Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][CH2:15][C:16]#[N:17])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:18]=[CH:19][CH:20]=[N:21][C:5]1=2.[OH-].[K+].Cl.C(OCC)(=[O:27])C>CS(C)=O>[CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][CH2:15][C:16]([NH2:17])=[O:27])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:18]=[CH:19][CH:20]=[N:21][C:5]1=2
Reactant: CCOC(C)=O
Reactant: COCN1c2cc(CCC#N)ccc2Sc2nccnc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCN1c2cc(CCC(N)=O)ccc2Sc2nccnc21
Temperature: 50 °C

Procedure:
200 mg of (10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl)acetonitrile was dissolved in 5 ml of dimethyl sulfoxide. After adding 200 mg of powdered potassium hydroxide, the resulting mixture was heated to 40 to 60° C. for 10 minutes. Then the reaction mixture was distributed into 1 N hydrochloric acid and ethyl acetate. The organic layer was extracted, washed successively with a saturated aqueous solution of sodium bicarbonate and water and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 35 mg of the title compound as yellow crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([NH:25][C:26](=[O:40])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]3=[O:39])=[CH:29][CH:28]=2)[CH2:9]1)=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[NH:14][C@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[NH:25][C:26](=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]2=[O:39])=[CH:29][CH:28]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:43]([OH:45])([C:42]([F:47])([F:46])[F:41])=[O:44]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)c2ccc(-n3ccccc3=O)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CCNC[C@H]1NC(=O)c1ccc(-n2ccccc2=O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cis-4-Benzyloxycarbonylamino-3-[4-(2-oxo-2H-pyridin-1-yl)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (22.2 mg, 0.041 mmol) was dissolved in 2 mL of anhydrous CH2Cl2 To this solution was added 2 mL of trifluoroacetic acid (TFA). The mixture was stirred for one hour at rt. The solvent was removed in vacuo to yield cis-{3-[4-(2-Oxo-2H-pyridin-1-yl)-benzoylamino]-piperidin-4-yl}-carbamic acid benzyl ester, CF3COOH salt (42.7 mg) as a viscous oil, which was used without any further purification. Anal. LC/MS (ESI) Shimadzu Phenomenex C18; 4.6×50 mm Luna; flow rate 4 mL/mn; detection at 220 nM; Gradient elution 0% to 100% B over 4 min; (A=10% MeOH, 90% H2O, 0.1% TFA & B=90% MeOH, 10% H2O, 0.1% TFA); 447.24 (M+H)+, tR=2.15 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:29]([O:31][C:32](=[O:43])[C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH2:40]Br)=[CH:35][C:34]=1[CH3:42])[CH3:30]>C1COCC1>[CH2:29]([O:31][C:32](=[O:43])[C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH2:40][N:8]2[C:9]3[C:5](=[CH:4][C:3]([Cl:2])=[CH:11][CH:10]=3)[C:6]([CH3:18])=[C:7]2[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:35][C:34]=1[CH3:42])[CH3:30]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)c1c(C)cc(CBr)cc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)cc(Cn2c(-c3cccnc3)c(C)c3cc(Cl)ccc32)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Chloro-3-methyl-2-pyridin-3-yl-1H-indole (Example 2, 1.350 g, 4.659 mmol) is suspended in THF (40 mL) and cooled to 0° C. KHMDS (0.5M in toluene, 32.6 mL, 16.3 mmol) is added dropwise. After 1 h, 4-bromomethyl-2,6-dimethyl-benzoic acid ethyl ester (4.95 g, 18.2 mmol) in THF (10 mL) is added dropwise. The mixture is allowed to warm to room temperature overnight. The mixture is then quenched with saturated aqueous ammonium chloride and diluted with dichloromethane. The aqueous phase is extracted with ethyl acetate, dried over MgSO4, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (dichloromethane-methanol, 1:0 to 99:1 to 49:1 to 97:3) affords 2,6-dimethyl-4-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid ethyl ester as an orange solid. MS (ESI) m/z 399 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[C:4]([CH2:19][CH:20]([NH:33][C:34](=O)[O:35]C(C)(C)C)[C:21]2[N:22]([CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:23]=[CH:24][N:25]=2)[CH:3]=1.Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH:54]1[CH2:59][CH2:58][CH:57]([N:60]2[CH2:69][C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[NH:62][C:61]2=[O:70])[CH2:56][CH2:55]1>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:19][CH:20]([NH:33][C:34]([N:54]2[CH2:55][CH2:56][CH:57]([N:60]3[CH2:69][C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[NH:62][C:61]3=[O:70])[CH2:58][CH2:59]2)=[O:35])[C:21]2[N:22]([CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:23]=[CH:24][N:25]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2cccnc2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nccn2Cc2cccnc2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 72 h

Procedure:
tert-Butyl 2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-(1-(pyridin-3-ylmethyl)-1H-imidazol-2-yl)ethylcarbamate (51.0 mg, 0.091 mmol) was dissolved in a minimum amount of ethyl acetate, and treated with hydrochloric acid (4 N in dioxane, 1.5 mL). The mixture was stirred under nitrogen for 3 days. After removal of the solvents, the crude mixture was treated with diethyl ether to give a precipitate which was filtered. The resulting solid was dissolved in dimethylformamide (1.0 mL), cooled to 0° C., and treated with carbonyl diimidazole (17.2 mg, 0.106 mmol, 1.05 equiv) and N′N-diisopropylethylamine (53.0 μL, 3 equiv). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (28.3 mg, 0.106 mmol, 1.05 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to afford 23.2 mg (43%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 1.50-1.67 (m, 4H), 2.45 (s, 3H), 2.68-2.72 (m, 2H), 3.71-3.79 (m, 3H), 4.01-4.15 (m, 2H), 4.20 (s, 2H), 4.31-4.43 (m, 1H), 5.16-5.35 (m, 3H), 6.80 (d, J=7.9, 1H), 6.84 (s, 1H), 6.93-7.21 (m, 8H), 7.26 (s, 1H), 7.92 (s, 1H), 8.27 (s, 1H), 8.32 (s, 1H). Mass spec.: 590.3 (MH)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[C:20]([OH:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[C:17]([OH:26])[C:16]=1[CH3:27])(=[O:3])[CH3:2].[C:28]([Si:32](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29].N1C=CN=C1>ClCCl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[C:20]([OH:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[C:17]([O:26][Si:32]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:16]=1[CH3:27])(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1c(O)c(C)c(CCCCCCCCCCOC(C)=O)c(O)c1OC
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1c(O)c(CCCCCCCCCCOC(C)=O)c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1OC
Temperature: 43 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
6-(10-Acetoxydecyl)-2,3-dimethoxy-5-methylhydroquinone (38.0 g) and tert-butylchlorodiphenylsilane (55.0 g) were dissolved in dichloromethane (50 ml). Imidazole (13.6 g) was added under a stream of nitrogen at room temperature. The mixture was stirred at 43° C. for 16 hours. The reaction mixture was washed with water (50 ml) and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with hexane/ethyl acetate (7:3) to obtain the desired compound (58.0 g).
Reaction SMILES: CS(C)=O.ClCCl.C(Cl)(=O)C(Cl)=O.[CH3:14][O:15][N:16]=[C:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]([OH:35])[CH:27]([OH:34])[C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1>ClCCl.CS(C)=O.C(N(CC)CC)C>[CH3:14][O:15][N:16]=[C:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26](=[O:35])[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[O:34])=[CH:23][CH:24]=2)[CH2:19][CH2:18]1
Reactant: CON=C1CCc2cc(C(O)C(O)c3ccncc3)ccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=C1CCc2cc(C(=O)C(=O)c3ccncc3)ccc21
Temperature: -60 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a mixture of DMSO (43 ml, 0.56 mol) and dichloromethane (800 ml) at −70° C. under argon, was added oxalyl chloride (71.4 g) and then a solution of the product of Step 3 (55 g, 0.185 mol) in a mixture of dichloromethane/DMSO (1000 ml/60 ml) over 2 hours at −60° C. After stirring for 2 hours at −60° C., triethylamine (154 ml) was added dropwise and the mixture then allowed to warm to room temperature overnight. The reaction mixture was then quenched with water, the organic phase separated then washed with water, dried (Na2SO4) and concentrated to yield the title compound (51 g, 94%) as a yellow solid. 1H NMR (CDCl3) 8.87 (2H, d), 7.89–7.77 (5H, m), 4.03 (3H, s), 3.09 (2H, m), 2.93 (2H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O(C(C)(C)C)[Na]>C1(C)C=CC=CC=1>[C:2]1([S:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: Sc1ccccc1
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: c1ccc(Sc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A 50 mL of reactor equipped with magnetic stir bar was charged with 252 mg (0.27 mmol) of {[(t-Bu)2P(OH)]2PdCl}2, 2.90 g (18.47 mmol) of bromobenzene, 1.98 g (18.0 mmol) of PhSH and 3.46 g (36.0 mmol) of NaO—tBu in 20.0 mL of toluene. The resulting mixture was refluxed for 15 h before the mixture was cooled to room temperature and quenched with 100 mL of H2O. The mixture was transferred to a separatory funnel, and extracted with EtOAc (2×200 mL). The layers were separated, and organic layer was washed with H2O (100 mL), brine (150 mL), and dried over mgSO4, filtered, and the solvents removed from the filtrate by rotary evaporation. The product was isolated by distillation. The final product was obtained as a colorless oil (2.24 g, 66% yield).
Reaction SMILES: [CH3:1][N:2]1[C:7]([SH:8])=[N:6][C:5](=[O:9])[C:4]([OH:10])=[N:3]1.C(N(CC)CC)C.[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[CH3:1][N:2]1[C:7]([SH:8])=[N:6][C:5](=[O:9])[C:4]([O:10][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:3]1
Reactant: Cn1nc(O)c(=O)nc1S
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(=O)nc1S

Procedure:
A solution of 2-methyl-3-mercapto-6-hydroxy-2,5-dihydro-1,2,4-triazin-5-one (0.8 g) in dry tetrahydrofuran (25 ml) was stirred for 30 min with triethylamine (0.835 ml) and tertbutyldiphenylsilylchloride (1.53 ml). The reaction mixture was partitioned between 1% aqueous NaHCO3 and ethyl acetate. Removal of the solvent from the dried organic layer left a residue which crystallized by trituration with light petrol affording 2-methyl-3-mercapto-6-tert-butyldiphenylsilyloxy-2,5-dihydro-1,2,4-triazin-5-one (1.34 g), m.p. 135° C. (decomp.);
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[CH2:7][C:8](=[O:10])[CH3:9]>>[N:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(=O)CCl
Reactant: c1cn[nH]c1
Product: CC(=O)Cn1cccn1
Temperature: 90 °C
Yield: 37.6 %

Procedure:
1H-pyrazole (1.0 g, 15 mmol) was dissolved in chloroacetone (3.0 g, 32 mmol) and heated at 90° C. for 10 hr. Purification by silica gel column, elution with 1:1 hexanes:DCM afforded the title compound (700 mg): 1H NMR (400 MHz DMSO) delta 2.05 (s, 3H), 5.09 (s, 2H), 6.29 (t, J=2.0 Hz, 1H), 7.47 (dd, J=0.4, 1.6 Hz, 1H), 7.67 (dd, J=0.4, 2.0 Hz, 1H).
Reaction SMILES: [P:1]([O-:42])([O-:41])([O:3][C:4](C(C)(C)C)(C(C)(C)C)[N:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:7][C:6]1=[O:32])=[O:2]>CC#N.O.CC(O)=O>[P:1]([OH:42])([OH:41])([O:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[C:13]2[CH:18]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:16]=[CH:15][C:14]=2[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:7][C:6]1=[O:32])=[O:2]
Reactant: CC(C)(C)C(OP(=O)([O-])[O-])(n1ccc(NC(=O)c2cc(C(F)(F)F)ccc2Oc2ccc(F)cc2)cc1=O)C(C)(C)C
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C(Nc1ccn(COP(=O)(O)O)c(=O)c1)c1cc(C(F)(F)F)ccc1Oc1ccc(F)cc1
Yield: 55.5 %

Procedure:
A solution of di-tert-butyl [4-[[2-(4-fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (22) (67 mg, 0.1090 mmol) in CH3CN (1.340 mL), water (1.340 mL) and AcOH (1.340 mL) was refluxed for 1 hour then evaporated to dryness. The material was then co-evaporated with CH3CN (3×), triturated with CH3CN, filtered, washed with CH3CN and desiccated to give [4-[[2-(4-fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate (18) (32 mg, 0.06052 mmol, 55.5%) as a white solid. ESI-MS m/z calc. 502.0553, found 503.4 (M+1)+; Retention time: 1.39 minutes. 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.83 (dd, J=8.8, 2.4 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.35-7.23 (m, 4H), 7.00 (d, J=8.7 Hz, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.45 (dd, J=7.6, 2.3 Hz, 1H), 5.53 (d, J=9.7 Hz, 2H) ppm. 31P NMR (162 MHz, DMSO-d6-85% H3PO4 aq. as internal standard—0 ppm) δ −2.11 (t, J=9.6 Hz) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:11]42[NH:15][C:14](=S)[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:20]>>[Br:1][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:11]42[N:15]=[C:14]([NH2:20])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: N
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCC1
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC1
Temperature: 90 °C
Yield: 65.1 %

Procedure:
6′-Bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 54 Step 3, 1.62 g, 4.83 mmol) and ammonia (7M in MeOH, 15.2 mL, 106 mmol) were mixed together in a microwave vial. The vial was sealed and the reaction was heated at 90° C. for 30 min in a microwave reactor. The mixture was concentrated and the residue was dissolved in ammonia (7M in MeOH, 15.2 mL, 106 mmol), and heated once more at 90° C. for 30 min in a microwave reactor. This cycle was repeated four more times. After evaporation of the solvent, the crude was acidified with 2 M aq. hydrochloric acid, and washed with EtOAc. The aqueous phase was treated with 2M NaOH until basic pH was reached and then it was extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated. The organic phase was then acidified with 2M citric acid. The aqueous phase was treated with 2M NaOH until basic pH was reached and then it was extracted with EtOAc. The organic phases containing the title compound were combined, dried over MgSO4 and concentrated. The residue was dissolved in EtOAc and was washed with 50% aq. NaOH The organic layer was dried over MgSO4 and concentrated to afford the title compound (1.0 g, 65% yield): NMR: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.48-1.67 (m, 4 H), 1.73-1.86 (m, 1 H), 2.08-2.17 (m, 1 H), 2.19 (s, 3 H), 3.06-3.20 (m, 2 H), 6.65 (br. s., 2 H), 6.71 (d, 1 H), 7.26 (d, 1 H), 7.35 (dd, 1 H); MS (ES+) m/z 318 [M+H]+.
Reaction SMILES: [OH:1]O.[CH3:3]/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CC(C)=O>[CH3:3][C@@H:4]1[O:1][C@H:5]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C/C=C/c1ccccc1
Reactant: OO
Solvent: CC(C)=O
Product: C[C@@H]1O[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 83 %

Procedure:
Unlike CF3COCH3, which gives higher conversion at high pH, acetone catalyzed epoxidation reactions proceeded at much faster rate at a lower pH (about 8.3). Because the decomposition of H2O2 was not very fast at this pH, the reaction can be done at room temperature. Although controlled experiment showed that significant amount of epoxidation also occurred in the absence of acetone at this pH (Payne epoxidation), the addition of acetone allowed the epoxidation to proceed much faster and gave higher conversion. For example, a 41% conversion of trans-β-methylstyrene was obtained in the absence of acetone after stirred at room temperature for 10 h. However, in the presence of acetone, an 83% yield of trans-β-methylstyrene oxide could be obtained after stirring for 5 h. Table 4 lists additional examples using acetone under similar conditions.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:5][CH2:4][CH2:3]1.N1C=CN=C1.[CH:31]([Si:34](Cl)([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])([CH3:33])[CH3:32]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[C:21]([O:23][Si:34]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:31]([CH3:33])[CH3:32])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:5][CH2:4][CH2:3]1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(-c2cc(O)ccc2F)c(C2=CCCC2(C)C)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc2F)c(C2=CCCC2(C)C)c1
Reaction time: 4 h
Yield: 80.2 %

Procedure:
To 66.14B (77.0 mg, 226 μmol) in DMF (10 mL) was added imidazole (30.8 mg, 452 μmol) and then triisopropylsilyl chloride (58.1 μL, 271 μmol). The resulting mixture was then stirred for 4 hours. The reaction was diluted with EtOAc and washed with 1N HCl, water, and brine. The organic phase was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (0 to 10% EtOAc/Hexanes) to provide 66.14C (90.0 mg, 80.1% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:18]3[C:17]4[CH2:19][NH:20][CH2:21][CH2:22][C:16]=4[NH:15][C:14]=3[N:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:23](OC(=O)C)(=[O:25])[CH3:24].C(N(CC)CC)C>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:18]3[C:17]4[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:16]=4[NH:15][C:14]=3[N:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccc(C)c(F)c4)c3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
(3-Fluoro-4-methyl-phenyl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (50 mg, 0.17 mmol), acetic anhydride (17 μL, 0.17 mmol), and triethylamine (70 μL, 0.51 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred overnight at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The Extrelut column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 58 (9 mg, 14% yield) as a tan powder. LC-MS (M+H=339, obsd.=339).
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=[O:14])[CH2:10][C:11]#[N:12])=[O:7])[CH2:2][CH2:3][CH3:4].[CH:16]1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C1COCC1.CO>[CH3:16][O:14][C:13](=[O:15])[C@@H:9]([CH2:10][C:11]#[N:12])[NH:8][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCCOC(=O)N[C@H](CC#N)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOC(=O)N[C@H](CC#N)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of N-butyloxycarbonyl-3-cyano-D-alanine (20.5 g, 97 mmol) and 4-dimethylaminopyridine (11.85 g, 97 mmol) in 150 mL THF and 33 mL methanol was added N,N'-dicyclohexylcarbodiimide (20 g, 97 mmol) and the solution was allowed to stir at room temperature for 2 hours. Insoluble material was removed by filtration and the solution was concentrated. The residue was taken up in ethyl acetate and the solution was washed with 5% citric acid, brine, NaHCO3 and brine, dried (MgSO4), and concentrated. Crystallization from ethyl acetate gave 18.8 g (85%) product. 1H-NMR: d (CDCl3) 5.48 (d, 1H); 4.54 (m, 1H); 3.84 (s, 3H); 2.98 (m, 2H); 1.44 (s, 9H). ES-MS: calcd M+1 229.2; found 229.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: ClCc1ccccc1Cl
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2Cl)c(Cl)c1
Temperature: 100 °C
Yield: 95.8 %

Procedure:
To a reaction flask were added 2-chloro-4-nitrophenol (5.205 g, 30 mmol), 2-chlorobenzyl chloride (5.313 g, 33 mmol), potassium carbonate (4.554 g, 33 mmol) and DMF (40 ml). The reaction mixture was heated to the temperature of 100° C. After the reaction finished, the reaction solution was poured into water (400 ml). The mixture was extracted with ethyl acetate (300 ml). The ethyl acetate layer was washed with saturated saline solution (200 ml) once and dried over anhydrous magnesium sulfate. The organic layer was filtered and the solvent was rotary-evaporated to dryness. The resultant substance was recrystallized with ethyl acetate to give 1-(2-chlorobenzyloxy)-2-chloro-4-nitrobenzene (8.567 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C:31](=[O:37])[C@@H:30]([OH:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([OH:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α,12β,25R)-3-(t-butyldimethylsilyloxy)spirostan-12-ol-11-one (see procedure G8) was converted into the title compound via reduction with lithium aluminum hydride in THF at room temperature according to the procedure described in J. Am. Chem. Soc., 1951, 73, 1777.