Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[I-].[K+].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1Cl)=NC2
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccccc1C1=NCc2nnc(CN3CCOCC3)n2-c2ccc(Br)cc21

Procedure:
In the manner given in Preparation 48, 8-bromo-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and morpholine in tetrahydrofuran are reacted to give 8-bromo-1-(morpholinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:23])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[C:24]([Mg]Br)#[C:25][CH3:26]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:16]([OH:23])([C:24]#[C:25][CH3:26])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: CC#C[Mg]Br
Reactant: O=C(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Solvent: C1CCOC1
Product: CC#CC(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of the above-mentioned ethanone (75.5 g, 216.8 mmol) dissolved in THF (450 mL) was added a solution of LaCl3.2LiCl (395.9 mL, 0.6 M in THF) at room temperature and stirred for 1 hour. The resulting solution was added dropwise to 1-propynylmagnesium bromide (650.5 mL, 0.5M in THF) at room temperature. After 1 hour at room temperature, the resulting mixture was quenched with a 10% aqueous solution of HCl and extracted with MTBE. The organic phase was washed with brine, dried and evaporated. The crude compound was stirred in a solution of MTBE/diisopropylether and filtrated to eliminate the starting material. The mother liquors were evaporated and purified on silica gel to give the title compound as a beige solid (31.1 g, HPLC-MS2 Rt=1.15 min, masse=388, m.p=137° C.).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([O:15][Si](C(C)(C)C)(C)C)=[CH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B-](F)(F)(F)[F:24].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([F:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OC1=CCC(OCc2ccccc2)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(OCc2ccccc2)CC1F

Procedure:
To a stirred solution of {[4-(benzyloxy)cyclohex-1-en-1-yl]oxy}(tert-butyl)dimethylsilane (11.5 g, 36.1 mmol) in DMF (75 mL) was added Selectfluor (25.6 g, 72.2 mmol) in small portions at 0° C. After completion of the reaction, the mixture was poured into 5% sodium bicarbonate solution. The resulting mixture was extracted with EtOAc, and the combined organics were washed with brine, dried, and concentrate to afford the title compound.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[C:15]([Si:19]([CH3:34])([CH3:33])[O:20][CH:21]1[C:30]2[C:25](=[C:26]([CH:31]=O)[CH:27]=[CH:28][CH:29]=2)[O:24][CH2:23][CH2:22]1)([CH3:18])([CH3:17])[CH3:16].[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>ClC(Cl)C>[C:15]([Si:19]([CH3:33])([CH3:34])[O:20][CH:21]1[C:30]2[C:25](=[C:26]([CH2:31][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:27]=[CH:28][CH:29]=2)[O:24][CH2:23][CH2:22]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OC1CCOc2c(C=O)cccc21
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OC1CCOc2c(CN3CCCCC3)cccc21
Reaction time: 1 h

Procedure:
NaBH(OAc)3 (3.86 g, 18.21 mmol) was added to a dichloroethane (30 mL) solution of 4-(tert-butyl-dimethyl-silanyloxy)-chroman-8-carbaldehyde (Step B) (2.66 g, 9.10 mmol) and piperidine (2.70 mL, 27.31 mmol) at RT. After stirring for 1 h, the reaction was quenched with MeOH (10 mL) while the stirring was continued for 20 more min. The reaction was diluted with CH2Cl2 (200 mL) and washed with saturated NaHCO3 solution and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo from heptane to provide the title compound.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][CH:39]=1)[CH2:17][NH:18][C:19]1[N:23]([C@@H:24]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]2[OH:26])[C:22]2[CH:33]=[CH:34][CH:35]=[CH:36][C:21]=2[N:20]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][CH:39]=1)[CH2:17][NH:18][C:19]1[N:23]([C@@H:24]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]2[OH:26])[C:22]2[CH:33]=[CH:34][CH:35]=[CH:36][C:21]=2[N:20]=1
Reactant: OC[C@H]1O[C@@H](n2c(NCc3cccc(NCCCCOCc4ccccc4)c3)nc3ccccc32)[C@H](O)[C@@H]1O
Agent: [Pd]
Solvent: CCO
Product: OCCCCNc1cccc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 60.2 %

Procedure:
2-[3-(4-Benzyloxybutylamino)benzylamino]-1-(β-D-ribofuranosyl)-1H-benzimidazole (44 mg) was dissolved in ethanol (5 mL). To the solution was added a catalytic amount of 10% palladium-carbon powder, and the mixture was stirred at 60° C. under a hydrogen atmosphere for 24 hour. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (22 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][CH:15]([CH2:17]Cl)[CH2:14][S:13]1.[CH3:19][NH2:20]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][CH:15]([CH2:17][NH:20][CH3:19])[CH2:14][S:13]1
Reactant: CN
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC(CCl)CS1
Product: CNCC1CSC(=Nc2ccc([N+](=O)[O-])cc2C)N1

Procedure:
2-Amino-1,3-propanediol was reacted with excess SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-4-(chloromethyl)-1,3-thiazolidine. The thiazolidine was reacted with N-methylamine according to Method D13a to give 2-(2-methyl-4-nitrophenylimino)-4-(N-methylaminomethyl)-1,3-thiazolidine, which was reacted with isobutyl bromide according to Method D2a to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-(N-isobutyl-N-methylaminomethyl)-1,3-thiazolidine.
Reaction SMILES: [ClH:1].[CH:2]([O:5][C:6]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9])([CH3:4])[CH3:3].[CH2:16]([OH:18])[CH3:17]>>[ClH:1].[CH:2]([O:5][C:6]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:7]=1[C:8](=[NH:9])[O:18][CH2:16][CH3:17])([CH3:4])[CH3:3]
Reactant: COc1ccc(C#N)c(OC(C)C)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(OC)cc1OC(C)C
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 99 %

Procedure:
Hydrogen chloride gas was passed through a solution of 2-isopropoxy-4-methoxy-benzonitrile (11.5 g, 60.14 mmol) in anhydrous ethanol (250 mL) cooled to −10° C. After 45 min, hydrogen chloride gas was stopped and the reaction mixture was stirred at room temperature in a closed reaction vessel for 2 weeks. The reaction vessel was cooled to 0° C. before the stopper was removed. Argon gas was passed through the solution to remove excess hydrogen chloride gas. The solvent was evaporated and the residue was triturated in diethyl ether (100 mL) to afford ethyl 2-isopropoxy-4-methoxy-benzimidate hydrochloride (16.3 g, 99%). It was used without further purification.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[S:7](Cl)(Cl)(=[O:9])=[O:8]>[W]>[CH3:3][CH:2]1[C:1](=[O:6])[O:5][S:7](=[O:9])(=[O:8])[CH2:4]1
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)C(=O)O
Agent: [W]
Product: CC1CS(=O)(=O)OC1=O

Procedure:
88 g. of isobutyric acid dissolved in 100 g. of sulfuryl chloride is heated at 80° C. and irradiated with a 300 watt tungsten lamp for 2 hours. Addition of ligroin precipitates an oil which has a boiling range 135°-140° at 4mm and is identified as 4-methyl-1,2-oxathiolane-5-one-2,2-dioxide by its equivalent weight, 75.
Reaction SMILES: [CH2:1]([C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:15]2=[O:27])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(C1C=CC(N2CCN(CC(OC(C)(C)C)=O)CC2)=CC=1)CCCCCCC>>[CH2:1]([C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]([OH:22])=[O:21])[C:15]2=[O:27])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(CN2CCN(CC(=O)OC(C)(C)C)C2=O)cc1
Agent: CCCCCCCCc1ccc(N2CCN(CC(=O)OC(C)(C)C)CC2)cc1
Product: CCCCCCCCc1ccc(CN2CCN(CC(=O)O)C2=O)cc1
Yield: 46 %

Procedure:
When the product of Step B was substituted for tert-butyl 2-(4-(4-octylphenyl)piperazin-1-yl)acetate in Example 9, Step F, the identical process afforded the title compound in 46% yield, as a colourless solid. 1H-NMR (CDCl3+CD3OD) 7.0 (m, 4H); 4.42 (s, 2H); 3.72 (s, 2H); 3.31 (m, 2H); 3.11 (m, 2H); 2.44 (t, 2H, J=7.8 Hz); 1.43 (m, 2H); 1.13 (m, 10H); 0.73 (t, 3H, J=7 Hz).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)[N:6]=1.C(O)(C(F)(F)F)=O.ClC1[C:34]([Cl:35])=[CH:33][N:32]=[C:31]([NH2:36])[C:30]=1[N+:37]([O-:39])=[O:38]>C(Cl)Cl>[Cl:35][C:34]1[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)[CH2:13][CH2:12]2)=[C:30]([N+:37]([O-:39])=[O:38])[C:31]([NH2:36])=[N:32][CH:33]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: Cc1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)cs1
Reaction time: 1 h
Yield: 49.1 %

Procedure:
tert-Butyl 4-((2-methylthiazol-4-yl)methyl)piperazine-1-carboxylate (0.380 g, 1.28 mmol, 1.1 eq) was dissolved in DCM (4 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (4 mL). Stirring was continued at this temperature for 1 h. Solvents were removed in vacuo and the resulting crude material was azeotroped with toluene and dried. 2-Methyl-4-(piperazin-1-ylmethyl)thiazole (supposedly 0.250 g, 1.28 mmol, 1.1 eq) was suspended in iPrOH (3.9 mL) and DIPEA (1 mL). To this solution, the 4,5-dichloro-3-nitropyridin-2-amine (0.240 g, 1.16 mmol, 1 eq) was added and the mixture heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.210 g, 44%); 1H-NMR (500 MHz, DMSO-d6): δ 2.52-2.59 (m, 4H, piperazine N(CH2)2), 2.63 (s, 3H, thiazole Me), 3.06 (m, 4H, piperazine N(CH2)2), 3.59 (s, 2H, NCH2), 6.94 (s, 2H, NH2), 7.28 (s, 1H, thiazole 5-H), 8.05 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): R=2.06 min—369/371 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]1)(C(C)(C)C)(C)C>C(Cl)Cl>[OH:8][CH2:9][CH2:10][C:11]1([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1(CCO[Si](C)(C)C(C)(C)C)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(CCO)CC1
Yield: 60.5 %

Procedure:
A solution of tert-butyl 1-(2-(tert-butyldimethylsilyloxy)ethyl)cyclopropylcarbamate (11.9 g, 37.8 mmol) and 3HF.TEA (22.0 g) in DCM (50 mL) was stirred at rt for 17 hrs. The mixture was concentrated and the residue was purified by silica gel column chromatography (0-20% gradient elution EtOAc/petroleum ether) to afford tert-butyl 1-(2-hydroxyethyl)cyclopropylcarbamate (4.6 g, 60%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1.[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH:32]1([S:35]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[C:11]4[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:21]3[CH2:22][CH2:23][N:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:25][CH2:26]3)[CH:6]=[CH:7][CH:8]=2)(=[O:37])=[O:36])[CH2:34][CH2:33]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN)c4)cc23)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)C5CC5)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a solution of 5-[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (35 mg, 0.079 mmol) in DMF (1.0 mL) and DCM (1.0 mL) was added cyclopropanesulfonyl chloride (11 mg, 0.079 mmol) and DIEA (14 μL, 0.079 mmol). Reaction was stirred at room temperature overnight. Compound was purified by Gilson Preparatory HPLC to give 7.2 mg the title compound (17%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([N:14]1[CH2:19][CH2:18][C:17]([CH2:21][NH2:22])([OH:20])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[CH2:7]([N:14]1[CH2:15][CH2:16][C:17]([CH2:21][NH:22][C:2](=[O:3])[O:4][CH2:5][CH3:6])([OH:20])[CH2:18][CH2:19]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: NCC1(O)CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCC1(O)CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 14.75 g of ethyl chloroformate in 125 ml of dichloromethane is added, at 0° C., to a solution of 30 g of 1-benzyl-4-aminomethyl-piperidin-4-ol and 13.8 g of triethylamine in 250 ml of dichloromethane. After 10 minutes' contact, the reaction mixture is washed with 0.1N sodium hydroxide solution and then dried over MgSO4. Concentration under reduced pressure enables the expected product to be isolated.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[Br:14][CH2:15][C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([NH:32][CH:33]=[O:34])[CH:19]=1)[OH:17]>ClCCl>[Br:14][CH2:15][C@H:16]([O:17][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([NH:32][CH:33]=[O:34])[CH:19]=1
Reactant: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 0 °C
Reaction time: 22 h
Yield: 91.9 %

Procedure:
A solution of tert-butyldimethylsilyl chloride (40.1 g, 0.26 mol) in dichloromethane (DCM) (37.5 mL) was added to a slurry of imidazole (21.86 g, 0.32 mol) and (R)-2-bromo-1-(3-formamido-4-benzyloxyphenyl)ethanol (74.54 g, 0.21 mol) in DCM (260 mL) over 8 min. The mixture was stirred for 22 h. The reaction was quenched with water (190 mL) and the aqueous layer was extracted with DCM (37.5 mL). The combined DCM layers were distilled at atmospheric pressure to a volume of ca. 110 mL. On cooling, spontaneous crystallisation occurred. Isooctane (750 mL) was added dropwise over 20 min. The slurry was cooled to 0° C. and the solids were collected by filtration then washed with 9:1 v/v isooctane:DCM (3×75 mL) and dried in vacuo to give the title compound as a colorless solid (89.65 g, 90% th). 1H NMR in accord with structure (400 MHz, CDCl3) δ (ppm): −0.06 (3H) s; 0.11 (3H) s; *0.12 (3H) s; *0.89 (9H) s; 0.90 (9H) s; *3.38-3.49 (2H) m; 4.78-4.87 (1H) m; *5.09 (2H) s; 5.10 (2H) s; 6.96 (1H) d, J=8.6 Hz; *7.06 (1H) d of d, J=8.3, 2.0 Hz; 7.11 (1H) d of d, J=8.3 Hz, 2.0 Hz; 7.25-7.27 (1H) m; 7.36-7.45 (5H) m; *7.70 (1H) d, J=11.0 Hz; 7.79 (1H) s; 8.38 (1H) d, J=2.0 Hz; 8.42 (1H) d, J=1.5 Hz; *8.76 (1H) d, J=11.8 Hz. * Peaks are due to ca 25M % of the minor rotamer.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19]C1C=CC(C(C)(C)C)=CC=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O[C@H](CO[C:49]1[CH:54]=[CH:53][C:52]([C:55](C)([CH3:57])[CH3:56])=[CH:51][CH:50]=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:50]1[CH:49]=[CH:54][CH:53]=[C:52]([CH:55]([CH3:57])[CH3:56])[CH:51]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cccc(C(C)C)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M−15, 0.1), 251 (18), 250 (100), 163 (6), 121 (21), 117 (5), 114 (10), 91 (9).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]1[CH2:40][C:39]2[CH:38]=[C:37]([OH:41])[CH:36]=[CH:35][C:34]=2[C@@H:33]2[C@@H:24]1[C@H:25]1[C@@:29]([CH2:31][CH2:32]2)([CH3:30])[C@@H:28]([OH:42])[CH2:27][CH2:26]1)[CH2:8][CH2:9][CH3:10]>O.CO>[CH2:7]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]1[CH2:40][C:39]2[CH:38]=[C:37]([OH:41])[CH:36]=[CH:35][C:34]=2[C@@H:33]2[C@@H:24]1[C@H:25]1[C@@:29]([CH2:31][CH2:32]2)([CH3:30])[C@@H:28]([OH:42])[CH2:27][CH2:26]1)=[O:2])[CH2:8][CH2:9][CH3:10]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCSCCCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCS(=O)CCCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reaction time: 18 h

Procedure:
A solution of sodium metaperiodate (0.016 g.) in water (0.5 ml.) was added to a solution of 7α-11-n-butylthioundecyl)oestra-1,3,5(10)-triene-3,17β-diol (Example 32; 0.035 g.) in methanol (1 ml.) and the mixture was stirred at laboratory temperature for 18 hours, evaporated to dryness and evaporated from toluene to remove the last traces of water. The residue was extracted three times with acetone and the combined extracts were evaporated to dryness. There was thus obtained as an oil 7α-(11-n-butylsulphinylundecyl)oestra-1,3,5(10)-triene-3,17β-diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:25])[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([F:21])[C:15]([F:22])=[C:14]([Cl:23])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C([N+]([O-])=O)=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:47][C:48]1[C:53]([F:54])=[CH:52][C:51]([F:55])=[C:50]([NH:56][C:57]([CH3:60])([CH3:59])[CH3:58])[N:49]=1>C(Cl)(Cl)Cl>[C:57]([NH:56][C:50]1[N:49]=[C:48]([N:47]2[C:13]3[C:12](=[C:17]([N+:18]([O-:20])=[O:19])[C:16]([F:21])=[C:15]([F:22])[C:14]=3[Cl:23])[C:11](=[O:25])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[C:53]([F:54])=[CH:52][C:51]=1[F:55])([CH3:60])([CH3:58])[CH3:59]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Reactant: CC(C)(C)Nc1nc(N)c(F)cc1F
Agent: CCOC(=O)CC(=O)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
To 10 ml of chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluoro-6-nitrobenzoyl)acrylate prepared from 3.25 g of ethyl 3-chloro-2,4,5-trifluoro-6-nitrobenzoylacetate by normal process was added 2.14 g of 2-amino-3,5-difluoro-6-t-butylaminopyridine. The solution was concentrated under reduced pressure, and to the residue were added 2.7 g of anhydrous potassium carbonate and 10 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 5 minutes and allowed to cool. The solution was separated by adding 100 ml of chloroform and 500 ml of 2% aqueous solution of citric acid, and the chloroform layer was washed twice with 500 ml of 2% aqueous solution of citric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitate was dispersed in ethanol, collected by filtration, washed with ethanol and diisopropylether successively to obtain 3.13 g of the title compound as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:29][O:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH2:30][CH2:31][OH:32])[N:9]=2)[CH:7]=1.C(OC(N1CCOC[C@H]1C(=O)NC1C=CC(C#CC2C(C3C=C(Cl)C=CC=3O)=NN(CCO)C=2)=CC=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C@@H:24]4[CH2:29][O:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH2:30][CH2:31][OH:32])[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)C1COCCN1
Agent: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@@H]1COCCN1

Procedure:
Using the same procedure for the preparation of 17A, treatment of compound 20A with TFA in methylene chloride to give the title compound 21A as white powder in similar yield. Its 1H NMR and LCMS data are identical with those of compound 17A.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.I[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:23]1([CH2:22][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=2)[C:18]([OH:20])=[O:19])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: ICC1CCCC1
Reactant: COc1ccc(CC(=O)O)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 43.8 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (58.5 mL of a 0.93M stock solution, 53.2 mmol) cooled to −78° C. was treated with (4-methoxy-phenyl)-acetic acid (4.21 g, 25.35 mmol) in tetrahydrofuran/ 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (25.3 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (5.85 g, 27.8 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reaction mixture was stirred at −78° C. for 45 min and at 0° C. for 1 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (10 mL). The excess solvent was removed in vacuo. The residue was acidified to pH=1 with a 1N aqueous hydrochloric acid solution. This mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The organics were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methoxy-phenyl)-propionic acid (2.76 g, 43.8%) as a yellow solid: mp 119-121° C.; EI-HRMS m/e calcd for C15H20O3(M+) 248.1412 found 248.1415.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].Cl.[NH2:22][C:23]([CH2:31][CH3:32])([CH2:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:27]([O:26][C:24](=[O:25])[C:23]([CH2:31][CH3:32])([NH:22][C:14]([C:12]1[CH:11]=[CH:10][C:9]([C:17]([F:20])([F:19])[F:18])=[C:8]([O:7][CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[N:13]=1)=[O:16])[CH2:29][CH3:30])[CH3:28]
Reactant: CCOC(=O)C(N)(CC)CC
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CCCO2)n1
Agent: Cl
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(C(F)(F)F)c(OCC2CCCO2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-((tetrahydrofuran-2-yl)methoxy)-5-(trifluoromethyl)picolinic acid and ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e=433.4 [M+H]+.