Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([OH:9])[C:7]=1[Cl:8].[Sn](Cl)Cl.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[NH2:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([Cl:8])[C:6]=1[OH:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(Cl)c(Cl)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A mixture of 5,6-dichloro-2-nitrophenol(1.8 g, 8.7 mmol) and tin (II) chloride (5.8 g, 26.1 mmol) in ethanol(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extrated with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(1.4 mg, 90%). 1H NMR (CD3OD): δ 6.71 (d, 1H), 6.45 (d, 1H).
Reaction SMILES: C1COCC1.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[N:13][OH:14])[CH:7]=1.ClN1C(=O)CCC1=O.[CH3:23][Si:24]([CH3:32])([CH3:31])[C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28]>C(OCC)(=O)C.C(N(CC)CC)C>[CH3:23][Si:24]([CH3:32])([CH3:31])[C:25]1[C:12]([C:8]2[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=2)=[N:13][O:14][C:26]=1[Si:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: ON=Cc1cccnc1
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)c1onc(-c2cccnc2)c1[Si](C)(C)C
Temperature: 65 °C
Reaction time: 18 h
Yield: 17 %

Procedure:
To a solution of anhydrous THF (250 ml) containing 3-pyridinealdoxim (61) (18.87 g, 154.7 mmol) were added 20.57 g (1.0 eq) of N-chlorosuccinimide. After the addition, the resulting solution was stirred for 18 hours at 65° C. Then the temperature of the reaction mixture was lowered to −30° C. and 1,2-bis-trimethylsilanyl-ethyne was added (26.4 g, 170.4 mmol), subsequently followed by triethylamine (2 eq, 42 ml, dropwise), while keeping the temperature <−25° C. After stirring for another 30 minutes, the mixture was allowed to warm to ambient temperature, diluted with ethyl acetate, washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE 1/1) to afford 3-(4,5-bis-trimethylsilanyl-isoxazol-3-yl)-pyridine (62) as an oil (4.45 g, 17%). 1H-NMR (400 MHz, CDCl3): δ 8.70 (dd, J=5 Hz, 2 Hz, 1H), 8.68 (d, J=2 Hz, 1H), 7.76 (dt, J=8 Hz, 2 Hz, 1H), 7.41-7.37 (m, 1H), 0.46 (s, 9H), 0.011 (s, 9H).
Reaction SMILES: N[C@@H](CC(C)C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.B.O1CCCC1.[CH:27]1(/[CH:33]=[C:34](/[N:41]2[CH:45]=[N:44][CH:43]=[N:42]2)\[C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.Cl>ClCCCl>[CH:27]1(/[CH:33]=[C:34](/[N:41]2[CH:45]=[N:44][CH:43]=[N:42]2)\[CH:35]([OH:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CC(C)(C)C(=O)/C(=C\C1CCCCC1)n1cncn1
Agent: B
Agent: CC(C)C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)C(O)/C(=C\C1CCCCC1)n1cncn1
Reaction time: 24 h

Procedure:
In a nitrogen atmosphere, a solution of 0.485 g (1.8 mmoles) of (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol in 5 ml of 1,2-dichloroethane was added dropwise at -78° C. to a solution comprising 1.8 ml (1.8 mmoles) of 1.00M borane-tetrahydrofuran solution and 2 ml of 1,2-dichloroethane, and the temperature of the mixture was raised from -78° C. to room temperature over about 2 hours. Thereafter, a solution of 0.31 g (1.2 mmoles, E/Z=99.9/0.1) of (E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-one in 3 ml of 1,2-dichloroethane was added dropwise to this solution, and stirring was carried out for 24 hours. The reaction product was decomposed with addition of 6 ml of 2N hydrochloric acid to the solution, and after removing (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol hydrochloride by filtration, the organic layer was washed with water and concentrated under reduced pressure. The residue was purified on a column packed with 2 g of silica gel with chloroform as a developing solvent to obtain (-)-(E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-ol. The conversion was 100%, and the composition of the product was: E-form alcohol, 99.1% and Z-form alcohol, 0.9%. The enantiomer ratio of the E-form alcohol was: (+)-isomer, 16.3% and (-)-isomer, 83.7%.
Reaction SMILES: [CH:1]1(/[CH:7]=[C:8](/[N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)\[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1(/[CH:7]=[C:8](/[N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)\[CH:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)C(=O)/C(=C\C1CCCCC1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(O)/C(=C\C1CCCCC1)n1cncn1
Yield: 55.1 %

Procedure:
26 g (0.1 mol) of (E)-1-cyclohexyl-4,4-dimethy-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one are taken up in 200 ml of methanol, and 4.5 g of sodium borohydride are added in portions, while stirring and cooling. When the reaction has ended, the reaction mixture is brought to pH 6 and concentrated. The residue is taken up 200 ml of methylene chloride, the mixture is washed with saturated sodium bicarbonate solution, dried over sodium sulphate and filtered and the filtrate is concentrated. The residue is recrystallised from petroleum ether. 14.5 g (55% of theory) of racemic (E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-ene of melting point 131° C. are obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].C(O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>CN(C1C=CN=CC=1)C.C1CCCCC1>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8]
Reactant: OCc1ccccc1
Reactant: COC(=O)C1CCCC1=O
Agent: CN(C)c1ccncc1
Solvent: C1CCCCC1
Solvent: CO
Product: O=C1CCCC1C(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
In a 4-liter flask fitted with a Dean-Stark apparatus and a condenser, methyl 2-oxo-cyclopentanecarboxylate (380 mL; 3 mol), benzyl alcohol (342 mL; 3.3 mol; 1.1 eq.) and DMAP (18.3 g; 0.15 mol; 0.05 eq.) are dissolved in 1800 mL of cyclohexane. The reaction mixture is stirred for 48 hours at reflux (temperature of the mixture: 90° C.) and the methanol formed is distilled off. After cooling, the reaction mixture is concentrated and taken up in 1500 mL of dichloromethane. The organic phase is washed with 1N hydrochloric acid, with water, and then with saturated sodium chloride solution. It is then dried, filtered and then evaporated.
Reaction SMILES: ClC[C:3](=O)[C:4]([OH:6])=[O:5].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=O)[C:13]2=[O:20].[OH-].[K+].S([O-])(O)=O.[Na+].Cl>O.CO.C(#N)C.C(OCC)(=O)C>[OH:20][C:13]1[CH:14]=[N:15][C:16]2[C:12]([C:3]=1[C:4]([OH:6])=[O:5])=[CH:11][C:10]([O:9][CH3:8])=[CH:18][CH:17]=2
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Reactant: O=C(O)C(=O)CCl
Agent: Cl
Agent: O=S([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COc1ccc2ncc(O)c(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 21.5 %

Procedure:
3-Chloro-2-oxo-propionic acid (11.46 g, 91.10 mmol, 1.61 eq) is added portionwise at room temperature to a stirred solution of 5-methoxy-1H-indole-2,3-dione (10.0 g, 56.45 mmol, 1.0 eq) and potassium hydroxide (30.5 g, 543.6 mmol, 9.6 eq) in water (60 mL). After 6 days stirring at room temperature, a solution of sodium hydrogen sulfite (2.3 g, 22.10 mmol, 0.4 eq) in water (4 mL) is added and the reaction mixture is acidified by the addition of concentrated hydrochloric acid (12N, 30 mL). The resulting yellow precipitate is collected by filtration, washed successively with a saturated sulfur dioxide aqueous solution and water, then purified by column chromatography (silica gel, eluent: ethyl acetate:acetonitrile:methanol, 70:5:5, v/v/v) to afford 3-hydroxy-6-methoxyquinoline-4-carboxylic acid as a light brown solid (2.66 g, 21% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[CH:9][C:10]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl

Procedure:
44.14 g (0.17 mol) of methyl 2-chloro-3-methyl-4-methylsulfonylbenzoate were dissolved in 600 ml of carbon tetrachloride and treated with 29.91 g (0.17 mol) of N-bromosuccinimide and 0.41 g of dibenzoyl peroxide. The mixture was then refluxed and illuminated with a 300 W lamp. The reaction mixture was filtered, the filtrate was concentrated and the residue was taken up in diethyl ether. The solution was treated with n-heptane, and the precipitated solid was filtered off with suction and dried.
Reaction SMILES: [N:1]1N=N[N:4]2[CH:9]=[C:8]([CH:10]3[O:15][CH2:14][C:13](=[O:16])[N:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11]3)[CH:7]=[CH:6][C:5]=12.Cl[Sn]Cl.Cl>CO>[NH2:1][C:5]1[N:4]=[CH:9][C:8]([CH:10]2[O:15][CH2:14][C:13](=[O:16])[N:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11]2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)N1CC(c2ccc3nnnn3c2)OCC1=O
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Product: CC(C)(C)N1CC(c2ccc(N)nc2)OCC1=O
Yield: 88.7 %

Procedure:
A solution of 2-(tetrazolo[1,5-a]pyrid-6-yl)-4-(1,1-dimethylethyl)-5-oxo-morpholine (550 mg), SnCl2 .2H2O (968 mg) and 0.2 ml of 12N hydrochloric acid in 60 ml of methanol was heated at reflux for 14.5 hours under nitrogen. The reaction mixture was concentrated under reduced pressure and then poured into ice water containing 5N sodium hydroxide. The basic aqueous mixture was repeatedly extracted with methylene chloride. The combined organic fractions were washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. Concentration gave 603 mg of crude product which was chromatographed on silica gel (95:5:1 methylene chloride:ethanol:ammonium hydroxide) to give 442 mg of product. Mass spectrum (FAB) 250 (M+1). 13C NMR (CDCl3) 27.9 49.5 57.7 69.2 74.3 108.5 123.6 135.8 146.3 158.7 167.4 ppm.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[CH:8][CH:7]=1)=[O:5].Cl[C:18]([O:20][CH3:21])=[O:19]>>[CH3:1][N:2]([CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[CH:8][CH:7]=1)=[O:5])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)Cl
Reactant: CN(C)CC(=O)c1ccc(OC(F)F)cc1
Product: COC(=O)N(C)CC(=O)c1ccc(OC(F)F)cc1
Yield: 60.2 %

Procedure:
By substantially following the procedure of Example 115b using 16.8 g (73 mmole) of 2-dimethylamino-4'-difluoromethoxy-acetophenone Example 126c and 7.6 g (81 mmole) of methyl chloroformate one obtain 12 g of 2-(N-methyl-N-(methoxycarbonyl)amino)-4'-difluoromethoxyacetophenone an oil. bp 150°-190° C. at 0.7 torr.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.C(Cl)CCl.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Br)cc1F
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1F)N1CCOCC1
Temperature: 25 °C
Yield: 77 %

Procedure:
4-Bromo-2-fluorobenzoic acid (5.00 g, 22.8 mmol, 1.00 equiv) and EDC (5.23 g, 27.4 mmol, 1.20 equiv) were dissolved in dichloromethane (100 mL). Morpholine (4.77 mL, 54.8 mmol, 2.40 equiv) was added and the solution was maintained at room temperature for 19 h. The reaction mixture was concentrated en vacuo and diluted with EtOAc and 1N HCl. The phases were separated and the organic phase was washed sequentially with water, saturated NaHCO3, and saturated NaCl. The organic phase was subsequently dried over Na2SO4, filtered and concentrated to afford 5.06 g (81%) of a colorless oil which was used without further purification in the next step. MS (ES) m/e 289 [M+H]+.
Reaction SMILES: [OH-:1].[Na+:2].CO.[CH:5]1[N:9]=[CH:8][N:7]([CH2:10][C:11]([P:17]([OH:20])([OH:19])=[O:18])([P:13]([OH:16])([OH:15])=[O:14])[OH:12])[CH:6]=1>O>[CH:5]1[N:9]=[CH:8][N:7]([CH2:10][C:11]([P:13]([O-:16])([OH:15])=[O:14])([P:17]([O-:19])([OH:20])=[O:18])[OH:12])[CH:6]=1.[OH2:1].[OH2:12].[OH2:12].[OH2:12].[Na+:2].[Na+:2]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=P([O-])(O)C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of sodium hydroxide (1.4 g) in a mixture of water (20% v/v)/Methanol (80% v/v, 10 volumes per grams of ZLD-Ac form I) (10 ml) was added drop-wise to a suspension of Zoledronic acid form I (5.0 g) in a mixture of water (20% v/v)/Methanol (80% v/v, 10 volumes per grams of ZLD-Ac) (53 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 17 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with Methanol (1×10 ml) and dried in a vacuum oven at 50° C. for 26 hours to give 5.6 g (97%) of Zoledronate disodium crystal form XIV (LOD by TGA=1.4%). Purity by HPLC 99.9%.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:13]([OH:16])([OH:15])=[O:14])([P:9]([OH:12])([OH:11])=[O:10])[OH:8])[CH:2]=1.[OH-:17].[Na+:18]>O>[CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:9]([O-:12])([OH:11])=[O:10])([P:13]([O-:15])([OH:16])=[O:14])[OH:8])[CH:2]=1.[OH2:17].[OH2:8].[OH2:8].[OH2:8].[Na+:18].[Na+:18]
Reactant: [OH-]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=P([O-])(O)C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 92 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A 0.5 liter reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, was loaded with Zoledronic acid form I (10.0 g) and water (130 ml). The suspension was heated to reflux temperature (92° C.) to obtain a clear solution. A 40% aqueous solution of Sodium hydroxide (6.9 g) was added drop-wise. The solution was then cooled to 25° C. was stirred at this temperature for about 16 hours. The solution was then concentrated to half of its volume to obtain a precipitate. The white precipitate was filtered and dried in a vacuum oven at 50° C. for 18.5 hours to obtain 2.8 g (23%) of Zoledronate disodium crystal form VII (LOD by TGA=10.2%). Purity by HPLC 100.0%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@H:4]([OH:6])[CH3:5].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:7])[C@H:4]([O:6][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1)[CH3:5]
Reactant: COC(=O)[C@@H](C)O
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: COC(=O)[C@@H](C)OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (R)-2-hydroxy-propionic acid methyl ester (10 g) and 3,4-dihydro-2H-pyran (15 mL) in DCM (400 mL) was added camphorsulfonic acid (50 mg) (exothermic reaction). The reaction mixture was stirred at ambient temperature for 2 hours, and washed with saturated bicarbonate solution (20 mL). The organic layer was dried, filtered and concentrated to obtain crude (R)-2-(tetrahydro-pyran-2-yloxy)-propionic acid methyl ester, which was used as is in the next step. To a stirred suspension of LAH (4 g) in anhydrous ether (400 mL) at 0-5° C. was added (R)-2-(tetrahydro-pyran-2-yloxy)-propionic acid methyl ester dropwise over 30 minute period. After completion of the addition, the cold bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was cooled to 0-5° C., and ethyl acetate was added dropwise to quench excess LAH, which was followed by the addition of saturated sodium sulfate solution and solid sodium sulfate. The resulting mixture was stirred at room temperature for 1 hour, the solid was filtered off, and the solid was washed with ether. The combined organic layer was dried over Na2SO4, filtered, concentrated and the residue was purified by column chromatography using a silica gel stationary phase (pre-treated with 0.1 triethylamine in hexanes) and hexanes in ethyl acetate to get (R)-2-(tetrahydro-pyran-2-yloxy)-propan-1-ol. 1H NMR (400 MHz, CDCl3): δ 4.51-4.75 (1H, m) 3.76-4.02 (2H, m) 3.42-3.62 (3H, m) 1.67-1.90 (2H, m) 1.46-1.63 (4 h, m) 1.10-1.24 (3H, m).
Reaction SMILES: CS(C)=O.[OH:5][CH2:6][CH:7]([S:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C@@H:8]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.ClCCl>C(OCC)(=O)C>[CH:6]([CH:7]([S:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C@@H:8]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5]
Reactant: COc1ccc(CSC(CO)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CSC(C=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Reaction time: 0.25 h

Procedure:
A solution of pyridinium-1-sulfonate (789 mg, 3 eq) and anhydrous dimethylsulfoxide (3.0 ml) was stirred at room temperature under argon. After 15 minutes, a solution of (1S)-[3-hydroxy-2-[[(4-methoxyphenyl)methyl]thio]-1(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (690 mg, 1.65 mmol), diisopropylethylamine (1.73 ml, 6 eq) and dry dichloromethane (5.0 ml) was added in one portion. After 15 minutes longer, the reaction was diluted with ethyl acetate and washed with water, 1N hydrochloric acid, 1N sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. Concentration of the filtrate yielded (1S)-[1-[formyl[[(4-methoxyphenyl)methyl]thio]methyl]-2-phenylethyl]carbamic acid, 1,1-dimethylethyl ester as a yellow solid: 610 mg (1.47 mmol); Rf =0.59 (silica gel, benzene:ethyl acetate 4:1).
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.C([Li])CCC.[F:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.Cl>C(OCC)C.CCCCCC.O>[F:15][C:16]1[CH:23]=[CH:22][C:19]([C:20](=[NH:3])[NH2:21])=[CH:18][CH:17]=1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: N=C(N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a solution of hexamethyldisilazane (19.4 g, 120 mmol) in diethyl ether (200 ml) was added dropwise a 1.6 N solution (75.0 ml, 120 mmol) of n-butyllithium in hexane under ice-cooling. Thereto 4-fluorobenzonitrile (7.01 g, 57.9 mmol) was added, followed by stirring at room temperature for 2 hours. Thereto 3 N hydrochloric acid (80 ml) was added dropwise under ice-cooling, and the reaction mixture was stirred under ice-cooling for 0.5 hour. Water (200 ml) was added thereto, and the diethyl ether layer was removed. The aqueous layer was basified with an aqueous 3 N sodium hydroxide solution, and then extracted with chloroform. The extracts were dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 4.90 g (61.3%) of the desired product as a solid.
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]>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: CNCC=C(F)C(F)(F)C(F)(F)F
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
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)-estra-1,3,5(10)-trien-17-one and 1.26 g of (3,4,4,5,5,5-hexafluoro-pent-2-enyl)-methyl-amine are dissolved in 20 ml of N-methylpyrrolidone and stirred for 3 hours at a bath temperature of 80° C. After the reaction solution is cooled to room temperature, the batch is added to saturated common salt solution, extracted with diethyl ether, dried and concentrated by evaporation in a vacuum. 1.86 g of 11β-fluoro-7α-{5-[(3,4,4,5,5,5-hexafluoro-pent-2-enyl)-methyl-amino]-pentyl}-3-hydroxy-estra-1,3,5(10)-trien-17-one is obtained as a crude product, which is used without purification in the next stage.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:2].C(N(CC)CC)C.[I:21]Cl>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[C:10]([I:21])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: ClI
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
To a cooled solution (5° C.) of (4-aminophenyl)acetic acid ethyl ester (25 g, 0.39 mol) in CH2Cl2 (150 mL) is added triethylamine (14.1 g, 0.139 mmol) followed by a solution of iodine monochloride (21.5 g, 0.132 mol) in CH2Cl2 (100 mL). Cooling is removed and the reaction mixture is stirred for 4 hours at room temperature. The solution is concentrated in vacuo and chromatographed with a gradient of hexane/ethyl acetate (5%-30%) within 1 hour to give the desired product (19.5 g, 46%). MS: 305.9 (M+1)+.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][CH:10]3[CH2:18][O:17][CH2:16][CH2:15][N:11]3[CH2:12][C:13]=2[CH:14]=1)([O-])=O.Cl.[H][H]>CO>[ClH:1].[ClH:1].[CH2:18]1[CH:10]2[N:11]([CH2:12][C:13]3[CH:14]=[C:5]([NH2:2])[CH:6]=[CH:7][C:8]=3[CH2:9]2)[CH2:15][CH2:16][O:17]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CN1CCOCC1C2
Reactant: [H][H]
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1)CN1CCOCC1C2
Yield: 235.6 %

Procedure:
To 8-nitro-3,4,5,6,11,11a-hexahydro-1H-[1,4]oxazino[4,3-b]isoquinoline hydrochloride (0.4 g) in methanol (50 ml) was added 6N hydrochloric acid (0.3 ml) and 5% Pd--C (100 mg). The mixture was treated with hydrogen at 50 psi on a Parr Hydrogenator. Hydrogen uptake was complete in 2.0 h. The catalyst was filtered off and the solvent removed under reduced pressure to yield the title product as a solid (0.4824 g).