Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[CH:20]=[CH:19][C:18]2[C:14](=[CH:15][N:16]([CH3:21])[N:17]=2)[C:13]=1[CH2:22][OH:23].C(N(CC)CC)C>ClCCl>[F:11][C:12]1[CH:20]=[CH:19][C:18]2[C:14](=[CH:15][N:16]([CH3:21])[N:17]=2)[C:13]=1[CH:22]=[O:23]
Reactant: Cn1cc2c(CO)c(F)ccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cn1cc2c(C=O)c(F)ccc2n1
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of dimethyl sulfoxide (7.56 mL, 107 mmol) in dichloromethane (100 mL) was added oxalyl chloride (4.86 mL, 53.3 mmol) at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added a solution of (5-fluoro-2-methyl-2H-indazol-4-yl)methanol (3.20 g, 17.8 mmol) in dichloromethane (78.0 mL), and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (22.5 mL, 160 mmol) at −78° C., and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (3.00 g, yield 95%).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.[C:45]([O:49][CH2:50][CH3:51])(=[O:48])[CH:46]=[O:47]>>[F:1][C:2]1[C:3]2[C:4]([CH:46]([OH:47])[C:45]([O:49][CH2:50][CH3:51])=[O:48])=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=7)=[C:24]([C:34](=[O:35])[NH:36][CH3:37])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C=O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Product: CCOC(=O)C(O)c1c2n(c3cccc(F)c13)COc1ccc(-c3cc4c(C(=O)NC)c(-c5ccc(F)cc5)oc4cc3N(C)S(C)(=O)=O)nc1-2
Temperature: 115 °C

Procedure:
A mixture of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (500 mg, 0.814 mmol) and ethyl glyoxalate (323 μl, 1.627 mmol) was heated at 115° C. for 3 hours in a sealed tube. The reaction mixture was cooled to room temperature, concentrated under vacuum then applied onto 2-EP column (30 mm×250 mm) eluted with 30% IPA/CO2. This resulted in 108 mg (18.5%) of ethyl 2-(11-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-12-yl)-2-hydroxyacetate (Compound 206) as a white solid. LC-MS (ES, m/z) C36H30F2N4O8S: 716. Found: 717 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=O.[OH-].[Na+].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>C(O)C>[O:7]=[C:5]1[N:1]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4]1
Reactant: N[C@H](CCC(=O)O)C(=O)O
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
D-glutamic acid (1.47 g, 10 mmol) was dissolved in 2N aqueous sodium hydroxide (10 ml, 20 mmol) and stirred for 15 minutes. The mixture was then treated with a solution of benzaldehyde (1.1 ml, 10 mmol) in ethanol (3 ml) and stirred at room temperature for 30 minutes. The mixture was cooled to 0° C. and treated with sodium borohydride (0.030 g). The mixture was allowed to warm to room temperature with stirring over 4 hrs and then washed with diethyl ether (three times) before acidifying with concentrated hydrochloric acid to pH2. The resulting precipitate was filtered off and washed with diethyl ether before slurrying in ethanol and azeotroping three times with more ethanol. Finally the remaining material was slurried in ethanol (50 ml) and heated at reflux for 16 hrs. The mixture was then cooled to room temperature and evaporated in vacuo. Drying afforded pure 5-oxo-1-(phenylmethyl)proline.
Reaction SMILES: ClC([O:4][C:5](Cl)(Cl)Cl)=O.Cl.[CH3:10][O:11][C:12](=[O:18])[C@H:13]([CH:15]([CH3:17])[CH3:16])[NH2:14]>O1CCOCC1>[N-:14]=[C:5]=[O:4].[CH3:10][O:11][C:12](=[O:18])[C@H:13]([CH:15]([CH3:17])[CH3:16])[NH2:14]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: [N-]=C=O

Procedure:
Trichloromethyl chloroformate (1.08 mL) was added to a stirred suspension of L-valine methyl ester hydrochloride (3.0 g, 17.9 mmol) in 10 mL dry dioxane. The mixture was refluxed for 1.5 h, concentrated, and the residue flash distilled (bath temperature 100°-125° C., 0.5 mm vacuum) to afford 1.0 g of L-valine methyl ester isocyanate. A solution of 0.55 g (3.5 mmol) of L-valine methyl ester isocyanate in 7.5 mL dry toluene was treated with 4M HCl in dioxane (79 mL, 0.315 mmol) at RT and stirred for 5 min. The resulting mixture was treated with 1.0 g solid K2HPO4 for 5 min, followed by the addition of Compound 104b (0.464 g, 3.15 mmol). The mixture was refluxed for 9 h, diluted with EtOAc and washed with sat. NaHCO3 followed by brine. The organic phase was dried (MgSO4), concentrated, and the crude product purified by flash chromatography (silica gel/hexane to EtOAc-hexane 1:9 to 1:4, stepwise gradient) to afford 0.51 g (53%) of Compound 104c as a yellow gummy solid. ##STR218##
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]5[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=5[F:40])=[CH:24][CH:23]=4)[CH2:20][CH2:19][N:18]([C:41]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[O:42])[CH2:17]3)[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[C:58](Cl)(=[O:60])[CH3:59]>ClCCl>[C:58]([NH:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]5[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=5[F:40])=[CH:24][CH:23]=4)[CH2:20][CH2:19][N:18]([C:41]([O:43][CH2:44][C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)=[O:42])[CH2:17]3)[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1)(=[O:60])[CH3:59]
Reactant: NCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOc4cc(F)ccc4F)cc3)cc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOc4cc(F)ccc4F)cc3)cc21

Procedure:
The solution of 0.220 g of benzyl 3-[4-(2-aminoethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[3-(2,5-difluorophenoxy)propoxy]phenyl}piperidine-1-carboxylate in 7.5 ml of dichloromethane is cooled to 0° C. with stirring and admixed with 0.042 ml of triethylamine. 0.023 ml of acetyl chloride in 0.50 ml of dichloromethane are slowly added dropwise. Subsequently, the mixture is stirred at 0° C. over 1 hour. The reaction mixture is poured onto ice-water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed with brine (20 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.75 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.46.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>CO>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][C:26]([CH3:34])([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(C)CCN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C(=O)O)CCN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-4-methylpiperidine-4-carboxylate (150 mg, 0.3 mmol) in MeOH (5 mL) was added NaOH (60 mg, 1.5 mmol, 5.0 eq) and H2O (0.5 mL). The reaction mixture was stirred at 85° C. for 2 h. The pH of the solution was adjusted to 6 with 3 N HCl. The mixture was filtered and the yellow solid was the desired product 1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-4-methylpiperidine-4-carboxylic acid (100 mg, yield: 80%). ESI-MS (M+1)+: 438.3, HPLC: 100%. 1HNMR (400 MHz, DMSO-d6) δ: 10.21 (s, 1H), 8.02 (br, 1H), 7.93˜7.88 (m, 2H), 7.67 (br, 1H), 7.48 (s, 1H), 7.26 (d, 1H), 4.51˜4.45 (m, 2H), 3.35 (s, 2H), 3.32 (br, 1H), 2.92 (br, 1H), 2.29˜2.14 (m, 4H), 1.92˜1.76 (m, 4H), 1.47˜1.12 (m, 9H), 0.93 (s, 9H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8](S(O)(=O)=O)=[CH:7][CH:6]=1.[C:16]1(C)C=CC=CC=1>>[CH3:15][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH3:16])[C:6]21[O:4][CH2:1][CH2:2][O:3]2
Reactant: Cc1ccccc1
Reactant: OCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1CCCC(C)C12OCCO2
Temperature: 120 °C

Procedure:
A reaction flask equipped with a Dean Stark trap was charged with 2,6-dimethyl cyclohehanone (190 g), ethylene glycol (155 g), p-toluenesulfonic acid (2 g) and toluene (200 mL). The reaction mass was heated to reflux (110-130° C.). Water (27 mL) was collected in the Dean Stark trap. When no water was recovered, the reaction mass was cooled to an ambient temperature, neutralized with 10% aqueous sodium carbonate (100 mL) and washed with brine. Purification by vacuum distillation afforded 6,10-dimethyl-1,4-dioxaspiro[4,5]decane (225 g), which had a boiling point of 93° C. at a pressure of 22 mmHg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](Cl)[N:9]=2)[N:5]=[CH:4][N:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[NH2:19].[CH3:26][O:27][CH2:28][C@@H:29]([NH2:31])[CH3:30]>O1CCCC1>[F:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:31][C@@H:29]([CH3:30])[CH2:28][O:27][CH3:26])[N:9]=3)[N:5]=[CH:4][N:3]=2)[CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1
Reactant: Nc1cc(F)cc([N+](=O)[O-])c1
Reactant: COC[C@H](C)N
Reactant: Clc1nccc(-c2ncnc(Cl)n2)n1
Solvent: C1CCOC1
Product: COC[C@H](C)Nc1nccc(-c2ncnc(Nc3cc(F)cc([N+](=O)[O-])c3)n2)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-4-(2-chloro-4-pyrimidinyl)-1,3,5-triazine (i.e., the product of Example 1, Step B) (68 mg, 0.30 mmol) in tetrahydrofuran (2.0 mL) was added 3-fluoro-5-nitroaniline (72 mg, 0.46 mmol), and the resulting mixture was stirred at 50° C. for 1 h to form a yellow suspension. To this suspension was added (S)-1-methoxy-2-propylamine (0.2 mL), and the resulting mixture was refluxed for 3 h. The solution was concentrated and purified using column chromatography on silica gel eluted with 70% ethyl acetate in hexanes to give 93 mg of the title compound as yellow solid.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14]C=1)[CH:6]1[O:11][CH2:10][CH2:9][NH:8][CH2:7]1>C1(C)C=CC=CC=1.COCCO[AlH2-]OCCOC.[Na+]>[NH:8]1[CH2:9][CH2:10][O:11][CH2:6][CH2:7]1.[C:5]1([O:4][C:3]2[CH:2]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccccc1OC(c1ccccc1)C1CNCCO1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C1COCCN1
Product: c1ccc(Oc2ccccc2)cc1
Reaction time: 4 h
Yield: 48.6 %

Procedure:
To a solution of morpholinone 2 (0.214 g, 0.750 mmol) in toluene (10 mL), Red-Al (65% solution in toluene, 1.5 mL) was added dropwise at 0° C. The reaction mixture was stirred at ice temperature for 4 h. Excess Red-Al was destroyed by dropwise addition of 2M NaOH solution (5 mL) and acidified to pH 2 with 6N HCl. The solution was neutralized with saturated NaHCO3 and extracted with toluene (2×10 mL). The combined organic extract was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the product was purified on a column of silica gel (ethyl acetate: methanol, 80:20) to give morpholine compound 3 as a colorless solid (Yield: 0.062 g, 31%), mp 156-158° C. 1H NMR (CDCl3) δ: 7.45-7.38 (m, 5H), 6.97 (m, 2H), 6.58 (m, 1H), 6.50 (d, 1H), 4.53 (d, 1H), 4.10 (m, 1H), 3.95 (m, 1H), 3.90 (m, 1H), 2.90 (m, 2H), 2.50 (m, 1H), 2.42 (m, 1H). MS (ES) m/z 285.98 [C17H19NO3+H]+. Analysis: Calcd for C17H19NO3 (0.5H2O) C, 69.37; H, 6.85; N, 4.76. Found: C, 69.68; H, 5.45; N, 4.44.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=CN=[C:12]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][CH:23]=[N:24]4)[CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C@@H](NC2[C:43]([N+:44]([O-])=O)=CN=C(Br)C=2)C)C=CC=CC=1.N1C2C=CC=C(B(O)O)C=2C=CC=1.[C:61](=O)([O-])[O-:62].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C@@H:7]([N:9]2[C:10]3[C:15](=[N:44][CH:43]=[C:12]([C:19]4[CH:28]=[CH:27][CH:26]=[C:25]5[C:20]=4[CH:21]=[CH:22][CH:23]=[N:24]5)[CH:11]=3)[NH:16][C:61]2=[O:62])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1cc(Br)ncc1[N+](=O)[O-])c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: C[C@H](Nc1cc(-c2cccc3ncccc23)ncc1[N+](=O)[O-])c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OB(O)c1cccc2ncccc12
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](c1ccccc1)n1c(=O)[nH]c2ncc(-c3cccc4ncccc34)cc21
Temperature: 85 °C
Yield: 77 %

Procedure:
((1S)-1-Phenylethyl)(5-nitro-2-(5-quinolyl)(4-pyridyl))amine. ((1S)-1-Phenylethyl)(2-bromo-5-nitro(4-pyridyl))amine (5.6 g, 1.75 mmol) and 5-quinolineboronic acid (393 mg, 2.27 mmole) were dissolved in DMF (25 ml). Nitrogen gas was bubbled into solution for 2 min. Potassium carbonate (970 mg, 7.00 mmol) in water (5 mL) was then added followed by tetrakis(triphenylphosphine)palladium (0) (0.175 mmol). The solution was then heated to 85° C. under nitrogen for 1 h. The solution was condensed under reduced pressure and the crude product was diluted with ethyl acetate and filtered through a plug of silica-gel. The resultant filtrate was condensed under reduced pressure to afford the title compound (500 mg, 77%). MS (ESI) m/z 371 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:16][CH:15]=2)[C@@H:10]([O:25][CH2:26][C:27]2[CH:36]=[C:35]3[C:30]([CH:31]=[CH:32][CH:33]=[N:34]3)=[CH:29][CH:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:16][CH:15]=2)[C@@H:10]([O:25][CH2:26][C:27]2[CH:36]=[C:35]3[C:30]([CH:31]=[CH:32][CH:33]=[N:34]3)=[CH:29][CH:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCO)cc2)[C@@H](OCc2ccc3cccnc3c2)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOS(C)(=O)=O)cc2)[C@@H](OCc2ccc3cccnc3c2)C1

Procedure:
In analogy to the procedure described in example 8(b), the (3R,4R)-4-[4-(3-hydroxy -propoxy)-phenyl]-3-(quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was reacted with methanesulfonyl chloride to yield the (3R,4R)-4-[4-(3-methanesulfonyloxy-propoxy)-phenyl]-3-(quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid; MS: 571 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1cccnc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and methyl (S)-2-amino-3-(3-pyridyl)propionate hydrochloride (Synthetech), the title compound was prepared as a solid (mp=101-103° C.). The reaction was monitored by tlc (Rf=0.48 in 10% MeOH/DCM) and the product was purified by silica gel column chromatography. NMR data was as follows:
Reaction SMILES: [CH3:1][C@:2]1([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]#[N:21])[CH:16]=3)[C:11]2=[O:22])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9].[ClH:23].O>CO.[Pd]>[ClH:23].[NH2:21][CH2:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:22])[N:10]([C@@:2]1([CH3:1])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9])[C:18]2=[O:19]
Reactant: C[C@]1(N2C(=O)c3ccc(C#N)cc3C2=O)CCC(=O)NC1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: C[C@]1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reaction time: 16 h
Yield: 66 %

Procedure:
A mixture of 2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonitrile (4.70 g, 15.8 mmol), 4N HCl (21 mL), and 10% Pd—C (1.88 g) in CH3OH (200 mL) was hydrogenated under 50 psi of H2 for 16 hours. Water (24 mL) was added, and the reaction mixture was filtered through Celite. The filter was washed with additional methanol (50 mL). The filtrate was concentrated and dried to give 3.5 g of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-isoindole-1,3-dione hydrochloride, in 66% yield; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 1.00 (97.70%); 1H NMR (DMSO-d6) δ 1.91 (s, 3H), 2.03-2.10 (m, 1H), 2.49-2.61 (m, 2H), 2.66-2.75 (m, 1H), 4.23 (s, 2H), 7.89-8.03 (m, 3H), 8.68 (br, 3H), 11.04 (s, 1H); 13C NMR (DMSO-d6) δ 20.9, 28.6, 29.0, 41.6, 58.9, 123.2, 123.5, 130.8, 131.4, 135.3, 141.2, 167.5, 167.6, 172.1, 172.2.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.Br[CH2:14][CH2:15][CH:16]=[CH2:17].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:17]([O:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:5][C:4](=[O:12])[CH:3]=1)[CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCBr
Reactant: O=c1cc(O)c2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCOc1cc(=O)oc2ccccc12
Temperature: 55 °C

Procedure:
4-Hydroxycoumarin (10.93 mmol, 1.77 g), 4-bromo-1-butene (10.93 mmol, 1.48 g) and K2CO3 (33 mmol, 4.55 g) is suspended in 50 mL of acetone, and the reaction is heated to 55° C. for 2.5 days the reaction mixture is filtered and the filtrate is evaporated under reduced pressure. A small amount of the resulting solid is purified by column chromatography to afford an analytically pure sample of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 7.78 (1H, dd, J=1.5, 7.75 Hz), 7.66 (1H, m), 7.38 (2H, m), 5.93 (1H, m), 5.92 (1H, s), 5.20 (2H, m), 2.59 (2H, m), 2.50 (2H, m); MS (ESI, Pos.) calcd for C13H12O3 m/z [M+H]=217.1, found 217.1.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:17]([CH2:18][CH:19]=1)=[C:16]1[C:12]([N:13]([CH2:20][CH:21](O)[CH3:22])[N:14]=[CH:15]1)=[CH:11]2.C(N(CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:31]([CH:21]([CH3:22])[CH2:20][N:13]1[C:12]2=[CH:11][C:10]3[C:17]([CH2:18][CH:19]=[C:8]([O:7][CH3:6])[CH:9]=3)=[C:16]2[CH:15]=[N:14]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=CCC2=c3cnn(CC(C)O)c3=CC2=C1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC1=CCC2=c3cnn(CC(C)N=[N+]=[N-])c3=CC2=C1
Yield: 82.4 %

Procedure:
1.15 ml (14.2 mmol) of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.74 g (7.12 mmol) of (RS)-1-(6-methoxy-1,4-dihydro-indeno[2,1-c]-pyrazol-1-yl)-propan-2-ol and 3.85 ml (28.5 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 50 minutes. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.92 g (14.2 mmol) of sodium azide and the reaction mixture was heated to 90° for 5 hours while stirring. After cooling, the solution was poured into 80 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.58 g (82%) of (RS)-1-(2-azido-propyl)-6-methoxy-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[C:12]([NH:14][C@H:15]([C:19]([NH:21][CH:22]([C:31](=[O:34])[CH2:32][F:33])[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1.C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[C:12]([NH:14][C@H:15]([C:19]([NH:21][CH:22]([C:31](=[O:34])[CH2:32][F:33])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13]
Reactant: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF)C(C)C)n(C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)O)C(=O)CF)C(C)C)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A solution of N-[(1,3-dimethylindole-2-carbonyl)valinyl]-3-amino-4-oxo-5-fluoropentanoic acid, t-butyl ester (40 mg) in anisole (0.2 mL) and methylene chloride (2 mL) was treated with trifluoroacetic acid (1 mL), and the resultant reaction mixture was stirred for 30 minutes under a nitrogen atmosphere at room temperature. The reaction mixture was concentrated and chased with methylene chloride to give a solid. The solid was triturated with ether to yield the title product as a brown powder (17 mg). TLC(methylene chloride/methanol/acetic acid, 20:1:1): Rf =0.40. MS for C21H26FN3O5 : MH+ =420; MH- =418.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].N1C=CC=CC=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(OCC)(=O)C>[C:20]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:13])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NCCCCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.19 h
Yield: 97.2 %

Procedure:
To a mixture of tert-butyl 4-hydroxybutylcarbamate (3.83 g) obtained in Reference Example 35 and ethyl acetate (20 mL) were added pyridine (1.80 mL) and acetic anhydride (2.27 g), and the mixture was stirred at room temperature for 0.19 hrs. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), an aqueous copper sulfate solution (30 mL), water (30 mL) and saturated brine (30 mL) and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (4.55 g) as a colorless oil.