Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[N:13]/[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])/[CH:3]=1.[CH3:29][N:30]1[C:34]([SH:35])=[N:33][N:32]=[N:31]1.N1C=CC=CC=1>C1COCC1>[CH3:29][N:30]1[C:34]([S:35][C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)/[C:4](=[N:13]/[S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:19][CH:18]=3)(=[O:16])=[O:15])/[CH:3]=2)=[N:33][N:32]=[N:31]1
Reactant: Cn1nnnc1S
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc21
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 99 %

Procedure:
81.6 mg 12b was dissolved in 2 ml THF. 1 ml THF solution containing 1 eq. 1-methyl-tetrazole-5-thiol and 1 eq. pyridine was added. The mixture was shaken for 30 min. The organic solvent was removed by V-10 (biotage). The residue was suspended in 10 ml water and sonicated thoroughly. The insoluble was filtered and washed with water. The solid was dried over air affording 96.5 mg (99.0%) title compound 13x.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH:10]([CH2:16][CH2:17][O:18][CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:19][O:18][CH2:17][CH2:16][CH:10]([CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:27]2[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)=[CH:3][CH:4]=1)=[O:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(CCOC)CC(=O)c1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)C(CCOC)CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
To a 150 mL 3-neck flask fitted with a reflux condenser was added ethyl 4-(4-bromophenyl)-2-(2-methoxyethyl)-4-oxobutanoate (1.06 g, 3.09 mmol) and 4-nitro-phenyl boronic acid (0.62 g, 3.70 mmol) dissolved in toluene (30 mL) and dioxane (8.50 mL), followed by addition of saturated aqueous sodium carbonate solution (8.50 mL). A thin-gauge needle was inserted into the bi-phasic mixture and degassed with argon over 30 minutes, at which point 1,2-bis[(diphenylphosphino) ferrocene]dichloropalladium(II) (0.13 g, 0.15 mmol) was added, followed by an additional 15 minutes of degassing. The reaction mixture was heated at 85° C. for 16 h, and then the resulting dark-colored reaction mixture was allowed to cool, and was diluted with ethyl acetate (75 mL) and saturated aqueous sodium chloride solution (75 mL). The layers were separated, the aqueous layer was extracted twice with ethyl acetate (50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (75 mL), dried over anhydrous magnesium sulfate, and filtered in vacuo through 2 cm Celite®/2 cm silica. The filtrate was concentrated in vacuo, leaving a dark red-brown oil, that was purified by flash chromatography (4:1 hexane/ethyl acetate, then 3:1 hexane/ethyl acetate, then 2:1 hexane/ethyl acetate) to afford ethyl 2-(2-methoxyethyl)-4-(4′-nitro-1,1′-biphenyl-4-yl)-4-oxobutanoate (1.04 g, 88%). LC-MS ret. time 3.38 min, t/z 385.9 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.27 (t, 3H), 1.80-1.95 (m, 1H), 1.95-2.10 (m, 1H), 3.10-3.25 (m, 2H), 3.40-3.58 (m, 3H), 4.17 (q, 2H), 7.67-7.82 (2d, 4H), 8.10 (d, 2H), 8.33 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](/[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)\[C:13]([OH:15])=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:23]O>S(=O)(=O)(O)O>[CH3:23][O:14][C:13](=[O:15])/[C:12](/[C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)=[CH:11]\[C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CO
Reactant: COc1cc(/C=C(\C(=O)O)c2ccc(O)cc2)cc(OC)c1
Agent: O=S(=O)(O)O
Product: COC(=O)/C(=C\c1cc(OC)cc(OC)c1)c1ccc(O)cc1
Yield: 35 %

Procedure:
Concentrated sulfuric acid (10 drops) was added to a stirred methanol suspension of thoroughly dried 19 (0.60 g, 2.0 mmol) under argon and heated at reflux for 18 h. Methanol was evaporated under reduced pressure, residue was taken up in ethyl acetate (20 mL) and washed with water (20 mL), saturated aqueous Na HCO3 (10 mL) and brine (10 mL). The organic layer was dried on anhydrous magnesium sulfate, filtered and the solvent was evaporated. The crude product obtained was purified by chromatography over silica gel and eluted with hexane-ethyl acetate (7:3) to yield 20 as white solid (0.24 g, 35%): 1HNMR (400 MHz, CDCl3) δ 7.26 (d, J=8.4 Hz, 2H), 6.82 (s, 1H), 6.76 (d, J=8.4 Hz, 2H), 6.45 (d, J=2.0 Hz, 2H), 6.34 (t, J=2.0 Hz, 1H), 4.97 (s, 1H), 3.73(s, 3H), 3.72(s, 6H).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[N:15][C:16]([N:19]2[CH2:26][CH:25]3[C:21]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)([NH:22][O:23][CH2:24]3)[CH2:20]2)=[N:17][CH:18]=1>O1CCCC1>[F:12][C:13]1[CH:18]=[N:17][C:16]([N:19]2[CH2:26][CH:25]3[C:21]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)([N:22]([C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[S:11])[O:23][CH2:24]3)[CH2:20]2)=[N:15][CH:14]=1
Reactant: Fc1cnc(N2CC3CONC3(c3cccnc3)C2)nc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)N1OCC2CN(c3ncc(F)cn3)CC21c1cccnc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 109.5 %

Procedure:
Benzoyl isothiocyanate (511 μL 3.79 mmol) is added drop wise to a stirred solution of 5-(5-fluoropyrimidin-2-yl)-6a-(3-pyridyl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole (640 mg, 2.23 mmol) in tetrahydrofuran (20 mL) at 0° C. The resulting mixture is stirred at 0° C. for 1 hour and is warmed to room temperature over 1 hour. The solvent is evaporated under vacuum and the resulting residue is purified by silica gel chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (1.1 g, quantitative). ES/MS (m/e): 451 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.FC(F)(F)C(O)=O.[NH2:37][C:38]1[CH:39]=[CH:40][C:41]([CH:49]2[CH2:53][CH:52]([OH:54])[CH:51]([OH:55])[CH2:50]2)=[C:42]2[C:46]=1[C:45](=[O:47])[N:44]([CH3:48])[CH2:43]2>CCOC(C)=O>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:37][C:38]3[CH:39]=[CH:40][C:41]([CH:49]4[CH2:50][CH:51]([OH:55])[CH:52]([OH:54])[CH2:53]4)=[C:42]4[C:46]=3[C:45](=[O:47])[N:44]([CH3:48])[CH2:43]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CN1Cc2c(C3CC(O)C(O)C3)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4CC(O)C(O)C4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (43 mg, 0.095 mmol) and 7-amino-4-(3,4-dihydroxycyclopentyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one trifluoroacetate (salt) (Compound 243A, 36 mg, 0.096 mmol). The reaction mixture was diluted with EtOAc (30 mL), washed with sat. aq. NaHCO3 (2×10 mL), brine (10 mL), and dried over anhydrous sodium sulfate. The solvents were evaporated under reduced pressure, and the residue was purified by silica gel chromatography (ISCO Combi-flash system, eluting with 0-10% MeOH:DCM) to give the title compound as a white solid, 34 mg, 52% yield. 1H NMR (CDCl3): 1.26 (t, J=7.1 Hz, 6H), 1.95-2.01 (m, 2H), 2.23-2.29 (m, 2H), 3.17 (d, J=21.7 Hz, 2H), 3.21 (s, 3H), 3.53 (m, 1H), 3.91 (s, 3H), 3.97-4.07 (m, 4H), 4.35 (s, 2H), 4.39-4.43 (m, 2H), 6.84 (s, 1H), 6.94 (m, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.67 (s, 1H), 8.26 (d, J=8.1 Hz, 1H), 8.38 (s, 1H), 8.54 (d, J=8.6 Hz, 1H), 10.31 (s, 1H). MS (ES+): m/z=680.14 [MH+]. HPLC: tR=3.60 min (ZQ3, polar—5 min).
Reaction SMILES: [S:1]([O:6]C)([O:4][CH3:5])(=[O:3])=[O:2].[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1([C:21]2[C:25]([CH3:26])=[C:24]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[N:23]([CH3:33])[N:22]=2)CCCCC1>CCOCC>[CH3:5][O:4][S:1]([O-:6])(=[O:3])=[O:2].[CH:8]1([C:14]2[N:22]([CH3:21])[N+:23]([CH3:33])=[C:24]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:25]=2[CH3:26])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccccc1
Reactant: Cc1c(C2CCCCC2)nn(C)c1C1CCCCC1
Solvent: CCOCC
Product: COS(=O)(=O)[O-]
Product: Cc1c(C2CCCCC2)n(C)[n+](C)c1C1CCCCC1
Temperature: 80 °C

Procedure:
Dimethyl sulfate (1.26 g. 0.01 mole) is added to an anhydrous toluene (50 ml) solution of 3,5-dicyclohexyl-1,4-dimethylpyrazole (1.7 g, 0.0064 mole) with constant stirring at 80° C. The reaction mixture is then heated to reflux and maintained at reflux, with stirring, for 6 hours. The reaction mixture is cooled, ether (75 ml) is added and the mixture stirred for 3 hours. The resulting solid is filtered and dried to give 1,8 g of the desired product, m.p. 176° C to 177° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:14]([C:15](=[O:18])[C:16]=1[OH:17])[CH2:13][CH:12]1[CH2:19][CH2:20][C:9]2([O:21][CH2:22][CH2:23][OH:24])[CH2:10][CH2:11]1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:14]([C:15](=[O:18])[C:16]=1[O:17][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:13][CH:12]1[CH2:19][CH2:20][C:9]2([O:21][CH2:22][CH2:23][OH:24])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(OCCO)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(OCCO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a solution of 5-hydroxy-1-(2-hydroxyethoxy)-6-oxo-3,7-diazatricyclo[7.2.2.02,7]trideca-2,4-diene-4-carboxylic acid ethyl ester (203 mg, 0.600 mmol) in DMF (1 mL) was added K2CO3 (249 mg, 1.80 mmol) and (bromomethyl)benzene (103 mg, 0.600 mmol) and the mixture stirred at room temperature overnight under N2. Additional (bromomethyl)benzene (206 mg, 1.2 mmol, 2 eq.) and K2CO3 (166 mg, 1.2 mmol, 2 eq.) were added and the mixture stirred overnight. The mixture was concentrated in vacuo to remove most of DMF, and the residue was diluted with ethyl acetate (15 mL),washed with water followed by brine, then dried (Na2SO4) and concentrated to provide an amber oil which was purified by silica gel column chromatography (18 g SiO2, 45% ethyl acetate/CH2Cl2) to gave the title compound (141 mg, 0.329 mmol, 55% yield) as an amber oil; HPLC: retention time=2.18 min (area percent=92%); LCMS: m/z 429 (M+H); 1H NMR (500 MHz, CDCl3) δ ppm 1.28 (3H, t, J=7.2 Hz), 1.63 (2H, ddd, J=14.3, 7.5, 7.2 Hz), 1.83-1.94 (2H, m), 2.06 (4H, t, J=7.6 Hz), 2.42 (1H, brs), 3.59 (2H, t, J=4 Hz), 3.70 (2H, d, J=4 Hz), 4.05 (2H, d, J=4.0 Hz), 4.31 (2H, q, J=7.2 Hz), 5.22 (2H, s), 7.27 (1H, t, J=7.4 Hz), 7.32 (2H, t, J=7.2 Hz), 7.46 (2H, d, J=6.7 Hz); 13C NMR (126 MHz, CDCl3) δ ppm 14.1, 23.2, 27.6, 30.5, 53.6, 62.1, 62.2, 65.3, 74.5, 76.7, 128.3, 128.5, 128.6, 136.8, 140.0, 142.4, 159.2, 161.3, 163.9.
Reaction SMILES: S(Cl)([Cl:3])=O.O[C@@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8].N1C=CC=CC=1.O>C(COC)OC>[Cl:3][C@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: COCCOC
Product: O=C(O)[C@H](Cl)Cc1ccccc1
Reaction time: 15 h
Yield: 60.9 %

Procedure:
Thionyl chloride (0.18 ml, 2.4 mmol) was added dropwise to a solution of 200 mg (1.2 mmol) of (2S)-2-hydroxy-3-phenylpropionic acid (optical purity 100% ee (S)) in 2 ml of dimethoxyethane at room temperature, and the mixture was stirred for 15 hours. To that reaction mixture was added 0.01 ml (0.12 mmol) of pyridine, and the mixture was stirred at 60° C. for 4 hours. Water (10 ml) was added to the reaction mixture and, after 30 minutes of stirring, the mixture was extracted with 50 ml of ethyl acetate. The organic phase was washed with 10 ml of a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The solvent was distilled off under reduced pressure to give 135 mg (yield 61%) of the desired (2R)-2-chloro-3-phenylpropionic acid. The optical purity of the product as determined by the same method as in Example 12 was 97.6% ee (R) (rate of configurational inversion 97.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:26]([Si:29]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)([CH3:28])[CH3:27]>C(#N)C.C(Cl)Cl>[CH:43]([Si:29]([CH:26]([CH3:28])[CH3:27])([CH:40]([CH3:42])[CH3:41])[O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[O:36])=[CH:33][CH:32]=1)([CH3:45])[CH3:44]
Reactant: CC(C)[Si](Oc1ccc(C(=O)Cl)cc1)(C(C)C)C(C)C
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)[Si](Oc1ccc(C(=O)Nc2ccc3cccc(N4CCN(C)CC4)c3c2)cc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.118 g, 0.489 mmol) and triethylamine (0.13 mL, 0.98 mmol) in acetonitrile (10 mL) was chilled to 0° C. and 4-triisopropylsilyloxybenzoyl chloride (0.16 g, 0.51 mmol) dissolved in methylene chloride was added all at once. The mixture was gently refluxed overnight; then 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.038 g, 0.16 mmol), 4-triisopropylsilyloxybenzoyl chloride (0.5 g, 1.6 mmol), and triethylamine (0.13 mL, 0.93 mmol) were added. The reaction was refluxed for an additional 24 hours, cooled and the solvent was removed at reduced pressure. The residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate and stirred vigorously for 5 hours. The phases were separated and the organic layer was washed with brine, dried over calcium sulfate and concentrated to a tan foam which was purified by flash chromatography on silica gel (1×3.5 inches). Elution with 25% ethyl acetate/hexane removed unweighed recovered acid chloride. Continued elution with an ethyl acetate/hexane gradient of from 1:3 to 3:1 followed by 100% ethyl acetate gave 0.238 g of 7-(4-triisopropylsilyloxybenzamido)-1-(4-methyl-1-piperazinyl)-naphthalene as a viscous tan oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:17]=O)[C:12]([CH:15]=[O:16])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.[NH2:24][CH2:25][C:26]#[N:27].C(N(CC)CC)C>CN(C=O)C>[O:16]=[C:15]1[C:12]2[C:11](=[CH:10][C:9]([O:8][CH2:7][C:6]3[CH:19]=[CH:20][C:3]([C:2]([F:22])([F:21])[F:1])=[CH:4][CH:5]=3)=[CH:14][CH:13]=2)[CH2:17][N:27]1[CH2:26][C:25]#[N:24]
Reactant: N#CCN
Reactant: O=Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCN1Cc2cc(OCc3ccc(C(F)(F)F)cc3)ccc2C1=O
Temperature: 25 °C
Yield: 7 %

Procedure:
To a cooled (0° C.) solution of 4-(4-trifluoromethyl-benzyloxy)-benzene-1,2-dicarbaldehyde (250.0 mg, 0.81 mmol) in DMF (7 mL) was added aminoacetonitrile HCl (150.1 mg, 1.62 mmol) and triethylamine (164.1 mg, 1.62 mmol) and the resulting mixture was warmed up to RT over 1 h and then heated at 50° C. for 1 h. After cooling to RT, the mixture was evaporated and the residue partioned between ethyl acetate and hydrochloric acid (1 N). The organic layer was then dried over sodium sulfate, filtered and evaporated to leave a clear oil which was purified by chromatography (SiO2, DCM:MeOH 9:1) to afford the title product (19.6 mg, 7%) as a light brown solid. MS m/e 345.2 (M−H−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:22])[C:16]=3[CH:15]=[CH:14]2)([CH2:11][CH3:12])[CH:9]=[CH2:10])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][S:31]([CH3:30])(=[O:33])=[O:32])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[CH:9]=[CH2:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: C=CC(CC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: C=CC(CC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 2 h

Procedure:
To a solution of the product of Step B (40 mg, 0.128 mmol) and N-methylmorpholine (26 mg, 0.256 mmol) in dichloromethane (2 mL) was added methanesulfonyl chloride (18 mg, 0.192 mmol) at room temperature. The mixture was stirred for 2 h, then diluted with water (10 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by PREP-TLC eluting with PE/EA (3/1, v/v) to give the title compound as a colorless solid. LC/MS m/z=388.9 [M+H]+.
Reaction SMILES: C=C1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.C[N+]1([O-])CC[O:17][CH2:16]C1.[C:21]([O-:24])(O)=O.[Na+]>C(O)(C)(C)C.O.CC(C)=O.O=[Os](=O)(=O)=O>[OH:17][CH2:16][C:21]1([OH:24])[CH2:3][O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[O:7][CH2:8]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C1COc2ccccc2OC1
Reactant: O=C([O-])O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: OCC1(O)COc2ccccc2OC1
Reaction time: 8 h

Procedure:
A cloudy solution of Example 280A (0.81 g, 5 mmol), 4-methylmorpholine N-oxide (644 mg, 5.5 mmol) in t-butanol (0.4 mL), water (2.5 mL) and acetone (1.5 mL) was treated with OsO4 (0.1 mL, 4% aq. solution) then stirred overnight. The reaction mixture was treated with 2 g NaHCO3, concentrated and partitioned between water and EtOAc. The organics were dried (MgSO4), filtered and concentrated to a white solid (740 mg, 75%). MS (ESI): 219 (M+Na)+.
Reaction SMILES: [C:1](/[C:3](=[CH:9]\[CH2:10][CH:11]([CH3:13])[CH3:12])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[N+]([CH:17]([CH3:19])[CH3:18])([O-])=O.[O-]CC.[Na+]>C(O)C>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:17]1([CH3:19])[CH3:18])#[N:2]
Reactant: CCOC(=O)/C(C#N)=C/CC(C)C
Reactant: CC(C)[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C#N)C(CC(C)C)C1(C)C
Yield: 95.4 %

Procedure:
A mixture of 490 mg (2.70 mmoles) of cyanoester 5 (produced in accordance with Example V), 0.25 mL (2.78 mmoles) of 2-nitropropane, and 4.0 mL of an 0.65M solution of sodium ethoxide (prepared from sodium metal and ethyl alcohol) in absolute ethyl alcohol was heated at reflux, protected from atmospheric moisture, for 31/2 hours. The product was isolated as described in the procedure of Example VIII, affording 575 mg (95% yield) of cyclopropanoid cyanoester 14: bp 80°-102° C. (bath temperature, 0.05 mm).
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.[F:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[CH:66][CH:65]=1>>[F:63][C:64]1[CH:70]=[CH:69][C:67]([NH:68][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[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:66][CH:65]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(F)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 46.8 %

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 (0.17 g, 0.71 mmol), then reacted with 4-fluoroaniline (Aldrich) (0.047 g, 0.43 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 (4-fluoro-phenyl)-amide as a yellow solid (Yield 0.094 g, 47%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])=[C:4]([CH3:10])[CH:3]=1
Reactant: BrCCCCCCCBr
Reactant: Cc1cc(Br)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Br)cc(C)c1OCCCCCCCBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-bromo-2,6-dimethylphenol (2.00 g) and 1,7-dibromoheptane (5.10 g) in N,N-dimethylformamide (20 ml) was treated with potassium carbonate (2.06 g), and the mixture was stirred for 5 hours at ambient temperature. To the reaction mixture was added water and methylene chloride, and the organic layer was separated and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting successively with the following solvents: (1) n-hexane, (2) n-hexane:ethyl acetate=4:1, (3) n-hexane:ethyl acetate=1:1. The fractions containing the object compound were concentrated in vacuo to give crude 5-bromo-2-(7-bromoheptyloxy)-1,3-dimethylbenzene, that was used in the next reaction directly, as a pale yellow oil.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]=1[CH2:20][C:21]([O:23]CC)=O.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[C:33]#[N:34]>C1COCC1>[N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:11][C:12]=1[CH2:20][C:21]([NH:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[C:33]#[N:34])=[O:23]
Reactant: N#Cc1ccncc1N
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccncc1NC(=O)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiHMDS (2.5 eq) was added to ethyl 2-benzimidazol-2-ylacetate (1.0 eq) in THF at −78° C. After 1 hour, 3-amino-4-cyanopyridine (0.8 eq) in THF was added. The resulting mixture was allowed to warm to room temperature overnight. The mixture was quenched with NH4Cl (aqueous saturated solution) and extracted with EtOAc. The organic layer washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a brown solid. The crude material was purified by silica gel chromatography (5:1 EtOAc:hexane) to yield the desired product. LC/MS m/z 278.3 (MH+), Rt 1.88 minutes.