (S)-2-phenylbutyric acid (0.5 g) in dry dichloromethane (15 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (0.98 g) and triethylamine (0.42 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 1.6 cm, height 9.7 cm), eluting with a mixture of ethyl acetate and cyclohexane (80/20 by volume) and collecting 30 cc fractions. The first fraction is concentrated to dryness under reduced pressure (2.7 kPa). The residue is re-chromatographed on a silica gel column (0.2-0.063 mm, diameter 1.3 cm, height 14.5 cm), eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 50 cc fractions. Fractions 1 to 3 are combined and concentrated to dryness under reduced pressure (2.7 kPa). (3aR,7aR)-7,7-diphenyl-2-[(S)-2-phenylbutyryl]-4-perhydroisoindolone (0.54 g) is obtained in the form of a white meringue. [α]D20 =-216° (c=1, methanol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:47]2[NH:48][C:49]3[C:54]([C:55]=2[CH2:56][CH2:57][NH2:58])=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]>>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:47]2[NH:48][C:49]3[C:54]([C:55]=2[CH2:56][CH2:57][NH:58][C:12](=[O:14])[CH2:11][CH2:10][C:6]2[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]4)=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]
Reactant: O=C(O)CCc1ccc2[nH]ccc2c1
Reactant: COc1ccc(-c2[nH]c3ccccc3c2CCN)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: COc1ccc(-c2[nH]c3ccccc3c2CCNC(=O)CCc2ccc3[nH]ccc3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.38 h
Yield: 89.8 %

Procedure:
To a solution of 3-(1H-indol-5-yl)propionic acid (50 mg in 2.5 mL N,N-dimethylformamide) at 0° C. was added 43 mg 1-hydroxy-benzotriazole followed by 71 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the mixture allowed to warm to room temperature. After 23 minutes, 155 mg of 2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]-ethylamine was added and the mixture stirred at room temperature for an additional hour. The reaction was then quenched by the addition of water and the mixture extracted with ethyl acetate. The combined organics were washed with water and brine, dried over sodium sulfate and the concentrated oil purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (111 mg).