Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:48](=[O:49])[N:30]2[CH:31]([C:35]([O:37]CC3C=CC([N+]([O-])=O)=CC=3)=[O:36])[C:32](=O)[CH2:33][C@H:29]12)[CH3:27].[C:50]([C@@H:53]1[CH2:57][C@H:56]([SH:58])[CH2:55][N+:54]1([CH3:60])[CH3:59])(=[O:52])[NH2:51]>C(#N)C.C(OCC)C>[C:50]([C@@H:53]1[CH2:57][C@H:56]([S:58][C:32]2[CH2:33][C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:48](=[O:49])[N:30]3[C:31]=2[C:35]([O-:37])=[O:36])[CH2:55][N+:54]1([CH3:60])[CH3:59])(=[O:52])[NH2:51]
Reactant: C[N+]1(C)C[C@@H](S)C[C@H]1C(N)=O
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOCC
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3C[C@@H](C(N)=O)[N+](C)(C)C3)C[C@H]12
Reaction time: 1 h

Procedure:
210 μl of diisopropylethylamine and 250 μl of diphenylphosphoryl chloride were simultaneously added, whilst ice-cooling, to a solution of 400 mg of 4-nitrobenzyl (5R, 6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate dissolved in 5 ml of dry acetronitrile, and the mixture was stirred for 1 hour, whilst ice-cooling. At the end of this time, a solution of 447 mg of the crude (2S, 4S)-2-carbamoyl-1,1-dimethyl-4-mercaptopyrrolidinium salt prepared as described in Example 1-(1) in 5 ml of dry acetonitrile was added to the mixture, whilst ice-cooling, and then the mixture was allowed to stand for 4 hours at the same temperature and then for 2 days in a refrigerator. The reaction mixture was then poured into diethyl ether and the resulting deposit was washed repeatedly by decantation. The crude product was dissolved in a mixture of 30 ml of tetrahydrofuran and 30 ml of a 0.1M phosphate buffer (pH 7.0) and hydrogenated at room temperature for 2.5 hours in the presence of 450 mg of 10% w/w palladium-on-charcoal. At the end of this time, insoluble materials were removed by filtration using a Celite filter aid. The aqueous layer was concentrated by evaporation under reduced pressure, and the residue was transferred to a column packed with Diaion HP-20AG (Mitsubishi Chemicals Industries, Ltd.). Fractions eluted with water were collected and lyophilized to afford the title compound as a powder. This was further purified using a Lobar column (Merck, LiChroprep RP-8 size B) and fractions eluted with a 5% by volume aqueous methanolic solution were collected and concentrated by evaporation under reduced pressure followed by lyophilization, to afford 208 mg of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=23)[S:7]1(=[O:19])=[O:18].C(N(CC)CC)C.[C:27]1([C:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:27]1([C:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=45)[S:7]3(=[O:19])=[O:18])[CH2:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCCN1CC=C(c2ccccc2)CC1
Temperature: 20 °C
Yield: 18.4 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(4-chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (10 g), triethylamine (4.8 cc) and 4-phenyl-1,2,3,6-tetrahydropyridine (5.4 g) in toluene (300 cc). The mixture is heated for 9 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystalline from boiling acetonitrile (10 cc), 2-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (2.6 g) is obtained, m.p. 101° C.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[O-]CC.[Na+].[C:15]([Si:19]([CH3:28])([CH3:27])[O:20][CH2:21][CH2:22][CH2:23][C:24](=[O:26])[CH3:25])([CH3:18])([CH3:17])[CH3:16]>>[CH2:9]([O:8][C:1](=[O:7])[C:2](=[O:4])[CH2:25][C:24](=[O:26])[CH2:23][CH2:22][CH2:21][O:20][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:27])[CH3:28])[CH3:10]
Reactant: CC(=O)CCCO[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)CCCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 16.6 %

Procedure:
Diethyl oxalate (4.048 g, 37.7 mmol) was added to solid sodium ethoxide (0.472 g, 69.3 mmol) at 0° C. followed by slow addition of 5-(tert-butyl-dimethyl-silanyloxy)-pentan-2-one (1.500 g, 69.3 mmol). The resulting orange solution was stirred at 0° C. for 10 minutes and at room temperature for 3 h. Purification by flash chromatography (19:1 hexanes:EtOAc to 9:1 EtOAc:MeOH) provided the title compound (1.982 g); MS 317 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:16]1=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:21]2[CH2:22][CH2:23][C:24]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:20]2)=[CH:6][CH:7]=1
Reactant: O=C1CCc2ccccc2C1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC1CCc2ccccc2C1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 3,4-dihydro-1H-naphthalen-2-one.
Reaction SMILES: [CH:1]1([C:4](=[O:18])[CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[ClH:19]>>[Cl:19][CH2:3][CH2:2][CH2:1][C:4](=[O:18])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cl
Reactant: O=C(C1CC1)C(c1ccccc1)c1ccccc1
Product: O=C(CCCCl)C(c1ccccc1)c1ccccc1

Procedure:
A mixture of 16 parts of 1-cyclopropyl-2,2-diphenylethanone and 300 parts of hydrochloric acid were stirred and refluxed for 4 hours. The reaction mixture was cooled and extracted with 2,2'-oxybispropane. The extract was washed with water and with a diluted sodium hydrogen carbonate solution, dried, filtered and evaporated, yielding 17 parts of 5-chloro-1,1-diphenyl-2-pentanone as a residue (intermediate 88).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[C:29]([NH:32][CH2:33][CH2:34][NH2:35])(=[O:31])[CH3:30].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[C:29]([NH:32][CH2:33][CH2:34][NH:35][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)NCCN
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(=O)NCCNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with N acetylethylenediamine using BOP reagent in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=460.4 [M+H]+.
Reaction SMILES: Br.[NH:2]=[C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][N:4]1[CH2:18][C:19](OCC)=O.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:19]1[N:2]=[C:3]2[CH:8]=[CH:7][C:6]([B:9]3[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]3)=[CH:5][N:4]2[CH:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=N
Agent: Br
Product: CC1(C)OB(c2ccc3nc(Cl)cn3c2)OC1(C)C
Temperature: 105 °C

Procedure:
8.78 g of ethyl [2-imino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-1-yl]acetate hydrobromide in 20 ml of POCl3 are placed in a round-bottomed flask. The reaction mixture is heated at 105° C. for 16 h, cooled to ambient temperature and concentrated under reduced pressure. The residue is taken up between dichloromethane and water at 0° C., and a 30% aqueous solution of NH4OH is added until a basic pH is obtained. The organic phase is separated, dried over magnesium sulphate and concentrated under reduced pressure. 4.3 g of compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]([O:16]C(Cl)=O)(Cl)Cl>C(Cl)Cl>[F:11][C:10]1[C:2]2[NH:1][C:13](=[O:16])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1c(F)cccc1C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=c1[nH]c2c(F)cccc2c(=O)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
To 2-amino-3-fluoro-benzoic acid (2.3 g) in DCM (20 mL) was added trichloromethylchloroformate (3.0 g) and the mixture was stirred at rt for 16 hours. The reaction was then concentrated to provide 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (2.5 g).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([NH:15][C@H:16]1[C:24]2[C:19](=[C:20]([F:29])[CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[CH2:18][CH2:17]1)=O)(C)(C)C>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH2:15][C@H:16]1[C:24]2[C:19](=[C:20]([F:29])[CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[CH2:18][CH2:17]1
Reactant: COC(=O)c1cc(F)c2c(c1)[C@H](NC(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(F)c2c(c1)[C@H](N)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (4 ml) was added at 0° C. to a solution of (R)-methyl 3-(tert-butoxycarbonylamino)-7-fluoro-2,3-dihydro-1H-indene-5-carboxylate (0.85 g, 2.75 mmol, 1.0 eq.) in DCM (10 ml), and the mixture was stirred for 1 hour at RT. After monitoring by TLC, the reaction mixture was concentrated under reduced pressure, dried and used in the next stage without being purified further. 2) Synthesis of the Acylated & Sulfonylated Amino Acid Esters (B, C & D) General Method for the Synthesis of Amino Acid Esters (B, C & D)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:12]([C:20]([OH:22])=O)[CH:11]=1)#[N:2].Cl.CN(C)[CH2:26][CH2:27][CH2:28][N:29]=[C:30]=NCC.O.ON1C2C=CC=CC=2N=N1.N1CCCC1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]([C:20]([N:29]2[CH2:30][CH2:26][CH2:27][CH2:28]2)=[O:22])[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:15]=1)#[N:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2C#N)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(C)cc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2′-cyano-5-(methoxycarbonyl)-4′-methylbiphenyl-3-carboxylic acid (0.20 g, 0.68 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.26 g, 1.4 mmol), 1-hydroxybenzotriazole hydrate (0.21 g, 1.4 mmol), and methylene chloride (10 mL) were added pyrrolidine (0.072 g, 1.0 mmol) and N,N-diisopropylethylamine (0.24 mL, 1.4 mmol). The mixture was stirred at room temperature overnight, and then concentrated. The residue was purified via flash chromatography (silica gel column, 0-100% EtOAc/hexane) to afford the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24](Br)[C:25]2[N:26]([CH:28]=[CH:29][N:30]=2)[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[C:25]2[N:26]([CH:28]=[CH:29][N:30]=2)[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Clc1cc(Br)c2nccn2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3cc(Cl)cn4ccnc34)nc2)CC1
Temperature: 100 °C
Yield: 77.9 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (60 mL), tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (1.5 g, 5.39 mmol), 8-bromo-6-chloroimidazo[1,2-a]pyridine 101a (3.7 g, 16.18 mmol), and cesium carbonate (3.52 g, 10.79 mmol). XantPhos (312 mg, 0.539 mmol) and Pd2(dba)3 (494 mg, 0.539 mmol) were added, and the reaction mixture was heated at 100° C. for 5 h under nitrogen. After this time the reaction was cooled to room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with 100:1 CH2Cl2/MeOH to afford 102a (1.8 g, 78%). MS: [M+H]+ 429.
Reaction SMILES: CC([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16](=O)[C:15]3[CH:18]=[CH:19][C:20]([O:22]C(C)=O)=[CH:21][C:14]=3[O:13][CH:12]=2)=[CH:7][CH:6]=1)=O.C([O-])=O.[NH4+]>[OH-].[OH-].[Pd+2].C(O)(=O)C>[CH2:16]1[C:15]2[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=2[O:13][CH2:12][CH:11]1[C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1ccc(-c2coc3cc(OC(C)=O)ccc3c2=O)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Oc1ccc(C2COc3cc(O)ccc3C2)cc1
Temperature: 25 °C
Reaction time: 1.4 h
Yield: 83.4 %

Procedure:
A 250-ml round bottom flask was equipped with reflux condenser, heating mantle, and magnetic stirrer, and was charged with 8.15 grams of daidzein diacetate (0.024 mole), 100 ml of acetic acid, 20 grams of ammonium formate (31 mole), and 5.0 grams of commercial Pearlman's catalyst. The mixture was stirred at relfux for 1.4 hours, at which time thin-layer chromatographic analysis indicated consumption of the starting material. The reaction mixture was cooled to room temperature, diluted with 100 ml of ethyl acetate, and filtered through a pad of diatomaceous earth filter aid. The resulting clear filtrate was poured into about 500 ml of water and shaken. The layers were allowed to separate and the top organic layer was separated, washed with water and then with 5% aqueous sodium bicarbonate solution to remove residual acetic acid. (The acetamide by-product is extracted into the water layers during this procedure.) The resulting clear solution was stripped of ethyl acetate under reduced pressure to give an off-white solid product. This material was triturated with about 15 ml of chloroform and the resulting white solid product filtered off and air-dried to afford 4.85 grams of (+/−)-equol (83.2% yield). The product was analyzed by IR and proton NMR spectroscopy and found to be of greater then 95% purity.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[N:32]1[C:36]([CH3:37])=[N:35][N:34]=[N:33]1)[C:26](O)=[O:27]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:20])([F:19])[F:21])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([N:32]3[C:36]([CH3:37])=[N:35][N:34]=[N:33]3)=[C:23]([F:22])[CH:24]=2)[CH2:2][CH2:3]1
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1
Reactant: Cc1nnnn1-c1ccc(C(=O)O)cc1F
Product: Cc1nnnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(C(F)(F)F)cc3F)CC2)cc1F

Procedure:
The title compound is prepared from cyclopropyl-(3′-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 3-fluoro-4-(5-methyl-tetrazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.58 min; Mass spectrum (ESI+): m/z=508 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.[BH3-]C#N.[Na+]>>[CH:23]1([NH:1][CH2:2][CH:3]2[CH2:12][CH2:11][CH2:10][C:9]3[C:8]([O:13][C:14]4[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=4)=[CH:7][CH:6]=[CH:5][C:4]2=3)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2cccc3c2CCCC3CNC2CCCC2)nc1
Yield: 37.5 %

Procedure:
Using a method similar to Example 204, using 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide (intermediate 20, 297 mg, 1.00 mmol), cyclopentanone (168 mg, 2.00 mmol), and NaBH3CN (125 mg, 2.00 mmol) gives the title compound (137 mg) as a white foam. Mass spectrum (ion spray): m/z=366 (M+1); 1HNMR (CDCl3): 8.56 (s, 1H), 8.15 (d, 1H), 7.22-7.15 (m 2H), 6.93-6.89 (m, 2H), 5.82 (br. s, 2H), 3.11 (m, 1H), 3.02 (m, 1H), 2.92-2.78 (m, 2H), 2.63-2.42 (m, 2H), 1.91-1.50 (m, 10H), 1.35 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C@@:22]([OH:33])(CCO)[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].F[C:52](F)(F)[C:53]([O:55][C:56](=[O:61])[C:57]([F:60])([F:59])[F:58])=O.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C@@:22]([OH:33])([CH2:52][CH2:53][O:55][C:56](=[O:61])[C:57]([F:60])([F:59])[F:58])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(=O)C(F)(F)F)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C

Procedure:
To a mixture of No. 5217614, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate (150 mg, 0.214 mmol) and dichloromethane (15 mL) were added trifluoroacetic acid anhydride (36 μL, 0.258 mmol), triethylamine (89 μL, 0.642 mmol), and DMAP (1.3 mg, 0.0107 mmol), and the mixture was stirred at room temperature. After being stirred for 3 hours, trifluoroacetic acid anhydride (72 μL, 0.516 mmol) was added again. After confirming the consumption of No. 5217614 by LCMS, formic acid (5.0 mL) was added and the mixture was stirred overnight. The solvent was distilled off under reduced pressure to obtain (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-12-oxo-2-[2-(2,2,2-trifluoro-acetoxy)-ethyl]-nonadec-4-enoic acid (ESI (LC/MS positive mode) m/z 740 (M+H); Rt 2.64 min.). To the obtained (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-12-oxo-2-[2-(2,2,2-trifluoro-acetoxy)-ethyl]-nonadec-4-enoic acid (16 mg, 0.0216 mmol) were added toluene (3.0 mL), methanol (1.0 mL), and trimethylsilyldiazomethane (0.6 M in n-hexane, 54 μL, 0.0324 mmol), and the mixture was stirred at room temperature. After being stirred for 1.5 hours, trimethylsilyldiazomethane (0.6 M in n-hexane, 54 μL, 0.0324 mmol) was added. After stirring for 1 hour, the organic solvent was distilled off under reduced pressure. The resulting residue was purified by preparative HPLC and then freeze-dried to obtain the title compound (17 mg, 99% yield, white solid).
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[C:7]([N+:17]([O-:19])=[O:18])[CH:6]=1)C.C1COCC1.[OH-].[Na+].Cl>C(O)C>[CH2:13]([CH:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:20])=[O:3])=[CH:6][C:7]=1[N+:17]([O-:19])=[O:18])[CH2:15][CH3:16])[CH3:14]
Reactant: CCOC(=O)c1ccc(NC(CC)CC)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(CC)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 100 %

Procedure:
30.0 g of 4-(1-ethyl-propylamino)-3-nitro-benzoic acid ethyl ester were dissolved in 100 ml ethanol and 10 ml THF and 107 ml of 2 M aqueous sodium hydroxide solution were added. After stirring at room temperature over night, the reaction mixture was brought to pH 1 by addition of 2 M aqueous hydrochloric acid and extracted with ethyl acetate three times. The combined organic phases were dried over magnesium sulphate and concentrated to yield 27.0 g (100%) of 4-(1-ethyl-propylamino)-3-nitro-benzoic acid as a yellow solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.Cl[P:17]1(=[O:22])[O:21][CH2:20][CH2:19][O:18]1>C(OCC)C>[C:1]([O:5][CH2:6][CH2:7][O:8][P:17]1(=[O:22])[O:21][CH2:20][CH2:19][O:18]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=P1(Cl)OCCO1
Reactant: C=CC(=O)OCCO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCOP1(=O)OCCO1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
2-Hydroxyethyl acrylate (11.5 ml, 0.1M) and triethylamine (14.6 ml) in dry diethyl ether (250 ml) were cooled to -25° C. under nitrogen as a solution of 2-chloro-2-oxo-1,3,2-dioxaphospholane (14.3 g) in dry diethyl ether was added over 20 minutes. The mixture was stirred for a further 1 hour at -20° C. and then allowed to warm to 10° C. over a further hour. The precipitate was filtered, washed with ethyl acetate (100 ml) and the combined filtrate and washings evaporated under reduced pressure to give a pale yellow oil (21 g).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1.[C:22]1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(N(CC)CC)C>COC(OC)(C)C.C(OCC)(=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9](=[CH:10][CH2:11]2)[CH:8]=[C:7]([O:21][CH3:22])[CH2:6][CH2:5]1
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: COC(C)(C)OC
Product: COC1=CC2=CC[C@@H]3[C@H]([C@@H](F)C[C@]4(C)C(=O)CC[C@@H]34)[C@H]2CC1

Procedure:
7.8 g of 11β-fluorooestr-4-ene-3,17-dione are stirred at 80° C. for 5 h with 780 mg of pyridinium toluene-4-sulphonate in 40 ml of 2,2-dimethoxypropane. 1.5 ml of triethylamine are then added, and the mixture is diluted with ethyl acetate and washed with saturated sodium chloride solution. After crystallization from methanol, 5.3 g of 11β-fluoro-3-methoxyoestra-3,5-dien-17-one of melting point 173° C. are obtained.