Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[CH:25](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[CH:25]=[N:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCC(CC)Nc1cc(C)nc2c1ncn2-c1c(C)cc(C)cc1C

Procedure:
A mixture of N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine (250 mg, 0.77 mmol), trimethyl orthoformate (0.081 g, 0.766 mmol), p-toluenesulfonic acid monohydrate (0.01 g) in benzene was heated at reflux using Dean-Stark apparatus for 24 hours. Benzene was removed and toluene was added and an excess of trimethyl orthoformate (0.084 ml) was added to the reaction mixture. The mixture was heated at reflux overnight. The mixture was quenched with water, sat. NaHCO3, extracted with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness. After purification, the title compound was isolated as a white crystal, mp 78–80° C.
Reaction SMILES: [O-]CC.[Na+].[C:5]([C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[OH:19])([CH3:8])([CH3:7])[CH3:6].[CH:20]12[O:25][CH:21]1[CH2:22][CH2:23][CH2:24]2>C(O)C>[CH3:6][C:5]([C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[O:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[OH:25])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: C1CC2OC2C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1ccc(O[C@@H]2CCC[C@H]2O)c(C(C)(C)C)c1
Reaction time: 0.08 h

Procedure:
To a solution of sodium ethoxide in ethanol (prepared by dissolving 230 mg of sodium in 25 ml of ethanol) was added 2.06 g (10.0 mmoles) of 2,4-di-t-butylphenol. The mixture was stirred for 5 minutes, and then 841 mg (10.0 mmoles) of cyclopentene oxide was added. After refluxing overnight, the mixture was cooled and evaporated, the residue partitioned between diethyl ether and dilute aqueous hydrochloric acid, the aqueous layer further extracted with ether, the combined organic extracts washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using 10% ethyl acetate-hexane as eluent gave the title compound, 1.25 g, as a white crystalline solid, m.p. 111.5°-112° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[C:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:17][CH:16]=2)=[CH:13][C:12]([CH2:29][N:30]([CH3:40])[C:31](=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[H][H]>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:17][CH:16]=2)=[CH:13][C:12]([CH2:29][N:30]([CH3:40])[C:31](=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCCCCCCC(=O)N(C)Cc1ccc(OCc2ccccc2)c(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)N(C)Cc1ccc(OCc2ccccc2)c(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Yield: 26.8 %

Procedure:
In a manner similar to that of Example 1(g), starting with 1 g (1.8 mmol) of N-[6-benzyloxy-4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methyloctanamide (obtained in Example 75) in ml of dioxane and 1 ml of triethylamine under 3 atm of hydrogen, 270 mg (27%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:19][CH2:18][C:17](=O)[CH2:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([NH2:31])[CH3:30])=[CH:25][C:24]=1[O:32][CH3:33]>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([NH:31][CH:17]2[CH2:18][CH2:19][C@H:15]([C:12]3[CH:13]=[CH:14][C:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])=[CH:10][CH:11]=3)[CH2:16]2)[CH3:30])=[CH:25][C:24]=1[O:32][CH3:33]
Reactant: COc1cc([C@@H](C)N)ccc1F
Reactant: O=C1CC[C@H](c2ccc(C(=O)N3CCOCC3)cc2)C1
Agent: Cl
Product: COc1cc([C@@H](C)NC2CC[C@H](c3ccc(C(=O)N4CCOCC4)cc3)C2)ccc1F

Procedure:
General procedure B was followed using (3S)-3-[4-(Morpholine-4-carbonyl)phenyl]-cyclopentanone (preparation 15) as the ketone and (1R)-1-(4-fluoro-3-methoxyphenyl)ethylamine hydrochloride as the amine. 1H NMR (600 MHz, DMSO) δ 7.30-7.27 (m, 2H), 7.23 (d, J=8.2 Hz, 2H), 7.16 (dd, J=8.6, 1.9 Hz, 1H), 7.10 (dd, J=11.5, 8.2 Hz, 1H), 6.89 (ddd, J=8.1, 4.4, 1.9 Hz, 1H), 3.82 (s, 3H), 3.73 (q, J=6.4 Hz, 1H), 3.57 (m, 4H), 3.32 (m, 4H), 3.27-3.19 (m, 1H), 3.06-3.00 (m, 1H), 2.11-1.90 (m, 2H), 1.78-1.72 (m, 1H), 1.65-1.57 (m, 1H), 1.53-1.41 (m, 2H), 1.24 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH2:1]([C@@H:3]1[C@@H:5]([CH:6]=[O:7])[N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2].[C-]#N.[Na+].[CH3:18][OH:19]>O=[Mn]=O>[CH2:1]([C@H:3]1[N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:5]1[C:6]([O:19][CH3:18])=[O:7])[CH3:2]
Reactant: CC[C@@H]1[C@@H](C=O)N1C(=O)OC(C)(C)C
Reactant: CO
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [Na+]
Product: CC[C@@H]1[C@@H](C(=O)OC)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The following step was run duplicate. To a 250 mL round-bottom flask equipped with a stir bar was added (2R,3S)-tert-butyl 2-ethyl-3-formylaziridine-1-carboxylate (one-half of the material isolated in step 1, assumed 20 mmol) as a solution in MeOH (100 ml). The solution was cooled to 0° C. To the solution was added sodium cyanide (1.96 g, 40.0 mmol). The solution was stirred for 10 minutes. To the solution was added oxidation-grade MnO2 (34.8 g, 400 mmol). The mixture was stirred for 10 minutes, then the ice bath was removed and the solution was allowed to warm to room temperature with stirring for 18 hours. The reaction mixture was filtered through a pad Celite and the filter cake was extracted with EtOAc (100 mL). The filtrate was concentrated in vacuo and the resulting orange solid residue was dissolved in water (100 mL) and EtOAc (100 mL) and transfered to a 1 L separatory funnel where the mixture was further diluted with saturated aq. NaCl (“brine”, 100 mL) and EtOAc (100 mL). The mixture was shaken and the phases were separated. The aq. phase was extracted with EtOAc (100 mL). The combined organics were washed with brine (100 mL); dried over MgSO4; filtered; then concentrated in vacuo. The resulting residue was combined with the duplicate run and the combined material was subjected to silica gel chromatography (hexanes:EtOAc, 50:50 to 0:100) to afford (2S,3R)-1-tert-butyl 2-methyl 3-ethylaziridine-1,2-dicarboxylate as a yellow liquid (3.055 g, 33% over two steps).
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24]1[CH:39]=[CH:38][CH:37]=[CH:36][C:25]=1[CH2:26][NH:27][C:28](=[O:35])[C@H:29]([C@H:31]([CH2:33][CH3:34])[CH3:32])[NH2:30].C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:27]([CH2:26][C:25]3[CH:36]=[CH:37][CH:38]=[CH:39][C:24]=3[O:23][CH3:22])[C:28](=[O:35])[C@H:29]([C@H:31]([CH2:33][CH3:34])[CH3:32])[NH2:30])=[O:16])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1OC
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1OC)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 79.5 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (179 mg, 0.61 mmol, 1.0 eq), L-isoleucine 2-methoxybenzylamide (308 mg, 1.23 mmol) and dichloromethane (2 mL), was treated with triethylamine (515 uL, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (783 uL, 2.0 eq), to provide 254 mg (79%) of L-isoleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] 2-methoxybenzylamide.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(OC)cc3)c(N(C)C(C)C)nc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (40 mg, 0.14 mmol, 1.00 equiv), 4-methoxyphenylboronic acid (62.6 mg, 0.41 mmol, 3.00 equiv), Pd(PPh3)4 (31.4 mg, 0.03 mmol, 0.20 equiv), K3PO4 (116 mg, 0.55 mmol, 4.00 equiv), 1,4-dioxane (3 mL). The resulting solution was stirred for overnight at 110° C. in an oil bath. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by prep-TLC with ethyl acetate/petroleum ether (1:8). This resulted in 40 mg (80%) of methyl 3-(isopropyl(methyl)amino)-2-(4-methoxyphenyl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15]>O1CCOCC1>[Br:1][C:2]1[S:6][C:5]([S:7]([NH:15][CH2:14][CH2:13][O:12][CH3:11])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: COCCN
Solvent: C1COCCO1
Product: COCCNS(=O)(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.2 %

Procedure:
A mixture of 5-bromothiophene-2-sulfonyl chloride (1 g, 3.82 mmol) and 2-methoxyethanamine (0.43 g, 5.73 mmol, 1.5 eq) in 1,4-dioxane (20 mL) was stirred at r.t. for 2.5 h. The mixture was evaporated under reduced pressure. The residue was purified by column chromatography (PE100%-EtOAc100%) to afford 5-bromo-N-(2-methoxyethyl)thiophene-2-sulfonamide (1 g, 87%). LC-MS (m/z)=301 [M+H]+.
Reaction SMILES: Cl.[NH2:2]O.[CH2:4]([O:6][C:7](=[O:36])[C:8](O)=[CH:9][C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:14][C:13]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:11])[CH3:5]>C(O)C>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:11][N:2]=1)=[O:36])[CH3:5]
Reactant: NO
Reactant: CCOC(=O)C(O)=CC(=O)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 25 °C

Procedure:
Hydroxylamine hydrochloride (0.89 g; 12.8 mmol) was added to a suspension of 4-(2,4-bis-benzyloxy-5-chlorophenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester (5.00 g; 10.7 mmol) in absolute ethanol (100 ml). The reaction mixture was heated at reflux for four hours then allowed to cool to ambient temperature (during this time the mixture remains heterogeneous but becomes lighter yellow in colour). The mixture was filtered and the filtered solid was washed with water (2×20 ml), ethanol (2×20 ml) and dried in vacuo at 45° C. This affords 5-(2,4-bis-benzyloxy-5-chlorophenyl)-isoxazole-3-carboxylic acid ethyl ester as a fluffy yellow solid, 4.49 g (91%) LCMS: [M+H]+ 466, 464 (37Cl; 35Cl)). 1H NMR (400 MHz, CDCl3) δ 1.42 (t, 3H), 4.42 (q, 2H), 5.13 (s, 2H), 5.14 (s, 2H), 6.62 (s, 1H), 7.01 (s, 1H), 7.35-7.43 (m, 10H), 8.00 (s, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:47]([O:49][C:50]([C:52]1[C:60]2[N:59]=[C:58]([NH2:61])[NH:57][C:56]=2[CH:55]=[C:54]([S:62]([CH2:65][CH3:66])(=[O:64])=[O:63])[CH:53]=1)=[O:51])[CH3:48]>CN(C=O)C>[CH2:47]([O:49][C:50]([C:52]1[C:60]2[NH:59][C:58]([NH:61][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:57][C:56]=2[CH:55]=[C:54]([S:62]([CH2:65][CH3:66])(=[O:64])=[O:63])[CH:53]=1)=[O:51])[CH3:48]
Reactant: CCOC(=O)c1cc(S(=O)(=O)CC)cc2[nH]c(N)nc12
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(S(=O)(=O)CC)cc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12

Procedure:
0.30 g (1.5 mmol) of isoquinoline-3-carboxylic acid and 800 mg (2.1 mmol) HBTU were dissolved in 3.0 mL of DMF and 0.6 mL of DIEA and treated with 0.28 g (0.94 mmol) of 2-amino-6-ethylsulfonyl-1H-benzoimidazole-4-carboxylic acid ethyl ester as described in general procedure A to produce 6-ethylsulfonyl-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid ethyl ester. LCMS: 453 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:28])[C:6]=2[CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2ccccn2)c2cc(Br)ccc2O1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.1 %

Procedure:
330 mg of 6-bromo-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 10 ml of dichloromethane at room temperature and 280 mg of m-chloroperbenzoic acid were added. After stirring at room temperature for 3 days the mixture was washed with sodium bisulphite solution, then with sodium bicarbonate solution and finally with water. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 4% (v/v) methanol/ethyl acetate for the elution to give 250 mg of 2-(6-bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide as a foam. NMR (300 MHz, CDCl3): 8.35-8.30 (1H, m), 7.26-7.15 (3H, m), 7.13-7.05 (1H, dd, 6.95 (1H, broad s), 6.75 (1H, d, 9Hz), 5.28 (1H, broad s), 2.42 (1H, dd, 13Hz, 6Hz), 1.7 (1H, broad s), 1.42 (3H, s), 1.37 (3H, s). MS (EI); 335 (M+ ]Br81 ], 333 (H+ ]Br79 ]), 318 (M+ [Br81 ]-OH), 316 (M+ [Br79 ]-OH).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.C(O)C.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:22]([NH2:32])[CH:21]=1>>[CH2:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:32][C:22]3[CH:21]=[C:20]([C:19]([F:18])([F:33])[F:34])[CH:25]=[CH:24][C:23]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)[CH2:13][CH3:14]
Reactant: Nc1cc(C(F)(F)F)ccc1-c1ccccc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(C(F)(F)F)ccc3-c3ccccc3)ccnc2n1
Temperature: 100 °C

Procedure:
The product from Example 2g as a 3.15M solution in ethanol (0.078 mL, 0.24 mmol) was reacted with the product from Example 218b (0.057 g, 0.24 mmol) for 64 h at 100° C. following the procedure from Example 1g. Consumption of starting material required periodic addition of the product from Example 2g (0.103 mL, 0.32 mmol) in all, and continued heating at 100° C. (70 hrs.). The crude title compound was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.0058 g, 5%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.96 (t, J=7.35 Hz, 3H) 1.73-1.92 (m, 2H) 2.90-3.02 (m, 2H) 6.37 (d, J=6.99 Hz, 1H) 7.32 (d, J=7.72 Hz, 3H) 7.48 (dd, J=7.91, 1.65 Hz, 2H) 7.80 (d, J=8.82 Hz, 1H) 7.86 (d, J=8.09 Hz, 1H) 7.94-8.03 (m, 2H) 8.35 (d, J=6.99 Hz, 1H) 8.91 (d, J=8.82 Hz, 1H); MS (ESI+) m/z 408.1 (M+H)+; (ESI−) m/z 406.2 (M−H)−.
Reaction SMILES: O[CH:2]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(N(S(F)(F)[F:26])CC)C.OP([O-])(O)=O.[Na+]>ClCCl>[F:26][CH:2]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOP(=O)(OCC)C(O)c1ccc([N+](=O)[O-])cc1
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(F)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
The title compound was prepared as described in Taylor, W P, et. Al, Bioorg. Med. Chem. 4:1515-1520 (1996). The product from Example 2, Part A (500 mg, 1.729 mmol) was dissolved in dichloromethane (10 mL) and treated by drop wise addition of (diethylamino)sulfur trifluoride (DAST) (2.5 mL, 18.9 mmol). The mixture was stirred at room temperature for 18 h. A solution of half saturated sodium phosphate monobasic (20 mL) was added followed by dichloromethane (20 mL) addition and separation of the resulting organic phase. The organic solution was dried and concentrated under vacuum, and then subjected to column chromatography using silica gel eluting with a 1/1 mixture of hexanes/ethyl acetate to provide the title compound as an oil (215 mg, 43%).
Reaction SMILES: C[Si](C)(C)[C:3]([F:6])([F:5])[F:4].[CH3:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl>O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[F:4][C:3]([F:6])([F:5])[C:10]([CH3:9])([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCCCCC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(C)(O)C(F)(F)F
Temperature: 48 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
24.9 g of trimethyl(trifluoromethyl)silane, 16.0 g of 2-heptanone, 38 g of tetrahydrofuran and 350 mg of tetrabutylammonium fluoride trihydrate were charged into a four-necked flask equipped with a nitrogen feeding tube, a reflux condenser, a dropping funnel and a thermometer, and a reaction was effected by a conventional method. Then, 17.5 g of hydrochloric acid was dropwise added to the reaction mixture at a temperature of 25 to 48° C. over 30 minutes, followed by stirring at about 48° C. for 2 hours. The reaction mixture was treated by a conventional method, and the resulting organic phase was washed with a saline solution, followed by drying with anhydrous magnesium sulfate. Thereafter, the resultant was concentrated under reduced pressure, thereby obtaining 26.4 g of 1,1,1-trifluoro-2-methyl-2-heptanol in the form of a pale brown oily matter.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10]Br)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[C:1]([NH:8][CH2:9][CH2:10][N:12]=[N+:13]=[N-:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCN=[N+]=[N-]
Temperature: 110 °C
Reaction time: 12 h
Yield: 79.4 %

Procedure:
BocNHCH2CH2Br (10.00 g, 44.62 mmol) was dissolved in DMF (200 mL). NaN3 (14.48 g, 223.1 mmol) was added, and the mixture was stirred at 110° C. for 12 h. The solvent was removed under reduced pressure, and the residue was dissolved in water (200 mL). The resulting aqueous solution was extracted with ethyl acetate (2×200 mL). The organic layers were combined and dried over anhydrous MgSO4(s). After filtering, the organic layer was concentrated under reduced pressure and the residue was dissolved in methylene chloride (10-20 mL) and purified by flash chromatography (silica gel, methylene chloride). BocNHCH2CH2N3 (6.60 g, 80%) was isolated as a colorless oil. HRMS (ESI) [M+Na]+ calcd for C7H14N4O2Na, 209.1014; found, 209.1010; 1H NMR (400 MHz, CDCl3) δ 4.88 (bs, 1H), 3.42 (t, J=5.3 Hz, 2H), 3.34-3.26 (m, 2H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.8, 79.8, 51.4, 40.2, 28.5.
Reaction SMILES: C([O:8][N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:10]([NH:12][CH3:13])=[O:11])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:13][NH:12][C:10]([N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[OH:8])=[O:11]
Reactant: CCCCCCCCCCN(OCc1ccccc1)C(=O)NC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCCCCCCCCN(O)C(=O)NC
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
Purification by chromatography on silica gave t-butyl N-benzyloxy-N-decylcarbamate as a colorless oil (8.39 g, 79% yield). To a solution of this urethane (7.0 g) in methylene chloride (15 ml) at room temperature under nitrogen was added trifluoroacetic acid (15 ml). After 30 minutes, the solution was evaporated at 40° C. lN NaHCO3 was added and solid Na2CO3 was added to bring the pH to 9. The mixture was extracted twice with methylene chloride, and the combined extracts were dried (MgSO4), filtered, and evaporated to give decyl-N-benzyloxyamine as a colorless oil (5.0g g, 100% yield). To a stirred solution of this amine (4.92 g, 18.8 mmol) in methylene chloride (30 ml) at room temperature under nitrogen was added methyl isocyanate (1.2 ml). After two hours, the reaction mixture was evaporated and triturated with cold pentane to give N-benzyloxy-N-decyl-N'-methylurea as a white solid (4.98 g, 83% yield). This urea (745 mg) was dissolved in ethanol (10 ml) under nitrogen at room temperature, and ammonium formate (0.8 g) was added. After 20 minutes, 10% palladium on carbon (0.25 g) was added. After stirring for two hours, the reaction mixture was filtered through celite and evaporated. Water was added, and the resulting solid was collected by filtration. Recrystallization from isopropanol gave the title compound as a white solid (420 mg, mp 96°-97° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH:40]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:11])=[CH:7][CH:8]=1)(=[O:40])[NH2:2]
Reactant: OO
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 10 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To the solution of rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide (0.12 g, 0.2 mmol) prepared in Example 88 in DMSO (1 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.36 g, 3.2 mmol), then aqueous solution (1N) of NaOH (1.1 mL, 1.1 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-phenyl)-amide as a white solid (Yield 66 mg, 53%)