Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.ClC1C=CC(C(C2N(C)N=NC=2)O)=CC=1.[Li]CCCC.[CH3:27][C:28]1[S:29][C:30]([CH:34]=[O:35])=[C:31]([CH3:33])[N:32]=1>C1COCC1>[CH3:27][C:28]1[S:29][C:30]([CH:34]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][CH:5]=2)[OH:35])=[C:31]([CH3:33])[N:32]=1
Reactant: Cn1ccnn1
Reactant: Cc1nc(C)c(C=O)s1
Agent: Cn1nncc1C(O)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(O)c2cnnn2C)s1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a flask containing 1-methyl-1H-1,2,3-triazole (1.60 g, 19.3 mmol, Intermediate 42, step a) was added THF (200 mL) and the solution was cooled to −40° C. To this colorless homogeneous solution was added n-BuLi (2.5 M in hexanes, 7.7 mL, 19.2 mmol) dropwise which immediately afforded a dark brown viscous mixture. The mixture was kept between −10 to −20° C. for 60 min, then 2,4-dimethylthiazole-5-carbaldehyde (3.03 g, 21.5 mmol) in THF (5 mL) was introduced and the reaction mixture began to stir much more easily, but still remained brownish. Once the aldehyde was added the reaction was placed in an ice-bath and maintained there until it warmed to room temp. After 3 hours the reaction was quenched by pouring into a saturated solution of NH4Cl at room temperature. The aqueous portion was extracted with EtOAc (5×100 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a brown oil-foam. Flash chromatography on silica gel (10-30% acetone increasing gradient to 10% MeOH-DCM) gave the title compound as a light orange foam.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=[N:27][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCc1ccccc1
Reactant: O=Cc1ccccc1OCCCN1CCCCC1
Solvent: Cc1ccccc1
Product: C(=NCCc1ccccc1)c1ccccc1OCCCN1CCCCC1

Procedure:
2-[3-(1-Piperidinyl)propoxy]benzaldehyde (47.6g) is reacted with 24g of phenethylamine in 190ml of toluene following the procedure described in Example 1A to yield 61.9g of product as an oil, boiling point 214°-218° C. at 0.2-0.3mm of Hg.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([O:7][C:8]([CH3:11])(C)C)=[O:6])=[O:3].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]CC.C1(C)C=CC=CC=1>C(O)(C)(C)C>[C:5]([O:7][CH2:8][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:6])[CH2:4][C:2]([CH3:1])=[O:3]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CCCCCCCCO
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)CC(C)=O
Yield: 83.2 %

Procedure:
Another procedure involved heating the alcohol and tBAA, (or beta-ketoester) in solvent, in a round-bottom flask with magnetic stirrer, 5-plate Oldershaw column and still head for removal of the t-butanol co-product. For example: a solution of n-octanol (13 g, 0.1 mol), tBAA (16.6 g, 0.105 mol) and 50 mL toluene was heated at reflux until the theoretical amount of t-butyl alcohol was obtained (ca. 15 min. after reflux). The reaction mixture was subsequently concentrated and distilled to give 17.8 g (83.2%) octyl acetoacetate b.p. 95°-110° C. (1.0 mm Hg).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[O:11])[CH2:4][CH2:3]1.B1C2CCCC1CCC2.[OH-:35].[Na+].OO>C1COCC1.C(Cl)Cl>[OH:35][CH2:1][CH:2]1[CH2:7][CH2:6][C:5]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[O:11])[CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: C=C1CCC(CNC(=O)c2ccccc2OC)(c2ccccc2)CC1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(CO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-methylidene-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)cyclohexane (Example 165, 117 mg, 0.35 mmol) was added 9-BBN (7 mL, 0.5 N, 3.5 mmol) in THF. The reaction mixture was stirred at rt for 1 h, and then heated to 45° C. for 3 h. To the solution was then added NaOH (3 mL, 10%) and H2O2 (4 mL, 30%) and the mixture was heated at 45° C. for 14 h. The reaction mixture was poured into CH2Cl2 and washed with 2N HCl and dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica, EtOAc/hexane, 2:1) to give the title compound as a 2:1 mixture of two diastereomers.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][N:22]=1>CS(C)=O.C(OCC)(=O)C>[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)[CH:12]=1)=[O:10]
Reactant: Clc1nccc2ccccc12
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cn(-c2nccc3ccccc23)c2ccccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
1.73 g (12.5 mmol) of potassium carbonate are added at 20° C. under an argon atmosphere to 0.876 g (5 mmol) of 3-methoxycarbonyl-1H-indole in 10 cm3 of dimethyl sulphoxide. After stirring at 20° C. for 1 hour, 0.818 g (5 mmol) of 1-chloroisoquinoline is added. After stirring at 100° C. for 19 hours, the reaction mixture is cooled and diluted with 20 cm3 of ethyl acetate and then washed with 3 times 20 cm3 of water and 20 cm3 of saturated aqueous sodium chloride solution. After separating the phases by settling, the organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.35 g of 3-methoxycarbonyl-1-(isoquinol-1-yl)-1H-indole in the form of a white solid melting at 140° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2].CC([O-])=O.[Na+].[Br:16]Br.C([O-])(O)=O.[Na+]>O.C(O)(=O)C>[Br:16][C:8]1[CH:7]=[N:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]=1[NH2:10]
Reactant: BrBr
Reactant: Nc1ccncc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(Br)cncc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 76.5 %

Procedure:
A mixture of 3-nitropyridin-4-amine (LVII) (10 g, 71.94 mmol) and acetic acid (120 mL) was added to a sealed tube followed by addition of NaOAc (29.50 g, 93.52 mmol) and dropwise addition of bromine (4.7 ml 359.7 mmol) under stirring. The sealed tube was heated at 100° C. for 28 h until TLC showed consumption of starting material. The reaction mixture was concentrated to obtain a solid which was dissolved in water, basified with NaHCO3 and extracted with EtOAc. The combined organic extracts were dried and concentrated to produce 3-bromo-5-nitropyridin-4-amine (LVIII) as a yellow solid (12 g, 55 mmol, 77% yield). 1H NMR (DMSO-d6) δ ppm 9.19 (s, 1H), 8.58 (s, 1H); ESIMS found for C5H4BrN3O2 m/z 217, 219 (M+, M+2).
Reaction SMILES: C(S([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:31])[CH:30]=3)=[CH:27][C:26]([F:32])=[CH:25][C:24]=4[N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=O)=O)C.C(N(CC)CC)C.[CH2:47]([N:49]=[C:50]=[O:51])[CH3:48]>C(Cl)Cl>[CH2:47]([NH:49][C:50]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:31])[CH:30]=3)=[CH:27][C:26]([F:32])=[CH:25][C:24]=4[N:33]3[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]3)=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:51])[CH3:48]
Reactant: CCS(=O)(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(F)cc(N5CCN(C)CC5)c4o3)cc2)CC1
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(F)cc(N5CCN(C)CC5)c4o3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-phenyl)-amide (Example 71) (150 mg, 0.216 mmol) was placed in a 50 mL flask with 10 mL of CH2Cl2. This suspension was treated with triethylamine (0.1 mL, 0.67 mmol) and ethylisocyanate (0.21 mL, 18.7 mg, 0.26 mmol) and the reaction stirred at room temperature for 18 hours. The reaction was concentrated (1 mm Hg pressure) and the concentrate purified by chromatography on silica eluting with 1% methanol in chloroform, then concentrated (1 mm Hg pressure). Then triturated with either to yield a yellow powder with was dried under high vacuum for 48 h at 50° C. (79 mg) LCMS−AP+537.4, mp=236–238° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([CH:15]1[CH2:19][CH:18]([O:20][C:21]2[C:30]3[C:25](=[C:26]([CH3:33])[C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[N:24]=[C:23]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[N:35]=3)[CH:22]=2)[CH2:17][CH:16]1[C:41](=[O:53])[NH:42][C:43]1([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:45][CH:44]1[CH:46]=[CH2:47])=[O:14])(C)(C)C.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:51]([O:50][C:48]([C:43]1([NH:42][C:41]([CH:16]2[CH2:17][CH:18]([O:20][C:21]3[C:30]4[C:25](=[C:26]([CH3:33])[C:27]([O:31][CH3:32])=[CH:28][CH:29]=4)[N:24]=[C:23]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[N:35]=4)[CH:22]=3)[CH2:19][CH:15]2[C:13]([OH:14])=[O:12])=[O:53])[CH2:45][CH:44]1[CH:46]=[CH2:47])=[O:49])[CH3:52]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3cccc(C)n3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3cccc(C)n3)nc3c(C)c(OC)ccc23)CC1C(=O)O)C(=O)OCC
Reaction time: 2 h
Yield: 79.7 %

Procedure:
TFA (24 mL) was added at room temperature to a solution of 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-[2-(6-methyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy]cyclopentanecarboxylic acid tert-butyl ester (98, 1.1 g, 1.75 mmol) and triethylsilane (510 mg, 2.5 eq) in CH2Cl2 (24 mL). After 2 h, the reaction mixture was concentrated under reduced pressure, and then co-evaporated with toluene. The residue was re-dissolved in AcOEt and successively washed with a solution of NaHCO3 and brine. The organic layer was dried (MgSO4), filtered and evaporated, to give 800 mg (80%) of the title compound 99 (800 mg, 80%): m/z=574 (M+H)+.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:15][O:16][CH3:17])[CH:11]=2)[C:6]1=[O:18])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26]>CN(C)C=O>[CH2:1]([C:5]1([CH2:26][CH2:25][CH2:24][CH:23]=[CH2:22])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:15][O:16][CH3:17])[CH:11]=2)[C:6]1=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Cc2cc(OCOC)ccc2C1=O
Reactant: C=CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCC1(CCCC)Cc2cc(OCOC)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of 2-butyl-5-(methoxymethoxy)-1-indanone (1.54 g, 6.2 mmol) in anhydrous N,N-dimethylformamide (DMF, 5 mL) was added to a suspension of sodium hydride (372 mg of a 60% dispersion in mineral oil, 9.3 mmol) in DMF (5 mL). The mixture was diluted with more DMF (2 mL, used to rinse in the indanone solution), placed under a nitrogen atmosphere, and stirred at room temperature for 25 minutes. 5-Bromo-1-pentene (1.47 mL, 12.4 mmol) was then added over 5 minutes, during which time the mixture clarified. After stirring at room temperature for an additional 5 hours, the mixture was quenched with saturated NH4Cl, dried over MgSO4, filtered through a pad of silica, and concentrated under vacuum to afford an oil. The crude product was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40S (4.0×7.0 cm) silica gel column, eluting with 19:1 hexanes-EtOAc. The product-containing fractions were evaporated under vacuum to afford 2-butyl-5-(methoxymethoxy)-2-(4-pentenyl)-1-indanone as an oil.
Reaction SMILES: [CH:1](=[N:8][CH:9]([CH2:15][CH2:16][C:17]#[N:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Li+].Cl[CH:26]([F:28])[F:27]>O1CCCC1>[CH:1](=[N:8][C:9]([CH:26]([F:28])[F:27])([CH2:15][CH2:16][C:17]#[N:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCC#N)N=Cc1ccccc1
Reactant: FC(F)Cl
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC#N)(N=Cc1ccccc1)C(F)F
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To the solution of crude ethyl 2-benzylideneamino-4-cyanobutyrate (4) obtained above, was added 0.35 L of tetrahydrofuran (THF) and 28.0 g of lithium t-butoxide (1.6 eq) at 5° C. The mixture was stirred at ˜5° C. for 0.5 h, at 20–25° C. for 2 h, and then warmed to 40° C. Chlorodifluoromethane (34.2 g, 1.8 eq) was slowly bubbled into the reaction mixture, and the temperature maintained at 40–50° C. When the exotherm subsided, bubbling was continued for another ˜15 min. and then stopped. The reaction mixture was stirred at 40° C. for 1–2 h. After the reaction was complete, the solvent was removed under reduced pressure. The crude product 5 was ready for use in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(O)C>[C:22]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:4][CH:3]=1)(=[O:24])[CH3:23].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(S(=O)(=O)O)c2ccccc12
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)Nc1ccc(S(=O)(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
12 g (0.05 mole) of 1-amino-4-naphthalenesulphonic acid, 7.2 ml of pyridine and 15 ml of acetic anhydride are placed in a flask provided with a stirrer and heater. The mixture is heated until the solution is clear, at which point 10 ml of absolute ethanol is added and the mixture is allowed to cool, first to ambient temperature and then in a refrigerator to 3° C. for 3 hours. The precipitate obtained is collected in a filter and is recrystallized in ethanol to give 11 g (Yield 59.4%) of pyridine N-acetyl-1-aminonaphthalene-4-sulphonate, having a m.p. of 172°-175° C. and whose IR spectrum (KBr) has the following bands: 3,400; 3,220; 1,640; 1,525; 1,370; 1,325; 1,200; 1,030; 850; 675; 635.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:19]([N-]C(C)C)(C)[CH3:20].[Li+].ICC.[Cl-].[NH4+]>C1COCC1>[CH2:19]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:8][CH2:7]1)[CH3:20]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
0.2 g (0.78 mmol) of tert-butyl 4-ethoxycarbonylpiperidine-1-carboxylate is dissolved in 4 mL of THF at −10° C. 0.8 mL (1.56 mmol) of lithium diisopropylamide is added dropwise. After 15 minutes, 0.09 mL (1.2 mmol) of iodoethane is added and the mixture is warmed to room temperature. It is stirred for 30 minutes and then poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried and then concentrated to dryness. The oil obtained is chromatographed on silica gel (eluent: 95/5 heptane/ethyl acetate). 183 mg of tert-butyl 4-ethyl-4-ethoxycarbonylpiperidine-1-carboxylate in the form of a yellow oil are obtained in a yield of 82%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=1.[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:18][N:15]1[CH:16]=[C:11]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[CH3:1])[CH:12]=[CH:13][C:14]1=[O:17]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(-c2ccc(=O)[nH]c2)cccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1c(-c2ccc(=O)n(C)c2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 5-(2-methyl-3-nitrophenyl)pyridin-2-one (9) (0.92 g, 4.0 mmol), DMF (40 mL), potassium carbonate (1.21 g, 8.80 mmol) and iodomethane (625 mg, 4.40 mmol) and purged with nitrogen. The reaction mixture was stirred at room temperature for 2 h. After this time the reaction was cooled to room temperature and partitioned between ethyl acetate (150 mL) and water (75 mL). The organic layer was separated and washed with water (2×50 mL) followed by brine (100 mL) and dried over magnesium sulfate. The drying agent was then removed by filtration and the filtrate concentrated under reduced pressure to afford 0.92 g (94%) of 1-methyl-5-(2-methyl-3-nitrophenyl)pyridin-2-one (10) as a white solid: mp 157-159° C.; 1H NMR (300 MHz, CDCl3) 7.81 (dd, 1H, J=7.8, 1.8 Hz), 7.41 (dd, 1H, J=7.8, 1.8 Hz), 7.38 (d, 1H, J=7.5 Hz), 7.53 (d, 1H, J=9.3 Hz), 7.32 (dd, 1H, J=9.3, 2.7 Hz), 7.27 (d, 1H, J=1.5 Hz), 6.68 (d, 1H, J=9.3 Hz), 3.62 (s, 3H), 2.37 (s, 3H); MS (ESI+) m/z 245 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([CH3:70])=[CH:66][CH:65]=1>>[C:67]1([CH3:70])[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:65][CH:66]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Cc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)C2NC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.2 g, 0.36 mmol), was reacted with diisopropylethylamine (0.18 g, 1.4 mmol), diphenylphosphinic chloride (0.25 g, 1.1 mmol), then reacted with p-toluidine (Aldrich) (0.057 g, 0.53 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid p-tolylamide as a white solid (Yield, 30 mg, 15%).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:8][CH:7]=1)([CH3:3])[CH3:2].[CH3:27]C1ON=C(C2C=CC=CC=2)C=1COC1C=CC(C(NC2CCOCC2)=O)=CN=1>>[CH:1]([N:4]([CH3:27])[C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:8][CH:7]=1)([CH3:3])[CH3:2]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC(C)C)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N(C)C(C)C)cn1
Yield: 33 %

Procedure:
As described for example 50, N-isopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide (200 mg, 0.6 mmol), instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide, was converted to the title compound (69 mg, 33%) which was obtained as a colourless gum. MS: m/e=366.3 [M+H]+.
Reaction SMILES: [CH2:1](OCC)C.[CH2:6]([O:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]([C:30]([OH:32])=[O:31])[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+](=C)=[N-]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:31][C:30](=[O:32])[C@H:21]([CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:14]([O:13][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:15])[NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
An ethyl ether solution of 1.48 g (3.9 mmol) of Nε -benzyloxycarbonyl-Nα -(tert-butoxycarbonyl)-L-lysine was combined with an ethyl ether solution of diazomethane at 0° C. The reaction mixture was evaporated to give a colorless oil in nearly quantitative yield (1.54 g). TLC Rf =0.38 (chloroform/ethyl acetate, 5:1). IR (neat) ν 3340, 1710, 1530 cm-1. NMR (CDCl3) δ 7.3 (5H, s), 7.25 (1H, m), 5.05 (2H, s), 5.0 (1H, m), 4.1 (1H, m), 3.8 (3H, s), 3.1 (2H, m), 2.0-1.1 (6H, m), 1.4 (9H, s). The product has the structural formula: ##STR82##
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4](NC1CC1)=[O:5].[C:13]1([CH2:23][CH2:24][NH2:25])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4]([NH:25][CH2:24][CH2:23][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: NCCc1cccc2ccccc12
Product: CC[C@H](N)[C@H](O)C(=O)NCCc1cccc2ccccc12

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide, Representative Procedure B, using 2-(naphthalen-1-yl)ethanamine in the seventh step (step B7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH3:24])[CH:11]3[C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[CH3:32])[C:5]2=[CH:4][CH:3]=1.C[O:35][CH:36]([Si](C)(C)C)[CH3:37].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:37][CH2:36][OH:35])[C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH3:24])[CH:11]3[C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[CH3:32])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(C)[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)cc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)N(CCO)c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-methyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.16 g, 0.26 mmol) prepared in example 56a in dichloromethane (10 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated. The residue was neutralized with saturated NaHCO3 aqueous solution, then extracted with ethyl acetate. The organic layer was separated, dried over MgSO4 and concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-methyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-ethanol (Yield 90 mg, 67.7%).