Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[F:5][C:6]([F:20])([C:16]([F:19])([F:18])[F:17])[CH2:7][O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.BrBr.N>C(O)(=O)C.O>[F:5][C:6]([F:20])([C:16]([F:17])([F:18])[F:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]=[C:2]([NH2:3])[S:1][C:14]=2[CH:15]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(OCC(F)(F)C(F)(F)F)cc1
Agent: BrBr
Agent: N
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc2ccc(OCC(F)(F)C(F)(F)F)cc2s1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
Potassium thiocyanate (4.27 g) is added to a solution of 4-(2,2,3,3,3-pentafluoropropoxy)aniline (2.65 g) in acetic acid (25 cc), and the mixture is stirred for 10 minutes at a temperature in the region of 20° C. To the solution thereby obtained, a solution of bromine (0.56 cc) in acetic acid (5 cc) is introduced dropwise in the course of 35 minutes at a temperature of between 22° C. and 35° C., and the mixture is then stirred for 16 hours at a temperature in the region of 20° C. The reaction mixture is poured into a mixture of water and ice (150 cc), alkalinized with 28% strength ammonia solution (35 cc) and extracted 3 times with ethyl acetate (170 cc in total). After settling has taken place, the organic solution is separated and washed with distilled water to pH 8, dried over magnesium sulphate, filtered and evaporated at 50° C. under reduced pressure (20 mm Hg; 2.7 kPa). The product obtained (3.2 g) is purified by chromatography on a column of silica (250 g; particle size: 0.063-0.200 mm) with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluant, and recrystallized in toluene (15 cc). 6-(2,2,3,3,3-Pentafluoropropoxy)-2-benzothiazolamine (1.27 g), m.p. 147° C., is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[CH:18][O:17][N:16]=3)[N:4]2[N:3]=1.[CH2:20]([N:23]1[C:27]([CH2:28][OH:29])=[N:26][CH:25]=[N:24]1)[CH2:21][CH3:22]>>[O:17]1[CH:18]=[CH:19][C:15]([C:14]2[N:4]3[N:3]=[C:2]([O:29][CH2:28][C:27]4[N:23]([CH2:20][CH2:21][CH3:22])[N:24]=[CH:25][N:26]=4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:16]1
Reactant: Clc1nn2c(-c3ccon3)nnc2c2ccccc12
Reactant: CCCn1ncnc1CO
Product: CCCn1ncnc1COc1nn2c(-c3ccon3)nnc2c2ccccc12

Procedure:
The title-compound was prepared from 6-chloro-3-(isoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine (described in Example 34 part b) and 2-propyl-3-hydroxymethyl-1,2,4-triazole prepared as described in WO-A-9804559 using the procedure given for Example 71, 1H NMR (360 MHz, CDCl3) δ 0.95 (3H, t, J=7.4 Hz, Ar—H), 1.91-2.01 (2H, m, CH2), 4.34 (2H, t, J=7.0 Hz, CH2), 5.85 (2H, s, CH2), 7.28 (1H, d, J=1.7 Hz, Ar—H), 7.83 (1H, t, J=8.3 Hz, Ar—H), 7.96-8.01 (2H, m, 2 of Ar—H), 8.21 (1H, d, J=7.9 Hz, Ar—H), 8.62 (1H, s, Ar—H), 8.70 (1H, d, J=7.1 Hz, Ar—H); MS (ES30) m/e 377 [MH]+; Anal. Found. C, 57.12; H, 3.87; N, 29.49. C18H16N8O2.0.05CH2Cl2 requires C, 56.96; H, 4.26; N. 29.44%.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([Br:29])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)C.[OH-].[Na+]>O1CCCC1>[Br:29][C:21]1[CH:20]=[C:19]([S:16]([NH:15][C@@H:10]2[CH2:11][CH2:12][CH2:13][C:14]3[N:6]([CH2:5][C:4]([OH:30])=[O:3])[N:7]=[CH:8][C:9]2=3)(=[O:18])=[O:17])[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=1
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of [(R)-4-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (18.0 mg, 0.035 mmol) in tetrahydrofuran (2 mL) was added an aqueous solution of sodium hydroxide (1 N, 2 mL). The resulting mixture was stirred at room temperature for 2 hours, then extracted with diethyl ether (6 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and then stirred with diethyl ether (2 mL) and petroleum ether (6 mL) at room temperature for 2 hours. The resulting mixture was filtered to afford [(R)-4-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid (13.3 mg, 78.8%) as a white powder. 1H NMR (400 MHz, CD3OD) δ ppm 8.34 (s, 1 H), 8.20 (s, 2 H), 6.81 (s, 1 H), 4.80 (s, 2 H), 4.48 (t, 1 H), 2.50 (m, 2 H), 2.00-1.72 (m, 4 H). MS calcd. for C16H15BrF3N3O4S 481, obsd. (ESI+) [(M+H)+] 482.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1.[H-].[Na+].[CH2:11](I)[CH2:12][CH3:13]>C1COCC1.CN(C=O)C>[CH3:1][C:2]1[N:3]([CH2:11][CH2:12][CH3:13])[CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1
Reactant: CCCI
Reactant: Cc1nc(C=O)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCn1cc(C=O)nc1C
Reaction time: 0.08 h

Procedure:
2-Methyl-1H-imidazole-4-carbaldehyde (940 mg, 8.5 mmol) was dissolved in THF (40 ml) with DMF (5 ml). NaH (380 mg of a 60% dispersion in mineral oil) was added carefully and the reaction mixture was allowed to stir 5 minutes under nitrogen. Propyl iodide (1.65 g, 9.7 mmol) was added and it was allowed to stir for 1 h, at which time the reaction was judged complete. The solvent was removed under vacuum, and the crude was purified on silica eluted with 100% ethyl acetate −1% MeOH/ethyl acetate to yield the title product as the main isomer (390 mg (30%), 2.6 mmol). 1H NMR (DMSO-d6): δ=9.68 (s, 1H), 8.02 (s, 1H), 3.97 (t, J=7.3 Hz, 2H), 2.31 (s, 3H), 1.71 (sextet, J=7.3 Hz, 2H), 0.85 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31].P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]3[O:16][C:15](=[O:17])[N:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Reactant: OCCOCCCCCCBr
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc(C3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (1.067 g) in DMF (10 ml) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 222 mg) and the mixture was stirred at 20° for 15 min. A solution of 2-[(6-bromohexyl)oxy]ethanol (1.157 g) in DMF (1 ml) was added and the mixture was stirred at 20° for 3.5 h. Phosphate buffer solution (pH 6.5, 20 ml) and water (30 ml) were added. The mixture was extracted with EtOAc (2×20 ml) and the combined extracts were washed with water (30 ml) and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified by flash chromatography on silica gel. Elution with MeOH-EtOAc (1:9) gave the title compound (1.42 g). LCMS RT=2.90 min, ES+ve 394 (MH)+.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH2:11][C:12]([F:16])([F:15])[CH2:13][CH3:14])[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4].O.[OH-].[Li+]>C1COCC1.O>[C:20]([O:19][C:17]([N:6]1[CH2:7][CH:8]([CH2:10][CH2:11][C:12]([F:15])([F:16])[CH2:13][CH3:14])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: CCC(F)(F)CCC1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(F)(F)CCC1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a solution of 4-(3,3-difluoro-pentyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (106 mg, 0.26 mmol, 1 equiv) in THF (2.4 mL) and water (0.8 mL) was added lithium hydroxide monohydrate (54 mg, 1.29 mmol, 5 equiv). The reaction mixture was stirred at rt overnight. THF was removed under vacuum. The residue was diluted with water (10 mL), washed with ether (20 mL). The aqueous layer was taken up in ethyl acetate (50 mL), partitioned with 10% citric acid (25 mL). The organic layer was washed with water (1×), brine (1×), dried and concentrated to give 4-(3,3-difluoro-pentyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester as a clear oil (82.1 mg, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])=[CH:15][CH:14]=1)=[CH:9][C:8]([Cl:24])=[CH:7][CH:6]=2.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:24][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[NH:1][C:33](=[O:35])[N:12]([C:13]4[CH:14]=[CH:15][C:16]([C:19]([CH3:22])([CH3:23])[C:20]#[N:21])=[CH:17][CH:18]=4)[C:11]=3[C:10]=2[CH:9]=1
Reactant: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Cl)cc23)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Cl)cc4c32)cc1
Reaction time: 0.33 h

Procedure:
A solution of 2-(4-(3-amino-6-Chloroquinolin-4-ylamino)phenyl)-2-methylpropanenitrile (Compound of Preparation G, 3.3 g, 9.8214 mmol) and triethylamine (1.34 g, 12.74 mmol) in CH2Cl2 (120 mL) was added over 40 min to a solution of triphosgene (3.5 g, 11.7852 mmol) in 80 mL of CH2Cl2 at 0° C. with an ice-bath. The reaction mixture was stirred for 20 min at this temperature then quenched with saturated aqueous NaHCO3, stirred for 5 min and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to obtain the title compound. Yield: 1.2 g (34%); 1H NMR (DMSO-d6, 300 MHz): δ 12.190 (s, 1H), 8.921 (s, 1H), 8.069-8.100 (d, 1H, J=8.7 Hz), 7.807-7.835 (d, 2H, J=8.4 Hz), 7.641-7.694 (m, 3H), 6.808-6.815 (d, 1H, J=2.1 Hz), 1.766 (s, 6H); MS: m/z 363 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=[O:5].C(N(CC)C(C)C)(C)C.[CH3:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C(Cl)Cl>[CH:17]1[C:8]2[CH2:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH2:12][N:6]([C:4]([C:3]3[CH:21]=[CH:22][C:23]([NH:25][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=4[CH3:35])=[CH:24][C:2]=3[Cl:1])=[O:5])[C:7]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.9 %

Procedure:
A mixture of 0.31 g of 5-(2-chloro-4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine and 0.15 g of N,N-diisopropylethylamine in 10 ml of methylene chloride is cooled in an ice bath while 0.18 g of 2-methylbenzoyl chloride is added. The bath is removed and the reactants stirred at room temperature for 18 hours. The mixture is washed with water, 1N HCl, water, 1M NaHCO3, brine and dried (Na2SO4). The methylene chloride is removed in vacuo to give 0.34 g of the desired product as crystalline solid, m.p. 138°-150° C. M+ =467.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[C:6]([O:10][C:11]1[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=1)([CH3:9])([CH3:8])[CH3:7]>CO>[C:6]([O:10][C:11]1[N:12]=[N:13][C:14]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:15][CH:16]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: C=CCS
Reactant: CC(C)(C)Oc1ccc(Cl)nn1
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(OC(C)(C)C)nn1

Procedure:
0.46 g(0.02 mol) of metallic sodium was dissolved in 30 ml of absolute methanol and then mixed with 1.99 ml(0.02 mol) of allylmercaptan. To this mixture was added 3.75 g(0.02 mol) of 3-(t-butoxy)-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a pale yellow oil.
Reaction SMILES: CN([CH:4]=[O:5])C.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:18][C:19]1[C:20]([Cl:46])=[N:21][C:22]2[C:27]([C:28]=1[NH:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:43]=[CH:44][CH:45]=1)[CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:26][CH:25]=[CH:24][CH:23]=2>N1C=CC=CC=1>[Cl:46][C:20]1[C:19]2[N:18]=[C:4]([OH:5])[N:29]([CH2:30][C:31]3[CH:32]=[C:33]([CH:43]=[CH:44][CH:45]=3)[CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:41])[CH3:39])[C:28]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNc2c(N)c(Cl)nc3ccccc23)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCc1cccc(Cn2c(O)nc3c(Cl)nc4ccccc4c32)c1
Temperature: 80 °C

Procedure:
DMF (150 mL), pyridine (10 mL), and 1,1′-carbonyldiimidazole (16.7 g, 103 mmol) were added to tert-butyl 3-{[(3-amino-2-chloroquinolin-4-yl)amino]methyl}benzylcarbamate (17.03 g, 41.24 mmol), and the reaction was heated at 80° C. overnight and allowed to cool. The volatiles were removed under reduced pressure. The residue was mixed with ethyl acetate, collected by filtration, and dried under vacuum for two hours to provide 12.06 g of tert-butyl 3-[(4-chloro-2-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl]benzylcarbamate as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([OH:8])[C@H:6]([OH:9])[C@@H:5]([CH2:10][OH:11])[O:4][C@H:3]1[N:12]1[CH:20]=[N:19][C:18]2[C:17](=[O:21])[NH:16][C:15]([NH2:22])=[N:14][C:13]1=2.O.[CH:24]1[C:36]2[CH:35]([CH2:37][O:38][C:39](ON3C(=O)CCC3=O)=[O:40])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH:24]1[C:36]2[CH:35]([CH2:37][O:38][C:39]([NH:1][C@@H:2]3[C@@H:7]([OH:8])[C@H:6]([OH:9])[C@@H:5]([CH2:10][OH:11])[O:4][C@H:3]3[N:12]3[CH:20]=[N:19][C:18]4[C:17](=[O:21])[NH:16][C:15]([NH2:22])=[N:14][C:13]3=4)=[O:40])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2NC(=O)OCC2c3ccccc3-c3ccccc32)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.5 %

Procedure:
To 3.31 g (10.61 mmol) of 9-(2-amino-2-deoxy-β-D-glucopyranosyl) guanine was added 72 mL of H2O. To this solution was added a 100 mL 1,4-dioxane solution containing 4.65 g (13.79 mmol) of N-(9-fluorenyl-methoxycarbonyloxy)succinimide. This resulted in a cloudy mixture. To this system was added 0.58 g (6.90 mmol) of NaHCO3. This mixture was stirred for 12 hours at room temperature. At this time, TLC indicated the consumption of starting material and the mixture was concentrated in vacuo to a dry residue. This residue was stirred for 3 hours in 310 mL of Et2O and 145 ml of H2O. The suspension was then filtered and the solid dried in a vacuum oven for 12 hours at 40° C. Thus was obtained 4.28 g (76%) of 9-(2-deoxy-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-β-D-glucopyranosyl)guanine. 1H NMR: (DMSO-δ6): guanine H-8 7.72 (s, 1H), anomeric H-1 5.37 (d, 1H), Fmoc-methine 4.05 (m, 1H). FAB-MS: m/z 535 for (M+1)+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:15]=1[NH:16][C:17]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:18]=1[C:19]([OH:21])=O.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>C1COCC1>[CH2:34]([O:41][NH:42][C:19](=[O:21])[C:18]1[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:17]=1[NH:16][C:15]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:14]=1[F:13])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
Carbonyldiimidazole (3.1 g, 19.1 mmol) was added to a suspension of 2-(2,4-difluoroanilino)-4,5-difluorobenzoic acid (Example H-4, 4.54 g, 15.9 mmol) in 120 mL of THF, and the mixture was stirred for 24 hours at 25° C. O-Benzylhydroxylamine hydrochloride (2.54 g, 15.9 mmol) and triethylamine (2.66 mL, 19.1 mmol) were added, and the mixture was heated to reflux for 4 hours. The reaction mixture was concentrated and washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 5.66 g of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([Br:10])=[CH:4][N:3]=1.[CH2:11]([O:18][C:19]([NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[C:27]2[S:32](Cl)(=[O:34])=[O:33])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[CH2:11]([O:18][C:19]([NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[C:27]2[S:32]([NH:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([Br:10])=[CH:4][N:3]=1)(=[O:34])=[O:33])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Nc1cccc2c(S(=O)(=O)Cl)cccc12)OCc1ccccc1
Reactant: COc1nc(Br)cnc1N
Solvent: CO
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(NC(=O)OCc3ccccc3)cccc12

Procedure:
The starting material 5-(N-benzyloxycarbonylamino)-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide was prepared using an analogous procedure to that described in Example 36, starting from proportionate amounts of 2-amino-5-bromo-3-methoxypyrazine and 5-(N-benzyloxycarbonylamino)-1-naphthalenesulphonyl chloride (obtained as described in Synlett., 1992, 661), in a yield of (11%; m.p. 226-228° C.; mass spectrum (+ve FAB, methanol/NBA): 543 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][OH:16])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[N:4]1.Br[C:20]1[S:21][CH:22]=[CH:23][N:24]=1>CN(C)C=O.CS(C)=O>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[O:16][CH2:15][CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)=[CH:18][CH:17]=1
Reactant: OCCOc1ccc(Cn2cccn2)cc1
Reactant: Brc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: c1cnn(Cc2ccc(OCCOc3nccs3)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
To a mixture of 10 ml of anhydrous N,N-dimethylformamide and 110 mg of sodium hydride (60% oil dispersion) was added dropwise an anhydrous dimethylsulfoxide (5 ml) solution of 500 mg of 2-[4-(1-pyrazolyl)methylphenoxy]ethanol (produced in Reference Production Example 1 described below) under stirring over 10 minutes. After stirring at 60° to 70° C. for 2 hours, the mixture was cooled to 5° to 10° C., to which an anhydrous N,N-dimethylformamide (5 ml) solution of 488 mg of 2-bromothiazole was added dropwise over 10 minutes. The mixture was then stirred at room temperature over-night and then at 60° to 70° C. for further 2 hours. The reaction mixture was poured into 50 ml of ice water, which was extracted with twice with 30 ml of toluene. The organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 280 mg of 4-(1-pyrazolyl)methylphenyl 2-(2-thiazolyl-oxy)ethyl ether (compound 5). Yield, 41%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.[K+].[C:18]([C:20]1[N:21]=[C:22]([C:33]([O-])=[O:34])[N:23](COCC[Si](C)(C)C)[CH:24]=1)#[N:19]>>[C:11]1([C:3]2[CH:4]=[C:5]([CH2:8][CH2:9][OH:10])[CH:6]=[CH:7][C:2]=2[NH:1][C:33]([C:22]2[NH:21][C:20]([C:18]#[N:19])=[CH:24][N:23]=2)=[O:34])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: Nc1ccc(CCO)cc1C1=CCCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: N#Cc1cnc(C(=O)Nc2ccc(CCO)cc2C2=CCCCC2)[nH]1

Procedure:
The title compound was prepared by coupling 2-(4-amino-3-cyclohex-1-enyl-phenyl)-ethanol (prepared in the previous step) and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (prepared in Example 11, step (d)) according to the procedure in Example 42, step (c) followed by SEM deprotection according to the procedure in Example 11, step (g). 1H-NMR (CD3OD, 400 MHz): δ 8.10 (d, J=8.3 Hz, 1H), 8.02 (s, 1H), 7.17 (dd, J=8.3, 1.9 Hz, 1H), 7.08 (d, J=1.9 Hz, 1H), 5.82 (s, 1H), 3.77 (t, J=7.0 Hz, 2H), 2.82 (t, J=7.0 Hz, 2H), 2.31-2.25 (m, 4H), 1.90-1.76 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C19H20N4O2, 337.2 (M+H), found 337.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.O[CH2:14][CH2:15][CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH2:15][CH:16]2[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:17]2)=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(CCO)C1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CCOc2ccc(Br)cc2C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 52.6 %

Procedure:
4-Bromo-2-(trifluoromethyl)phenol (3 g), tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (2.81 g) and triphenylphosphine (3.92 g) were dissolved in DCM (25 ml). The reaction mixture was placed under a nitrogen atmosphere and cooled to 0° C. then DIAD (2.94 ml) was added dropwise. The mixture was stirred at room temperature for 16 hours then solvent evaporated under reduced pressure. The resulting residue was dissolved in ether (10 ml), heptane (15 mL) was then added and the suspension stirred for 45 minutes. The mixture was filtered (solid was washed with 3:2 heptane/ether) and the filtrate washed with NaOH (1M, 2×40 mL). Organics were dried over sodium sulphate and solvent evaporated under reduced pressure to yield crude product as a clear oil (6.05 g). Purification by flash chromatography (100 g silica column, 10% to 25% EtOAc in heptane gradient) afforded tert-butyl 3-(2-(4-bromo-2-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylate (52.6% yield) as a clear oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][C:24](OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42][CH2:43][C:44]([CH2:48]C)([OH:47])[CH2:45][CH3:46].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:48][C:44]([CH2:45][CH3:46])([OH:47])[CH2:43][CH3:42])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(O)(CC)CCBr
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(CC)CCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 121.1 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (82.8 mg, 0.143 mmol), 5-bromo-3-ethyl-3-pentanol (139 mg, 0.715 mmol), tetrahydrofuran. (1 ml) and 1M KOH solution in methanol (1 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane : ethyl acetate=8:1, developed once) to give 99.6 mg of a product, which was directly used in the subsequent reaction because it was difficult to separate from 5-bromo-3-ethyl-3-pentanol.