Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:9])[CH3:18]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 4′-chloroacetophenone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E- and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]([CH3:50])[CH2:44][C@@H:45]1[CH2:49][CH2:48][CH2:47][O:46]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]([CH3:50])[CH2:44][C@@H:45]2[CH2:49][CH2:48][CH2:47][O:46]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CN(C[C@@H]1CCCO1)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)C[C@@H]2CCCO2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 20.9 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-[(S)-tetrahydrofuran-2-ylmethyl]acetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.4 mg) was obtained.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20][OH:21])[C:14]=2[CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]1[C:15]2=[CH:16][CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[C:14]2[CH2:13][CH2:12]1
Reactant: OCc1cccc2c1CCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1cccc2c1CCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
DMSO (8.10 mL, 114 mmol) was added at -78° C. to a stirred solution of oxalyl chloride in CH2Cl2 (40 mL of a 2M solution). A solution of (2,3-dihydrobenzofuran-4-yl)methanol (8.53 g, 56.9 mmol) in CH2Cl2 (35 mL) was added dropwise, and the solution stirred at -78° C. for 30 min. Triethyl amine (33 mL, 228 mmol) was added cautiously to quench the reaction. The resulting suspension was stirred at room temperature for 30 min and diluted with CH2Cl2 (100 mL). The organic layer was washed three times with water, and twice with brine, and then concentrated in vacuo to an oil (8.42 g, 100%) that was used without purification.
Reaction SMILES: [CH:1]1([C:7]([O:9]CC)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]1([CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH:1]1([C:7](=[O:9])[CH2:21][C:20](=[O:22])[CH2:19][CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)CCc1ccccc1
Reactant: CCOC(=O)C1CCCCC1
Product: O=C(CCc1ccccc1)CC(=O)C1CCCCC1

Procedure:
Using ethyl cyclohexane carboxylate (63 g, 0.4 mol) and 4-phenyl-2-butanone (20 g, 0.13 mol), the reaction was carried out in the same manner as described in Example 2, (1) and crude dark orange oil (23 g) was chromatographed on silica gel (Wako Gel C-200) eluting with n-hexane/ethyl acetate (100:1→100:2→100:3) to afford the title compound as a yellow oil which was an ca 3:17 mixture of Keto/Enol by the methylene singlet at δ3.55 ppm and the methine singlet at δ5.45 ppm in the 1HNMR spectrum; yield: 2.5 g.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>O.CCO>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
To a mechanically stirred solution of 5.0 g NaOH in 35 ml H2O and 25 ml EtOH at 15° C. was added 12.0 g (0.100 mole) of acetophenone and 12.4 g (0.100 mole) of 4-fluorobenzaldehyde. After a brief exotherm to 25° C., the temperature returned to 15° C., and the cooling bath was removed. The reaction mixture was stirred at room temperature for 1.5 hour, and the thick slurry was transferred to a beaker to cool overnight at 10° C. This mixture was filtered, and the solids were washed with distilled H2O until the washings were neutral to litmus. Upon drying in vacuo, 20.8 g of a pale yellow solid was obtained, m.p. 86°-87° C. IR (Nujol): 1660, 1605, 1590, 1580 cm-1. 1H NMR (200 MHz, CDCl3): δ 7.12 (d, J=16 Hz, 1H), 7.42-7.68 (m, 7H), 7.78 (d, J=16 Hz, 1H), 8.02 (m, 2H).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].O=[CH:14][C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1>CO>[OH:21][C:20]1[CH:22]=[CH:23][C:15]([CH:14]=[CH:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCCCCCCC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCC(=O)C=Cc1ccc(O)c(OC)c1
Temperature: 35 °C
Yield: 43.5 %

Procedure:
100 g potassium hydroxide were dissolved in 500 g of methanol and heated up to reflux under stirring. A solution of 142 g of nonanone and 152 g of vanillin in 120 g of methanol were subsequently added continuously over a period of 1 hour. After that, the mixture was stirred for further 24 hours at the same temperature. After distilling 400 g of methanol from the mixture in vacuo, 400 g of toluene were added to the remaining residue, and after cooling to approximately 30-40° C. additionally 800 g of water were added. The mixture was then acidified with approximately 380 g of diluted sulphuric acid (20% in water) to a pH value of 4-5. After phase separation, the organic phase was washed with 200 g of water. After distillation, 120 g of the intermediate product 1-(4-hydroxy-3-methoxy-phenyl)-dec-1-en-3-one were obtained. Melting point: 45° C., yield: 42% of theory.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[CH3:12][NH2:13]>O>[CH:9]([C:6]1[S:7][CH:8]=[C:4]([CH2:3][NH:13][CH3:12])[N:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)c1nc(CCl)cs1
Reactant: CN
Agent: Cl
Solvent: O
Product: CNCc1csc(C(C)C)n1
Reaction time: 1 h
Yield: 55 %

Procedure:
A solution of 40 g of 4-(chloromethyl)-2-isopropylthiazole hydrochloride in 100 ml of water was added dropwise with stirring to 400 ml of 40% aqueous methylamine. The resulting solution was stirred for 1 h, then concentrated in vacuo. The residue was taken up in chloroform, dried over Na2SO4, and concentrated in vacuo. Purification of the residue by silica gel chromatography using 10% methanol in chloroform provided 21.35 g (55%) of the desired compound. 1H NMR (DMSO-d6) δ1.34 (d, J=7 Hz, 6 H), 2.56 (s, 3H), 3.30 (heptet, J=7 Hz, 1H), 4.16 (s, 2H), 7.63 (s, 1H). Mass spectrum: (M+H)+ =171.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:5]=[C:6]([F:18])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][OH:16])[CH2:10][CH2:9]1.C1C=C([O:36]O)C(C(O)=O)=C(C(O)=O)C=1>CO>[F:18][C:6]1[CH:5]=[C:4]([N:19]2[CH2:23][C@@H:22]([CH2:24][NH+:25]([O-:36])[C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][OH:16])[CH2:10][CH2:9]1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Solvent: CO
Product: CC(=O)[NH+]([O-])C[C@@H]1CN(c2cc(F)c(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(S)-N-[[3-[3,5-Difluoro-4-[4-(hydroxyacetyl)- 1-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]- acetamide (VIII-A, R1═COCH3, R2═H, X1═X2═F) (0.13 g) is dissolved in 5 mL of methanol. Monoperoxyphthalic acid, magnesium salt hexahydrate (80% pure, 0.2 g) is added and the resulting suspension is stirred at 25° C. for 72 hours. An additional 0.2 g of monoperoxyphthalic acid is added and the reaction is stirred an additional 48 hours. The reaction mixture is filtered and the filtrate is concentrated to afford a light-yellow oil. This material is chromatographed on silica gel using 20% methanol (saturated with ammonia) in chloroform as eluent to afford 55 mg of the N-oxide.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[O:6]=[S:7]1(=[O:29])[C:12]2[CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=3)[CH:15]=[CH:16][C:11]=2[N:10]2[CH2:26][CH2:27][CH2:28][CH:9]2[NH:8]1>>[O:29]=[S:7]1(=[O:6])[C:12]2[CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:1](=[O:3])[CH3:2])=[CH:20][CH:19]=3)[CH:15]=[CH:16][C:11]=2[N:10]2[CH2:26][CH2:27][CH2:28][CH:9]2[NH:8]1
Reactant: CC(=O)Cl
Reactant: NCc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1
Agent: Cl
Product: CC(=O)NCc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1

Procedure:
The procedure is as in Example 2, replacing the methanesulphonic anhydride by acetyl chloride and using as starting material the amine obtained in Example 20.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Cl:25][CH2:26][C:27]([NH:29][C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][N:31]=1)=[O:28]>CC#N>[Cl-:25].[F:36][C:35]1[C:30]([NH:29][C:27]([CH2:26][N+:1]23[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]2)[C@@H:3]([O:9][C:10]([C:12]2([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:2]3)=[O:28])=[N:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: O=C(CCl)Nc1ncccc1F
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1ncccc1F
Product: [Cl-]
Yield: 55.6 %

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (Example 14e) (0.30 mmol) and 2-chloro-N-(3-fluoro-pyridin-2-yl)-acetamide (Example 53a) (0.36 mmol) in MeCN (1.5 mL) were stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue purified by silica gel chromatography eluting with 0-10% MeOH/dichloromethane to give the title compound as a white solid (86 mg).
Reaction SMILES: S([NH:11][N:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(C1C=CC(C)=CC=1)(=O)=O.C[O-].[Na+]>CO>[C:14]1([CH:13]=[N+:12]=[N-:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)NN=Cc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=Cc1ccccc1
Reaction time: 2 h

Procedure:
In an oven-dried round bottom flask was placed benzaldehyde tosylhydrazone (1.15 g, 4.2 mmol), followed by 4.3 mL of a 1.0M solution of sodium methoxide in methanol (2.3 g Na metal dissolved in absolute methanol and diluted to 100 mL). The mixture was swirled until all the contents dissolved. Most of the solvent was removed via romy evaporation and the last traces of solvent by evacuation of the flask under high vacuum for 2 hours. The solid obtained was subjected to a Kugelrohr distillation at 215° C. and 200 millitorr for 1 hour. At 68-70° C., the title compound, as a red oil, was collected in a receiver flask in a quantitative yield.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[CH2:10]([O:12][P:13]([O-:17])[O:14][CH2:15][CH3:16])[CH3:11]>>[CH2:10]([O:12][P:13]([O-:17])[O-:14])[CH3:11].[CH2:1]([N+:5]1[CH:9]=[CH:8][N:7]([CH2:15][CH3:16])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:1]([N+:5]1[CH:9]=[CH:8][N:7]([CH2:10][CH3:11])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccnc1
Reactant: CCOP([O-])OCC
Product: CCCC[n+]1ccn(CC)c1
Product: CCOP([O-])[O-]
Yield: 93 %

Procedure:
1-Butylimidazole (60 g) and diethylphosphite (67 g) were added into a 500 mL two-necked flask with a reflux condenser, and mixed at 120° C. for 12 hours. After the reaction was completed, the products were washed with ethylacetate or diethylether several times to remove unreacted 1-butylimidazole and diethylphosphite, followed by vacuum drying at 60° C., thereby providing the title ionic liquid (yield 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[C:17]=2[CH2:18][C:19](O)=[O:20])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH:29][CH2:30][CH2:31][O:32][CH3:33]>>[ClH:1].[CH3:33][O:32][CH2:31][CH2:30][N:29]([CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1)[C:19](=[O:20])[CH2:18][C:17]1[N:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]2=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Cc1ccn2c(CC(=O)O)c(-c3ccc(Cl)cc3)nc2c1
Reactant: COCCNCc1ccccn1
Product: COCCN(Cc1ccccn1)C(=O)Cc1c(-c2ccc(Cl)cc2)nc2cc(C)ccn12
Product: Cl
Yield: 46 %

Procedure:
According to the method of Example 14, 2-(4-chlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetic acid and N-(2-pyridinylmethyl)-2-methoxyethylamine were used as raw materials for synthesis, white solid powder, yield 46.0%. m.p. 238-239° C., ESI-MS m/z: 450[M+H]+, 1H NMR(D2O, 400 MHz)δ: 2.37(s, 2.5H), 2.39(s, 0.5H), 3.10(s, 0.5H), 3.14(s, 2.5H), 3.52(t, 2H, J=4.76 Hz) 3.74(t, 2H, J=4.76 Hz), 4.15(s, 0.4H), 4.41(s, 1.6H), 4.76(s, 1.6H), 4.85(s, 0.4H), 7.15-7.23(m, 1H), 7.30-7.47(m, 4H), 7.50(s, 1H), 7.60-7.70(m, 2H), 8.09-8.11(m, 1H), 8.25-8.45(m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[C:18]([C:23]([OH:25])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[N:12]4[C:26](=[O:28])[NH:27][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1.[CH3:30]O>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[C:18]([C:23]([O:25][CH3:30])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[N:12]4[C:26](=[O:28])[NH:27][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1cccnc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ncccc1C1COc2c(-c3c(C)noc3C)ccc3[nH]c(=O)n1c23
Temperature: 80 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxylic acid (294 mg, 0.7493 mmol) in methanol (60.0 mL) was treated with one drop of concentrated sulfuric acid and heated in a sealed tube overnight at 80° C. The reaction mixture was then concentrated to a crude residue. This residue was diluted with ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution and stirred at room temperature for 1 hour. After dissolution, the aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (300 mg, 99%) as a racemic mixture. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (dd, J=4.6, 1.5 Hz, 1H), 7.56 (dd, J=8.1, 4.6 Hz, 1H), 7.29 (dd, J=8.1, 1.4 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.00 (dd, J=2.9, 2.9 Hz, 1H), 4.53 (d, J=2.9 Hz, 2H), 3.91 (s, 3H), 2.26 (s, 3H), 2.09 (s, 3H); LCMS calculated for C21H19N4O5 (M+H)+: m/z=407.1. found: 407.0.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27][CH:28]=[CH2:29])([CH3:20])[C@@H:18]([O:30]CC3C=CC=CC=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1.[F:38][C:39]([F:66])([C:56]([F:65])([F:64])[C:57]([F:63])([F:62])[C:58]([F:61])([F:60])[F:59])[CH2:40][CH2:41][CH2:42][CH:43]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]C=C)[C:44]([O:46]CC)=[O:45]>>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C@@H:22]3[CH2:27][CH2:28][CH2:29][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH:43]([CH2:42][CH2:41][CH2:40][C:39]([F:38])([F:66])[C:56]([F:64])([F:65])[C:57]([F:63])([F:62])[C:58]([F:61])([F:59])[F:60])[C:44]([OH:46])=[O:45])([CH3:20])[C@@H:18]([OH:30])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1
Reactant: C=CCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Product: C[C@]12C[C@H](CCCCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Starting with the 3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10),9(11)-tetraene prepared in Example 20 and ethyl 2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoate prepared separately, the same procedure as shown in Example 20 was repeated to give 10-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH3:28][O:29][C:30]([CH3:39])([CH3:38])[CH2:31][N:32]1[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13]([NH:37][C:34]2[CH:35]=[CH:36][N:32]([CH2:31][C:30]([O:29][CH3:28])([CH3:38])[CH3:39])[N:33]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: COC(C)(C)Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CC(=O)C2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(C)(C)Cn1ccc(NC(=O)[C@H](CC2CC(=O)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 50.8 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclobutyl)-propionic acid (65 mg, 0.20 mmol) in methylene chloride (8 mL) was cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 120 μL, 0.24 mmol) and N,N-dimethylfomamide (one drop) which was then stirred at 0° C. for 20 minutes and 40 min at 25° C. After this time, the reaction was concentrated in vacuo and azeotroped with methylene chloride (10 ml). In a separate flask a solution of 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (36 mg, 0.22 mmol), 2,6-lutidine (34 μL, 0.29 mmol) in methylene chloride (8 mL) was cooled to 0° C. in an ice bath. To this solution was then added the solution of the prepared acid chloride in methylene chloride (5 mL) dropwise. After addition was complete the reaction was then stirred at 0° C. for 15 min and at 25° C. for 18 h. After this time the reaction was concentrated in vacuo. Purification on an AnaLogix Intelliflash system (40 g column, 50% ethyl acetate/hexanes to 100% ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(3-oxo-cyclobutyl)-propionamide (49 mg, 52%) as an off-white solid: [α]29589=−14.0° (c=0.55, CHCl3); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04, 1.05 (2×s, 6H, 2×CH3), 1.93-2.40 (m, 3H, CH and CH2), 2.69-2.84 (m, 2H, 2×CH or 2×CH2), 2.99-3.12 (m, 2H, 2×CH or 2×CH2), 3.14 (s, 3H, OCH3), 3.34 (s, 3H, SO2CH3), 3.88 (t, J=7.8 Hz, 1H, ArCHCO2), 3.98 (s, 2H, NCH2), 6.47 (d, J=2.3 Hz, 1H, Ar), 7.49 (d, J=2.3 Hz, 1H, Ar), 7.61 (dd, Jm=1.2 Hz, Jo=8.3 Hz, 1H, Ar), 7.73 (d, Jm=1.2 Hz, 1H, Ar), 8.02 (d, Jo=8.3 Hz, 1H, Ar), 10.84 (s, 1H, NH).
Reaction SMILES: [Si]([O:8][C@@H:9]([C@H:11]1[C:17](=[O:18])[N:16]2[C@@H:12]1[C@@H:13]([CH3:27])[C:14]([S:25][CH3:26])=[C:15]2[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH3:10])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[OH:8][C@@H:9]([C@H:11]1[C:17](=[O:18])[N:16]2[C@@H:12]1[C@@H:13]([CH3:27])[C:14]([S:25][CH3:26])=[C:15]2[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH3:10]
Reactant: C=CCOC(=O)C1=C(SC)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C1=C(SC)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 24 h
Yield: 80.8 %

Procedure:
Allyl (4R,5S,6S)-6-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-methyl-3-methylthio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (100 mg) was added to a mixture of 70% aqueous tetrabutylammonium fluoride (0.71 g) and acetic acid (121 mg) in tetrahydrofuran (2 ml) and the mixture was allowed to stand at ambient temperature for 24 hours. The solution was diluted with ethyl acetate (6 ml), washed with water, aqueous sodium bicarbonate solution and brine, and dried. The solvent was removed off under reduced pressure and the residue was crystallized from n-hexane to afford allyl (4R,5S,6S)-6-((1R)-1-hydroxyethyl)-4-methyl-3-methylthio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (58.4 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:13])[C:8]=2[NH2:12])[CH:3]=1.[C:14]([O:18][C:19]([N:21]1[C@H:26]([C:27](O)=[O:28])[C@H:25]2[CH2:30][C@@H:22]1[CH2:23][CH2:24]2)=[O:20])([CH3:17])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH:13][C:27]([C@@H:26]1[C@H:25]2[CH2:30][C@H:22]([CH2:23][CH2:24]2)[N:21]1[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[O:28]
Reactant: Nc1ccc2cc(Br)ccc2c1N
Reactant: CC(C)(C)OC(=O)N1[C@H]2CC[C@H](C2)[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H]2CC[C@H](C2)[C@H]1C(=O)Nc1ccc2cc(Br)ccc2c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 6-bromonaphthalene-1,2-diamine (1.08 g, 4.56 mmol), and (1S,3S,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.10 g, 4.56 mmol) and HATU (2.08 g, 5.47 mmol) in methylene chloride (45 mL) was added DIPEA (3.98 mL, 22.79 mmol). The mixture was stirred at room temperature for two hours. Upon completion, the reaction was concentrated in vacuo, diluted with ethyl acetate and washed with water. The aqueous layer was back extracted with ethyl acetate twice. The combined organic layers were washed with brine, concentrated, and purified by normal phase chromatography (30-80% ethyl acetate (5% MeOH) in hexanes) to give (1S,3S,4R)-tert-butyl 3-(1-amino-6-bromonaphthalen-2-ylcarbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (2.01 g, 95%). LCMS-ESI+: calc'd for C22H26BrN3O3: 459.12 (M+); Found: 460.9 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]=O.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[OH:15])[CH:10]=[O:11]>C(O)C>[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH2:1][N:2]([CH3:4])[CH3:3])[C:14]=1[OH:15])[CH:10]=[O:11]
Reactant: C=O
Reactant: CNC
Reactant: O=Cc1ccc(O)c(Br)c1
Solvent: CCO
Product: CN(C)Cc1cc(C=O)cc(Br)c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
22.8 g (0.19 mol) of a 40% aqueous dimethylamine solution were added to 15.2 g (0.19 mol) of a 37% aqueous formaldehyde solution in 110 ml of ethanol. Then 25.0 g (0.12 mol) of 3-bromo-4-hydroxybenzaldehyde were added thereto. The reaction mixture was refluxed for 30 minutes and then stirred for 24 hours at room temperature. The batch was stored overnight at 0 to 5° C. in the refrigerator. The precipitated white solid was filtered out and dried.