Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:2]1.[NH:17]1[C:25]2[C:20](=[C:21]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[NH:17]1[C:25]2[C:20](=[C:21]([N:26]3[CH2:31][CH2:30][N:29]([C@@H:13]4[CH2:14][CH2:15][C@H:10]([C:3]5[C:4]6[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=6)[NH:1][C:2]=5[CH3:32])[CH2:11][CH2:12]4)[CH2:28][CH2:27]3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: O=C1CCC(c2c[nH]c3ccccc23)CC1
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1[nH]c2ccccc2c1[C@H]1CC[C@@H](N2CCN(c3cccc4[nH]ccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
A solution of 4-(1H-indol-3-yl)-cyclohexanone (1.44 g, 6.33 mmol), 1-(indol-4-yl)piperazine (1.27 g, 6.33 mmol), sodium triacetoxyborohydride (1.88 g, 8.86 mmol) and acetic acid (0.76 mg, 12.6 mmol) in 1,2-dichloroethane (100 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (80 ml), extracted with methylene chloride (3×300 ml), and washed with brine (150 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum to afford an off-white solid. Trituration of the solid with warm methylene chloride (80 ml) followed by filtration afforded 0.88 g of white solid. The mother liquor was concentrated and chromatographed (2% methanol-methylene chloride) to afford another 0.18 g (total yield 40.7%) of product as a white solid: mp 279-280° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.OC[CH2:39][N:40]1[C:48](=[O:49])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]1=[O:50].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][CH2:39][N:40]2[C:48](=[O:49])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]2=[O:50])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCN4C(=O)c5ccccc5C4=O)cc3C)c2cc1OC
Yield: 68.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-(2-hydroxyethyl)-1,3-isoindolinedione (44 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (57 mg, yield 66%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C)cc1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(C)cc1

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-p-tolyl-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.93 min; [M+H]+=248.02.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18]C(=O)CCl)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][CH2:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])=[O:4]
Reactant: O=C(CCl)Oc1ccccc1CCC1SCCN1C(=O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C(CCl)N1CCSC1CCc1ccccc1O
Yield: 89.9 %

Procedure:
A solution of 3-chloroacetyl-2-[2'-(o-chloroacetoxyphenyl)ethyl]thiazolidine (5.5 g) in dry methanol is treated with p-toluenesulphonic acid (0.5 g) at room temperature for 2 days. The excess of solvent is evaporated in vacuum and then the mixture is diluted with water (80 ml). The crystalline precipitate is collected by filtration, dried in vacuum and recrystallized from Et2O to give 3.9 g of 3-chloroacetyl-2-[2'-(o-hydroxyphenyl)ethyl]thiazolidine m.p. 98° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][C@@H:4]([NH2:8])[C:5]([OH:7])=[O:6].[OH-].[Na+].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>O1CCCC1>[C:16]1([CH2:15][O:14][C:12]([NH:8][C@H:4]([CH2:3][CH:2]=[CH2:1])[C:5]([OH:7])=[O:6])=[O:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CC[C@@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 411.3 %

Procedure:
A mixture of D-allylglycine (2.8 g, 24.3 mmol), 1M aqueous sodium hydroxide solution (25 ml), and tetrahydrofuran (10 ml, distilled from ketyl) was stirred at room temperature until homogeneous then cooled in an ice-bath. To the resulting rapidly stirred solution was added about 5 mL of 1.0M aqueous sodium hydroxide solution then dropwise about 1 g of benzyl chloroformate. This was repeated 4 additional times until a total of 28 mL of 1.0M aqueous sodium hydroxide solution and 4.80 g (95%, 27 mmol) of benzyl chloroformate were added. The reaction mixture was stirred for 15 minutes at 0° C. then 30 minutes at room temperature and then extracted with 50 mL of ether. The aqueous layer was acidified (pH=1.5) the by addition of 6N hydrochloric acid solution (about 10 mL) then extracted with three-50 mL portions of ether. The three ether extracts were combined, dried (magnesium sulfate) and concentrated in vacuo to afford 6.01 g of title product as a colorless oil.
Reaction SMILES: Br[C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[C:15]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]([CH3:22])=[N:17]2.[CH3:28][Zn]C>O1CCOCC1.C(Cl)Cl>[C:24]([NH:23][C:15]1[C:16]([CH3:22])=[N:17][C:18]2[C:13]([N:14]=1)=[C:12]([C:3]1[NH:4][C:5]3[CH2:10][CH2:9][NH:8][C:7](=[O:11])[C:6]=3[C:2]=1[CH3:28])[CH:21]=[CH:20][CH:19]=2)([CH3:27])([CH3:26])[CH3:25]
Reactant: C[Zn]C
Reactant: Cc1nc2cccc(-c3[nH]c4c(c3Br)C(=O)NCC4)c2nc1NC(C)(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3[nH]c4c(c3C)C(=O)NCC4)c2nc1NC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (349) (61 mg, 0.14 mmol), dimethylzinc in hexanes (0.39 mL of 10% wt. in hexanes, 0.570 mmol, Strem Chemicals, Inc.,), and (A-Phos)2PdCl2 (10 mg, 0.014 mmol) in dioxane (1.42 mL) was stirred at 80° C. for 2 h when product was observed via lcms. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (2×75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 1-4% of 2 M NH3 in MeOH/DCM to give impure 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one contaminated with starting material. The impure product was purified via SFC [IC (3×15 cm, 5 μm), 60% 0.2% DEA in MeOH: EtOH: isopropanol (1:1:1) (NH4OH)/CO2, 100 bar; 65 mL/min, 220 nm; inj vol.: 1.5 mL, 3.5 mg/mL in MeOH] to give 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (350, 10 mg, 0.028 mmol, 19% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.60 (s, 9H) 2.55 (s, 3H) 2.69 (s, 3H) 2.95 (t, J=6.85 Hz, 2H) 3.61 (td, J=6.85, 2.54 Hz, 2H) 4.79 (s, 1H) 5.18 (br. s., 1H) 7.42 (t, J=7.92 Hz, 1H) 7.68 (dd, J=8.12, 1.27 Hz, 1H) 7.85 (dd, J=7.53, 1.08 Hz, 1H) 11.62 (br. s., 1H). MS (ESI, pos. ion) m/z: 364.2 (M+1).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1([CH3:14])[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[NH:7]1.[CH2:15]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[CH2:24]([N:23]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:1]([N:7]1[C:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][CH2:11][C:6]1([CH3:14])[CH3:5])=[O:2])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: CCCCCCCCNCCCCCCCC
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCN(CCCCCCCC)C(=O)N1C(C)(C)CCCC1(C)C

Procedure:
To a solution of phosgene in toluene (24.7 ml of a 20% solution, corresponding to 0.05 mol of phosgene) is added dropwise at -30°, within one hour, the solution of 14.2 g (0.1 mol) of 2,2,6,6-tetramethylpiperidine in 25 ml of toluene. Stirring is maintained at 0° for a further 2 hours; there are then added dropwise, within 2 hours, 26.7 g (0.11 mol) of di-n-octylamine in 25 ml of toluene, and the mixture is subsequently stirred for 16 hours at room temperature. In further processing, the salt which has precipitated is filtered off; the filtrate is afterwards repeatedly washed with a small amount of water, dried over sodium sulfate, and the solvent is completely distilled off in a water-jet vacuum. The crude compound is further purified by column chromatography on silica gel (eluant: hexane/diethyl ether 9:1) to obtain the pure 1-di-n-octylcarbamoyl-2,2,6,6-tetramethylpiperidine (compound No. 11) as a viscous liquid; nD20 : 1.4728.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10]N.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>S(=O)(=O)(O)O.O1CCOCC1>[Cl:2][C:3]1[C:4]2[NH:10][C:16]3[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][C:15]=3[C:5]=2[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: CN1CCC(=O)CC1
Reactant: NNc1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3c(Cl)cc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2,4-Dichlorophenyl hydrazine hydrochloride (1 equiv.) is taken in 7% sulfuric acid in 1,4-dioxan. N-Methylpiperidine-4-one (0.76-1.4 equiv.) is added and the contents are stirred at RT for 15 min., followed by heating at 80° C. for 14 h. After completion of the reaction, as monitored by LCMS, the solvent is removed in vacuo, basified with saturated aq. NaHCO3 and extracted with EtOAc. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated. The resulting crude product is purified by column chromatography to afford 6,8-dichloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].CO[C:10](=O)[C@H:11]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>C1COCC1>[C:16]([O:15][C:13]([NH:12][CH:11]([C:10]1[O:5][N:4]=[C:1]([CH3:2])[N:3]=1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(C(Cc2ccccc2)NC(=O)OC(C)(C)C)n1
Yield: 48.7 %

Procedure:
To a solution of acetamide oxime [2.67 g, J. Saunders et al., J. Med. Chem., 33, 1128 (1990)] in THF (125 ml) was added 60% sodium hydride (1.44 g) in oil, and the mixture was refluxed under heating for 1 hour. Then, the reaction mixture was allowed to cool, and a solution of N-tert-butoxycarbonyl-L-phenylalanine methyl ester (8.38 g) in THF (40 ml) was added at room temperature. The mixture was refluxed under heating for 20 minutes. The mixture was allowed to cool, and water (10 ml) was added, which was followed by concentration under reduced pressure. A 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1 v/v) to give 4.43 g of N-tert-butoxycarbonyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-phenylethylamine. This compound was added to a 4N hydrogen chloride-dioxane solution (50 ml), and the mixture was stirred at room temperature for 2 hours. Toluene was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ether was added to the residue for crystallization to give the title compound (3.25 g, yield 47%).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][CH2:7][C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([NH:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][O:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:13]=1)(=[O:26])=[O:25]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1cccc(COCCC2CC2)n1
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1cccc(COCCC2CC2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(2-cyclopropyl-ethoxymethyl)-pyridin-2-ylamine (0.08 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.117 g) as a light yellow gum (0.088 g). MS (ESI−): 413.1 ([M−H]−).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH:6]1[CH2:8][O:7]1)([CH3:3])[CH3:2].[CH3:9][CH:10]([CH3:12])[O-:11].[K+].C(O)(=O)C>CCCCCC.C(O)(C)C>[CH:10]([O:11][CH2:8][CH:6]([OH:7])[CH2:5][O:4][CH:1]([CH3:3])[CH3:2])([CH3:12])[CH3:9]
Reactant: CC(C)[O-]
Reactant: CC(C)OCC1CO1
Agent: [K+]
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(C)OCC(O)COC(C)C
Temperature: 80 °C

Procedure:
2-(Isopropoxymethyl)oxirane (23.23 g, 25.1 mL, 200 mmol) was dissolved in hexane (20 mL) and placed in reactor. Separately (1.2 g, 20 mmol) of KH was slowly added to (90.1 g, 115 mL, 1.5 Mol) of isopropanol at RT. After deprotonation was complete the solution of potassium isopropoxide in isopropanol was added to the reactor. All operations were performed in a glove box. The reactor was sealed and heated 80° C. for 24 hours. After cooling acetic acid (20 mmols) and ca. 5 g. of powdered talc were added to the reaction mixture followed by filtration through a plug of celite. The solvent was evaporated and the residue distilled under vacuum affording 20.09 g of 1,3-diisopropoxypropan-2-ol.
Reaction SMILES: [P:1]([O-:63])([O:59][CH2:60][CH2:61]Br)([O:3][CH:4]([C@H:32]1[C@H:37]([O:38][C:39](=[O:58])[NH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:36][CH2:35][CH2:34][O:33]1)[C@H]1[C@H](OC(=O)NCCCCCCCCCCCCCCCCC)CCCO1)=[O:2].[CH3:64][N:65]([CH3:67])[CH3:66]>C(Cl)(Cl)Cl.C(O)(C)C.CN(C)C=O.C(=O)([O-])[O-].[Ag+2]>[P:1]([O-:63])([O:59][CH2:60][CH2:61][N+:65]([CH3:67])([CH3:66])[CH3:64])([O:3][CH2:4][C@H:32]1[C@H:37]([O:38][C:39](=[O:58])[NH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:36][CH2:35][CH2:34][O:33]1)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCNC(=O)O[C@@H]1CCCO[C@H]1C(OP(=O)([O-])OCCBr)[C@@H]1OCCC[C@H]1OC(=O)NCCCCCCCCCCCCCCCCC
Reactant: CN(C)C
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCNC(=O)O[C@@H]1CCCO[C@H]1COP(=O)([O-])OCC[N+](C)(C)C
Reaction time: 6 h

Procedure:
1.402 g of dl-[trans-3-(N-heptadecylcarbamoyloxy)tetrahydropyran-2-yl]methyl 2-bromoethyl phosphate (prepared as described in Example 1f) was dissolved in a 3:5:5 by volume mixture of chloroform, isopropanol and dimethylformamide, and 7.0 g of gaseous trimethylamine were introduced into the solution. The mixture was heated, under a nitrogen atmosphere, on an oil bath kept at 50° for 6 hours, whilst stirring, and was then cooled, after which 0.483 g of silver carbonate was added The mixture was heated under reflux for 1 hour, and then the solvent was distilled off. Methanol was added to the residue and insolubles were separated by filtration. The solvent was stripped from the resulting solution by evaporation under reduced pressure. The residue was purified by liquid chromatography [using 30 g of silica gel and a Lobar column (size B)], giving 0.930 g of the title compound as a white powder from the fractions eluted with a 32:7:1 by volume mixture of methylene chloride, methanol and water.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:34])[C@@H:16]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:17][C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]2)=[N:10]1)(C)(C)C.C(O)C>Cl.C(#N)C>[OH:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:34])[C@@H:16]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=2)[CH2:17][C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]2)=[N:10]1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2cccc(C(F)(F)F)c2)n1
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: O=C1CC[C@H](C[C@@H](C(=O)Nc2ccn(CCO)n2)c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
In a flask containing (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (70 mg, 0.13 mmol) was added ethanol (2 mL) and concentrated hydrochloric acid (three drops) and it was stirred at 25° C. for 1 h. It was then diluted with acetonitrile and absorbed onto silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes to 10% methanol/ethyl acetate) to afford (R)—N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (49 mg, 89%) as a yellow foam: [α]25589=−79.3° (c=0.14, methanol); ES-HRMS m/e calcd for C20H22N3O3F3 (M+H)+ 410.1686, observed 410.1687; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.73-2.30 (m, 8H, 4×CH2), 3.66 (m, 2H, OCH2), 3.95 (m, 1H, ArCHCO), 3.99 (m, 2H, NCH2), 4.83 (t, J=5.4 Hz, 1H, OH), 6.41 (d, J=2.0 Hz, 1H, Ar), 7.54 (d, J=2.0 Hz, 1 H, Ar), 7.60 (m, 2H, Ar), 7.69 (brd, 1H, Ar), 7.73 (brs, 1H, Ar), 10.79 (s, 1H, NH).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[Cl:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:21])[N:4]=1.I([O-])(=O)(=O)=[O:23].[Na+].CN(C=O)C>CCOC(C)=O>[Cl:21][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[Cl:20])[C:3]([CH:2]=[O:23])=[N:4]2
Reactant: Fc1ccc(Cl)c(-c2nc3c(Cl)cccc3nc2CBr)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(bromomethyl)-5-chloro-3-(2-chloro-5-fluorophenyl)quinoxaline (Prepared in Example 100, 0.5625 g, 1.457 mmol) and sodium metaperiodate (0.1613 mL, 2.914 mmol) in DMF (9.714 mL, 1.457 mmol) was heated at 150° C. with stirring. After 3 h, the mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 20 min, then 10 to 20% gradient of EtOAc in hexane over 20 min, then 20% isocratic of EtOAc for 3 min as eluent to give 5-chloro-3-(2-chloro-5-fluorophenyl)quinoxaline-2-carbaldehyde as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.16 (1 H, s), 8.35-8.41 (1 H, m), 8.29-8.34 (1 H, m), 8.07 (1 H, dd, J=8.4, 7.6 Hz), 7.68 (1 H, dd, J=8.8, 4.9 Hz), 7.44-7.58 (2 H, m); LC-MS (ESI) m/z 321.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH:16](OS(C)(=O)=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@H:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][CH2:14][Cl:13]
Reactant: CS(=O)(=O)OC(CCCl)c1ccccc1
Reactant: Clc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCC[C@@H](c1ccccc1)n1ccc2c(Cl)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloroindole (0.222 g) in dry DMF (7.5 ml) was added sodium hydride (0.064 g) at room temperature. The mixture was stirred at the same temperature for 30 minutes and then the crude methanesulfonic acid 3-chloro-1-phenyl-propyl ester from the previous step was dissolved in DMF (5 ml) and added at 0° C. to the reaction mixture and stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was washed twice with water and once with brine, then dried over magnesium sulfate, filtered and evaporated to dryness to afford an oil. Purification of the crude product was done by column chromatography on silica gel, eluting the desired product with ethyl acetate-hexane (1:9). The (S) 4-chloro-1-(3-chloro-1-phenyl-propyl)-1H-indole thus produced weighed 0.251 g, sufficiently pure for use in the following step.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([CH3:16])([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:17])[CH:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([CH3:16])([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:17])[CH:3]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:26])[CH3:25]
Reactant: CC(C)(c1ccccc1)N1CCC(O)C(c2ccccc2)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1CCN(C(C)(C)c2ccccc2)C(=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.6 g (0.0117 mol) of 4-hydroxy-1-(α,α-dimethylbenzyl)-3-phenyl-2-piperidone prepared by the method of Reference Example 19 and 10 ml of acetic anhydride were dissolved in 20 ml of pyridine, and the mixture was stirred at room temperature for one day and night. After completion of the reaction, the reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4.1 g (quantitatively) of the desired compound.