Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:12][C:11]3[C:13](B(O)O)=[CH:14][S:15][C:10]=3[C:9](=[O:19])[CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[C:28]([OH:36])=[C:29]([C:32]([O:34][CH3:35])=[O:33])[S:30][CH:31]=1>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(COC)OC>[OH:36][C:28]1[C:27]([C:13]2[C:11]3[O:12][C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:8][C:9](=[O:19])[C:10]=3[S:15][CH:14]=2)=[CH:31][S:30][C:29]=1[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)c1scc(Br)c1O
Reactant: O=c1cc(N2CCOCC2)oc2c(B(O)O)csc12
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: [Cs+]
Solvent: COCCOC
Product: COC(=O)c1scc(-c2csc3c(=O)cc(N4CCOCC4)oc23)c1O
Temperature: 140 °C

Procedure:
A 2 mL conical microwave vial was charged with a magnetic stirring bar, 5-morpholino-7-oxo-7H-thieno[3,2-b]pyran-3-ylboronic acid (69) (57 mg, 0.16 mmol), cesium carbonate (102 mg, 0.31 mmol), methyl 4-bromo-3-hydroxythiophene-2-carboxylate (56 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.08 mmol), and dimethoxyethane (0.5 mL). The reaction mixture was magnetically stirred and heated via microwave irradiation for 15 minutes at 140° C. Upon cooling to room temperature, the reaction was concentrated in vacuo and purified using high-pressure liquid chromatography to give methyl 3-hydroxy-4-(5-morpholino-7-oxo-7H-thieno[3,2-b]pyran-3-yl)thiophene-2-carboxylate (21).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:13]3=[C:12]([CH2:24][CH2:25][NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[O:28])[C:11]=2[N:34]=1.O.C(=O)([O-])O.[Na+]>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:13]3=[C:12]([CH2:24][CH2:25][NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[O:28])[C:11]=2[N:34]=1
Reactant: COc1ccc2c(n1)c(CCNC(=O)c1ccco1)c1n2CCCc2ccccc2-1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(NCCc1c2n(c3ccc(O)nc13)CCCc1ccccc1-2)c1ccco1

Procedure:
Under an inert atmosphere, 582 mg (4.36 mmol) of aluminium chloride are added to a solution of 350 mg (0.87 mmol) of the compound of Example 11 in 15 ml of dichloromethane. The reaction mixture is refluxed for 6 hours before being hydrolysed with water. The aqueous phase is neutralised with a sodium hydrogen carbonate solution and extracted with dichloromethane. After drying over magnesium sulphate and removal of the solvents by evaporation, the residue is purified by flash chromatography over silica gel (eluant:ethyl acetate/methanol, 95:5) and then by washing with a hexane/diethyl ether mixture to yield the title compound in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.[N+:14]([C:17]1[CH:18]=[C:19]([CH2:23][S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]>C(#N)C.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][S:24]([CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=1)(=[O:25])=[O:26]
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Reactant: COCCCN
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCCCNS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-metoxypropylamine (0.184 mL, 1.80 mmol) and triethylamine (0.3 mL) were added to a solution of (3-Nitrophenyl)methanesulfonyl chloride (0.35 g, 1.50 mmol) in acetonitrile (10 mL). The resulting solution was vigorously stirred for 3 h at room temperature and then diluted with cold water (30 ml), which lead to the formation of a precipitate. The precipitate was filtered off, washed with water (2×10 mL) and dried. Yield of N-(3-methoxy-propyl)-C-(3-nitro-phenyl)-methanesulfonamide 0.31 g (72%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12].C1(CC#N)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([O:9][S:11](=[O:13])(=[O:12])[NH2:14])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: N#Cc1cccc(O)c1
Solvent: Cc1ccccc1
Solvent: N#CCc1ccccc1
Product: N#Cc1cccc(OS(N)(=O)=O)c1
Yield: 85 %

Procedure:
Using the procedure described in Example 75, the title compound was prepared in 85% yield from 10.3 g (0.086 mole) of 3-cyanophenol and 8.3 ml (0.086 mole) of chlorosulfonyl isocyanate in 75 ml of toluene as a white solid, mp 101°-104° C. (benzene-acetonitrile).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH3:20][C:21]([O:24][C:25]([N:27]1[CH2:33][C:32]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=2[O:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])[CH3:22].C(N(C(C)C)CC)(C)C.ClCCl>O1CCOCC1.C(OCC)(=O)C>[CH3:18][CH:17]([CH3:19])[CH2:16][O:15][C:13]([N:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:31]3[O:30][CH2:29][CH2:28][N:27]([C:25]([O:24][C:21]([CH3:22])([CH3:20])[CH3:23])=[O:26])[CH2:33][C:32]=3[CH:34]=2)=[CH:3][CH:4]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Reactant: CC(C)COC(=O)n1ccnc1-c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)COC(=O)n1ccnc1-c1ccc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CCO3)cc1
Temperature: 80 °C
Yield: 42 %

Procedure:
A solution of isobutyl 2-(4-bromophenyl)-1H-imidazole-1-carboxylate (example 4, step 5) (0.50 g, 1.55 mmol), (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 1, step 2) (0.63 g, 1.70 mmol) and diisopropyethylamine (1.50 mL, 8.50 mmol) in 20% aqueous 1,4-dioxane (10 mL) was deoxygenated for five minutes by bubbling nitrogen gas into it, followed by the addition of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) complex with dichloromethane (70 mg, 0.085 mmol). The reaction mixture was heated to 80° C. for 2 hours. On cooling to room temperature the mixture was diluted with ethyl acetate (250 mL) then filtered through a pad of Celite. The organic filtrate was washed with 10% aqueous citric acid (50 mL), brine then dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel column chromatography (hexane-ethyl acetate 9:1 to 7:3) provided 1,1-dimethylethyl 7-[4-(1-{[(2-methylpropyl)oxy]carbonyl}-1H-imidazol-2-yl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.32 g. 43%). 1H NMR (400 MHz, d6-DMSO): 7.73 (d, 1H), 7.67 (s, 4H), 7.56 (m, 2H), 7.14 (d, 1H), 7.08 (m, 1H), 4.56 (br s, 1H), 4.51 (br s, 2H), 4.13 (br s, 1H), 4.08 (m, 2H), 3.74 (m, 2H), 1.86 (m, 1H), 1.34 (s, 1H), 1.32 (s, 9H), 0.77 (d, 6H). MS (EI) for C28H33N3O5: 492 (MH+).
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:53][C:54]1[CH:55]=[C:56]([CH:60]([NH2:62])[CH3:61])[CH:57]=[CH:58][CH:59]=1.[Cl:63][C:64]1[CH:80]=[CH:79][C:67]2[CH2:68][CH2:69][N:70]([C:73](=[O:78])[C:74]([F:77])([F:76])[F:75])[CH2:71][CH2:72][C:66]=2[C:65]=1OS(C(F)(F)F)(=O)=O>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:63][C:64]1[CH:80]=[CH:79][C:67]2[CH2:68][CH2:69][N:70]([C:73](=[O:78])[C:74]([F:75])([F:77])[F:76])[CH2:71][CH2:72][C:66]=2[C:65]=1[NH:62][CH:60]([C:56]1[CH:57]=[CH:58][CH:59]=[C:54]([F:53])[CH:55]=1)[CH3:61]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(N)c1cccc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1cccc(F)c1
Temperature: 95 °C
Yield: 55.4 %

Procedure:
Add palladium(II) acetate (27 mg, 0.12 mmol), BINAP (146 mg, 0.24 mmol), cesium carbonate (270 mg, 0.8 mmol) and (±)-1-(3-fluorophenyl)-ethylamine (230 mg, 1.6 mmol) to a solution of 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (250 mg, 0.6 mmol) in toluene (9 mL). Degas the slurry and fill with nitrogen. Heat the mixture to 95° C. for 16 h. Add additional palladium(II) acetate (0.1 equiv.) and BINAP (0.2 equiv.) and continue heating the reaction for an additional 24 h. Cool the mixture, dilute with EtOAc (50 mL) then filter through Celite®. Concentrate the filtrate and purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) followed by SCX chromatography to obtain (±)-7-chloro-6-[1-(3-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (138 mg, 56%). GC-MS m/z: 414 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[C:9]([CH3:15])[C:8]=1[OH:16])[CH3:2].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[C:9]([CH3:15])[C:8]=1[O:16][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1)[CH3:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCOC(=O)CCc1c(CO)cnc(C)c1O
Product: CCOC(=O)CCc1c(CO)cnc(C)c1OCc1ccc(C#N)cc1
Yield: 69.5 %

Procedure:
The coupling of 3-(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-yl)-propionic acid ethyl ester (35) (3.4 g, 14.2 mmol) and α-bromo-p-tolunitrile (4.2 g, 21.4 mmol), as described in Example 1, gave 3-[3-(4-cyano-benzyloxy)-5-hydroxymethyl-2-methyl-pyridin-4-yl]-propionic acid ethyl ester (36) (3.5 g, 70% yield).
Reaction SMILES: [Na][Na].[CH2:3]([N:10]1[CH2:13][C:12](C(O)=O)([C:14]([OH:16])=[O:15])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O>C1(C)C(CC(O)=O)=CC=CC=1.O>[CH2:3]([N:10]1[CH2:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C1(C(=O)O)CN(Cc2ccccc2)C1
Agent: Cc1ccccc1CC(=O)O
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: O
Product: O=C(O)C1CN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of the disodium salt of N-benzylazetidine-3,3-dicarboxylic acid and sodium carbonate (approximately 2:1 by weight, total weight 7.5 g) were dissolved in 100 ml of a toluene-acetic acid mixture (2/1, v/v), with immediate evolution of carbon dioxide from the sodium carbonate. The mixture was warmed and stirred, and then refluxed over a Dean and Stark water separator. After 1/2hour evolution of carbon dioxide had ceased and 1.5 ml of an acetic acid-water mixture had separated. The slightly hazy solution was cooled to room temperature. A white fluffy solid comprising sodium acetate (3.6 g) was removed by filtration. Distillation of the clear filtrate yielded 4.5 g of N-benzyl-3-carboxy-azetidine.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:20][CH:11]2[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH-].[K+]>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11](=[O:20])[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc(C2OC2C(=O)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Cc1ccc(C(=O)O)cc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a solution of 5.63 g of 3-(4-carboxyphenyl)-1-phenyl-2,3-epoxy-1-propanone in 100 ml of ethanol at 85°-90°C was added a solution of 6 g of potassium hydroxide in 100 ml of ethanol with stirring over 5 min. The reaction mixture was heated at 85°-90°C for 5 min. and then allowed to cool to room temperature. The solution was evaporated to dryness and the residue was dissolved in 300 ml of ice-water and acidified with 125 ml of hydrochloric acid. After stirring for 30 min., the precipitate was collected and washed with water. The precipitate was dissolved in 600 ml of ethyl acetate and the solution was dried and filtered. The filtrate was evaporated to give 5.63 g (100%) of 3-(4-carboxyphenyl)-1-phenyl-1,2-propanedione as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:33][C@@H:34]1[CH2:36][O:35]1>C(O)C>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:33][C@H:34]([OH:35])[CH3:36])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: C[C@@H]1CO1
Solvent: CCO
Product: C[C@@H](O)CN1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 16.5 %

Procedure:
To a solution of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (55 mg, 0.123 mmol) and (R)-2-methyl-oxirane (250 mg, 4.3 mmol) in 5 mL of ethanol is heated at 70° C. for 18 h. Following SiO2 chromatography, eluting with 0-10% (2M NH3 in MeOH)/dichloromethane] gave 7-cyclopentyl-2-{5-[4-((R)-2-hydroxy-propyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (10 mg, 16%). MS(ESI) m/z 493.3 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[C:4]([C:11]([OH:13])=O)[CH:3]=1.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15]C(C)=O.C(N(CC)CC)C>C(OC(=O)C)(=O)C>[CH2:21]([O:20][C:14]([CH:15]1[C:8](=[O:10])[C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][C:4]=2[C:11]1=[O:13])=[O:19])[CH3:22]
Reactant: Cc1cc(C(=O)O)c(C(=O)O)cn1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C(=O)c2cnc(C)cc2C1=O
Reaction time: 8 h

Procedure:
6-Methyl-pyridine-3,4-dicarboxylic acid (440 mg) (see, Emil J. Moriconi and Francis A. Spano, J. Am. Chem. Soc., Vol. 86, pp. 38-46, 1964) was suspended in acetic anhydride (10 ml) and the mixture was refluxed for 10 minutes. Ethyl acetoacetate (0.325 ml) and triethylamine (0.745 ml) were dropwise added to the mixture at room temperature and the mixture was stirred overnight. The mixture was concentrated to dryness and purified by silica gel column chromatography developed by dichloromethane and by dichloro-methane-methanol (15:1). The desired compound was obtained as a dark red oil which contained 1 equivalent of triethylamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][NH:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=1.ClCCl.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][NH:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2ccncc2)cc1
Yield: 5.6 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(pyridin-4-ylmethyl)benzamide was prepared according to method B with pyridin-4-ylboronic acid (0.030 g; 0.242 mmol), N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.080 g; 0.231 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (0.018; 0.023 mmol), sodium iodide (0.070 g; 0.461 mmol) and sodium carbonate (0.049 g; 0.461 mmol) in dimethoxyethane (3 mL) and water (1 mL) was irradiated in the microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 75 to 100% ethyl acetate in heptane) furnished 0.005 g (5%) of the title compound as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:41]([OH:43])=O)=[CH:34][N:35]2[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1.[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][N:46]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.C(OCC)(=O)C>[F:54][C:51]([F:52])([F:53])[C:48]1[CH:49]=[CH:50][C:45]([NH:44][C:41]([C:33]2[C:32]3[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=3)[N:35]([CH:38]([CH3:39])[CH3:40])[CH:34]=2)=[O:43])=[N:46][CH:47]=1
Reactant: CC(C)n1cc(C(=O)O)c2ccc(Cl)cc21
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)n1cc(C(=O)Nc2ccc(C(F)(F)F)cn2)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 16.5 %

Procedure:
A solution of triphenylphosphine (243 mg, 0.92 mmol) in methylene chloride (3 mL) cooled to 0° C. was treated with N-bromosuccinimide (165 mg, 0.92 mmol). This solution was stirred at 0° C. for 15 min. At this time, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (200 mg, 0.84 mmol). This solution was stirred at 0° C. for 15 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 2-amino-5-(trifluoromethyl)pyridine (340 mg, 2.10 mmol) and was stirred at 25° C. for 18 h. At this time, the reaction was diluted with water (50 mL) and ethyl acetate (50 mL). This mixture was treated with a saturated aqueous sodium bicarbonate solution (15 mL). The organic layer was separated and was washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 hexanes/ethyl acetate) afforded 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide (53 mg, 19%) as a pale yellow solid: mp 179-181° C.; EI-HRMS m/e calcd for C18H15ClF3N3O (M+) 381.0856, found 381.0851.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]([CH3:16])([CH3:15])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9](Br)[CH:8]=1.[C:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].COCCOCCN(CCOCCOC)CCOCCOC>C(OCC)(=O)C.CN(C)C=O>[F:1][CH:2]([F:17])[C:3]([CH3:16])([CH3:15])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18](=[O:20])[CH3:19])[CH:8]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: CC(C)(COCc1ccc(F)c(Br)c1)C(F)F
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N(c1ccccc1)c1cc(COCC(C)(C)C(F)F)ccc1F
Yield: 38.6 %

Procedure:
A mixture of 1,1-difluoro-2,2-dimethyl-3-(3-bromo-4-fluorobenzyloxy)propane (1.5 g), acetanilide (0.716 g), cuprous chloride (0.1 g); potassium carbonate (0.67 g), dry N,N-dimethylformamide (10 cm3) and tri[2-(2-methoxyethoxy)ethyl]amine (catalytic quantity) was heated at 158° C. for 4 days under an atmosphere of nitrogen; the mixture was then stood at the ambient temperature for 1 week. The combined organic extracts were washed with water and brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave a dark oil which was subjected to flash column chromatography on a silica gel support, eluting firstly with petroleum ether (boiling range 40°-6° C.) containing 2% by volume ethyl acetate (to give starting materials and a small amount of the deacylated product) and secondly with petroleum ether (boiling range 40°-60° C.) containing 50% by volume ethyl acetate, to give the title compound as a dark oil (0.68 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([NH:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2C(F)(F)F)CC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CN(C)CCNc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 4-(5-bromo-3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester from step (b) above (174 mg, 0.42 mmol), N-(2-aminoethyl)-N,N-dimethylamine (56 μL, 0.51 mmol, Aldrich), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct (22 mg, 0.021 mmol, Strem Chemicals), biphenyl-2-yl-di-tert-butyl-phosphane (13 mg, 0.042 mmol, Strem Chemicals), sodium t-butoxide (65 mg, 0.63 mmol, Aldrich) in toluene (2 mL) was subjected to microwave irradiation at 150° C. for 0.5 h. The mixture was cooled to room temperature and was filtered. The filtrate was purified by silica gel column chromatography, eluting with 5%-100% (2M NH3 in MeOH) in dichloromethane, to give the title product as a brown solid. MS (ESI, positive ion) m/z: 418 (M+1).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][S:29]C(=O)C)[CH2:12][C@@H:11]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42][CH2:43][C:44]([CH3:47])([OH:46])[CH3:45].CO.[OH-].[K+]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][S:29][CH2:42][CH2:43][C:44]([OH:46])([CH3:47])[CH3:45])[CH2:12][C@@H:11]([O:33][Si:34]([C:37]([CH3:40])([CH3:38])[CH3:39])([CH3:35])[CH3:36])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(O)CCBr
Reactant: CC(=O)SC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)CCSC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(acetylthiomethyl)androsta-5,7-diene (135 mg, 0.223 mmol) and 4-bromo-2-methylbutan-2-ol (186 mg, 1.12 mmol) in tetrahydrofuran (1.5 ml), was added a 1M potassium hydroxide methanol solution (1.5 ml), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, followed by the addition of a saturated aqueous ammonium chloride solution and the extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The thus obtained residue was purified by preparative thin layer chromatography (4 sheets (each 0.5 mm thickness), dichloromethane:ethyl acetate=9:1, developed once) to give the titled compound (131 mg, 90%) as a colorless oil.