Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[S:32](Cl)(=[O:34])=[O:33].C(N(CC)C(C)C)(C)C>C1COCC1.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([S:32]([C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[Cl:24])(=[O:34])=[O:33])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3ccc(Cl)cc3Cl)CC2)c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.8 %

Procedure:
To a 0° C. solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 110 mg, 0.35 mmol) and 2,4-dichlorobenzenesulfonyl chloride (171 mg, 0.7 mmol) in THF (6.0 mL) was added N,N-diisopropylethylamine (183 μL, 1.05 mmol). The resulting light yellow solution was allowed to warm to room temperature during 2 hours and then it was stirred for 15 hours at room temperature under nitrogen. The reaction mixture was diluted with water and brine solution and the organic compound was extracted into ethyl acetate (2×50 mL). The combined extracts were washed with brine solution and dried over MgSO4. Filtration and concentration gave the crude product which was purified by flash chromatography (40 g ISCO column, eluting with 0-60% ethyl acetate in hexanes) to give {4-[1-(2,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (119 mg, 65%) as an off-white solid. MS cald. for C20H25FNO4S [(M+H)+] 524, obsd. 523.8.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].COC1C=C(OC)C=CC=1C1C=CC(C(O)=O)=CC=1C.[CH3:33][C:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[C:37]([CH3:48])[O:36][N:35]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:33][C:34]1[C:38]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH3:12])=[C:37]([CH3:48])[O:36][N:35]=1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(-c2ccc(C(=O)O)cc2C)c(OC)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2c(C)noc2C)c(C)c1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
Methyl 4-bromo-3-methylbenzoate (Intermediate 17, step 1) (4 g; 17.46 mmol; 1 eq.), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)isoxazole (4.28 g; 19.21 mmol; 1.10 eq.), potassium carbonate (12.07 g; 87.31 mmol; 5 eq.), tetrakis(triphenylphosphine)palladium(0) (2.02 g; 1.75 mmol; 0.10 eq.) were taken in Toluene (20 mL) and water (20 mL) under N2 atmosphere. The reaction mixture was degassed with N2 and then refluxed for 4 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (200 mL). The filtrate was concentrated to afford a brown oil which was taken up in EtOAc (250 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution (100 mL), water (100 mL) and brine (100 mL), dried over MgSO4 and concentrated affording methyl 4-(3,5-dimethylisoxazol-4-yl)-3-methylbenzoate (4.2 g, 99%, HPLC (Method A) Rt 3.93 min) as an orange solid, which was used without further purification. A solution of methyl 4-(3,5-dimethylisoxazol-4-yl)-3-methylbenzoate (3 g; 12.23 mmol; 1 eq.) in EtOH (90 mL) at RT was treated with sodium hydroxide (7.34 mL; 5 M; 36.69 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was concentrated to give a brown solid which was taken up in water (100 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with HCl cc to pH 2. Then it was concentrated until precipitation (volume divided by 2). The suspension was filtered affording the title compound as a brown solid. It was washed with diethyl ether affording the title compound as a beige solid. 1H NMR (DMSO-d6, 300 MHz) δ 13.03 (br s, 1H), 7.95 (s, 1H), 7.86-7.84 (dd, J=7.88, 1.31 Hz, 1H), 7.34-7.32 (d, J=7.88 Hz, 1H), 2.26 (s, 3H), 2.19 (s, 3H), 2.07 (s, 3H). HPLC (Method A) Rt 3.13 min (Purity: 97.1%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:12]2([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)[CH:24]=3)[C:20]3[C:15](=[C:16]([F:21])[CH:17]=[CH:18][CH:19]=3)[C:14]([NH2:22])=[N:13]2)[CH:6]=[C:7]([CH3:11])[C:8]=1[O:9][CH3:10].[C-:35]#[N:36].[K+]>CC#N>[NH2:22][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:12]([C:5]2[CH:6]=[C:7]([CH3:11])[C:8]([O:9][CH3:10])=[C:3]([CH2:2][C:35]#[N:36])[CH:4]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)[CH:24]=2)[N:13]=1
Reactant: COc1c(C)cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CC#N
Product: COc1c(C)cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1CC#N
Temperature: 25 °C
Yield: 13.8 %

Procedure:
To a solution of 1-(3-(bromomethyl)-4-methoxy-5-methylphenyl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine (185 mg, 0.36 mmol) in MeCN (5 mL) was added potassium cyanide (69.8 mg, 1.07 mmol) and the reaction mixture was stirred at rt over night. The mixture was filtered and the filtrate was concentrated in vacuo and purified by preparative HPLC to give 23 mg (12%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][C:26]([N:28]([CH3:30])[CH3:29])=[N:25][C:24]=3[CH:31]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C[C:34]([N:36](C)C)=O>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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:34]#[N:36])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][C:26]([N:28]([CH3:30])[CH3:29])=[N:25][C:24]=3[CH:31]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccc4oc(N(C)C)nc4c3)cc2c1O
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4oc(N(C)C)nc4c3)cc2c1O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 1-chloro-6-(2-dimethylamino-benzooxazol-5-yloxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (115 mg, 0.25 mmol), tris(dibenzylideneacetone)dipalladium(0) (12 mg, 0.01 mmol), 1,1′-bis(diphenylphosphino)ferrocene (14 mg, 0.02 mmol), zinc cyanide (18 mg, 0.15 mmol), zinc (2 mg, 0.03 mmol) and dimethylacetamide (0.6 mL) was stirred at 120° C. for two hours before it was cooled to room temperature, partitioned between ethyl acetate and water, filtered. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (53 mg): MS: (+) m/z 447.00 (M+1); (−) m/z 445.20 (M−1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:14]([CH3:35])([CH3:34])[CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH:56]1[O:61][CH2:62][CH2:63]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O>[C:30]([Si:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:16][CH2:15][C:14]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:63][CH2:62][O:61][CH:56]3[CH2:57][CH2:58][CH2:59][CH2:60][O:55]3)[CH:8]=2)[N:5]=1)([CH3:35])[CH3:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(O)c2)n1
Reactant: OCCOC1CCCCO1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Temperature: 0 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
A mixture of Intermediate 153d (0.53 g, 1.09 mmol) in dry TI-IF (8 mL) was treated with triphenylphosphine (0.57 g, 2.18 mmol) and 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (0.22 mL, 1.64 mmol). The mixture was cooled to 0° C. then diisopropylazodicarboxylate (0.43 mL, 2.18 mmol) was added dropwise. After stirring at ambient temperature for 20 h the mixture was treated with water (0.1 mL) and concentrated in vacuo to a yellow oil. The oil was purified by FCC, using 0-30% EtOAc in cyclohexane, to give the title compound as an orange oil (0.41 g, 61%). LCMS (Method 3): Rt 5.25 min, ink 614.6 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([Si](CCC)(CCC)CCC)[CH:6]=[CH:5][C:4]=2[C:3]=1[C:21]([OH:23])=O.F[P-](F)(F)(F)(F)F.[N:31]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O.N.O>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:21]([NH2:31])=[O:23]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCC[Si](CCC)(CCC)n1ccc2c(C(=O)O)c(F)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A mixture of 5-fluoro-1-(tripropylsilyl)-1H-indole-4-carboxylic acid (500 mg, 1.49 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (851 mg, 2.24 mmol), and TEA (452 mg, 4.48 mmol) in DMF (5 mL) was stirred at RT for 1 hour. To the mixture was added ammonia water (1 mL), followed by stirring at RT overnight. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography using petroleum ether/EtOAc (2:1) as eluting solvents to afford 5-fluoro-1H-indole-4-carboxamide as a white solid (260 mg, 52.2%). MS (ESI): m/z=179.2 [M+1]+.
Reaction SMILES: CC1C2C(=CC=CC=2)C(B(O)O)=CC=1.Br[C:16]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][C:23](Br)=[CH:24][CH:25]=3)[C:20](C)=[C:19](C)[C:18]=2[CH:17]=1.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:22]1[C:21]2[CH:20]=[CH:19][C:18]3[C:27](=[CH:28][CH:29]=[CH:16][CH:17]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1c(C)c2cc(Br)ccc2c2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(B(O)O)c2ccccc12
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: c1ccc2c(c1)ccc1ccccc12

Procedure:
A degassed, efficiently stirred suspension of 37.2 g (200 mmol) of 4-methylnaphtalene-1-boronic acid, 18.0 g (50 mmol) of 2,7-dibromo-9,10-dimethylphenanthrene and 52.2 g (210 mmol) of potassium phosphate 1-hydrate in a mixture of 75 ml of dioxane, 150 ml of toluene and 200 ml of water was admixed with 457 mg (1.5 mmol) of tri-o-tolylphosphine and then with 56 mg (0.25 mmol) of palladium(II) acetate. After heating under reflux for 16 h and cooling the reaction mixture, the precipitated solid was filtered off with suction and washed three times with 100 ml each time of water and three times with 100 ml each time of ethanol. After drying under reduced pressure (1 mbar, 80° C., 16 h), the product was extracted in a Soxhlett extractor with chloroform through a glass fibre extraction sleeve (pore size 0.5 μm) in order to remove palladium traces. The product which remained after concentration of the chloroform was recrystallized three times from chlorobenzene (approx. 25 ml/g) and three times from DMF (approx. 60 ml/g), and subsequently sublimed twice under high vacuum (p=5×10−5 mbar, T=320-330° C.). The yield at a purity of 99.9% by HPLC was 15.6 g (32 mmol), corresponding to 64.2% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7]([OH:9])=[O:8].[C:15](Cl)(Cl)=[O:16]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[NH:14][C:15](=[O:16])[O:9][C:7](=[O:8])[C:6]2=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1cc2[nH]c(=O)oc(=O)c2cc1OC
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a mixture of 10.0 g (51.0 mmol) of 4,5-dimethoxyanthranilic acid in 80 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene in toluene, at room temperature. The mixture was stirred overnight. The mixture was concentrated to yield a residue which was triturated with ethyl acetate-hexane (1:4), filtered, washed with hexane and dried to afford 11.0 g (97.2%) of the 4,5-dimethoxyisatoic anhydride as a gray solid. MS (Cl mode) m/z 206 (M-18, 100%), 224 (M+H, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:17]=[C:16]([NH2:18])[S:15][C:5]=2[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.N1C=CC=CC=1.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>ClCCl.O1CCCC1>[C:29]1([O:28][C:26](=[O:27])[NH:18][C:16]2[S:15][C:5]3[C:6]([N:9]4[CH2:10][CH2:11][O:12][CH2:13][CH2:14]4)=[N:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=3[N:17]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Reaction time: 3 h

Procedure:
To a stirred suspension of 500 mg (1.88 mmol) 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine and 0.46 ml (5.63 mmol) pyridine in 15 ml dichloromethane and 5 ml tetrahydrofuran was added 0.28 ml (2.25 mmol) phenyl chloroformate and stirring continued at 50° C. for 3 h. The reaction mixture was then filtered and the filtrate concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) afforded 535 mg 74%) (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester as a white solid. ES-MS m/e (%): 387 (M+H+, 100).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][C:9]=1[C:10](OC)=[O:11].O.[OH-].[Na+]>C1COCC1>[Cl:7][C:8]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][C:9]=1[CH2:10][OH:11]
Reactant: COC(=O)c1cc(-c2ccccn2)ccc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(-c2ccccn2)ccc1Cl
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
A cooled (−10° C.) suspension of LiAlH4 (37 mg; 0.97 mmol) in anh. THF (1.5 ml) was treated with a solution of methyl 2-chloro-5-(pyridin-2-yl)benzoate (220 mg; 0.88 mmol) in anh. THF (1 ml). The mixture was further stirred at −10° C. for 20 min. Water (37 μl), 15% aq. NaOH (37 μl), and water (110 μl) were then successively added, and the resulting mixture was further stirred at rt for 1 h. Filtration, concentration to dryness under reduced pressure, and additional drying under HV afforded (2-chloro-5-(pyridin-2-yl)phenyl)methanol as a colorless solid. LC-MS (conditions A): tR=0.42 min.; [M+H]+: 219.94 g/mol.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][C:9]([OH:11])=O)[CH:3]=1.[N+]([O-])(O)=O.[O:16]([CH2:20][CH2:21][NH2:22])[N+:17]([O-:19])=[O:18].C(OC(C)C)(C)C>>[O:16]([CH2:20][CH2:21][NH:22][C:9](=[O:11])[CH2:8][O:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)[N+:17]([O-:19])=[O:18]
Reactant: Cc1cc(OCC(=O)O)no1
Reactant: NCCO[N+](=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: Cc1cc(OCC(=O)NCCO[N+](=O)[O-])no1
Yield: 36.9 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.40 g of 5-methyl-3-isoxazolyloxyacetic acid and 0.43 g of nitroxyethylamine nitrate, 0.23 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:28]=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:30]=1[OH:31])[C:8]([O:10][C:11]1[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]=1[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([OH:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:36]([O:54][C:15](=[O:16])[C:14]1[CH:18]=[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]([O:10][C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:30]([OH:31])=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:28]=2)=[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:13]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CC(C)(C)c1cc(C(=O)Oc2c(C(C)(C)C)cc(C(=O)Cl)cc2C(C)(C)C)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1cc(C(C)(C)C)c(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 102 %

Procedure:
10.0 grams of 4-(3,5-di-t-butyl-4-hydroxybenzoyloxy)-3,5-di-t-butylbenzoyl chloride (0.02 moles) 5.4 grams of n-octadecanol (0.02 moles) and 2.0 grams of triethylamine were stirred together in 100 ml. of benzene at room temperature for 2 hours and then heated for 1 hour at 60° to 70° C. The reaction mixture was cooled to room temperature and the precipitate filtered. The benzene solution was washed with water and dried over sodium sulfate. The benzene solution was then concentrated at reduced pressure yielding about 15 grams of the product. The product was crystallized twice from isopropanol yielding white crystals melting at 75° to 76° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[Ca+2].[C:15](Cl)(Cl)=[S:16]>C(Cl)(Cl)Cl>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1)=[C:15]=[S:16]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: S=C=Nc1ccc(S)cc1
Temperature: 35 °C

Procedure:
A solution of 4-aminothiophenol (7.00 g, 0.056 mol) in chloroform (75 ml) was added to a stirred, cooled (0° C.) solution of water (40 ml), chloroform (20 ml), calcium carbonate (6.60 g, 0.066 mol), and thiophosgene (6.95 g, 0.060 mol) at 0°-5° C. The mixture was heated at 35° C. for 1 hour and poured into water (50 ml) before separating the two layers. The organic layer was washed with hydrochloric acid (1%, 100 ml) and dried (MgSO4). The solvent was removed in vacuo to afford an orange semi-solid which was used in the next step without purification.
Reaction SMILES: [CH2:1]([CH:5]1[C:10](=[N:11]O)[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([CH:5]1[CH:10]([NH2:11])[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CN(CCc2ccccc2)CCC1=NO
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCC1CN(CCc2ccccc2)CCC1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Butyl-1-phenethyl-piperidine-4-one oxime (218 mg) was dissolved in THF (10 ml) and LAH (261 mg) was added in one portion. The suspension was then allowed to stir at RT for 24 hours. The reaction mixture was carefully pipetted onto 5% aq. NaHCO3 solution and the aqueous layer was extracted with DCM. The organic layer was washed with brine, dried (MgSO4) and evaporated to give a colorless oil. This was purified by flash chromatography (gradient of MeOH in DCM containing 1% NH4OH) to give the product as cis and trans diastereomers (cis: 127 mg; trans: 36 mg). MS (ESI): 261.4 (MH+).
Reaction SMILES: [C:1]1([N:7]2[CH:13]([CH3:14])[C:11](=[O:12])[NH:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][C:16]([Cl:20])([Cl:19])[S:17]Cl.[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl>[C:1]1([N:7]2[CH:13]([CH3:14])[C:11](=[O:12])[N:10]([S:17][C:16]([Cl:20])([Cl:19])[Cl:15])[C:8]2=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClSC(Cl)(Cl)Cl
Reactant: CC1C(=O)NC(=O)N1c1ccccc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1C(=O)N(SC(Cl)(Cl)Cl)C(=O)N1c1ccccc1
Reaction time: 0.17 h
Yield: 108.7 %

Procedure:
A stirred mixture of 8.0 g (0.042 mole) 1-phenyl-5-methylhydantoin, 8.6 g (0.046 mole) trichloromethylsulfenyl chloride and 1.0 g Aliquat® 336 in 100 ml methylene chloride was cooled in an ice bath. To that mixture a pre-cooled sodium hydroxide solution (4.2 g of 50% sodium hydroxide diluted to 20 g with water) was added at once. The temperature of the reaction mixture rose from 3° C. to 5° C.; stirring was continued for 10 minutes. The methylene chloride layer was separated and washed well with water, dried over magnesium sulfate and stripped to give 15.5 g of an oil. After being washed with cold hexane, the oil slowly solidified. The solid was crystallized from hexane-toluene to give 9.9 g of the above-identified product as a white solid, melting point 113°-114° C.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])=O.[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[F:1][CH:2]([F:12])/[C:3](=[N:19]\[S@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11]
Reactant: O=C(c1ccccc1F)C(F)F
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[S@](=O)/N=C(/c1ccccc1F)C(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Under an inert atmosphere the light yellow solution of 2,2-difluoro-1-(2-fluorophenyl)ethanone (8.0 g, 45.9 mmol) in THF (280 ml) was treated at r.t. with (S)-2-methylpropane-2-sulfinamide (5.68 g, 45.9 mmol) followed by titanium(IV)ethoxide (21.0 g, 19.3 ml, 91.9 mmol). The light yellow solution was heated to reflux and stirred for 2 hours. The reaction mixture was cooled to r.t., poured into half-saturated brine, diluted with AcOEt (100 ml) and stirred vigorously for 1 hour. After filtration through a layer of Dicalite® and washing with AcOEt the aqueous layer was separated and extracted with AcOEt (2×150 ml). The organic layers were dried over MgSO4 and evaporated at reduced pressure. The crude product was purified by flash chromatography on silica gel (eluent: heptane/AcOEt 10:1) to give (S,Z)—N-(2,2-difluoro-1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (8.27 g, 64.9% yield) as a yellow oil. MS: m/z=278.0 [M+H]+.
Reaction SMILES: [C:1]([C@H:3]1[C@H:8]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C:5](=[O:25])[CH2:4]1)[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[O:24])[CH2:15][C@:16]1(O)[CH3:22])[CH2:11][CH2:10]3)#[N:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(O)(=O)C.C(OCC)(=O)C>[C:1]([C@H:3]1[C@H:8]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C:5](=[O:25])[CH2:4]1)[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[O:24])[CH:15]=[C:16]1[CH3:22])[CH2:11][CH2:10]3)#[N:2]
Reactant: C[C@]12[C@@H](CC[C@H]3[C@@H]4[C@H](C#N)CC(=O)[C@@]4(C)CC[C@@H]31)CC(=O)C[C@@]2(C)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1=CC(=O)C[C@@H]2CC[C@H]3[C@@H]4[C@H](C#N)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]12C
Temperature: 0 °C
Yield: 89.7 %

Procedure:
2.0 g of 15β-cyano-1β-hydroxy-1α-methyl-5α-androstane-3,17-dione is stirred in 20 ml of glacial acetic acid with 6 ml of trifluoroacetic anhydride at room temperature. After 4 hours the solution is added to ice/water. The precipitated product is suctioned off, dissolved in ethyl acetate and washed with water. 1.7 g of 15β-cyano-1-methyl-5α-androst-1-ene-3,17-dione with a melting point of 193° C. is obtained.