Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:28][N:29](C)[C:30](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:44]>C(OCC)(=O)C.CC(O)C>[ClH:44].[F:1][C:2]1[C:3]([CH2:28][NH:29][CH3:30])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:18]=2)(=[O:15])=[O:16])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(CS(C)(=O)=O)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccc(CS(C)(=O)=O)c2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-({3-[(methylsulfonyl)methyl]phenyl}sulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (266 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and water to give the title compound as a white solid (yield 187 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].Br[C:23]1[CH:28]=[CH:27][C:26]([CH:29]([OH:31])[CH3:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([OH:31])[CH3:30])=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Reactant: CC(O)c1ccc(Br)cc1
Product: CC(O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one and 1-(4-bromo-phenyl)-ethanol. White solid. MS (ESI): 449.1 MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([CH3:19])=[N:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].C([O-])(=O)C.[NH4+:24]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([CH3:19])=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:24])=[O:13]
Reactant: [NH4+]
Reactant: Cc1nccc(C(=O)O)c1Nc1ccc(I)cc1F
Agent: CC(=O)[O-]
Product: Cc1nccc(C(N)=O)c1Nc1ccc(I)cc1F

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-2-methyl-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.2 mmol of 3-[(2-fluoro-4-iodophenyl)amino]-2-methyl-isonicotinic acid and 0.4 mmol of ammonium acetate. LC/MS [1.85 min; 372 (M+1)].
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14]C)=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].B(Br)(Br)Br>ClCCl>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc2c(cnn2CC(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)Cn1ncc2cc(O)ccc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a cooled (−78° C.) solution of 1-isobutyl-5-methoxy-1H-indazole (2.57 g, 12.6 mmol) in dichloromethane (100 mL) was added BBr3 (25 mL of 1M solution in dichloromethane). The mixture was stirred at −78° C. for 2 hours and then warmed to room temperature and stirred for 18 hours. The reaction mixture was poured into ice water and extracted with dichloromethane. The organic extract was filtered and concentrated under reduced pressure to afford 2.3 g of solid (96% yield).
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=2)=[O:20])=[CH:15][CH:14]=1>C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[CH2:8][O:20]2)=[CH:15][CH:14]=1
Reactant: C[S+](C)C
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(I)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Clc1ccc(C2(c3ccc(I)cc3)CO2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
Sodium hydride (60% dispersion in oil, 128 mg, 3.2 mmol) was placed under N2 then DMSO (5 mL) was added. Trimethylsulfonium iodide (0.66 g, 3.2 mmol) was added as a solid after 15 min, followed after a further 30 min by (4-chloro-phenyl)-(4-iodo-phenyl)-methanone. The mixture was stirred at room temperature for 24 hours then diluted with ethyl acetate and washed with 1:2 water/brine, water and brine (×2). The organic phase was dried (MgSO4), filtered and concentrated to give the title compound (1.01 g, 97%), which was used without further purification. LCMS (PS-A2) Rt 4.07 min [M−H]− 355.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[S:9][CH:10]=1)=[O:5])[CH3:2].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1csc(Br)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1csc(N2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
A mixture of 2-bromo-thiazole-4-carboxylic acid ethyl ester (1.4 g, 5.93 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.16 g, 1.05 eq.) and DIPEA (1.15 g, 1.5 eq.) in 1,4-dioxane (20 mL) was heated to reflux overnight. After cooling, the solvent was removed in vacuo. The crude product was purified on silica gel (EtOAc:hexanes=1:4) to afford the desired product as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1F)[C:15]#[N:16].C(=O)([O-])O.[Na+]>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:15]#[N:16]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(CNc2ccc(C#N)cc2F)cc1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
4-Methoxybenzylamine (5.6 ml, 43.1 mmol) was added dropwise to a solution of commercially available 3,4-difluorobenzonitrile (2.0 g, 14.4 mmol) in anhydrous di(ethylene glycol) dimethyl ether (10 ml) cooled to 0° C. with stirring. The resulting mixture was stirred at 120° C. for 1 hour. At the end of this time, the reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution at room temperature. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane was added to the crystalline residue to give 3-fluoro-4-[(4-methoxybenzyl)amino]benzonitrile (2.26 g, yield 61%) as white fluffy crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=1)([CH3:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>O1CCOCC1>[CH:1]([C:4]1[CH:8]=[C:7](/[N:9]=[CH:12]/[N:13]([CH3:15])[CH3:14])[NH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(N)[nH]n1
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CC(C)c1cc(/N=C/N(C)C)[nH]n1
Yield: 97.1 %

Procedure:
A mixture of 3-isopropyl-1H-pyrazol-5-amine (1.25 g, 10 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (12 g, 100 mmol) in dioxane (30 mL) was heated at reflux for 10 hours. The mixture was concentrated under reduced pressure and the residue was purified by chromatography (CH2Cl2-MeOH 9:1) to afford 1.75 g of title compound. MS (DCI/NH3) m/z 181 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)=[N:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33])=[C:19]([CH2:25][CH3:26])[CH:18]=4)=[N:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OC[C@H](O)CCl
Reactant: CCc1cc(-c2nnc(-c3cc(OC)nc(C4CCCC4)c3)o2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2nnc(-c3cc(OC)nc(C4CCCC4)c3)o2)cc(C)c1OC[C@@H](O)CO
Temperature: 70 °C
Reaction time: 48 h
Yield: 71.8 %

Procedure:
A mixture of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,3,4]oxadiazol-2-yl]-2-ethyl-6-methyl-phenol (100 mg, 264 μmol) and (S)-3-chloro-propane-1,2-diol (244 mg, 2.64 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1 mL) is stirred at 70° C. for 48 h. The mixture is diluted with EA (50 mL), washed with 1 M aq. NaOH solution (20 mL) followed by brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (86 mg) as a white solid; LC-MS**: tR=0.83 min, [M+H]+=454.12; 1H NMR (CDCl3): δ1.33 (t, J=7.5 Hz, 3H), 1.65-1.80 (m, 2H), 1.83-1.96 (m, 4H), 2.05-2.15 (m, 2H), 2.42 (s, 3H), 2.78 (q, J=7.3 Hz, 2H), 3.19-3.30 (m, 1H), 3.82-3.99 (m, 4H), 4.02 (s, 3H), 4.15-4.23 (m, 1H), 7.22 (s, 1H), 7.48 (s, 1H), 7.84 (s, 1H), 7.86 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9]C23C=CC=CC2C(NC3=O)=O)[C:4](=[O:21])[C:3]1=[O:22].O.[NH2:24]N.O.[ClH:27]>C(O)C>[ClH:27].[NH2:24][CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:22])[C:4]1=[O:21]
Reactant: NN
Reactant: CN1CCN(CCC23C=CC=CC2C(=O)NC3=O)C(=O)C1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1CCN(CCN)C(=O)C1=O
Temperature: 40 °C
Yield: 85 %

Procedure:
To a solution of 3.60 g (11.95 mmol) of 2-[2-(4-methyl-2,3-dioxo-1-piperazinyl)ethyl]phthalimide in 30 mL of ethanol was added 695 μL (14.34 mmol) of hydrazine monohydrate and the mixture was stirred at 40° C. for over night. The reaction mixture was cooled to room temperature, then, 25 mL of water and 6 mL of 6N—HCl were added to this mixture and the mixture was stirred for 5 hours at room temperature. After removed off the insoluble substances by filtration, the filtrate was concentrated and the residue was re-crystallized by 2% water-ethanol solution to give 2.12 g (85%) of the title compound.
Reaction SMILES: C([Mg]Br)C.[CH3:5][Si:6]([CH3:12])([CH3:11])[O:7][CH2:8][C:9]#[CH:10].[N:13]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1.[Cl-].[NH4+]>O1CCCC1>[OH:19][C:16]1([C:10]#[C:9][CH2:8][O:7][Si:6]([CH3:12])([CH3:11])[CH3:5])[CH2:15][CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:17]1
Reactant: C#CCO[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C#CCO[Si](C)(C)C)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
Ethyl magnesium bromide in tetrahydrofuran (55 mL, 1M, 55 mmol) was slowly added to a solution of trimethyl(prop-2-yn-1-yloxy)silane in tetrahydrofuran (40 mL) maintaining a temperature of 0° C. After the complete addition the mixture was stirred at ambient temperature for 45 min before a solution of tert-butyl piperidin-4-one-1-carboxylate (10 g, 50 mmol) in tetrahydrofuran (40 mL) was slowly added at 0° C. Subsequently the reaction mixture was stirred for 18 h at ambient temperature. Then saturated ammonium chloride solution was added and the mixture was stirred vigorously until the dissolution of all solids. The phases were separated and the aqueous was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 16.42 g of desired product (96%) as a yellow oil.
Reaction SMILES: [NH2:1][OH:2].C(=O)([O-])O.[Na+].[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OCC)(=O)C>[C:8]([NH:1][OH:2])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(NO)c1ccccc1

Procedure:
To 156 mg of said compound (26) were added 3 ml of ethyl acetate, 3 ml of aqueous saturated sodium hydrogencarbonate, and 0.035 ml of benzoyl chloride and the mixture was reacted at room temperature for 3 hours to obtain a benzoylamino-alcohol compound (compound (27), C52H65NO14Si, molecular weight of 956.17).
Reaction SMILES: C(O[C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=O)(C)(C)C.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH2:27][NH2:28])[CH2:25][NH2:26])=[C:20]([CH3:29])[CH:19]=1.C(O)(C)(C)C>CN(C)C=O>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:27][N:28]3[C:6](=[O:16])[NH:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:14]3=[N:26][CH2:25]2)=[C:20]([CH3:29])[CH:19]=1
Reactant: Cc1cc(N)ccc1C(CN)CN
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C=O
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: Cc1cc(N)ccc1C1CN=C2c3ccccc3NC(=O)N2C1
Temperature: 75 °C
Yield: 13.1 %

Procedure:
A flask was charged with (2-Formyl-phenyl)-carbamic acid tert-butyl ester (8.8 g, 0.040 mol), 2-(4-Amino-2-methyl-phenyl)-propane-1,3-diamine (10.0 g, 0.056 mol), t-butanol (177 mL), and N,N-dimethylformamide (53 mL) and purged well with nitrogen. The mixture was stirred at 75° C. for at least 3 h. To the cooled mixture were added anhydrous potassium carbonate (16.6 g) and iodine (12.2 g). The batch was stirred at 80° C. for 10 h. The cooled mixture was filtered through a celite pad (4.4 g) and the filter cake was rinsed with methanol (177 mL). The filtrate and wash were diluted with toluene (88 mL) and concentrated to dryness under reduced pressure. The residue was stirred with aqueous 15 wt % sodium thiosulfate pentahydrate (88 mL) and saturated aqueous sodium chloride (44 mL) for 1 h at ambient temperature. The resulting mixture was extracted with CH2Cl2 (2×177 mL). The separated organic layer was dried over anhydrous magnesium sulfate (4.4 g), filtered, and concentrate to dryness in vacuo. The concentrate (20 g) was dissolved with methanol (20 mL) and loaded onto a KP-Sil samplet (34 g). The sample was allowed to dry before loading it into a Biotage KP-Sil SNAP cartridge (340 g). A Biotage unit was used to elute the cartridge with a ethyl acetate-hexane gradient (0% to 90%). Clean fractions were collected, combined, and concentrated to dryness under reduced pressure to provide the title compound as a yellow solid (1.6 g, 13% yield).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10]([O:12]S(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.C[Mg]Br>C(OCC)C>[CH:7]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
A solution of 1-(diphenylmethyl)-3-(methanesulphonyloxy) azetidine (1.0 g) in. THF (17 mL) was treated with 3.0 M methylmagnesium bromide (1.2 mL) in diethyl ether at 0° C. The reaction was stirred for 1.5 hours at 0° C. and then quenched with saturated aqueous sodium bicarbonate, filtered through Celite, and concentrated. The residue was then take up in methylene chloride and washed with saturated aqueous sodium bicarbonate, followed by brine. The organic layer was dried over magnesium sulfate, filtered, concentrated and purified by column chromatography (0 to 60% EtOAc/hexanes) to provide 640 mg of the title compounds as a clear, yellow oil. ESMS: 240.19 (M+1), 1.22 minutes, Method D.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH2:16][C:17](=[O:29])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH:9]=1)[C:4](O)=[O:5])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.CC(C)([O-])C.[K+].[CH2:50]([C@H:57]1[CH2:61][O:60][C:59](=[O:62])[NH:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>O1CCCC1>[CH2:1]([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH2:16][C:17](=[O:29])[NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=2)[CH:9]=1)[C:4]([N:58]1[C@@H:57]([CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:61][O:60][C:59]1=[O:62])=[O:5])[CH3:2]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCC(Cc1ccc(OC)c(CC(=O)Nc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(Cc1ccc(OC)c(CC(=O)Nc2ccc(C(F)(F)F)cc2)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Yield: 13.4 %

Procedure:
(±)-2-Ethyl-3-[4-methoxy-3-[[N-[4-(trifluoromethyl)phenyl]carbamoyl]methyl]phenyl]propanoic acid (compound in Example 88: 14.2 g, 34.7 mmol) and dehydrated tetrahydrofuran (100 mL) were mixed under an argon atmosphere, and triethylamine (4.86 ml, 35.0 mmol) and pivaloyl chloride (4.27 mL, 34.7 mmol) were added dropwise under stirring and cooling with ice. Thereafter, the mixture was stirred for 1 hour at room temperature to synthesize mixed acid anhydride. On the other hand, potassium tert-butoxide (4.67 g, 41.6 mmol) and dehydrated tetrahydrofuran (45 mL) were mixed under cooling with ice and argon atmosphere in another vassel, and (S)-4-benzyl-oxazolidine-2-one (7.38 g, 41.6 mmol) dissolved into dehydrated tetrahydrofuran (60 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred for 30 minutes. Next, a suspension of the mixed acid anhydride synthesized previously was added dropwise while filtering under an atmosphere of argon. After completion of the drop-wise addition, the reaction mixture was concentrated and then poured in water, which was extracted with ethyl acetate. The extracte was washed with 5% hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate and brine, then dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by means of silica gel column chromatography (eluent: isopropyl ether) to afford 2.65 g (13%) of (4S)-3-[2-ethyl-3-[4-methoxy-3-[[N-[4-(trifluoromethyl)phenyl]carbamoyl]methyl]phenyl]-propanoyl]-4-benzyloxazolidine-2-one with high polarity as a oily product. Also, 3.84 g (20%) of (4S)-3-[2-ethyl-3-[4-methoxy-3-[[N-[4-(trifluoromethyl)phenyl]carbamoyl]-methyl]phenyl]propanoyl]-4-benzyloxazolidine-2-one with low polarity were obtained by purifying by silica gel column chromatography, followed by further recrystallization from a mixed solvent of n-hexane with isopropyl ether, as colorless powder.
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:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I.[F:28][C:29]([C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH2:31][NH:32][CH3:33].[Cl-].[Na+]>CN1CCCC1=O>[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:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:32]([CH2:31][CH:30]=[C:29]([F:28])[C:34]([F:39])([F:40])[C:35]([F:36])([F:37])[F:38])[CH3:33]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Reactant: CNCC=C(F)C(F)(F)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(CC=C(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 80 °C
Reaction time: 3 h
Yield: 181.7 %

Procedure:
880 mg of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)oestra-1,3,5(10)-trien-17-one and 1.26 g of (3,4,4,5,5,5-hexa-fluoropent-2-enyl)methylamine are dissolved in 20 ml of N-methylpyrrolidone and stirred at a bath temperature of 80° C. for 3 hours. After the reaction solution has cooled to room temperature, the mixture is added to saturated sodium chloride solution, extracted with diethyl ether, dried and concentrated in vacuo. 1.86 g of 11β-fluoro-7α-{5-[(3,4,4,5,5,5-hexafluoropent-2-enyl)methylamino]pentyl}-3-hydroxyestra-1,3,5(10)-trien-17-one are obtained as a crude product which is employed in the next stage without purification.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:26](Cl)(=[O:29])[O:27][CH3:28]>C(Cl)Cl>[C:1]1([CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][N:8]2[C:26]([O:27][CH3:28])=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 107.4 %

Procedure:
Methyl 2-phenylpiperidine-4-carboxylate (4.33 g, 19.75 mmol) was dissolved in DCM (150 mL) and DIPEA (3.78 mL, 21.72 mmol), then methyl carbonochloridate (1.710 mL, 21.72 mmol) was added. The solution was stirred at room temperature for 1 h 45 min. More DIPEA (1.720 mL, 9.87 mmol) and methyl carbonochloridate (0.777 mL, 9.87 mmol) were added and the reaction continued at room temperature for another 30 min. The reaction mixture was washed with 0.1 M HCl and satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-phenylpiperidine-1,4-dicarboxylate (5.88 g, quant.) as a yellow oil. MS m/z 278 (M+H)+
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1.[NH:26]1[CH2:29][CH2:28][C@H:27]1[C:30]([OH:32])=[O:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:14][C:12]1[CH:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([N:26]3[CH2:29][CH2:28][C@H:27]3[C:30]([OH:32])=[O:31])=[N:7][CH:6]=2)[CH:9]=[C:10]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:11]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(F)nc2)c1
Reactant: O=C(O)[C@@H]1CCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(N3CC[C@H]3C(=O)O)nc2)c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
N-[3-(6-Fluoropyridin-3-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (15.0 g, 43.1 mmol), (2S)-azetidine-2-carboxylic acid (5.23 g, 51.7 mmol) and tripotassium phosphate (18.3 g, 86.0 mmol) are flushed and purged with N2(g) (3×) and DMSO (107 mL) was added. The reaction mixture was heated to 130° C. for 6 hours, then cooled to room temperature and was stirred overnight. The CELITE was added to the reaction mixture, filtered and precipitated by addition of acetonitrile (ca. 300 mL). The crude product was collected by filtration and purified by reverse phase chromatography to yield (2S)-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]azetidine-2-carboxylic acid. MS ESI calc'd for C21H19F3N5O2 [M+H]+ 430. found 430. 1H NMR (600 MHz, CDCl3) δ 8.64 (d, J=4.7 Hz, 1H), 8.29 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.43 (s, 1H), 7.27 (s, 1H), 7.06-6.94 (m, 2H), 6.50 (d, J=8.6 Hz, 1H), 4.88 (t, J=8.1 Hz, 1H), 3.90 (dd, J=8.2 Hz, 16.3 Hz, 2H), 3.03-2.88 (m, 1H), 2.49 (d, J=8.3 Hz, 1H), 2.40 (s, 3H).