Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(OCC)(=[O:28])C>CS(C)=O.C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:28])[CH2:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1C(O)CC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolving 1.63 g of 2-(1-benzylpiperidin-4-yl)-1-(2-methoxyphenyl)ethanol in 5 ml of dimethylsulfoxide, 4.2 ml of triethylamine was added, a solution of 2.39 g of sulfur trioxide-pyridine complex in dimethylsulfoxide (15 ml) was added dropwise and the mixture was stirred for 30 minutes at room temperature. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain 1.38 g of 1-(1-benzylpiperidin-4-yl)-2-(2-methoxyphenyl)ethanone. After dissolving this in 12 ml of 1,2-dichloroethane, 0.55 ml of 1-chloroethyl chloroformate was added while stirring on ice, and the mixture was heated to reflux for 1 hour. The solvent was distilled off under reduced pressure, 10 ml of methanol was added to the residue and heating to reflux was continued for 30 minutes. The solvent was distilled off under reduced pressure. A 1N sodium hydroxide solution was added to the residue and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound (750 mg, 64% yield).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]3[C:14](=[O:21])[CH:13]=[C:12]2[CH3:22])[CH:18]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH3:25]N(C)C=O.CC(C)([O-])C.[K+].S(OC)(OC)(=O)=O>O>[F:5][C:4]([F:7])([F:6])[C:3]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]3[C:14](=[O:21])[CH:13]=[C:12]2[CH3:22])[CH:18]=1)([O:8][CH3:25])[C:2]([F:1])([F:23])[F:24]
Reactant: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)CC2
Reactant: CN(C)C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COC(c1cc2c3c(c1)c(C)cc(=O)n3CC2)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 49 %

Procedure:
To a stirred mixture of 3.5 g of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-6-methyl-4H-pyrrolo[3,2,1-ij]quinolin-4-one and 20 ml of dry dimethylformamide is added 1.3 g (0.012 mole) of potassium tert-butoxide in a dry nitrogen atmosphere. The mixture is heated gently to 100° and is allowed to cool. Then 1 ml (1.35 g, 0.011 mole) of dimethyl sulfate is added, and the mixture is warmed gently to 100°. The mixture is allowed to cool to room temperature and is poured into 100-200 ml of water. The precipitate is filtered off and then is triturated with 10% sodium hydroxide solution. The insoluble material is filtered off, washed with water, and dried. Recrystallization from alcohol gives 1.8 g (49%) of 1,2-dihydro-8-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)-ethyl]-6-methyl-4H-pyrrolo[3,2,1-ij]quinolin-4-one, m.p. 242°-243°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([NH:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.CCN(CC)CC.Cl[C:37]([O:39][CH3:40])=[O:38]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([NH:15][N:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:37]([O:39][CH3:40])=[O:38])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1c(-c2ccccc2)nc2ccccc2c1C(=O)NNc1ccccc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N(NC(=O)c1c(OC)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.1 %

Procedure:
To a solution of 3-methyloxy-N′,2-diphenyl-4-quinolinecarbohydrazide (100 mg, 0.27 mmol) and Et3N (56 μL, 0.41 mmol) in CH2Cl2 (7 mL) was added methyl chloroformate (27 μL, 0.35 mmol). After stirring at room temperature for 4 h the mixture was diluted with CH2Cl2 and washed with 1N HCl (20 mL), 1N NaOH (20 mL) and brine (20 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with isohexane:ethyl acetate (2:1), to afford the title compound (59 mg, 51%) as a colourless foam. 1H NMR (CDCl3, 360 MHz), δ 8.43 (1H, s), 8.16-8.13 (2H, m), 8.02-8.00 (2H, m), 7.69 (1H, dt, J=6.9 and 1.3 Hz), 7.61-7.41 (8H, m), 7.30 (1H, t, J=7.4 Hz), 3.91 (3H, s), 3.57 (3H, s). MS (ES+) C25H21N3O4 requires: 427, found: 428 (M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([F:28])[CH:16]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.CC([O:33][C:34]([O:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=O)(C)C.C(#[N:46])C>CN(C1C=CN=CC=1)C>[C:34]([NH:46][C:19]([OH:21])=[O:20])([OH:36])=[O:33].[C:40]([O:39][C:37]([NH:1][C:2]1[C:3]([C:15]2[CH:27]=[CH:26][C:18]([C:19]([O-:21])=[O:20])=[C:17]([F:28])[CH:16]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][N:7]=1)=[O:38])([CH3:41])([CH3:42])[CH3:43]
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCC(=O)CC3)cnc2N)cc1F
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ncc(C2CCC(=O)CC2)nc1-c1ccc(C(=O)[O-])c(F)c1
Product: O=C(O)NC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-(3-amino-6-(4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (3 g, 7.78 mmol) in acetonitrile (130 mL) was added Boc2O (6.33 mL, 27.2 mmol) and DMAP (0.048 g, 0.389 mmol). The reaction mixture was stirred overnight at room temperature. After volatile materials were removed on rotavap under reduced pressure, the crude product was purified by flash chromatography eluting with 0-50% of EtOAc/heptane to provide imidodicarbonic acid, 4-(3-((tert-butoxycarbonyl)amino)-6-(4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate, 1,3-bis(1,1-dimethylethyl) ester (4.34 g, 7.41 mmol, 95%). LCMS (m/z): 586.5 (MH+), 1.24 min; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.52-8.41 (m, 1H), 7.97 (t, J=7.7 Hz, 1H), 7.61-7.44 (m, 2H), 3.46-3.30 (m, 1H), 2.68-2.52 (m, 4H), 2.38 (dd, J=3.0, 13.7 Hz, 2H), 2.28-2.10 (m, 2H), 1.69-1.61 (m, 9H), 1.42-1.29 (m, 18H).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=CC=3)=NOC=2C)=NC=1.[NH2:49][CH:50]([CH3:53])[CH2:51][OH:52]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:49][CH:50]([CH3:53])[CH2:51][OH:52])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Reactant: CC(N)CO
Agent: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Product: CC(CO)NC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 71 %

Procedure:
As described for example 220, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.31 mmol) was converted, instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, using rac-2-amino-1-propanol instead of 3-amino-1-propanol, to the title compound (80 mg, 71%) which was obtained as a colourless gum. MS: m/e=372.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=[O:27])[C:24](Cl)=[O:25].[CH2:29]([OH:31])[CH3:30]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:23](=[O:27])[C:24]([O:31][CH2:29][CH3:30])=[O:25])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCO
Reactant: c1ccc(Cn2ccc3cc(-c4ccccc4)ccc32)cc1
Product: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccccc3)cc12
Yield: 66 %

Procedure:
Ethyl {1-benzyl-5-phenyl-1H-indol-3-yl}(oxo)acetate was prepared from 1-benzyl-5-phenyl-1H-indole (0.846 g, 2.99 mmol), oxalyl chloride (0.78 mL, 9.0 mmol), and ethanol (2 mL), following the procedure described in Step 3 of Example 1. Purification by flash chromatography (Biotage apparatus) using 5-7.5% ethyl acetate in hexane as an eluant yielded the title compound as a light yellow solid (0.754 g, 66%), mp: 116-117° C. Mass spectrum (+ES, [M+H]+) m/z 384; 1HNMR (500 MHz, DMSO-d6): δ 8.7 (s, 1H), 8.4 (d, 1H, J=0.92 Hz), 7.6-7.7 (m, 3H), 7.55-7.6 (m, 1H), 7.45 (t, 2H, J=7.7 Hz), 7.3-7.4 (m, 6H), 5.65 (s, 2H), 4.35 (q, 2H, J=7.1 Hz), and 1.35 ppm (t, 3H, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18]C2CCN(C3CCCN(CC4C=CC=CC=4)C3)CC2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH2:18])=[CH:6][CH:7]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(C4CCCN(Cc5ccccc5)C4)CC3)nc3ccccc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1nc2ccccc2n1Cc1ccc(F)cc1
Yield: 91.5 %

Procedure:
A mixture of 11.3 parts of 1-[(4-fluorophenyl)methyl]-N-[1'-(phenylmethyl) -[1,3'-bipiperidin]-4-yl]-1H-benzimidazol-2-amine and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 8.5 parts (91.5%) of N-([1,3'-bipiteridin]-4-yl)-1-[(4-fluorophenylmethyl]-1H-benzimidazol-2-amine (57).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)C=O.C(OC1C=CC(OB(O)O)=CC=1)C1C=CC=CC=1.[Br:36]C1C=CC(O)=CC=1.C(Cl)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:11]([O:10][C:9]1[CH:8]=[CH:7][C:4]([Br:36])=[CH:3][CH:2]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(OCC2CCCCC2)c(Br)c1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)Oc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Solvent: ClCc1ccccc1
Product: Brc1ccc(OCc2ccccc2)cc1

Procedure:
The intermediate 32 (1.76 g), 4-benzyloxyphenyl boric acid [6.75 g, 4-benzyloxy bromobenzene was prepared according to a process described in the process c-1 in example 1 from 4-bromophenol (Tokyo Chemical Ind. Co., Ltd.) and benzyl chloride (Tokyo Chemical Ind. Co., Ltd.), and the product was prepared according to a method described in the reference Y Satoh et al. SYNTHESIS page 1146, 1994], anhydrous potassium carbonate (4.09 g) and tetrakis (triphenylphosphine)palladium (0)(342 mg) were reacted according to the method described in the process i in example 23 to obtain the compound in the title (2.30 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([O:5][C:6](=O)C(F)(F)F)=[O:4].O[CH2:15][N:16]([N+:18]([O-:20])=[O:19])C>ClCCl>[F:1][C:2]([F:13])([F:12])[C:3]([O:5][CH2:6][N:16]([N+:18]([O-:20])=[O:19])[CH3:15])=[O:4]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(CO)[N+](=O)[O-]
Solvent: ClCCl
Product: CN(COC(=O)C(F)(F)F)[N+](=O)[O-]

Procedure:
Trifluoroacetic anhydride (20 ml, 103.6 g, 0.49 moles) was added to a stirred solution of 1-hydroxy-2-nitro-2-azapropane (40.0 g, 0.38 moles) in dichloromethane (60 ml) at -5° to 0° C. during 11/2 hours. The resulting solution was then distilled without warming at 20 mm, then to 3 mm. The product was distilled at 1.5 mm, 65° C. to give 2-nitro-2-azapropyl trifluoroacetate; yield: 48 g (63%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].C1C=CC=CC=1>O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[N:14]=[C:1]([CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC(=O)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CC(=Nc1cccc(Cl)c1)c1ccccc1

Procedure:
A solution of acetophenone (130 ml), m-chloroaniline (130 ml) and benzene (200 ml) was refluxed in the presence of molecular sieve (50 g) with continuous removal of water. m-Chloro-N-(α-methyl benzylidene) aniline (XIX) was obtained by fractional distillation. XIX had a boiling point of 110° C. at 0.025 millimeter.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C([Li])(C)(C)C.CCCCC.[C:26](=[O:28])=[O:27]>O1CCCC1>[C:11]([O:10][C:9]([NH:8][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:26]([OH:28])=[O:27])=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1F
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-fluorophenylcarbamate (44.0 g, 208 mmol) in tetrahydrofuran (660 mL) at −78° C. was added tert-butyllithium in pentane (1.7 M, 306 mL, 2.5 equiv) drop wise. After addition was complete, the reaction was stirred at −78° C. for 30 min. The solution was allowed to gradually reach −20° C. before being recooled to −78° C. and transferred via canula to a slurry of carbon dioxide (excess) and tetrahydrofuran (500 mL). The solution was allowed to slowly warm to room temperature. The reaction mixture was concentrated to remove most of the tetrahydrofuran, and poured into a sep funnel containing water and diethyl ether. The layers were separated, and the aqueous extracted with diethyl ether twice more. The ethereals were discarded. The aqueous was acidified with 5% citric acid, extracted with diethyl ether (3×). The ethereal was dried over magnesium sulfate, and concentrated to give a light yellow solid which was recrystallized from hot toluene to give 37.1 g (70%) as a faint yellow solid. 1H-NMR (CDCl3, 500 MHz) δ 1.50 (s, 9H), 6.25 (bs, 1H), 7.18 (ddd, J=7.9, 7.9, 4.9, 1H), 7.33 (dd, J=9.5, 9.2, 1H), 7.79 (d, J=7.9, 1H), 7.94 (s, 1H). Mass spec.: 278.21 (MNa)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[CH3:12][C:13]1[C:14]([N:18]=[C:19]=[S:20])=[CH:15][S:16][CH:17]=1.C(Cl)Cl.CO>C1COCC1>[NH2:11][C:5]1[C:4]([C:1]([OH:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][C:19]([NH:18][C:14]1[C:13]([CH3:12])=[CH:17][S:16][CH:15]=1)=[S:20]
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: Cc1cscc1N=C=S
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cc1cscc1NC(=S)Nc1cccc(C(=O)O)c1N

Procedure:
is obtained analogously to the procedure described in example 25 a) from 3-carboxy-1,2-diaminobenzene and 4-methyl-3-thienyl isothiocyanate in anhydrous THF, followed by medium-pressure chromatography on silica gel using a mixture of 12 parts of methylene chloride and 1 part of methanol. Amorphous product.
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: FC(F)(F)C(F)(F)CCCSC[C@@H]1CCCN1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1CCC2=O
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).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:31])[C:27](OC)=[O:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1.[C:32]([Mg]Cl)([CH3:35])([CH3:34])[CH3:33]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:31])[C:27](=[O:28])[C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1
Reactant: COC(=O)C(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)nc2)CC1
Reactant: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)C(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)nc2)CC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A solution of methyl {4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinyl}(oxo)acetate (Example 137, 95 mg, 0.21 mmol) in THF (4 mL) at −78° C. was treated with tert-butylmagnesium chloride (1M in THF, 0.26 mL, 0.26 mmol). The mixture was stirred at −78° C. for 3 h. Additional tert-butylmagnesium chloride (1M in THF, 0.22 mL, 0.22 mmol) was added. The mixture was stirred at −78° C. for 3 h. More tert-butylmagnesium chloride (1M in THF, 0.25 mL, 0.25 mmol) was added. The reaction mixture was stirred at −78° C. for 1 h, quenched with saturated aqueous NH4Cl and extracted with EtOAc (50 mL×2). The combined organic extracts were washed with brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a viscous light brown oil. The crude material was purified by flash chromatography on a silica gel column eluted with 1:10 acetone/CH2Cl2 to give 50 mg (50%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.42 (d, 1H, J=2.9 Hz), 8.23 (t, 1H, J=7.8 Hz), 7.85-7.77 (m, 2H), 7.73 (dd, 1H, Ja=10.3 Hz, Jb=1.5 Hz), 7.30-7.25 (m, 1H), 4.65-4.55 (m, 1H), 3.95-3.85 (m, 2H), 3.55-3.45 (m, 1H), 3.15-3.05 (m, 4H), 2.80-2.70 (m, 1H), 2.25-2.10 (m, 1H), 2.00-1.85 (m, 2H), 1.50-1.30 (m, 2H), 1.27 (s, 9H); LRMS (ESI), m/z 477 (M+H).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:7]=[C:8]([CH3:15])[C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:5][C:6]1[CH:7]=[C:8]([CH3:15])[C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1
Reactant: Cc1cc(NC(=O)C(F)(F)F)cc2ccoc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc(N)cc2ccoc12
Yield: 99.7 %

Procedure:
A mixture of 2,2,2trifluoro-N-(7-methyl-benzofuran-5-yl)-acetamide (580 mg) and potassium carbonate (1.64 g) in methanol (25 ml) and water (2.5 ml) was heated at reflux for 2.5 hours. The residue was extracted with dichloromethane (3×25 ml) and the combined, dried (MgSO4) organic phase was evaporated in vacuo to give the title compound as a colourless oil (350 mg).
Reaction SMILES: [CH2:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH2:2][CH3:3].O1CCCC1.O.[OH-].[Li+]>CO>[CH2:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1noc2ccc(C(=O)OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCc1noc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.9 %

Procedure:
To a solution of methyl 3-propyl-1,2-benzisoxazole-5-carboxylate (90 mg, 0.4 mmol) in a 2:1:1 mixture of tetrahydrofuran, water, and methanol (4 mL) was added lithium hydroxide (50 mg, 1.2 mmol) and the resulting reaction mixture stirred at room temperature for 2.5 h. The reaction mixture was concentrated under reduced pressure, and partitioned between water and ethyl ether. The aqueous layer was washed twice with ether and acidified to pH 1 with 6 M hydrochloric acid. The resulting aqueous layer was extracted with ethyl acetate, dried (sodium sulfate), and concentrated under reduced pressure to afford 3-propyl-1,2-benzisoxazole-5-carboxylic acid (73 mg): 1H NMR (300 MHz, CD3OD): δ 8.28-8.27 (m, 1H), 8.09-8.06 (m, 1H), 7.64-7.61 (m, 1H), 2.99-2.94 (m, 2H), 1.96-1.86 (m, 2H), 1.08-1.02 (m, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[C:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])[CH3:13].N1CCCCC1.C(Cl)Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:13]/[C:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:14])=[CH:2]1
Reactant: CC(=O)c1cccnc1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CO
Solvent: ClCCl
Solvent: C1CCNCC1
Product: O=C(/C=C/c1c[nH]c2ccccc12)c1cccnc1
Temperature: 25 °C

Procedure:
Indole-3-carboxaldehyde (100 mg, 0.69 mmol) was added to a dried 100 mL round bottom flask and dissolved in anhydrous methanol (5 mL). 3-Acetyl-pyridine (113 μL, 1.03 mmol, 1.5 equiv.) and piperidine (69 μL, 0.7 mmol) were added and the reaction stirred under reflux. After twelve hours, the reaction was cooled to room temperature, upon which a precipitate formed. The solid was filtered, yielding 54 mg. However, there was significant aldehyde present on a crude NMR. This mixture was dry-loaded onto silica and purified by column chromatography (methylene chloride:methanol 9:1), producing 33 mg pure, yellow solid (19%). NMR: 1H NMR (600 MHz, d6-DMSO): δ 12.004 (s, 1H, N—H), 9.292-9.289 (d, J=1.8, 1H, pyr-H2), 8.808-8.797 (dd, J1=4.8, J2=1.8, 1H, pyr-H6), 8.467-8.447 (dt, J1=7.8, J2=2.1, 1H, pyr-H4), 8.174 (s, 1H, indole-H2), 8.154-8.140 (dd, J1=6.6, J2=1.8, 1H, indole-H4), 8.120-8.095 (d, J=15.0, 1H, C═CH), 7.665-7.639 (d, J=15.6, 1H, C═CH), 7.607-7.585 (m, 1H, pyr-H5), 7.506-7.492 (dd, J1=6.9, J2=1.5, 1H, indole-H7), 7.268-7.223 (qd, J1=6.6, J2=1.5, 1H, indole-H5,6). 13C NMR (150 MHz, d6-DMSO): δ 187.9, 152.7, 149.3, 139.9, 137.6, 135.7, 134.1, 133.7, 125.1, 123.9, 122.9, 121.3, 120.7, 115.0, 112.9, 112.5. Melting Point: 192-194° C. TLC (methylene chloride:methanol 9:1) Rf=0.26. Elemental analysis calculated for C16H12N2O: C, 77.40; H, 4.87; N, 11.28. found: C, 77.00; H, 4.80; N, 11.12.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=O.[NH2:12]C(N)=O>ClCCl>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]#[N:12]
Reactant: O=C(O)c1ccc(Cl)cc1Br
Reactant: NC(N)=O
Solvent: ClCCl
Product: N#Cc1ccc(Cl)cc1Br

Procedure:
588 mg of 2-bromo-4-chlorobenzoic acid and 300 mg of urea are dissolved in dichloromethane/methanole and deposited onto 364 mg of aluminum oxide on a rotary evaporator. The residue is irradiated for 60 min in a microwave at 150° C. After cooling the residue is stirred with ethyl acetate and water, the mixture is filtered and the aqueous phase is removed. The organic phase is washed with a sodium hydrogencarbonate solution dried over sodium sulfate, concentrated on a rotary evaporator and then dried under high vacuum. The product is reacted further without additional purification.