Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:8]=1)([O-:3])=[O:2].CC(C)([O-])C.[K+].[CH3:22][N:23]=[C:24]=[S:25].[Cl-].[NH4+]>O1CCCC1.CN(C)C=O.O>[CH3:22][NH:23][C:24]([C:9]1([N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]2)[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])=[S:25]
Reactant: CN=C=S
Reactant: O=C1CCCCC1n1cnc([N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CNC(=S)C1(n2cnc([N+](=O)[O-])c2)CCCCC1=O
Yield: 45.5 %

Procedure:
In a nitrogen atmosphere, a suspension of 76.40 g (0.365 mol) of the 2-(4-nitroimidazol-1-yl)-cyclohexanone prepared in the Preparative Example 10 in 1.2 l of tetrahydrofuran was cooled with ice, followed by the addition of 45.16 g (0.402 mol) of potassium t-butoxide. The obtained reddish-purple reaction mixture was stirred under cooling with ice for one hour, followed by the addition of a solution of 27.5 ml (0.402 mol) of methyl isothiocyanate in 100 ml of tetrahydrofuran and 300 ml of dimethylformamide in this order. The reaction mixture was stirred for one hour, while the temperature thereof was raised to room one. A saturated aqueous solution of ammonium chloride and water were added to the resulting mixture successively, followed by the extraction with chloroform. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The residue was triturated with chloroform to give 46.93 g of the title compound as a light-brown powder. The mother liquor was concentrated in a vacuum and the residue was triturated with chloroform again to give 9.97 g of the title compound as a light-brown powder. Further, the mother liquor was concentrated in a vacuum and the residue was triturated with ethyl acetate to give 3.24 g of the title compound as a brown powder. Thus, 60.14 g of the title compound was obtained in total (yield: 58%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[CH2:27][CH2:26][S:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1)([O-:14])=[O:13]>ClCCl>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]2[CH2:27][CH2:26][S:25](=[O:9])[CH2:24][CH2:23]2)=[CH:19][CH:20]=1)([O-:14])=[O:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(CN2CCSCC2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CN2CCS(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
11.7 g (58 mmol) of m-chloroperbenzoic acid are added to a solution of 11.5 g (48 mmol) of 4-(4-nitrophenylmethyl)-thiomorpholine in 100 ml of dichloromethane at ambient temperature. The reaction solution is stirred for 4 hours at ambient temperature and then washed with 1N sodium hydroxide solution and water and evaporated to dryness. Chromatography on silica gel (dichloromethane/methanol=9:1) yields the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[C:16]([CH:19]([CH:21]4[CH2:26][CH2:25][CH:24]([O:27]C(C)([Si](C)(C)C)C)[CH2:23][CH2:22]4)O)[CH:17]=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[C:16]([CH2:19][C@H:21]4[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]4)[CH:17]=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(OC1CCC(C(O)c2ccn3ncnc(Nc4ccc(F)c(Cl)c4)c23)CC1)[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O[C@H]1CC[C@H](Cc2ccn3ncnc(Nc4ccc(F)c(Cl)c4)c23)CC1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A mixture of [4-(3-chloro-4-fluoro-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-[4-(1-methyl-1-trimethylsilanyl-ethoxy)-cyclohexyl]-methanol (448 mg, 0.887 mmole) triethylsilane (1.03 g, 8.87 mmole) in TFA (8 mL) under N2 in a pressure flask was heated at 75° C. overnight. The solvents were removed and the residue was dissolved in CH3OH (10 ml) and solid Na2CO3 (2.0 g) was added. After stirring vigorously for 1 h, the solvent was removed and the residue was partitioned between DCM (200 ml) and H2O (50 ml). The organic phase was separated, dried over Na2SO4, and the solvent was removed. Purification via radial chromatography (2 mm silica gel plate, gradient elution with 0 to 4% NH3 in MeOH (2N) in DCM) afforded the title compound (209 mg, 63%) as a solid: MS: 375 (M+H)+; HPLC Ret Time: 1.49 min (Xterra 3.0×50 mm S7 column, 2 min gradient, 5 mL/min).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[C:21]([F:29])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:29][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[C:25]([F:28])([F:27])[F:26])[CH2:18][C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:33][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(C(F)(F)F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(C(F)(F)F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 93.6 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.781 g, 1.80 mmol) (from example 140, step 1) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.072 g, 1.80 mmol) dissolved in water (1 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.12 mL, 1.96 mmol) was added over 1 min and stirring continued at −40° C. for 2 h 15 min. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Crude trans-methyl 2-(3-fluoro-4-(trifluoromethyl)-benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (678 mg, 94%) was isolated as an off-white foam. MS m/z 403 (M+H)+
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1O)([O-:19])=[O:18]>N1C=CC=CC=1.CCOC(C)=O.C(O)(C)C>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([O:10][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N+:17]([O-:19])=[O:18])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Oc1ccccc1[N+](=O)[O-])C(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of diphenylacetic acid (30.0 g; 141 mmol) and o-nitrophenol (39.3 g; 282 mmol) in pyridine (250 mL) was cooled to 0° C. N,N1 -dicyclohexylcarbodiimide (27.6 g; 134 mmol) was added at 0° C. The solution was stirred at 0° C. for several hours, warmed to room temperature and stirred overnight. The resulting heterogeneous solution was diluted with EtOAc and filtered. The filtrate was concentrated to afford a thick oil which was dissolved in a minimal amount of warm isopropanol. Upon cooling the sub-title compound began to crystallize from solution. The crystals were collected and dried under vacuum to afford the sub-title compound (37.3 g; 82%) as an off-white powder.
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[N:5]([CH3:19])[C:4](=[O:20])[CH:3]=1.[CH:21]([Mg]Cl)([CH3:23])[CH3:22].Cl>C1COCC1.CN1CCCC1=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH:21]([C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[N:5]([CH3:19])[C:4](=[O:20])[CH:3]=1)([CH3:23])[CH3:22]
Reactant: CC(C)[Mg]Cl
Reactant: Cn1c(=O)cc(Cl)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CC(C)c1cc(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a mixed solution of 6-chloro-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 56) (149 mg) in THF (5 ml) and N-methylpyrrolidone (0.5 ml) were added under nitrogen atmosphere iron(III) acetylacetonate (26 mg) and isopropylmagnesium chloride (2M THF solution, 1 ml), and the resulting mixture was stirred at room temperature for two and a half hours. The reaction solutions were added to 1N hydrochloric acid, and the resulting mixture was extracted with ethyl acetate (20 ml×2). The organic layer washed with saturated saline (20 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 6-isopropyl-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (53 mg).
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>O1CCOCC1.C(Cl)Cl>[Cl:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:11][NH2:12])[C:7]=1[I:8]
Reactant: NN
Reactant: Clc1ccnc(Cl)c1I
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: NNc1nccc(Cl)c1I
Temperature: 80 °C

Procedure:
To a solution of 2,4-dichloro-3-iodopyridine [CAS 343781-36-3] (4.7 g, 17.16 mmol) in 1,4-dioxane (240 ml), was added hydrazine monohydrate (5.096 ml, 102.962 mmol). The reaction mixture was heated in a sealed tube at 80° C. for 16 h. After cooling, the solvent was concentrated in vacuo. The white solid residue thus obtained was dissolved in DCM and washed with NaHCO3 (aqueous saturated solution). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue was washed with Et2O. The solid thus obtained was discarded. The mother liquours were concentrated in vacuo to yield intermediate compound D32 (2.31 g, 49%)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[CH2:16]([CH:18]1[O:20][CH2:19]1)Br.Cl>O>[O:20]1[CH2:19][CH:18]1[CH2:16][NH:13][S:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[O:11])=[O:12]
Reactant: BrCC1CO1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NCC2CO2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.3 %

Procedure:
p-Nitrobenzene sulphonamide (6.06 g, 30 mmol) was added portionwise to a solution of sodium hydroxide (1.32 g, 33 mmol) in water (60 ml) at room temperature. Epibromohydrin (4.5 g, 33 mmol) was added quickly dropwise and the solution stirred at room temperature for 24 hours. The mixture was acidified to pH 1 with 2M hydrochloric acid and extracted with DCM (2×30 ml). The combined organic extracts were dried with sodium sulphate, filtered and the volatiles removed by evaporation. The resulting yellow oil was purified by chromatography on silica eluting with DCM/methanol (100:0) increasing in polarity to (99:1) to give the title compound as a pale yellow solid (2.5 g, 32%); NMR (CDCl3) 2.65 (m, 1H), 2.80 (t, 1H), 3.10 (m, 2H), 3.50 (m, 1H), 5.08 (brs, 1H), 8.08 (d, 2H), 8.38 (d, 2H); m/z: 257.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:13](=[O:32])[N:12]1[CH:8]([CH2:9][CH:10]([O:33][C:34]([N:36]3[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][C:42]=4[F:45])[CH2:37]3)=[O:35])[CH2:11]1)[C:7](=[O:46])[NH:6]2)=[O:4].C([O-])(=O)C.[Na+]>COCCOC.O>[CH3:1][O:2][C:3]([C:5]12[CH2:23][CH:22]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[C:13](=[O:32])[N:12]1[CH:8]([CH2:9][CH:10]([O:33][C:34]([N:36]3[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][C:42]=4[F:45])[CH2:37]3)=[O:35])[CH2:11]1)[C:7](=[O:46])[NH:6]2)=[O:4]
Reactant: COC(=O)C12CC1C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(OC(=O)N3Cc4cccc(F)c4C3)CC1C(=O)N2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C12CC1CCCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(OC(=O)N3Cc4cccc(F)c4C3)CC1C(=O)N2
Temperature: 95 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To 14-tert-butoxycarbonylamino-18-(4-fluoro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid methyl ester (392 mg, 0.61) in DME (3 mL) and water (1 mL) was added tosyl hydrazide (682 mg, 3.66 mmol) and sodium acetate (600 mg, 7.32 mmol). The reaction was heated to 95° C. and allowed to stir 1 hour. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica (40→60% EtOAc/Hexanes) to provide 14-tert-butoxycarbonylamino-18-(4-fluoro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadecane-4-carboxylic acid methyl ester (319 mg, 81% yield). LCMS found 644.8 [M+H]+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:5]([C:13]2[CH:18]=[C:17]([OH:19])[C:16]([Cl:20])=[CH:15][C:14]=2[F:21])[N:6]=[C:7]2[C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8]2.Cl[CH:23]([F:25])[F:24].Cl>O.C(O)(C)C>[Cl:3][C:4]1[N:5]([C:13]2[CH:18]=[C:17]([O:19][CH:23]([F:25])[F:24])[C:16]([Cl:20])=[CH:15][C:14]=2[F:21])[N:6]=[C:7]2[C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8]2
Reactant: Oc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl
Reactant: FC(F)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Fc1cc(Cl)c(OC(F)F)cc1-n1nc2c(c1Cl)CCCC2
Reaction time: 1 h

Procedure:
To a solution of 36 ml of isopropanol, 21 ml of water and 6.0 ml of sodium hydroxide was added 5.28 g of 3-chloro-2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-indazole II-2, and the resultant mixture was heated at 50° to 60° C. to give a solution. Excessive chlorodifluoromethane gas was introduced, and each 4.5 g of 50% aqueous sodium hydroxide was added 1.5 and 3 hours after starting the gas inlet and further said gas inlet was continued for additional one hour. After cooling, the reaction mixture was neutralized with 2N hydrochloric acid and extracted with dichloromethane. The organic layer was dried and concentrated. The residue was chromatographed on a column of silica gel, eluting with n-hexane-ethyl acetate (4:1 v/v). The eluate was concentrated to give 5.24 g of the titled compound I-2.
Reaction SMILES: [CH3:1][CH2:2][O:3][N:4]=[C:5]([C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][N:9]=1)[CH2:6][NH2:7].C(N(CC)CC)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28].O>ClCCl>[Cl:14][C:13]1[C:8]([C:5](=[N:4][O:3][CH2:2][CH3:1])[CH2:6][NH:7][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[C:24]([F:23])([F:34])[F:35])=[N:9][CH:10]=[C:11]([Cl:15])[CH:12]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCON=C(CN)c1ncc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Yield: 56.1 %

Procedure:
To a solution of 200 mg of 2-amino-1-(3,5-dichloropyridin-2-yl)ethanone-β-ethyloxime and 90 mg of triethylamine in 3 ml of dichloromethane, 169 mg of 2-(trifluoromethyl)benzoyl chloride was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 30 minutes. After completion of the reaction, the reaction mixture was mixed with 10 ml of water and extracted with ethyl acetate (15 ml×1), the resulting organic layer was washed with water (10 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 190 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:12]([N:14]([CH3:21])[S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Zn](CC)[CH2:23][CH3:24].O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:23]([C:2]1[CH:3]=[C:4]([C@H:12]([N:14]([CH3:21])[S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH3:24]
Reactant: CC[Zn]CC
Reactant: C[C@H](c1cc(Br)cc(C(F)(F)F)c1)N(C)[S@@](=O)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc([C@@H](C)N(C)[S@@](=O)C(C)(C)C)cc(C(F)(F)F)c1
Temperature: 6 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
A mixture of (S)-N-((R)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethyl)-N,2-dimethyl propane-2-sulfinamide (1 g, 2.6 mmol), Pd(PPh3)2Cl2 (182 mg, 0.26 mmol) and Et2Zn (640 mg, 5.2 mmol) in THF (10 mL) under N2 atmosphere was stirred at 6° C. for 16 h. The reaction was poured into water (15 mL) and then extracted with EtOAc (2×30 mL). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=10/1 to 1/1) to give the title compound (700 mg, yield: 80.3%); m/z (ES+): 336 [M+H]+.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.Cl.[N+:10]([C:13]1[CH:14]=[C:15]([C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH2:25][S:26][C:27](=[NH:29])[NH2:28])[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11].C(=O)(O)[O-].[Na+].CCOCC>C(O)(C(F)(F)F)=O>[N+:10]([C:13]1[CH:14]=[C:15]([C@:19]23[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[CH2:25][S:26][C:27]([NH2:28])=[N:29]3)[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: N=C(N)SCC1=C(c2cccc([N+](=O)[O-])c2)CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cccc([N+](=O)[O-])c3)CCCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoromethanesulfonic acid (1.00 mL) was added to a solution of 2-[2-(3-nitrophenyl)cyclohex-1-enylmethyl]isothiourea hydrochloride obtained in Preparation Example 4-(4) (2.04 g) in TFA (10.0 mL) in an ice bath. The reaction solution was warmed to room temperature, followed by stirring overnight. Trifluoromethanesulfonic acid (1.00 mL) was further added to the reaction solution, followed by stirring for two days. After confirming completion of the reaction, the reaction mixture was carefully poured into a mixed solution of a saturated sodium bicarbonate solution and ether in an ice bath. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by NH-silica gel column chromatography to obtain the title compound (1.62 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:14]1)=O.B.C1COCC1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@@H](c2ccc(C(F)(F)F)cc2)C1
Agent: B
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc([C@@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)cc1
Yield: 48.2 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(4-trifluoromethylphenyl)piperidin-1-yl]methanone (13 mg, 0.033 mmol) was treated with BH3THF according to the above general procedure. Flash chromatography gave 6 mg of the title compound.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:32][CH3:33])=[C:14]([C:16](=[N:30][OH:31])[CH2:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=3[O:28][CH3:29])[CH:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C)C1C=CN=CC=1.ClCCl>[C:34]([O:31][N:30]=[C:16]([C:14]1[CH:15]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:11]=[CH:12][C:13]=1[NH:32][CH3:33])[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccc(C(=O)NCC2CCCC2)cc1C(Cc1ccc(C(=O)OC)cc1OC)=NO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CNc1ccc(C(=O)NCC2CCCC2)cc1C(Cc1ccc(C(=O)OC)cc1OC)=NOC(C)=O
Yield: 85 %

Procedure:
A solution of methyl 4-[2-[5-(N-cyclopentylmethylcarbamoyl)-2-methylaminophenyl]-2-(hydroxyimino)ethyl]-3-methoxybenzoate (79.9 mg), 4-(dimethylamino)pyridine (22mg), and acetic anhydride (0.17 ml) in dichloromethane (11 ml) was stirred under a nitrogen atmosphere for 15 hours. The solution was diluted with dichloromethane, washed with 5% w/v sodium hydrogen sulfate, water, and brine, then dried (MgSO4), and evaporated to give methyl 4-[2-(acetoxyimino)-2-[5-(N-cyclopentylmethylcarbamoyl)-2-methylaminophenyl]ethyl]-3-methoxybenzoate (74.1 mg, 85%) as a pink solid; NMR (80 MHz, CDCl3): 1.2-1.8 [8H, (CH2)4 ], 2.1 (s, 3H, CH3CO), 3.0 (d, 3H, NCH3), 3.3 (dd, 2H, CH2NH), 3.9 (2s, 6H, 2×OCH3), 4.3(s, 2H, ArCH2), 5.8 (broad, 1H, NHCO), 6.7(d, 1H), 7.0 (d, 1H), 7.4-7.6 (m, 3H), 7.8 (d, 1H), 8.5 (broad, 1H, CH3NH).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[NH2:12][C@H:13]1[CH2:17][CH2:16][C@H:15]([O:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[NH:26][C:27]2[C:28]3[C:35]([CH3:36])=[C:34]([C:37]([NH2:39])=[O:38])[S:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([NH:12][C@H:13]1[CH2:17][CH2:16][C@H:15]([O:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[NH:26][C:27]2[C:28]3[C:35]([CH3:36])=[C:34]([C:37]([NH2:39])=[O:38])[S:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:14]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](N)C3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Acetyl chloride (21 μl) was added at 0° C. to a mixture of 4-[2-((1S,3S)-3-amino-cyclopentyloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid amide trifluoroacetate (cpd. 229, 206 mg) and DIPEA (348 μl) in DCM (25 ml) and stirred at rt for 4 hours. The reaction mixture was concentrated, diluted with water and extracted with DCM. The organic layer was dried, concentrated and the crude was purified by chromatography to give the desired product.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3(O)[CH2:12][CH2:13][C@@H:14]2[O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:6]1)(=[O:3])[CH3:2].S(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C:11]3=[CH:12][CH2:13][C@@H:14]2[O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@]12CC[C@H](OC(C)=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)C(C)(C)C)CC[C@]12O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC[C@]12CC[C@H](OC(C)=O)C[C@@H]1CC[C@H]1C3=CC[C@H](OC(=O)C(C)(C)C)[C@@]3(C)CC[C@@H]12
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of 140 mg of 3β,19-diacetoxy-14β-hydroxy-17β-pivaloxy-5α-androstane in 7.0 ml of pyridine was added 0.14 ml of thionyl chloride. The mixture was left to stand under nitrogen for 40 minutes whereupon it was poured into 70 ml of an ice-water mixture. Extraction with ether followed by washing of the ethereal phase with water and evaporation at reduced pressure gave 3β,19-diacetoxy-17β-pivaloxy-5α-androst-14-ene as a resinous material which was used as the starting material in the reaction described in the following example.