Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>N1C=CC=CC=1>[F:31][C:30]([F:32])([F:33])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:21]=1[O:20][CH3:19])[C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)=[O:26]
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(OC)c(C(F)(F)F)c4)cc3)sc2c1
Yield: 86.1 %

Procedure:
Prepared as described in the Amide Coupling section using 2-(4-aminophenyl)-6-methoxybenzothiazole (0.5 g, 1.95 mmol) and 4-methoxy-3-trifluoromethylbenzoyl chloride (0.47 g, 1.95 mmol) in dry pyridine (15 ml) to give the title compound (0.77 g, 87%) as pale yellow feathery crystals after work-up and recrystallisation from acetic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:13]([N:15]([CH2:16][CH3:17])[C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2)=[O:12])[CH3:14]
Reactant: CCNCC
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1cccc2cc[nH]c12
Yield: 98.6 %

Procedure:
A solution of 1H-indole-7-carboxylic acid (0.48 g, 3 mmol), diethylamine (0.93 mL, 9 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.74 g, 9 mmol), 1-hydroxybenzotriazole (1.23 g, 9 mmol), triethylamine (1.26 mL, 12 mmol) in dimethylformamide (30 mL) is stirred at room temperature for 4 hours. The mixture is diluted with ethyl acetate, washed with 1N HCl, water, a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated brine, dried over magnesium sulfate, and concentrated to give the desired 1H-indole-7-carboxylic acid diethylamide (0.64 g, yield: 99%).
Reaction SMILES: [OH-:1].[Na+].[C:3]([OH:22])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Mn]([O-])(=O)(=O)=[O:24].[K+].S(=O)(O)O>O>[OH:1][CH:11]([CH:12]([OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:22])=[O:21]
Reactant: [OH-]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=S(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCC(O)C(O)CCCCCCCC(=O)O
Temperature: 5 °C
Yield: 84.4 %

Procedure:
To a solution of NaOH (5.03 g) in water (200 ml) was suspended oleic acid (4.96 g), and the mixture to which ice had been added, was stirred at 5° C. A solution of potassium permanganate (4 g) in water (500 ml) was added, and the mixture was stirred for 5 minutes. Then, aqueous sulfurous acid was added until the mixture turned white, and the resulting precipitates were collected by filtration. The precipitates were washed with water and eluted with a mixture of chloroform-methanol (1:1), and the eluate was concentrated to give 9,10-dihydroxyoctadecanoic acid (4.69 g). To the suspension of 9,10-dihydroxyoctadecanoic acid in acetone was added conc. sulfuric acid (0.1 ml), and the mixture was stirred for 8 hours. After acetone was removed by distillation and water was added, the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate to give an acetonide (4.70 g). To the acetonide (3.70 g) were added para-nitrophenol (1.44 g) and N,N'-dicyclohexylcarbodiimide (3.21 g), and the mixture was stirred in N,N-dimethylformamide (DMF) for 12 hours. After precipitates produced were removed by filtration and the solvent (DMF) was removed by distillation, the residue was subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (50:1) to give the active ester of 9,10-dihydroxyoctadecanoic acid 9,10-acetonide (3.05 g). The active ester was dissolved in DMF together with 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (400 mg), and after triethylamine (2.0 ml) was added, the mixture was stirred for 12 hours. The reaction mixture was concentrated, and the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (7:1 to 5:1) to give SPK123 in the yield of 113.9 mg.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH3:25])[C:16]2=[O:26])=[CH:11][CH:10]=1)C1C=CC=CC=1.CCOC(C)=O>CN(C=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH3:25])[C:16]2=[O:26])=[CH:13][CH:14]=1
Reactant: Cc1ccnc2c1n(C)c(=O)n2-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccnc2c1n(C)c(=O)n2-c1ccc(O)cc1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1,7-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.0 g) and 10% Pd—C (0.308 g) in DMF (10 mL)-EtOAc (100 mL) was hydrogenated under balloon pressure at 20° C. for 1 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 50%-100% EtOAc in hexane) to give 3-(4-hydroxyphenyl)-1,7-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.30 g) as a light brown solid. This product was subjected to the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[CH3:20][C:21]1([CH3:33])[CH2:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30](Cl)=[O:31])[C:23]=2[O:22]1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7]/[C:6]/1=[N:12]\[C:30]([C:29]1[C:23]2[O:22][C:21]([CH3:33])([CH3:20])[CH2:25][C:24]=2[CH:26]=[CH:27][CH:28]=1)=[O:31]
Reactant: CC1(C)Cc2cccc(C(=O)Cl)c2O1
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cccc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.1 %

Procedure:
To a solution of the product of Example 126A (0.20 g, 1.1 mmol) and Et3N (0.45 mL, 3.2 mmol) in 30 mL THF was added 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbonyl chloride (Acros, 0.34 g, 1.6 mmol). This mixture was warmed to reflux and allowed to stir for 2 hours. The mixture was then cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with 10 mL EtOAc and washed with 5 mL saturated, aqueous NH4Cl. The layers were separated and the aqueous layer was extracted 2×5 mL EtOAc. The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via flash column chromatography (SiO2, 4:1 hexanes:EtOAc) to provide the title compound (0.21 mmol, 0.57 mmol, 53% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.55 (s, 6H), 2.22 (s, 3H), 2.27 (s, 3H), 3.02 (s, 2H), 3.31 (s, 3H), 3.77-3.89 (m, 2H), 4.33-4.50 (m, 2H), 6.85 (t, J=7.5 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 8.00 (d, J=8.1 Hz, 1H); MS (DCI/NH3) m/z 361 (M+H)+; Anal. calculated for C19H24N2O3S: C, 63.31; H, 6.71; N, 7.77. Found: C, 63.19; H, 6.50; N, 7.66.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1cc(Cl)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(Cl)ccc1C(=O)NNC(=O)OC(C)(C)C
Yield: 86.4 %

Procedure:
A solution of 4-chloro-2-methoxybenzoic acid (4.3 g, 23.1 mmol), tert-butyl carbazate (3.5 g, 26.5 mmol), EDCI.HCl (5.0 g, 26.1 mmol), and triethylamine (3.5 mL, 2.6 g, 25.3 mmol) in CH2Cl2 (50 mL) was stirred at room temperature overnight. The next day the reaction was diluted with EtOAc (200 mL), then washed with IM H3PO4, saturated NaHCO3, and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under vacuum, giving the product (6.0 g, 87%). MS (DCI) m/e 301 & 303 (M+H)+, 318 & 320 (M+NH4)+; 1H NMR (300 MHz, CDCl3) δ 9.40 (br s, 1H), 8.15 (d, J=8.2 Hz, 1H), 7.08 (dd, J=8.2, 1.7 Hz, 1H), 6.98 (d, J=1.7 Hz, 1H), 6.67 (v br s, 1H), 4.00 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[C:8]1[C:18]([O:20]CC)=[O:19])(=[O:3])[CH3:2].[OH-].[Na+].O.Cl>C(O)C>[C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[C:8]1[C:18]([OH:20])=[O:19])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(OC)cc2n1CCNC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2cc(C(=O)O)n(CCNC(C)=O)c2c1

Procedure:
Dissolve 0.69 g of the compound obtained in Step B in 10 ml of absolute ethanol and add 2.5 ml of sodium hydroxide solution (1M) and reflux for 16 hours. Cool and add 20 ml of water and acidify the reaction mixture with hydrochloric acid (5M). Filter off the precipitate and wash it with water. The title product is obtained in the form of a white solid.
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][C:32]([F:35])([F:34])[F:33])[CH:25]=2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.IC.[C:38](=O)([O-])[O-].[K+].[K+]>O>[OH:1][C:2]1([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:38])=[C:26]([O:31][C:32]([F:34])([F:35])[F:33])[CH:25]=2)[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2ccc(O)c(OC(F)(F)F)c2)C2(O)CCCCC2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1ccc(C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)C2(O)CCCCC2)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
A solution of tert-butyl 4-{(1-hydroxycyclohexyl)[4-hydroxy-3-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate (0.35 g 0.72 mmol) (See Example 400, step 1) and iodomethane (0.16 g, 1.08 mmol) in N-N′-dimethylformamide (5 mL) was treated with potassium carbonate (0.12 g, 0.86 mmol), and the solution was stirred at room temperature for 16 hours. The reaction was then poured into water and extracted 3 times with ethyl acetate. The combined extracts were washed twice with water, then dried over magnesium sulfate and concentrated to afford 0.31 g of tert-butyl 4-{(1-hydroxycyclohexyl)[4-methoxy-3-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate). The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:24][C:25](=[O:33])[CH2:26][CH:27]([NH2:32])[CH:28]([OH:31])[CH2:29][F:30])([CH3:23])([CH3:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:20]([O:24][C:25](=[O:33])[CH2:26][CH:27]([NH:32][C:17]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:19])[CH:28]([OH:31])[CH2:29][F:30])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1C(=O)OCc1ccccc1)C(O)CF
Temperature: 25 °C
Yield: 89 %

Procedure:
A stirred mixture of (S)-1-(benzyloxy carbonyl)-2-piperidinecarboxylic acid (4.82 g, 18.31 mmol), 3-amino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (3.99 g, 19.25 mmol), HOBt (2.72 g, 20.13 mmol), DMAP (2.57 g, 21.04 mmol) and anhydrous THF (60 ml) was cooled to 0° C. before EDC (3.86 g, 20.13 mmol) was added. The mixture was allowed to warm to room temperature over 16 hrs before being concentrated under reduced pressure. The residue was purified by flash chromatography (60% ethyl acetate in hexane) to afford the sub-title compound as a white foam (7.3754 g, 72%): 1H NMR (400 MHz, CDCl3) δ 1.31-1.80 (14H, m), 2.20-2.38 (1H, m), 2.49-3.07 (3H, m), 3.11-3.70 (1H, m), 3.80-4.58 (4H, m), 4.70-5.28 (1H, m), 6.58-7.05 (1H, m), 7.23-7.48 (5H, m).
Reaction SMILES: [OH-].[Na+].C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]3[CH:24]=[CH2:25])=[CH:16][C:15]=2[F:30])[CH2:10][CH2:9]1)=O)C>C(O)(=O)C>[F:30][C:15]1[CH:16]=[C:17]2[C:22](=[N:23][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[N:21]([CH:24]=[CH2:25])[CH:20]=[C:19]([C:26]([OH:28])=[O:27])[C:18]2=[O:29]
Reactant: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C(=O)OCC)CC3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)nc21
Yield: 80.1 %

Procedure:
Ethyl 1-(2-chloroethyl)-7-(4-ethoxycarboxyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (2.27 g) was dissolved in ethanol (15 ml) by heating, and to the solution was added a solution of potassium hydroxide (0.84 g) in ethanol (15 ml). The resulting solution was heated to reflux for 2 hours with stirring. The resulting crystals were collected by filtration and washed with ethanol. The crystals were then dissolved in 20 ml of water by heating, and the solution was adjusted to pH 4-5 with 10% acetic acid. The resulting crystals were collected by filtration, washed with ethanol and recrystallized from a mixture of ethanol and chloroform to give 1.74 g of 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylic acid (mp 246°-248° C.). Five percent sodium hydroxide solution (30 ml) was added to 1.5 g of 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylic acid. The mixture was heated to reflux for 5 hours with stirring. After cooling, the solution was adjusted to pH 7 with acetic acid. The resulting precipitate was collected by filtration. The precipitate was dissolved in aqueous 10% acetic acid under heating, and the solution was adjusted to pH 9 with ammonia solution. The resulting precipitate was collected by filtration to give 0.98 g of 6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1-vinyl-1,8-naphthyridine-3-carboxylic acid, m.p. 256°-260° C.
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=C[C:10]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].Cl.CONC.C(N(C(C)C)CC)(C)C>ClCCl>[F:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([N:9]([O:8][CH3:4])[CH3:10])=[O:27]
Reactant: O=C(O)c1cccnc1F
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cccnc1F
Temperature: 25 °C
Yield: 80 %

Procedure:
TBTU coupling agent (13 g, 40 mmol) was added to a solution of 2-fluoronicotinic acid (5.6 g, 40 mmol), N-methoxy-N-methylamine hydrochloride (4.4 g, 45 mmol) and diisopropylethylamine (16 ml, 0.1 mol) in dichloromethane (100 ml) under nitrogen. The reaction mixture was stirred at room temperature for eighteen hours. It was diluted with more dichloromethane (200 ml), washed with a 2M aqueous hydrochloric acid solution (50 ml), a saturated sodium bicarbonate solution (100 ml), and brine (100 ml). The organic was dried over magnesium sulfate and, after filtration, concentrated in vacuo. The residue was purified by flash chromatography (120 g SiO2, pentane/ethyl acetate) to afford the title compound as a colourless oil (6 g, 80%). 1H NMR (CDCl3): 3.40-3.45 (3H, s), 3.55-3.65 (3H, s), 7.75-7.80 (1H, t), 7.90-7.95 (1H, t), 8.28-8.30 (1H, d).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:51]=[C:17]2[N:18]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH:48]([CH3:50])[CH3:49])=[CH:43][CH:42]=3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:51]=[C:17]2[N:18]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH:48]([CH3:50])[CH3:49])=[CH:43][CH:42]=3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:3][C:4](=[O:7])[O:5][N:39]=4)=[CH:30][CH:31]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)C)cc2)c2nc(C)nn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(OC(C)C)cc2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.81 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({2-methyl-4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.4 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.15 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.24 g, 53%).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[CH2:4][CH2:3]1.O[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(O)(C(F)(F)F)=O>C1COCC1>[O:23]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]2)[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:12])=[O:13])[CH2:4][CH2:3]1
Reactant: O=S1(=O)CCN(CCO)CC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCN1CCS(=O)(=O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCN1CCS(=O)(=O)CC1)CCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 119.2 %

Procedure:
N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide (0.500 g, 1.38 mmol) was combined with 4-(2-hydroxyethyl)thiomorpholine 1,1-dioxide (0.296 g, 1.65 mmol) in THF (10 mL). To this mixture was added triphenylphosphine (0.541 g, 2.06 mmol) and diethyl azodicarboxylate (0.359 g, 2.06 mmol). The resulting mixture was stirred at rt for 72 h. The mixture was concentrated in vacuo, then redissolved in acetonitrile. Purification by reverse phase preparative HPLC gave the title compound as a pale yellow solid (0.863 g, 83% yield) bis-TFA salt. LCMS: m/z 525 (M+H+), retention time 1.25 min (method 11). 1H NMR (500 MHz, MeOD) δ ppm 2.85 (t, J=6.71 Hz, 4H) 3.14 (d, J=5.49 Hz, 8H) 3.18 (d, J=5.80 Hz, 8H) 3.51 (t, J=6.71 Hz, 4H) 7.71-7.75 (m, 1H) 7.75-7.84 (m, 2H) 8.05 (d, J=7.63 Hz, 1H).
Reaction SMILES: OC[C@@H:3]1[CH2:8][C@H:7]2[CH2:9][C@@:6]32[C@H:10]2[C@H:19]([CH2:20][CH2:21][C@:4]13[CH3:5])[C@@H:18]1[C:13](=[CH:14][C:15](=[O:22])[CH2:16][CH2:17]1)[CH2:12][C@H:11]2[CH3:23].N1C=CC=CC=1.C(OC(=O)C)(=O)C>O1CCCC1>[CH3:23][CH:11]1[CH2:12][C:13]2[C@H:18]([CH2:17][CH2:16][C:15](=[O:22])[CH:14]=2)[C@@H:19]2[C@@H:10]1[C@:6]13[CH2:9][CH:7]1[CH2:8][CH2:3][C@:4]3([CH2:21][CH2:20]2)[CH3:5]
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@H](CO)C[C@H]4C[C@]43[C@@H]21
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)CCC4C[C@@]43[C@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.6 %

Procedure:
A solution of (7α,14β,15β,17α)-17-(hydroxymethyl)-7-methyl-14,15-methyleneestr-4-en-3-one (Example 1, 0.20 g) in a mixture of dry pyridine (1.76 ml) and dry tetrahydrofuran (8.8 ml) was treated with acetic anhydride (1.06 ml). The mixture was stirred at room temperature overnight and then quenched with water. After 1 h stirring the product was extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (7α,14β,15β,17α)17-[(acetyloxy)methyl)]-7-methyl-14,15-methyleneestr-4-en-3-one (0.22 g). 1H NMR (CDCl3) δ5.80 (t, 1H, J=2.8 Hz), 4.05 (dd, part A of AB system, 1H, J=11.0 and 6.3 Hz), 3.95 (dd, part B of AB system, 1H, J=11.0 and 7.1 Hz), 2.03 (s, 3H), 1.08 (s, 3H),. 0.62 (d, 3H, J=7.1 Hz), 0.48 (dd, 1H, J=8.3 and 5.1 Hz), 0.27 (dd, 1H, J=5.1 and 3.5 Hz).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[C:19]([O:23][CH3:24])=[C:18]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(C)C.C(OCC)(=O)C>CC(C)=O.O>[CH3:24][O:23][C:19]1[C:20](=[O:22])[O:21][CH:17]([CH2:16][C:15]([OH:3])=[O:14])[C:18]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)=O
Reactant: COC1=C(c2ccccc2)C(CCO)OC1=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COC1=C(c2ccccc2)C(CC(=O)O)OC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2N Jones reagent (8 ml) was diluted with acetone (12.5 ml). To this solution was added a solution of 5-(2-hydroxyethyl)-3-methoxy-4-phenyl-2(5H)-furanone (1.25 g) in acetone (12.5 ml) at 0° C. over a period of 50 minutes. The mixture was stirred at ambient temperature for 15 minutes and isopropylalcohol (5 ml) was added thereto. The mixture was poured into a mixture of ethyl acetate and water. The organic layer was separated, washed with water and brine, and dried. Evaporation of the solvent gave 2-(2,5-dihydro-4-methoxy-5-oxo-3-phenyl-2-furyl)acetic acid (865 mg) which was recrystallized from diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([CH:11]2[C:18](=[O:19])[N:17]3[C@@H:13]([C@@H:14]([O:20][Si](C(C)(C)C)(C)C)[CH2:15][CH2:16]3)[C@@:12]2([OH:32])[C:28]([F:31])([F:30])[F:29])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([CH:11]2[C:18](=[O:19])[N:17]3[C@@H:13]([C@@H:14]([OH:20])[CH2:15][CH2:16]3)[C@@:12]2([OH:32])[C:28]([F:29])([F:30])[F:31])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(C2C(=O)N3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@]2(O)C(F)(F)F)ccc(C#N)c1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1c(C2C(=O)N3CC[C@H](O)[C@H]3[C@@]2(O)C(F)(F)F)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a plastic vial containing compound 3B (20 mg, 0.041 mmol) in 0.2 mL of THF was added 100 μL of HF pyridine solution (Aldrich), and stirred at RT overnight. It was concentracted and purified on prepHPLC to give the title compound (10.2 mg). MS (ES) m/z 375 [M+H]+.