Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:3]2[CH:2]=[CH:8][C:6]([NH2:7])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (2 g, 11.59 mmol) in dioxane (100 ml) and water (10 ml) was added (4-chlorophenyl)boronic acid (3.6 g, 23.02 mmol), K3PO4 (5.01 g, 23.18 mmol) and Pd(PPh3)4 (0.7 g, 0.58 mmol) with stirring for 4 h at 95° C. maintained with an inert atmosphere of nitrogen. Then the resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 2% to 5% ethyl acetate in petroleum ether to afford 4-(4-chlorophenyl)-2-nitroaniline as a yellow solid (2.0 g, 69%). Next, to a solution of 5-(4-chlorophenyl)-2-nitroaniline (300 mg, 1.21 mmol) in ethanol (10 ml) was added hydrogen chloride (0.5 ml, 3.63 mmol) and Zn powder (800 mg, 12.3 mmol) in portions at room temperature and stirred for 2 h at 85° C. The resulting mixture was concentrated under vacuum to give a residue and dissolved in water (100 ml), adjusted to pH 8 with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3×100 ml) and dried and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% to 20% ethyl acetate in petroleum ether to produce 4-(4-chlorophenyl)benzene-1,2-diamine as an off-white solid (200 mg, 76%). Finally, a solution of 4-(4-chlorophenyl)benzene-1,2-diamine (150 mg, 0.69 mmol) in heptafluorobutanoic acid (2 ml) was stirred for 8 h at 120° C. Then the reaction was quenched with water (50 ml), adjusted to pH 7 with sodium bicarbonate and extracted with ethyl acetate(3×100 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 5% to 10% ethyl acetate in petroleum ether to produce 6-(4-chlorophenyl)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a white solid (49.5 mg, 18%).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:15]1[N:16]=[C:17]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:18]2[C:19](=[O:27])[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH3:14].C(N(CC)C(C)C)(C)C>C(O)C>[CH3:32][C:28]1[N:18]2[C:19](=[O:27])[C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:15]([CH:12]([NH:11][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH2:13][CH3:14])[N:16]=[C:17]2[CH:31]=[CH:30][CH:29]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CCC(N)c1nc2cccc(C)n2c(=O)c1-c1ccccc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1-c1ccccc1

Procedure:
A mixture of 6-bromo-9H-purine (Aldrich, 0.0152 g, 0.07656 mmol), 2-(1-aminopropyl)-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.019 g, 0.064 mmol), and N,N-diisopropylethylamine (0.0134 mL, 0.07666 mmol) in ethanol (0.5 mL) was refluxed under nitrogen overnight. The mixture was cooled and purified on RP-HPLC at pH 10 (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to provide the product as the free base. LCMS calculated for C23H22N7O (M+H)+: m/z=412.2. Found: 412.4. 1H NMR (DMSO-d6, 300 MHz) δ 8.07 (2H, m), 7.60 (1H, dd, J=9.0 and 6.9 Hz), 7.39-7.32 (7H, m), 7.00 (1H, m), 6.85 (1H, br d, J=6.9 Hz), 5.13 (1H, m), 2.81 (3H, s), 1.72 (2H, m), 0.65 (3H, t, J=7.2 Hz) ppm.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:24]([O:31][NH2:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31]/[N:32]=[C:21](/[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[N:13][N:14]=2)[N:17]=1)\[CH3:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NOCc1ccccc1
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Product: C/C(=N\OCc1ccccc1)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1

Procedure:
The title compound was prepared from 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2) and O-benzylhydroxylamine (intermediate H) using the same procedure described in the synthesis of example 41. 1H-NMR (400 MHz, CHCl3-d1) δ ppm 8.87 (d, 1H), 8.06 (m, 2H), 7.95 (d, 1H), 7.84 (s, 1H), 7.80 (m, 2H), 7.38 (m, 6H), 5.30 (s, 2H), 4.77 (s, 2H), 2.32 (s, 3H). LC-MS (method J): [MH]+=409.1, tR=2.42 min.
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH2:42][C:43]34[C:49]([F:51])([F:50])[CH:48]3[CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([OH:38])=O)[CH2:30][CH2:29]1.CS(N)(=O)=O.[N:57]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1>>[N:57]1([S:61]([NH:64][C:36](=[O:38])[C:35]2[CH:39]=[C:31]([CH:28]3[CH2:29][CH2:30]3)[C:32]([O:41][CH2:42][C:43]34[C:49]([F:51])([F:50])[CH:48]3[CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:33][C:34]=2[F:40])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-(((1SR,6RS)-7,7-difluorobicyclo-[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a white gum (0.051 g, 81%): 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 7.64 (d, J=9.1 Hz, 1H), 6.54 (d, J=14.1 Hz, 1H), 4.25 (t, J=7.9 Hz, 4H), 3.98 (s, 2H), 2.32-2.22 (m, 2H), 2.09-2.00 (m, 1H), 1.96-1.57 (m, 4H), 1.49-1.25 (m, 5H), 0.98-0.92 (m, 2H), 0.72-0.67 (m, 2H); MS (ES+) m/z 459.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([CH2:15][NH2:16])[OH:14]>>[OH:14][CH2:13][CH2:15][NH:16][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:16][CH2:15][CH2:13][OH:14])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Reactant: NCCO
Product: O=[N+]([O-])c1c(NCCO)cc(Cl)cc1NCCO
Temperature: 0 °C

Procedure:
0.132 mole (30 g) of 2,4,6-trichloronitrobenzene were heated at 95° C. in 120 ml of ethanolamine. After 30 minutes the reaction medium was poured over 240 g of an ice-water mixture. The desired product precipitated out and was filtered, washed with water and then dried under vacuum in the presence of phosphorus pentoxide. After recrystallization from absolute ethanol, it melted at 154° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[F:23][C:24](=[CH2:28])[C:25](Cl)=[O:26]>C(OCC)C>[F:23][C:24](=[CH2:28])[C:25]([O:8][C:3]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)([C:2]([F:1])([F:14])[F:15])[C:4]([F:7])([F:6])[F:5])=[O:26]
Reactant: OC(c1ccco1)(C(F)(F)F)C(F)(F)F
Reactant: C=C(F)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(F)C(=O)OC(c1ccco1)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
A solution of 20 g (0.085 mol) of hexafluoro-2-(2-furyl)-2-propanol and 8.65 g (0.085 mol) of triethylamine in 25 ml of dry diethyl ether was added dropwise with stirring at a temperature of 20° C. to a solution of 9.8 g (0.09 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 25 ml of dry diethyl ether in the course of 30 minutes. The reaction mixture was then stirred at a temperature of 20° C. for a further 4 hours. The resulting solid was filtered off. The filtrate was distilled under reduced pressure after addition of 0.005 g of hydroquinone monomethyl ether. 15.9 g (61 percent of theory) of hexafluoro-2-(2-furyl)-2-propyl α-fluoroacrylate having a boiling point of 55° to 57° C. (under 8 mbar were obtained.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][N:31]1[C:35]2[CH:36]=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][C:34]=2[N:33]([CH3:49])[C:32]1=[O:50].C([O-])([O-])=O.[K+].[K+]>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>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:38]3[CH:37]=[CH:36][C:35]4[N:31]([CH3:30])[C:32](=[O:50])[N:33]([CH3:49])[C:34]=4[CH:39]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cn1c(=O)n(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)n(C)c(=O)n4C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (75 mg, 0.15 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)one (182 mg, 0.63 mmol), then Pd(PPh3)4 (22 mg, 0.02 mmol). The vial was flushed with argon, diluted with dioxane (1.5 mL) and to this was added 2M aqueous K2CO3 (0.25 mL, 0.5 mmol). The vial was sealed, heated to 100° C. for 2 hours, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (40-100% EtOAc/Hex gradient) to afford the desired product. LCMS-ESI+: calc'd for C31H33ClN3O4S: 578.2 (M+H+); Found: 578.3 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]2=[O:21])=[CH:6][CH:5]=1)([O-:3])=[O:2].CI.[C:24](=O)([O-])[O-].[K+].[K+]>O>[CH3:24][N:12]1[C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][C:15](=[O:16])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]1=[O:21]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc([N+](=O)[O-])cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To the stirred reaction mixture containing the crude 3-(4-nitrophenyl)-6-trifluoromethyluracil (14.5 grams--0.048 mole) from the preceding step was added 13.6 grams (0.096 mole) of methyl iodide and 3.3 grams (0.096 mole) of potassium carbonate. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for about five hours, after which the reaction mixture was poured into water, and the resultant solid was collected by filtration. The solid was washed with petroleum ether and dried, yielding 13.0 grams of 1-methyl-3-(4-nitrophenyl)-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(SCC(O)=O)(=[O:3])C.ON1C(=O)CCC1=O.[CH:17]1([N:23]=[C:24]=[N:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCOCC1>[CH:26]1([NH:25][C:24]([NH:23][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:3])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(=O)SCC(=O)O
Agent: O=C1CCC(=O)N1O
Solvent: C1COCCO1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 16 h
Yield: 66 %

Procedure:
S-Acetyl-2-mercaptoacetic acid (75 mmoles) and N-hydroxysuccinimide (75 mmoles), were dissolved in 150 ml dioxane and reacted with cooling in ice with N,N'-dicyclohexylcarbodiimide (75 mmoles) and the mixture was kept at 4° C. for 16 h. The N,N'-dicyclohexylurea formed was removed by filtration and the solvent evaporated in vacuo. The residue was twice recrystallized from 2-propanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[C:14]2=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[F:29][C:30]([F:41])([F:40])[C:31]([O:33][C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[O:32]>ClCCl.N1C=CC=CC=1>[F:29][C:30]([F:41])([F:40])[C:31]([OH:33])=[O:32].[CH3:19][C:16]1([CH3:20])[C:17](=[O:18])[N:13]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:10])[F:12])=[C:2]([NH:1][C:34](=[O:39])[C:35]([F:36])([F:37])[F:38])[CH:3]=2)[C:14](=[O:28])[N:15]1[CH2:21][C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(N)c2)C(=O)N1Cc1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC(=O)C(F)(F)F)c2)C(=O)N1Cc1ccncc1
Product: O=C(O)C(F)(F)F
Temperature: 0 °C

Procedure:
394 mg (1.0 mmol) of 3-(3-amino-4-trifluoromethoxyphenyl)-5,5-dimethyl-1-pyridin-4-ylmethylimidazolidine-2,4-dione were dissolved in 5 ml of 4:1 dichloromethane/pyridine and cooled to 0° C., and 252 mg (1.2 mmol) of trifluoroacetic anhydride dissolved in 5 ml of 4:1 dichloromethane/pyridine were added dropwise at 0° C. After stirring at RT, the mixture was added to ice-water, extracted with CH2Cl2, concentrated and dried. The remaining residue was purified by means of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA).
Reaction SMILES: [Br:1][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.C([OH:30])C.O.[BH4-].[Na+]>O1CCCC1>[C:21]([O-:25])(=[O:30])[CH3:22].[Br:1][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@@H:12]([OH:27])[CH2:11][CH2:10]1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCBr)[C@H]3[C@@H]1CCC2=O
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)[O-]
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCBr)[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 16.2 g of 7α-(5-bromopentyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one in 162 ml of tetrahydrofuran as well as 90 ml of ethanol and 36 ml of water are mixed in portions at 0° C. with 4.7 g of sodium borohydride and stirred for 2 hours at 0° C. Then, it is added to water, extracted four times with ethyl acetate, washed with water and common salt solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. 17.1 g of crude product is obtained. After chromatography on silica gel with hexanelethyl acetate, 15.6 g of pure 7α-(5-bromopentyl)-11β-fluoro-estra-1,3,5(10)-triene-3,17β-diol is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32][CH:33]2CC[CH2:35][CH2:34]2)[CH:3]=1.Br[CH2:39]C1CC1>>[CH3:39][O:24][C:22](=[O:23])[CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:12]2[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)=[CH:15][CH:16]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Reactant: BrCC1CC1
Product: COC(=O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CC3)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 19, from 3-{4-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-phenyl}-propionic acid methyl ester (Example 59, intermediate b) and bromomethyl-cyclopropane (CAS Reg. No. 7051-34-5). Brown solid (54%). MS (Turbo Spray): m/z=511.2 (M+H).
Reaction SMILES: [K].[OH:2][C:3]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([OH:25])(=O)=[O:23])=[CH:18][CH:17]=2)=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].CN(C)C=O.S(Cl)([Cl:33])=O.[Cl-].[Na+]>C1(C)C=CC=CC=1>[OH:2][C:3]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([Cl:33])(=[O:25])=[O:23])=[CH:18][CH:17]=2)=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)O)cc2)ccc1O
Agent: [Cl-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Cl)cc2)ccc1O

Procedure:
Ethyl 2-hydroxy-5-[(4-sulfophenyl]ethynyl]benzoate potassium salt (19 g, 50 mmol) was suspended in toluene (100 ml). Dimethylformamide (1 ml) and thionyl chloride (12 g) were added and the suspension was refluxed for 1 h. The reaction mixture was added to a nearly saturated sodium chloride solution and the precipitated oil was extracted with toluene. The solution was dried and taken to dryness. The product was sufficiently pure for the next step. Yield 16 g, 88%.
Reaction SMILES: OO.[C:3]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([OH:31])[C:25]([CH3:33])([CH3:32])[CH2:24]1)(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].S([O-])([O-])=O.[Na+].[Na+].[OH:40][C:41]([CH3:75])([CH3:74])[CH2:42][O:43][N:44]1[C:49]([CH3:51])([CH3:50])[CH2:48][CH:47]([O:52][C:53](=[O:71])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[CH2:46][C:45]1([CH3:73])[CH3:72]>C(O)(C)(C)C>[C:3]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH2:75][C:41]([CH3:74])([OH:40])[CH2:42][O:43][N:44]2[C:49]([CH3:50])([CH3:51])[CH2:48][CH:47]([O:52][C:53](=[O:71])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[CH2:46][C:45]2([CH3:73])[CH3:72])[C:25]([CH3:32])([CH3:33])[CH2:24]1)(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(OCC(C)(C)O)C(C)(C)C1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(O)C(C)(C)C1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(OCC(C)(O)CON2C(C)(C)CC(OC(=O)CCCCCCCCCCCCCCCCC)CC2(C)C)C(C)(C)C1

Procedure:
Aqueous hydrogen peroxide is added to a mixture of 4-octadecanoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-50° C. Excess peroxide is decomposed with aqueous sodium sulfite solution. The organic layer is concentrated to obtain a mixture which includes 1-(2-hydroxy-2-methylpropoxy)-4-octadecanoyloxy-2,2,6,6-tetramethylpiperidine and the title compound. The title compound is separated from the mixture by high pressure liquid chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]2[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:24]([F:38])[CH:23]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([O:14][Si](C(C)(C)C)(C)C)[CH2:9]2)=[CH:6][N:7]=1.C(=O)(O)[O-].[Na+].C(O)(C(F)(F)F)=O>Cl.C1COCC1.CO>[NH2:1][C:2]1[C:3]([C:22]2[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:24]([F:38])[CH:23]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(c2cnc(N)c(-c3ccc(C(=O)NCc4ccccc4)c(F)c3)n2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Nc1ncc([C@@H]2CCC[C@H](O)C2)nc1-c1ccc(C(=O)NCc2ccccc2)c(F)c1
Reaction time: 2 h

Procedure:
A mixture of 4-(3-amino-6-(3-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin-2-yl)-N-benzyl-2-fluorobenzamide (61 mg, 0.114 mmol) in 6N HCl (0.29 mL),THF (0. 57 mL) and MeOH (0.285 mL) was stirred for 2 h. Solid sodium bicarbonate was added to neutralize the reaction mixture. Solvent was evaporated and 25% of the residue was dissolved in DMSO, and purified with auto-prep to provide 15 mg of desired cis racemate compound as a TFA salt. LCMS (m/z): 421.3 (MH+), 0.74 min. 1H NMR (400 MHz, MeOD-d4) δ ppm 7.82-7.69 (m, 2H) 7. 62-7. 45 (m, 2H) 7.37-7.12 (m, 5H) 4.52 (s, 2H) 3.66-3.52 (m, 1H) 2.75-2.60 (m, 1H) 2.11-2.01 (m, 1H) 1.97-1.70 (m, 3H) 1.52-1.29 (m, 3H) 1.24-1.08 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[C:21]([CH3:24])[CH:20]=[C:19]([OH:25])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:26](=[O:28])[NH2:27])[CH:7]=[CH:8][CH:9]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[CH3:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[C:21]([CH3:24])[CH:20]=[C:19]([O:25][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:26](=[O:28])[NH2:27])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(Cn2c3cc(C)cc(O)c3c3c(C(N)=O)cccc32)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)COc1cc(C)cc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C)c1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
60% Sodium hydride in mineral oil (79.8 mg, 2.0 mM) was added to a solution of 9-[(3-methylphenyl)methyl]-2-methyl-4-hydroxy-5-carbamoyl carbazole (0.55 g, 1.60 mM) in 56 mL DMF and 12 ml THF. After 10 minutes, methyl bromoacetate (0.20 ml, 2.16 mM) was added and the resultant mixture stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate and washed with H2O. The aqueous layer was extracted with ethyl acetate. The combined organic layers were extracted with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with methylene chloride/acetone gradient) to afford 0.51 g (76%) of {9-[(3-methylphenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester. 1H NMR (DMSO-d6) δ7.5 (m, 2H), 7.35 (dd, J=8 and 8 Hz, 1H), 7.2-7.1 (m, 2H), 7.05-6.95 (m, 4H), 6.85 (d, J=8 Hz, 1H), 6.45 (s, 1H), 5.6 (s, 2H), 4.9 (s, 2H), 3.75 (s, 3H), 2.4 (s, 3H), 2.2 (s, 3H). MS (FD) m/e 400, 417.