Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[SH:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([S:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH2:12])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2ccccc2N)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
The title compound was prepared from 1-Chloro-4-methyl-2-nitro-benzene (3.00 g, 17.5 mmol), 2-Amino-benzenethiol (2.41 g, 19.23 mmol), and K2CO3 (4.22 g, 30.6 mmol) heated in DMF at 100° C. for 16 hrs. Reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate. (0.990 g, 21%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH3:30])[C:20]3[C:25]([NH:26][CH:27]([CH3:29])[CH3:28])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.N1C=CC=CC=1.[C:37]1(=[O:53])[N:41]([CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45])[C:40](=[O:48])[C:39]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:38]12>C(Cl)Cl.O>[C:40]1(=[O:48])[N:41]([CH2:42][CH2:43][S:44]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]([CH3:30])[C:20]4[C:25]([NH:26][CH:27]([CH3:28])[CH3:29])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:15][CH2:14]2)=[O:12])=[CH:5]3)(=[O:45])=[O:46])[C:37](=[O:53])[C:38]2=[CH:52][CH:51]=[CH:50][CH:49]=[C:39]12
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: CC(C)Nc1cccnc1N(C)C1CCN(C(=O)c2cc3cc(N)ccc3[nH]2)CC1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)Nc1cccnc1N(C)C1CCN(C(=O)c2cc3cc(NS(=O)(=O)CCN4C(=O)c5ccccc5C4=O)ccc3[nH]2)CC1
Reaction time: 72 h

Procedure:
To a solution of 1-[5-aminoindole-2-carbonyl]-4-[N-methyl-N-(3-(1-methylethylamino)-2-pyridinyl)amino]piperidine (PREPARATION 56, 606 mg) in dry methylene chloride (5 ml) under nitrogen is added pyridine (127 μl, 1.05 equivalents) and 2-phthalimidoethanesulfonyl chloride (400 mg). The mixture is stirred at 20°-25° for 3 days and then diluted with methylene chloride (40 ml) and water (20 ml). The layers are separated and the organic phase is washed with saline (15 ml), dried over sodium sulfate, and concentrated under reduced pressure to give a residue which is then chromatographed on silica gel (230-400 mesh, 85g, 8 psi), eluting with a gradient of methanol/chloroform (1/99-2.5/97.5). The appropriate fractions (Rf =0.33, TLC, methanol/chloroform, 5/95) are pooled and concentrated to give the title compound, NMR (CDCl3) 10.33, 7.80, 7.76-7.63, 7.35, 7.22, 6.95, 6.85, 6.69, 4.65, 4.51, 4.13, 3.60-3.40, 3.40-2.90, 2.64, 1.94, 1.65 and 1.22 δ.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[F:27][C:28]([F:35])([F:34])[CH2:29][CH2:30][C:31]([OH:33])=[O:32].Br[CH2:37][S:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1.C(O)(=O)C.C(OCC)(=O)C>[C:40]1([CH2:39][S:38][CH2:37][CH:30]([CH2:29][C:28]([F:35])([F:34])[F:27])[C:31]([OH:33])=[O:32])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)CCC(F)(F)F
Reactant: BrCSCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)C(CSCc1ccccc1)CC(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of lithium diisopropylamide [prepared using freshly distilled diisopropylamine (4.47 g., 44.4 mmol) and n-butyl lithium/hexane (18 mL, 45 mmol, 2.5M)] in dry tetrahydrofuran (35 mL) was added a solution of 4,4,4-trifluorobutyric acid (3.0 g., 21.0 mmol) in tetrahydrofuran (25 mL). After stirring at 0° C. for 1.5 hours, the solution was cooled to -78° C. and treated with a solution of benzyl bromomethyl thioether in tetrahydrofuran (10 mL). The solution was allowed to stir overnight as the temperature rose to ambient. Volatiles were removed in vacuo and the residue was dissolved in ethyl acetate and extracted with 1N sodium hydroxide (50 mL) and water (2×20 mL). The combined basic extracts were acidified with concentrated hydrochloric acid (8 mL) and extracted with ethyl acetate (2×100 mL). The organic extracts were washed with water and brine, combined, dried (MgSO4), and concentrated in vacuo to give 3.82 g. of an oil. Flash chromatography on 350 mL of silica gel and elution with ethyl acetate:hexanes:acetic acid, 50:100:1 gave 1.36 g. of the title A product, TLC Rf =0.38 (ethyl acetate:hexanes:acetic acid, 50:50:1).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:16]3=[C:17]4[C:3]=1[C:4]([S:26]([O-:29])(=[O:28])=[O:27])=[C:5]([S:22]([O-:25])(=[O:24])=[O:23])[C:6]([S:18]([O-:21])(=[O:20])=[O:19])=[C:7]4[CH:8]=[CH:9][C:10]3=[CH:11][CH:12]=[CH:13]2.[Na+:30].[Na+].[Na+].[C:33](OC(=O)C)(=[O:35])[CH3:34].C([O-])(=O)C.[Na+]>CN(C)C=O>[Na+:30].[Na+:30].[Na+:30].[C:33]([O:1][C:2]1[CH:15]=[C:14]2[C:16]3=[C:17]4[C:3]=1[C:4]([S:26]([O-:29])(=[O:28])=[O:27])=[C:5]([S:22]([O-:25])(=[O:23])=[O:24])[C:6]([S:18]([O-:21])(=[O:20])=[O:19])=[C:7]4[CH:8]=[CH:9][C:10]3=[CH:11][CH:12]=[CH:13]2)(=[O:35])[CH3:34]
Reactant: O=S(=O)([O-])c1c(S(=O)(=O)[O-])c2ccc3cccc4cc(O)c(c1S(=O)(=O)[O-])c2c34
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2cccc3ccc4c(S(=O)(=O)[O-])c(S(=O)(=O)[O-])c(S(=O)(=O)[O-])c1c4c32

Procedure:
10 grams of trisodium hydroxypyrenetrisulfonate, 50 mls of acetic anhydride and 1.6 grams of sodium acetate are added to 200 mls of dimethylformamide in a 500 ml flask. The flask is equipped with a condenser having a drying tube and a stirring bar. The contents of the flask are stirred at 50° to 70° C. for one to two hours. The reaction mixture is filtered and the filtrate collected. The filtrate is vacuum evaporated to yield a crude solid product. This crude solid product is extracted into boiling methanol. The volume of the methanol is reduced to 100 mls and cooled. The first batch of product crystallizes out and is filtered. The methanol is again reduced to approximately 20 mls to yield a second crop of product. This is filtered and combined with the first batch and dried for twenty to forty minutes at 60° C.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:21]=[CH:20][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][CH3:19])=[CH:13][CH:12]=2)=O)=[CH:7][CH:6]=1.O.[NH2:23][NH2:24]>C(O)(=O)C>[Cl:4][C:5]1[CH:21]=[CH:20][C:8]([C:9](=[N:23][NH2:24])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][CH3:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: NN
Reactant: CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CSCc1ccc(C(=NN)c2ccc(Cl)cc2)cc1

Procedure:
An ethanol solution (50 ml) of 4-chloro-4'-methylmercaptomethylbenzophenone (9.3 g), hydrazine hydrate (6 ml) and acetic acid (3 ml) was heated for 20 hours with refluxing. The solvent was distilled off under reduced pressure, and then the obtained oily substance was diluted with dichloromethane and washed successively with an aqueous 5% sodium hydroxide solution, water and an aqueous saturated a sodium chloride solution, followed by drying over anhydrous magnesium sulfate. The solvent was then distilled off to obtain 4-chloro-4'-methylmercaptomethylbenzophenone hydrazone (7.1 g) as an isomer mixture (syn form/anti form=about 1:1).
Reaction SMILES: [N:1]([CH2:4][C:5]([CH2:24][O:25][C:26]([C:35]([F:38])([F:37])[F:36])([C:31]([F:34])([F:33])[F:32])[C:27]([F:30])([F:29])[F:28])([CH2:9][O:10][C:11]([C:20]([F:23])([F:22])[F:21])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[C:6]([OH:8])=[O:7])=[N+]=[N-]>[Pd].CO>[NH2:1][CH2:4][C:5]([CH2:9][O:10][C:11]([C:12]([F:13])([F:14])[F:15])([C:20]([F:21])([F:22])[F:23])[C:16]([F:17])([F:18])[F:19])([CH2:24][O:25][C:26]([C:27]([F:29])([F:28])[F:30])([C:31]([F:34])([F:33])[F:32])[C:35]([F:38])([F:37])[F:36])[C:6]([OH:8])=[O:7]
Reactant: [N-]=[N+]=NCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)C(=O)O
Agent: [Pd]
Solvent: CO
Product: NCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)C(=O)O
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A mixture of Palladium on carbon (2.5 g) in methanol (200 mL) was degassed for 2 minutes and stirred under a hydrogen atmosphere for 30 minutes. A solution of acid 12 (10.7 g, 17.5 mmol) in methanol (10 mL) was then added and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for additional 30 hours. After removal solvent, the resulting residue was purified by flash column chromatography on silica gel (methanol/dichloromethane=10/1) to give the amino acid 1 as a solid (10.1 g, 98%). mp. 182-184° C.; 1H NMR (400 MHz, CD3OD) δ 2.99 (s, 2H), 4.22 (d, J=9.2 Hz, 2H), 4.49 (d, J=8.4 Hz, 2H); 19F NMR (376 MHz, CD3OD) δ −71.00 (s); 13C NMR (100.7 MHz, CD3OD) δ 41.7, 52.1, 69.9, 80.9 (m), 121.7 (q, J=292.6 Hz), 175.0; MS (CI) m/z 586 (M++1, 100); HRMS (CI) Calcd for C13H10F18NO4: 586.0322, Found: 586.0285.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9](O)[CH2:10][CH3:11])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.P(Br)(Br)([Br:24])=O>C(OCC)(=O)C>[Br:24][CH:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)[CH2:10][CH3:11]
Reactant: O=P(Br)(Br)Br
Reactant: CCC(O)c1cnc(Cl)nc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(Br)c1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of (±)-1-(2,4-dichloro-pyrimidin-5-yl)-propan-1-ol (0.26 g; 1.26 mmol) (from Example 7a supra) in diisopropylethylamine (0.55 mL; 3.13 mmol) (Aldrich) was cooled slightly (18° C.) to help offset the exothermicity of the reaction. Neat phosphorus oxybromide (0.35 g; 1.36 mmol) (Aldrich) was added in one portion. The cooling bath was removed and reaction mixture stirred at room temperature. After 15 minutes, the reaction mixture was diluted with ice and ethyl acetate. The organic phase was then washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage 12M; 5:95 ethyl acetate-hexanes) gave crude (±)-5-(1-bromopropyl)-2,4-dichloro-pyrimidine which was used in subsequent steps without further purification. (Yield 0.23 g). The material showed 3 peaks for the pyrimidine ring proton in its NMR spectrum indicating some displacement of the ring chlorines with bromine.
Reaction SMILES: [CH3:1][C:2]([S:9][CH3:10])([CH3:8])[C:3]([O:5]CC)=O.[C:11](#[N:13])[CH3:12]>>[CH3:8][C:2]([S:9][CH3:10])([CH3:1])[C:3](=[O:5])[CH2:12][C:11]#[N:13]
Reactant: CC#N
Reactant: CCOC(=O)C(C)(C)SC
Product: CSC(C)(C)C(=O)CC#N
Yield: 81 %

Procedure:
The title compound was prepared from ethyl 2-methyl-2-(methylthio)propionate and acetonitrile, using a method similar to that of preparation 2, as a colourless oil in 81% yield.
Reaction SMILES: C(N(CC)CC)C.[C:8]([Cl:11])(Cl)=[O:9].[S:12]([N:16]1[CH2:20][CH2:19][NH:18][C:17]1=[O:21])(=[O:15])(=[O:14])[NH2:13]>ClCCl>[Cl:11][C:8]([N:18]1[CH2:19][CH2:20][N:16]([S:12](=[O:15])(=[O:14])[NH2:13])[C:17]1=[O:21])=[O:9]
Reactant: O=C(Cl)Cl
Reactant: NS(=O)(=O)N1CCNC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Reaction time: 17 h

Procedure:
A solution of 17.8 parts by vol. of triethylamine in 30 parts by vol. of dichloromethane was added dropwise over the course of 2 hrs. to a mixture of 100 parts by vol. of dichloromethane, 6.15 parts by vol. of (condensed) phosgene and 7.0 parts by wt. of 1-sulphamyl-2-oxo-imidazolidine at 20° C and the mixture was then left to stand for 17 hrs. The precipitate present was removed by filtration, the filtrate was concentrated by evaporation in vacuo and the residue was repeatedly extracted with ethyl acetate at 20° C. The ethyl acetate extracts were combined. On evaporation, they left a hard varnish. The IR spectrum showed a strong acid chloride band at 1,805 cm-1 (Nujol). Furthermore, it could be seen from the IR spectrum that the substance still contained considerable amounts of the starting product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([C:21]([N:23]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@H:24]2[CH2:29][C@@H:28]([C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:31])[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]2)=[O:22])[N:10]=[N:9]1>C(OCC)(=O)C.Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:11]([C:21]([N:23]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@H:24]2[CH2:29][C@@H:28]([C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:31])[CH2:27][NH:26][CH2:25]2)=[O:22])[N:10]=[N:9]1
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1COc1ccccc1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1COc1ccccc1)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 86.1 %

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(2-fluorophenyl)-5-(phenoxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (119 mg) was dissolved in 1M hydrogen chloride-ethyl acetate (4 ml), and the mixture was stirred at room temperature for 13 hr and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed successively with 3.5M aqueous potassium carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane-methanol (10:90:0-100:0:0-85:0:15) was concentrated under reduced pressure. The residue was dissolved in methanol (2 ml), fumaric acid (7.9 mg) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to give the object product (87 mg).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:18](O)=[O:19]>>[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][CH:18]=[O:19])=[CH:5][CH:4]=1
Reactant: O=CO
Reactant: NCc1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=CNCc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
Into a mixture of 9.87 g of 4-bromobenzylamine hydrochloride and 5.04 g of triethylamine, 20 mL of a formic acid solution was dropped and the resultant reaction mixture was stirred at 80° C. for 3.5 hours. After the completion of the reaction, the reaction mixture was charged into 100 mL of ice water and the resultant reaction mixture was extracted with ethyl acetate (30 mL×2). The organic phase was dehydrated and dried over a saturated brine and anhydrous sodium sulfate in this order and the solvent was distilled off under reduced pressure. The residual solid was washed with hexane to obtain 9.29 g of the objective substance as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:12](=[O:20])[C:13]([C:15]([O:17][CH2:18]C)=[O:16])=[CH:14][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][NH:6]3.S(OC)(O[CH3:25])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:12](=[O:20])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:25]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cn2c3c(c(Cl)ccc3c1=O)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cn2c3c(c(Cl)ccc3c1=O)CCN2C
Temperature: 120 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
To 810 mg (2.8 mmol) of the compound (144) obtained in Example 29, 5 ml (55 mmol) of dimethyl sulfate was added, and the solution was heated for at 120° C. for 5.5 hours. After air-cooling, to 45 ml of ice/water containing 7.5 g (55 mmol) of anhydrous potassium carbonate, was added the solution, and was stirred for 1 hour. The solution was extracted with 50 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by the column chromatography (silica gel 8 g, eluent solvent; chloroform:methanol=100:1) to obtain 371 mg of the subject compound (145) in a 46% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O-])(O)=O.[Na+]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCc1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 314 %

Procedure:
A stirred solution of 1H-indole-5-carbonitrile (4.0 g, 28.1 mmol) in THF (50 ml) at 0° C. was treated dropwise with lithium aluminum hydride in THF (1M, 98 ml, 98 mmol). The resultant mixture was stirred, warming to room temperature overnight. Sat. aq. NaHCO3 (60 ml) was added at 0° C. and resultant mixture was filtered through filter agent celite 521 and washed with THF. Evaporation of the solvent gave the crude product which was purified by chromatography (SiO2, gradient elution with 95:5 CH2Cl2:MeOH; 90:10 CH2Cl2:MeOH; 90:10:1 CH2Cl2:MeOH:NH3) to give the desired product (white powder, 12.9 g, 71%). 1H NMR (CD3OD) δ 4.10 (s, 2H), 6.50 (d, 1H), 7.15 (d, 1H), 7.30 (d, 1H), 7.40 (d, 1H), 7.60 (s, 1H). LRMS m/z=147.2 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH4+:20].[OH-]>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:20])=[O:5]
Reactant: [NH4+]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1cccc([N+](=O)[O-])c1Cl

Procedure:
DMF (3 drops) was added to a mixture of 2-chloro-3-nitrobezoic acid (0.99 g, 4.9 mmol), oxalyl chloride (0.47 mL, 5.4 mmol) in CH2Cl2 (20 mL) at 25° C. stirring under N2. After gas formation ceased, all the solid went into solution. After 3 hours the solvent was removed under reduced pressure to leave a light yellow solid which was treated with cold NH4OH (20 mL). 2-Chloro-3-nitrobenzamide was collected as an off-white solid (1.02 g, 100%).
Reaction SMILES: [Si:1]([Cl:5])(Cl)([Cl:3])[Cl:2].[CH3:6][Si:7]([CH3:14])([CH3:13])[NH:8][Si](C)(C)C>>[Cl:2][Si:1]([Cl:5])([Cl:3])[NH:8][Si:7]([CH3:14])([CH3:13])[CH3:6]
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)N[Si](Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
70 g of silicon tetrachloride (0.41 mol) and 12.5 g of hexamethyldisilazane (0.08 mol) were brought together in a 250 ml three-necked flask and stirred at room temperature for 20 hours. Subsequent fractional distillation in a short Vigreux column yielded 16.2 g (92%) of 1,1,1-trichloro-3,3,3-trimethyldisilazane as a colourless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][N:6]=[C:7]([CH3:9])[CH3:8])=[O:4].C(N(CC)CC)C.CC(C)=O.[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>O.C1C=CC=CC=1>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]=[C:7]([CH3:9])[CH3:8])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COC(=O)NN=C(C)C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)N(N=C(C)C)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
6.5 g of 1-methoxycarbonyl-2-isopropylidene hydrazine (prepared from methoxycarbonyl hydrazine and acetone), 5.3 g of triethylamine and 100 ml of acetone were placed in a 200 ml round-bottom flask, and while stirring with ice-water cooling, 11.0 g of p-bromobenzoyl chloride was added dropwise. Thereafter, the resulting mixture was stirred at room temperature for one hour to complete the reaction. The reaction mixture was added with 50 ml each of benzene and water. The separated organic layer was taken out by fractionation, dried with anhydrous sodium carbonate and then distilled to remove the solvent. The white crystalline mass thus obtained was recrystallized from a mixed solvent of hexane/acetone to yield 13.6 g (87%) of 1-p-bromobenzoyl-1-methoxycarbonyl-2-isopropylidene hydrazine as white crystals having a melting point of 103°-104° C.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[C:12]([N:15]1[CH2:19][CH2:18][N:17]([CH2:20][C@@H:21]2[CH2:25][C@@H:24]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][N:22]2[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:32])[C:16]1=[O:44])(=O)[CH3:13].CO>O1CCCC1>[CH2:12]([N:15]1[CH2:19][CH2:18][N:17]([CH2:20][C@@H:21]2[CH2:25][C@@H:24]([O:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH2:23][N:22]2[C:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=2)=[O:32])[C:16]1=[O:44])[CH3:13]
Reactant: CC(=O)N1CCN(C[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CCN1CCN(C[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
To a suspension of sodium borohydride (0.16 g) in tetrahydrofuran (11 ml) was dropwise added boron trifluoride etherate (2.83 ml) under ice-cooling and the mixture was stirred at the same temperature for 15 minutes. To this solution was added a solution of (2S,4R)-2-(3-acetyl-2-oxoimidazolidin-1-yl)methyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.12 g) in tetrahydrofuran (2.83 ml) under ice-cooling and the mixture was stirred at ambient temperature overnight. To the reaction mixture was added dropwise methanol (30 ml) and the mixture was filtrated. The filtrate was evaporated in vacuo. The resulting residue was dissolved in methanol (30 ml) and conc. hydrochloric acid (0.5 ml) and the solution was allowed to stand at ambient temperature overnight. The reaction mixture was evaporated in vacuo and dissolved in ethyl acetate (50 ml). The solution was washed successively with saturated aqueous sodium hydrogen carbonate and aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-2-(3-ethyl-2-oxoimidazolidin-1-yl)methyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.04 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C:12](=[O:27])[CH2:11][CH2:10]1.[I-].[Li+].[F:30][C:31]([F:46])([C:42]([F:45])([F:44])[F:43])[CH2:32][CH2:33][CH2:34][S:35][CH2:36][C@@H:37]1[CH2:41][CH2:40][CH2:39][NH:38]1>CN1CCCC1=O>[F:26][C@H:16]1[CH2:15][C@@:13]2([CH3:14])[C@@H:9]([CH2:10][CH2:11][C:12]2=[O:27])[C@H:8]2[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:25])=[CH:22][C:23]=1[CH2:24][C@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:38]1[CH2:39][CH2:40][CH2:41][CH:37]1[CH2:36][S:35][CH2:34][CH2:33][CH2:32][C:31]([F:46])([F:30])[C:42]([F:43])([F:44])[F:45]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1CCC2=O
Reactant: FC(F)(F)C(F)(F)CCCSC[C@@H]1CCCN1
Agent: [I-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCCC4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CCC2=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 44.2 %

Procedure:
A solution of 785.9 mg of 7α-(5-chloropentyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one in 7 ml of N-methyl-2-pyrrolidinone is mixed with 535.5 mg of lithium iodide and 520 mg of (2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidine, and it is stirred for 2.5 hours at a bath temperature of 100° C. Then, it is poured onto water, extracted 3 times with diethyl ether, washed neutral, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 525 mg of pure 11β-fluoro-3-hydroxy-7α-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-17-one is obtained. [α]D22 =+29.3° (c=0.5% in chloroform).