Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1.[CH3:19][C:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[NH:22][N:21]=1.C(N(CC)CC)C>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:25]([C:23]3[NH:22][N:21]=[C:20]([CH3:19])[CH:24]=3)=[O:26])[CH2:16][CH2:17]2)=[CH:6][CH:5]=1
Reactant: O=C(CN1CCNCC1)c1ccc(F)cc1
Reactant: Cc1cc(C(=O)O)[nH]n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCN(CC(=O)c3ccc(F)cc3)CC2)[nH]n1
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-(piperazin-1-yl)ethanone dihydrochloride (29.5 mg, 0.100 mmol, from Step B of Example 1.1), 3-methyl-1H-pyrazole-5-carboxylic acid (18.9 mg, 0.150 mmol), and triethylamine (0.139 mL, 1.00 mmol) in DMF (0.5 mL) was added 1-propylphosphonic acid anhydride solution (50 wt. % in ethyl acetate, 122 μL, 0.200 mmol). The mixture was stirred for 2 h, quenched with water and purified by preparative HPLC/MS. The resultant lyophilate was dissolved in DCM, treated with MP-carbonate resin (˜100 mg). The mixture was stirred for 30 min and filtered to remove the resin. The solvent was removed under reduce pressure to afford the title compound (26.0 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.34 (s, 3H), 2.66 (bs, 4H), 3.82 (s, 2H), 3.88 (bs, 2H), 4.02 (bs, 2H), 6.38 (s, 1H), 7.14 (t, J=8.59 Hz, 2H), 7.99-8.09 (m, 2H). Exact mass calculated for Cl17H19FN4O2: 330.2. Found: LCMS m/z=331.3 (M+H+).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].[C:14]([O-])(O)=O.[Na+]>CO>[CH3:14][O:5][C:4](=[O:6])[CH:3]([OH:2])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])O
Reactant: O=C(O)C(O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Hydrogen chloride was bubbled for 15 minutes into a solution of 2-hydroxy-3-phenyl-propionic acid (10.0 g, 60 mmol) in 100 mL of methanol at room temperature. The vessel was sealed and then stirred overnight at room temperature. The reaction was made basic by the addition of 5% NaHCO3 and then concentrated under reduced pressure to remove the methanol. The residue was diluted with water and extracted with ethyl acetate. The organic layer was extracted with saturated NaCl, dried (MgSO4), filtered and the solvent removed under reduced pressure to give 2-hydroxy-3-phenyl-propionic acid methyl ester (9.7 g, 90%) as a yellow oil, MS m/z 180 [M]+. Elemental Analysis for C10H12O3 Calc'd: C, 66.65; H, 6.71; N, 0.00. Found: C, 66.52; H, 6.86; N, 0.29
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24]CC=C)=[C:20]([C:28]([O:30][CH3:31])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].Cl[C:33]1[CH:38]=CC=C[C:34]=1Cl>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:38][CH:33]=[CH2:34])[C:21]([OH:24])=[C:20]([C:28]([O:30][CH3:31])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1ccc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc1C(=O)OC
Product: C=CCc1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc(C(=O)OC)c1O

Procedure:
A solution of 1 g of 2-(3,4-diethoxyphenyl)-4-(4-allyloxy-3-methoxycarbonylphenyl)thiazole in 25 ml of o-dichlorobenzene was refluxed for 15 hours with heating. After the completion of a reaction, the solvent was removed by distillation. The residue was recrystallized from diisopropyl ether to obtain 1 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-allylphenyl)thiazole.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:16][CH3:17])[C:5]([NH:8][C:9](=[O:15])[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[N:6][CH:7]=1.[H-].[Na+].[I:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([O:16][CH3:17])[C:5]([N:8]([C:9]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:15])[S:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[I:20])(=[O:29])=[O:28])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1I
Reactant: COc1nc(Cl)cnc1NC(=O)OCC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(Cl)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
Isobutyl N-(5-chloro-3-methoxypyrazin-2-yl)carbamate (3.34 g) was added to a stirred suspension of sodium hydride (60% dispersion in oil; 0.56 g) in dry N, N dimethylformamide (20 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour and then a solution of 2-iodobenzenesulphonyl chloride (obtained as described in J Org Chem, 1977, 42, 3265) (4.68 g) was added. The mixture was stirred for 2 hours and then volatile material was removed by evaporation. The residue was dissolved in water (50 ml) and the solution was acidified with 20% aqueous citric acid and extracted with ethyl acetate (3×20 ml). The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 10-35% ethyl acetatesohexane through a silica gel Mega Bond Elut column to give N-(5-chloro-3-methoxypyrazin-2-yl)- N-(isobutoxycarbonyl)-2-iodobenzenesulphonamide (2.64 g); 1H NMR (d6 -DMSO): 0.67 (s, 6H), 1.65-1.8 (m, 1H), 3.9 (d, 2H), 4.0 (s, 3H), 3.9 (s, 3H), 7.4 (dd, 1H), 7.8 dd, 1H), 8.2 (d, 1H), 8.3 (d, 1H), 8.4 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Br:23])=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(OCc2ccccc2)ncn1Cc1ccccc1
Solvent: CN(C)C=O
Product: O=c1c(Br)c(OCc2ccccc2)ncn1Cc1ccccc1
Temperature: 0 °C

Procedure:
3-benzyl-6-(benzyloxy)-pyrimidin-4(3H)-one (from Step 1) (5.00 g, 17.1 mmol) and N-bromosuccinimide (3.15 g, 17.7 mmol) are stirred in 100 ml anhydrous dimethylformamide for 20 hours. The solution is poured onto 1 L of ice with stirring and allowed to come to room temperature, when the product is collected by filtration. (5.97 g). The product is recrystallized from 60 mL hot acetonitrile (4.75 g, 75%) 1H-NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.28-7.44 (overlapping m, 9H), 7.24 (s, 1H), 5.43 (s, 2H), 5.12 (s, 2H). LC/MS tr=5.89 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 254 nm, at 50° C.) ES-MS m/z 371 (M+H). HRMS m/z 371 (M+H) 371.0399, calc. 371.0395.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].Cl[C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:13][C:12]=1[N+:24]([O-:26])=[O:25].Cl.[N+](=C)([O-])[O-]>C1COCC1.O>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C:11]1[CH:23]=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[N+:24]([O-:26])=[O:25])[C:1]([O:8][CH3:9])=[O:7]
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)CC(=O)OC
Agent: C=[N+]([O-])[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Yield: 87.3 %

Procedure:
Sodium hydride (13.5 g of a 60% dispersion in oil, 0.34 mol) was washed with petroleum ether (×3) under nitrogen and suspended in dry THF (400 mL). A solution of dimethyl malonate (40.4 mL, 0.35 mol) in THF (50 mL) was added dropwise over 45 min with water-bath cooling, keeping the internal temperature below 30° C., and the resulting gel was broken up with more dry THF (300 mL). The above t-butyl 4-chloro-3-nitrobenzoate (21.7 g, 84 mmol) was added and the mixture was stirred at reflux under nitrogen for 15 h. The red-brown solution was cooled, poured into water, and aqueous HCl (2 N, ca. 60 mL) added slowly until the red nitronate colour was dispersed. The THF was evaporated and the aqueous phase extracted with CH2Cl2 (×3), the extracts were dried (Na2SO4) and evaporated. Formic acid (100 mL) was added to the residue and the mixture was stirred at 50° C. for 4 h (when tlc analysis showed no remaining t-butyl ester). The formic acid was evaporated and the residue was taken up in EtOAc and washed with water (×3). The organic layer was extracted with aqueous NaHCO3 (×2), and the aqueous phase was acidified (conc. HCl), and extracted with CH2Cl2 (×2). The organic layer was dried (Na2SO4), evaporated, and the resulting cream solid recrystallized from benzene (ca. 250 mL) to give dimethyl(4-carboxy-2-nitrophenyl)malonate as cream prisms (21.8 g, 87%), mp 147-149° C. 1H NMR ((CD3)2SO) δ13.77 (br s, 1H, CO2H), 8.52 (d, J=1.7 Hz, 1H, H-3), 8.28 (dd, J=8.1, 1.7 Hz, 1H, H-5), 7.70 (d, J=8.1 Hz, 1H, H-6), 5.62 (s, 1H, ArCH), 3.71 (s, 6H, CO2Me); 13C NMR δ166.9, 165.1 (COOMe, COOH), 148.2, 134.0, 133.1, 132.3, 132.1, 125.5 (C-1,2,3,4,5,6), 54.3 (ArCH), 52.9 (OMe). Anal. Calculated for C12H11NO8 : C, 48.5; H, 3.7; N, 4.7. Found: C, 48.7; H, 3.5; N, 4.7%.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].C1(C)C(C)=CC=CC=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]1[C:23](=O)[CH2:22][NH:21][C:20]1=[O:25]>O>[NH2:5][C:23]1[CH2:22][NH:21][C:20](=[O:25])[C:19]=1[C:15]1[S:14][CH:18]=[CH:17][CH:16]=1
Reactant: [NH4+]
Reactant: O=C1CNC(=O)C1c1cccs1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Solvent: O
Product: NC1=C(c2cccs2)C(=O)NC1
Yield: 99 %

Procedure:
To a round bottom flask with a Dean-Stark distilling receiver, ammonium acetate (20.90 g, 271 mmol) and xylene (215 mL) were charged and kept at 60° C. Then 3-thiophen-2-yl-pyrrolidine-2,4-dione (19.0 g, 105 mmol) was added portionwise. The mixture was heated to reflux until there was no more water collected by the receiver (about 15 mL water) and a sticky gel was formed at the bottom. After cooling, toluene was decanted and the sticky gel was further washed by toluene and water and dried under vacuum at 80° C. Finally, a sticky gel was obtained (18.3 g, yield 99%), which can be used directly for the preparation of various compounds having one or more pyrrolo[3,2-b]pyrrole-2,5(1H,4H)-dione-3,6-diyl units. 1H NMR (d6-DMSO, 500 MHz), δ=7.23 (s, 1H), 7.22 (s, 1H), 7.10 (s, 1H), 7.00 (dd, J=5.0, 4.0 Hz, 1H), 6.77 (s, 2H), 3.82 (s, 2H).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([O:15][C:16](=[O:37])[CH2:17][O:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:30][O:31]C(OCC)C)[CH3:14]>CCO>[CH2:13]([O:15][C:16](=[O:37])[CH2:17][O:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:30][OH:31])[CH3:14]
Reactant: CCOC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1COC(C)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CO
Reaction time: 18 h
Yield: 76.4 %

Procedure:
p-Toluenesulfonic acid hydrate (267 mg, 1.40 mmol) was added to a solution of {(Z)-4-[(R)-2-(1-ethoxyethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-enyloxy}-acetic acid ethyl ester (from example 50, step 2, 477 mg, 1.33 mmol) in EtOH (6 mL). After 18 h at rt, the reaction was concentrated in vacuo and quenched with saturated aqueous NaHCO3 (20 mL). The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 290 mg (76%) of [(Z)-4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-enyloxy]-acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[I-:13].[Na+].C(Cl)(=O)C>C(#N)C>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:5]([I:13])=[N:6][CH:7]=1
Reactant: FC(F)(F)c1cc(Cl)ncc1Br
Reactant: [I-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: FC(F)(F)c1cc(I)ncc1Br
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 39.5 %

Procedure:
Prepared using General Procedure 17: To a stirred a solution of 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (150 mg, 0.576 mmol) in acetonitrile (2 mL) was added sodium iodide (518 mg, 3.45 mmol). The reaction mixture was heated to 40° C. and acetyl chloride (26.0 mg, 0.345 mmol) was added. The reaction mixture was stirred at 40° C. for 90 min. Once cooled, the reaction was quenched with NaHCO3 (5 mL) and extracted with EA (3×5 mL). The combined organics were washed with brine (10 mL), dried over MgSO4 and concentrated to give 80.0 mg (40%) of 5-bromo-2-iodo-4-(trifluoromethyl)pyridine as a white crystalline solid which was used in the subsequent step without purification. LCMS-ESI (m/z) calculated for C6H2BrF3IN, 351.9; found 352.5 [M+H]+, tR=3.91 min. (Method 1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:23]=[CH:22][C:11]2[N:12]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13](=[O:16])[N:14]([CH3:15])[C:10]=2[CH:9]=1.[OH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>O.C1COCC1>[CH3:19][C:18]([CH3:21])([CH3:20])[CH2:17][N:12]1[C:11]2[CH:22]=[CH:23][C:8]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:24])[CH:30]=3)=[CH:9][C:10]=2[N:14]([CH3:15])[C:13]1=[O:16]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(Br)cc21
Reactant: OB(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(O)c3)cc21
Reaction time: 0.25 h

Procedure:
A solution of Cesium carbonate (3.66 g, 11.2 mmol, 3.0 eq) in Water (1 ml) was charged with a solution of 5-bromo-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1-5, 1.37 g, 3.74 mmol) dissolved in anhydrous THF (19 ml). 3-Hydroxyphenyl boronic acid was introduced and the solution was deoxygenated. The 1,1′-Bis(diphenylphosphino) ferrocene-palladium(II)dichloride dichloromethane complex (153 mg, 0.19 mmol, 0.05 eq) was introduced and the mixture was irradiated in a microwave at 125 deg C. for 15 min. LC/MS analysis showed ˜50% conversion, so more of each reagent was added and the reaction was irradiated again at 120 deg C. for 30 min. The completed reaction was partitioned between EtOAc (2×25 ml) and saturated aqueous NaHCO3 (25 ml), and the combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography (SiO2: 100% Hex to 60:40 EtOAc/Hex), affording 1-(2,2-dimethylpropyl)-5-(3-hydroxyphenyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1479) as a pink-orange solid. 1H NMR (500 MHz, CDCl3) δ 7.34-7.29 (m, 2H), 7.21-7.15 (m, 2H), 7.11-7.06 (m, 2H), 6.81 (d, 1H, J=5.4 Hz), 3.68 (s, 2H), 3.47 (s, 3H), 1.07 (s, 9H). LRMS m/z: Calc'd for C19H22N2O2 (M+H) 311.4, found 311.1.
Reaction SMILES: [NH:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(C(C)C)CC)(C)C.[Br:29][C@H:30]([CH3:34])[C:31](Cl)=[O:32]>ClCCl>[Br:29][C@H:30]([CH3:34])[C:31]([N:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:32]
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Reactant: C[C@@H](Br)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Br)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21
Reaction time: 1 h

Procedure:
Introduce 200 g of benzyl (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylate and 1.5 liters of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0° C. and add 201 ml of diisopropylethylamine followed by 132 g of (2R)-2-bromo-propionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with a dilute acetic acid solution. The benzyl (2S,3aS,7aS)-1-[(2R)-2-bromopropionyl]octahydro-1H-indole-2-carboxylate solution so obtained is used as it is in the following Step.
Reaction SMILES: C[O-].[Na+].[C:4]1(C)[CH:9]=CC=C[CH:5]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].C(Cl)C=C>O>[CH2:9]([N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])[CH:4]=[CH2:5]
Reactant: O=C1CCCN1
Reactant: Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C=CCCl
Product: C=CCN1CCCC1=O
Yield: 89.9 %

Procedure:
To a 5 liter volume flask of glass equipped with a stirrer, a fractional distillation column, a thermometer and a dropping funnel, there were added 270.1 g (5.0 mol) of sodium methoxide and 2 liters of toluene. After 425.6 g (5.0 mol) of 2-pyrrolidone was dropwise added to the flask through the dropping funnel at room temperature, the resulting methanol was completely removed by the fractional distillation column. 6.9 g (25 mmol) of (Butyl-)4NCl was added as a phase transfer catalyst and 382.7 g (5.0 mol) of allyl chloride was dropwise added to the reaction mixture at a temperature ranging from 60° to 70° C. through the dropping funnel to react them. After the completion of the reaction, water was added to dissolve salts formed during the reaction and then the organic phase was removed. Then the organic phase was distilled to separate the fractions having a boiling point ranging from 75° to 76° C./4 mmHg. Thus, 562.5 g of 1-allyl-2-oxopyrrolidine was obtained in a yield of 89.9%.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[C:14]3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)=[C:14]3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1)(=[O:35])[CH3:34]
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (example D.f6) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:21])[C@@H:15]([NH2:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.Br[CH2:39][CH:40]=[C:41]([CH3:43])[CH3:42]>C1COCC1>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:21])[C@@H:15]([NH:20][CH2:39][CH:40]=[C:41]([CH3:43])[CH3:42])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=1
Reactant: CC(C)C[C@H](N)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)=CCBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)=CCN[C@@H](CC(C)C)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
To a solution of (S)-2-amino-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide monohydrochloride (0.36 g, 0.88 mmol, Example 7) in THF (15 mL) were added, in succession, N,N-diisopropylethylamine (0.30 mL, 1.7 mmol) and 1-bromo-3-methyl-2-butene (0.10 mL, 0.87 mmol) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 12 hours at that temperature, 16 hours at 50° C., cooled to ambient temperature, and concentrated in vacuo. The desired product was purified by flash chromatography (50% EtOAc in hexanes) and was dissolved in 10 mL of ethyl ether. To this solution was added saturated HCl solution in ethyl ether until no more white precipitate formed. Filtration and drying overnight under vacuum afforded 0.14 g (36%) of the titled compound as a yellow foam; mp 58-72° C. APCI-MS m/z 443.3 (MH+).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH:30]=[O:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]([Si:41]([CH3:55])([CH3:54])[O:42][CH2:43][C@@H:44]1[CH2:53][N:52]2[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]2)[CH2:46][NH:45]1)([CH3:40])[CH3:39].[Cl-].[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:45]3[C@H:44]([CH2:43][O:42][Si:41]([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:54])[CH3:55])[CH2:53][N:52]4[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]4)[CH2:46]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH:30]=[O:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1C=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)cc1-c1ccccc1C=O
Temperature: 90 °C
Yield: 18 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-formyl phenyl)-3-pyridinyl]-N,2-dimethylpropanamide (D59, 106 mg, 0.201 mmol), (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D51, 72 mg, 0.251 mmol) were dissolved in toluene (2 mL). Bis tritertbutylphosphine palladium (27 mg, 0.052 mmol), followed by hexadecyltrimethylammoium chloride (30 μL, 25% aq sol), and finally sodium hydroxide solution (0.25 mL, 50% aq sol) were added. The mixture was degassed for 5 minutes before heating at 90° C. for 2 hours. Reaction cooled to R.T., diluted with EtOAc, washed with sat NaHCO3 solution, dried (MgSO4). Filtered. Solvent evaporated. Residue purified eluting with 0-50% EtOAc/Pent. Solvent evaporated under reduced pressure to afford a pale yellow solid in 18% yield.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Cc1cccc2sc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 42.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-methylbenzothiazole (84 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 66 mg (43%) of the title compound as an amorphous solid. mp 134°-142° FDMS: m/e =408. α[D]589 =+62.80 (c=0.74, chloroform).