Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[SH:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.Cl>C1COCC1>[S:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[S:20][CH2:1][CH:2]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([OH:5])=[O:4]
Reactant: Sc1cccs1
Reactant: C=C(CCC(=O)OCC)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCC(CSc1cccs1)C(=O)O
Temperature: 25 °C
Yield: 53.9 %

Procedure:
Under N2, a mixture of 2-methylene-4-ethoxycarbonylbutyric acid (17 g, 0.09 mol), triethylamine (4.3 g, 0.04 mol) in THF (120 ml) and 2-mercaptothiophene (11 g, 0.095 mol) was heated at reflux. After 24 hours the reaction mixture was cooled to room temperature and poured into 3N HCl (400 ml). The aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were backwashed with saturated NaCl, dried, filtered and concentrated to dryness. The residue was chromatographed on a Still column and the product eluted with 15% CH3OH-CHCl3 saturated with NH3 to yield 14 g of 1 wherein R1, R2, R3 and R4 are each H.
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>>[CH3:1][N:2]([CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(C)NC
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCN(C)C(C)CC(=O)OCC
Temperature: 110 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
A mixture of 54.4 gm (0.374 mole) ethyl 3-(N-methylamino)butanoate and 100 gm (0.999 mole) ethyl acrylate was heated at 110° C. with stirring for 18 hours. The reaction mixture was cooled to room temperature and then distilled under reduced pressure to provide 61.7 gm (67.1%) of the desired compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:14])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:15][S:16][CH2:17][CH:18]([NH2:20])[CH3:19]>C1(C)C=CC=CC=1>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:20][CH:18]([CH3:19])[CH2:17][S:16][CH3:15])[N:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Clc1cc(-c2ccnc(Cl)n2)ccn1
Reactant: CSCC(C)N
Solvent: Cc1ccccc1
Product: CSCC(C)Nc1nccc(-c2ccnc(Cl)c2)n1
Temperature: 60 °C
Yield: 88 %

Procedure:
To a solution of 2-chloro-4-(2-chloro-4-pyridinyl)pyrimidine (i.e., the product of Example 6, Step A) (350 mg, 1.5 mmol) in toluene (4.0 mL) was added 1-(methylthio)-2-propanamine (i.e., the product of Step B) (1 mL, 9.5 mmol) in one portion; this mixture was heated at 60° C. for 18 h. The mixture was allowed to cool and silica gel (300 mg) was added. The excess solvent was removed under reduced pressure, and the resulting solid was chromatographed on silica gel eluted with a solvent gradient of 5% to 60% ethyl acetate in hexanes to give 400 mg (88%) of the title compound as a tan solid, m.p. 103-106° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:25])[N:11]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1.FC1C=CC(C2N=CN(C3CCN([CH2:52][C:53]4[CH:57]=[CH:56][O:55][N:54]=4)CC3)C=2C2C=CN=C(NC)N=2)=CC=1.CO>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH3:25])[N:11]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:52][C:53]4[CH:57]=[CH:56][O:55][N:54]=4)[CH2:21][CH2:20]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:6][CH:7]=1
Reactant: CNc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(Cc3ccon3)CC2)n1
Reactant: Cc1nc(-c2ccc(F)cc2)c(-c2ccncn2)n1C1CCNCC1
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(-c2ccc(F)cc2)c(-c2ccncn2)n1C1CCN(Cc2ccon2)CC1

Procedure:
Compound 14 was prepared from 4-[4-(4-fluorophenyl)-2-methyl-1-piperidin-4-yl-1H-imidazol-5-yl]pyrimidine (C31) according to the general procedure for the synthesis of 4-{4-(4-fluorophenyl)-1-[1-(isoxazol-3-ylmethyl)piperidin-4-yl]-1H-imidazol-5-yl}-N-methylpyrimidin-2-amine (5) in Example 5, except that extractions were carried out with dichloromethane, and the eluant employed for chromatography was 5% methanol in dichloromethane. The product was obtained as a solid. Yield: 10 mg, 0.024 mmol, 23%. LCMS m/z 419.6 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.95-2.00 (m, 2H), 2.15 (ddd, J=11.8, 11.8, 2.0 Hz, 2H), 2.27-2.37 (m, 2H), 2.65 (s, 3H), 3.01 (br d, J=11.6 Hz, 2H), 3.67 (s, 2H), 4.48 (tt, J=12.4, 4.0 Hz, 1H), 6.39 (d, J=1.7 Hz, 1H), 6.96 (dd, J=8.8, 8.8 Hz, 2H), 7.12 (dd, J=5.3, 1.5 Hz, 1H), 7.29 (dd, J=8.8, 5.4 Hz, 2H), 8.38 (d, J=1.7 Hz, 1H), 8.55 (d, J=5.3 Hz, 1H), 9.30 (d, J=1.4 Hz, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.CC(C)([O-])C.[K+]>CS(C)=O.C(OCC)C>[N:8]1[CH:9]=[CH:10][C:11]([O:14][N:20]2[CH2:21][CH2:22][CH2:17][CH2:18][CH2:19]2)=[CH:12][CH:13]=1
Reactant: Clc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: c1cc(ON2CCCCC2)ccn1
Reaction time: 16 h
Yield: 159.7 %

Procedure:
To a solution of N-BOC-4-hydroxypiperidine (3.00 g, 14.9 mmol) in dimethylsulfoxide (10 mL) are sequentially added 4-chloropyridine hydrochloride (2.35 g, 15.6 mmol) and potassium-t-butoxide (30.5 mL of a 1.0 M solution in tetrahydrouran, 30.5 mmol). After 16 hr at ambient temperature, the reaction mixture is diluted with diethyl ether (100 mL) and washed with H2O (3×) and brine, and then dried over sodium sulfate Na2SO4). Concentration of the organic solution gives the desired 4-pyridyloxypiperidine (4.24 g, 100%) as a white solid. Analytical calculation for C15H22N2O3: C, 64.73; H, 7.97; N, 10.06. Found: C, 64.48; H, 8.14; N, 9.82.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:36](O)[CH2:37][CH2:38][OH:39].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])(=[O:12])=[O:11])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:36][CH2:37][CH2:38][OH:39]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2C(F)(F)F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of 5-methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenol (665 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol), and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at room temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (2:1 hexane/ethyl acetate) to give the title compound as a colorless oil (745 mg, 94%). 1H-NMR (300 MHz, CDCl3) δ 8.13 (d, J=7.2 Hz, 1 H), 7.99 (d, J=7.2 Hz, 1 H), 7.80 (t, J=7.6 Hz, 1 H), 7.70 (t, J=7.3 Hz, 1 H), 6.63 (s, 1 H), 6.48 (s, 1 H), 6.46 (s, 1 H), 4.02 (t, J=6.0 Hz, 2 H), 3.81 (m, 2 H), 2.25 (s, 3 H), 1.99 (m, 2 H), 1.61 (s, 1 H).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2/[C:9](=[N:19]\[NH2:20])/[NH:8][C:7]1=[O:21])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:22]([O-])([O-])OCC>>[CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:16])([F:18])[F:17])[NH:11][C:10]=2[C:9]2=[N:19][N:20]=[CH:22][N:8]2[C:7]1=[O:21])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOC([O-])[O-]
Reactant: CCCCCn1c(=O)[nH]/c(=N/N)c2[nH]c(C(F)(F)F)nc21
Product: CCCCCn1c(=O)n2cnnc2c2[nH]c(C(F)(F)F)nc21
Temperature: 100 °C

Procedure:
(6E)-3-Pentyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione-6-hydrazone (0.15 g, 0.20 mmol) was mixed with ethyl orthoformate (2 mL, 10 mmol). The mixture was heated at 100° C. for 30 min, concentrated under reduced pressure and purified by preparative HPLC to yield the desired product. LCMS calculated for C12H14F3N6O (M+H): 315.1. found: 315.1.
Reaction SMILES: [Se](=O)=[O:2].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1>O.O1CCOCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:2])[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1
Reactant: O=C(Cc1ccc(F)cc1)c1ccncc1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(C(=O)c1ccc(F)cc1)c1ccncc1

Procedure:
A solution of selenium dioxide (4.82 g, 43.4 mmol) in H2O (20 mL) was added to a solution of 1-(4-fluorophenyl)-2-(4-pyridyl)-2-ethanone (9.33 g, 43.4 mmol) in dioxane (100 mL) and the resulting mixture was heated at reflux for 2 h. This mixture was concentrated in vacuo, triturated with ethyl acetate and filtered. The residue was purified by column chromatography using ethyl acetate/hexane (1:1) as an eluent to give 1-(4-fluorophenyl)-2-(4-pyridyl)-1,2-ethandione. A mixture of ammonium acetate (25.25 g, 0.328 mol) and hexamethylenetetraamine (9.18 g, 65.5 mmol) was added to a solution of the isolated dione dissolved in acetic acid (150 mL). This mixture was stirred at 80° C. for 2 h, poured into concentrated ammonium hydroxide (200 mL) and the resulting precipitate was filtered, washed with H2O and dried to give the title compound as a solid: mp 242-44.3° C.; MS 240 (MH+).
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH2:8]=[O:9]>C(Cl)(Cl)Cl>[CH3:6][C:5]1([CH3:7])[CH2:4][C:2](=[O:1])[CH2:3][CH2:8][O:9]1
Reactant: CC(=O)C=C(C)C
Reactant: C=O
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)CCO1
Temperature: 165 °C
Reaction time: 16 h

Procedure:
Mesityl oxide (11.6 mmol) and aqueous formaldehyde (11.6 mmol) were combined and heated at 165° C. for 2 hours. The reaction mixture was cooled, partitioned between ethyl acetate and brine, dried over sodium sulfate and evaporated to an oil. The crude reaction product was subjected to flash column chromatography (silica gel) eluting with ethyl acetate-hexane (1:9) to give an oil. The oil was dissolved in chloroform (250 ml), amberlyst 15 resin (11 g) was added and the mixture stirred for about 16 hours. Filtration and evaporation yielded the crude product which was subjected to flash column chromatography (silica gel) eluting with diethyl ether-hexane (1:9) to give the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[O:15]1[CH2:19][CH2:18]OC1=O.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-]>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:18][CH2:19][OH:15])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.66 g, 49.8 mmol), 1,3-dioxolan-2-one (21 g, 238 mmol) and cesium carbonate (16 g, 49.1 mmol) were combined in a 100 mL round bottom flask. The reaction was warmed from room temperature to 100° C. in an oil bath, by which time the carbonate had melted and served as the solvent for the reaction, which remained a slurry. After heating for 3.5 hours, the reaction was cooled to room temperature and diluted with ethyl acetate, then filtered through Celite washing repeatedly with ethyl acetate. The filtrate was concentrated, then purified by chromatography on an Analogix® Intelliflash™ purification system using a SF60-200 g column at a flow rate of 80 mL/min, eluting as follows: 5 minutes at 20% ethyl acetate/hexanes, then ramped from 40% to 90% ethyl acetate/hexanes over 35 minutes, then 100% ethyl acetate for another 20 minutes, to provide the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[CH3:30][N:31]([CH3:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH3:30][N:31]([CH3:41])[C:32]1[CH:37]=[CH:36][C:35]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=2[CH3:29])=[CH:34][CH:33]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccc(N(C)C)cc1)OCC2c1ccc(C(C)C)cc1
Yield: 17 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (4-(dimethylamino)phenyl)boronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 17%. Melting point: 180-181° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C([Mg]Cl)(C)C.[CH:16](N1CCCCC1)=[O:17].Cl>C1COCC1>[F:10][C:4]1[CH:3]=[C:2]([CH:16]=[O:17])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: O=CN1CCCCC1
Reactant: N#Cc1ccc(Br)cc1F
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-bromo-2-fluorobenzonitrile (5.00 g, 25 mmol) in dry THF (50 mL) at −10° C. under argon was treated with a solution of isopropylmagnesium chloride (2M in THF, 15.0 mL, 30.0 mmol) dropwise before stirring at this temperature for 3 h. A solution of N-formylpiperidine (3.89 g, 35.0 mmol) in dry THF (15 mL) was added dropwise and the mixture allowed to warm to room temperature before stirring for 1.5 h. The resultant solution was treated with 4M aq HCl (250 mL each) and the organics extracted with EtOAc. The combined organics were dried (MgSO4), filtered and evaporated before purification of the residue by column chromatography (SiO2; eluting with 30% to 50% EtOAc in cyclohexane) to afford 2-fluoro-4-formyl-benzonitrile VII-a as a pale yellow solid (2.73 g, 73%). 1H NMR (300 MHz, CDCl3) δ 10.07 (d, J=1.7 Hz, 1H), 7.90-7.79 (m, 2H), 7.74 (dd, J=8.5, 0.8 Hz, 1H).
Reaction SMILES: [F:1][CH:2]([F:10])[C:3](=O)[CH2:4][C:5](OC)=[O:6].[CH3:11][NH:12][NH2:13]>CO>[F:1][CH:2]([F:10])[C:3]1[CH:4]=[C:5]([OH:6])[N:12]([CH3:11])[N:13]=1
Reactant: COC(=O)CC(=O)C(F)F
Reactant: CNN
Solvent: CO
Product: Cn1nc(C(F)F)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a solution of methyl 4,4-difluoro-3-oxobutanoate (64 g, 0.38 mol) in methanol (500 mL) was added methylhydrazine (20.5 mL, 0.38 mol). The reaction mixture was left to stir overnight at room temperature. The volatiles were removed in vacuo, toluene was added (400 mL), the mixture was evaporated again, and this procedure was repeated. The resulting solid residue was purified chromatographically on silica gel using ethyl acetate/dichloromethane mixture (1:2, Rf=0.35). The resulting oil was crystallized from ether (200 mL) and dried under the vacuum of a membrane pump (10 mm Hg) for 3 h to give 28 g (49.8%) of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:25][CH:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN1CCC(N)CC1
Product: CN1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Yield: 86.7 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (510 mg, 1.64 mmol) was reacted with 1-methylpiperidin-4-amine (375 mg, 3.28 mmol) to afford the desired product (552 mg, 87%) as a brown solid: 1H NMR (300 MHz, CD3OD) δ 9.12 (s, 1H), 8.38 (d, J=2.0 Hz, 1H), 7.84 (dd, J=8.9, 2.1 Hz, 1H), 7.79-7.71 (m, 1H), 4.20-3.97 (m, 1H), 2.93-2.69 (m, 3H), 2.47-2.19 (m, 5H), 2.19-2.03 (m, 2H), 1.86-1.60 (m, 2H), 1.32-1.16 (m, 2H), 1.16-1.00 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[O:14][CH3:15].C[Si](C)(C)[O:18][C:19]([CH:21]=[CH2:22])=[CH2:20].C1(C)C=CC=CC=1.Cl>C(OCC)(=O)C>[CH3:15][O:14][C:4]1[CH:5]=[C:6]([CH:9]2[CH:10]([N+:11]([O-:13])=[O:12])[CH2:22][CH2:21][C:19](=[O:18])[CH2:20]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1OC
Reactant: C=CC(=C)O[Si](C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(C2CC(=O)CCC2[N+](=O)[O-])cc1OC
Temperature: 140 °C
Reaction time: 48 h

Procedure:
90.0 g of 3,4-dimethoxy-ω-nitrostyrene (compound G2), 90 ml of 2-trimethylsilyloxy-1,3-butadiene and 180 ml of abs. Toluene are put in an autoclave, where the mixture is stirred at 140° C. for 2 days and then cooled. After addition of 1000 ml of ethyl acetate, 300 ml of a 2 N solution of hydrochloric acid are dropped under stirring. The phases are separated and the aqueous layer is extracted three times with dichloromethane. The combined organic extracts are washed with saturated sodium hydrogencarbonate solution, dried over magnesium sulfate and the solvents are removed under reduced pressure to give 150 g of the crude title compound. Further purification is carried out by chromatography on silica gel using petroleum ether/ethyl acetate in the ratio 1/1 as eluent to give 81.5 g (67% of theory) of the pure title compound.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([O:8][C:9](=[O:23])[CH2:10][C:11](=O)[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:7].Cl.[NH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=O>O.C(O)C>[CH2:6]([O:8][C:9]([C:10]1[C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:26][NH:25][C:11]=1[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:23])[CH3:7]
Reactant: NCC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)CCNC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)c[nH]c1CCNC(=O)OC(C)(C)C
Yield: 91.4 %

Procedure:
A stirred solution of anhydrous sodium acetate (2.05 g, 25 mmol) in water (12.5 ml) was added with the solution of 5-tert-butoxycarbonylamino-3-oxo-pentanoic acid ethyl ester (3.23 g, 12.5 mmol) in anhydrous ethanol (2 ml), then the mixture was added with 2-amino-1-(4-fluoro-phenyl)-ethanone hydrochloride (2.37 g, 12.5 mmol), heated to reflux for 3 hours. The resulting mixture was extracted with ethyl acetate (50 ml×3) and the combined extracts were washed with brine (50 ml×3), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(2-tert-butoxycarbonylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester (4.3 g, 91.7%) as a yellow solid.
Reaction SMILES: [I:1]I.[C:3]([O:6][CH:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16](=[CH:17][C:18](=[O:26])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)(=[O:5])[CH3:4]>C(O)(=O)C>[C:3]([O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16](=[CH:17][C:18](=[O:26])[CH:19]([I:1])[CH2:20]1)[CH2:15][CH2:14]3)(=[O:5])[CH3:4]
Reactant: CC(=O)OC1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: II
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C(I)C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 98.6 %

Procedure:
2.79 g (11 mmol) of iodine is added to 3.28 g (10 mmol) of 17-acetoxy-androst-4-en-3-one and 0.875 g (11 mmol) of CuO in 30 ml of glacial acetic acid with stirring at room temperature. The reaction solution is stirred under nitrogen atmosphere for 24 hours at 60° C. Under reduced pressure, acetic acid is distilled off, and the residue is taken up in 50 ml of water. The water phase is extracted 3 times with 50 ml of ethyl acetate each, the ethyl acetate phases are washed with sodium thiosulfate solution and dried on sodium sulfate. Concentration by evaporation of the solution yields 4.5 g of crude product. After recrystallization from ethyl acetate, 2.85 g of 17β-acetoxy-2-iodo-androst-4-en-3-one (65% of theory) of melting point 92° C. is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][C:16]=2[CH3:24])[CH2:7][CH2:6]1.[CH3:28][N:29]1[C:38]2[NH:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[NH:34][CH2:33][C:32]=2[CH:31]=[N:30]1.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:34]3[CH2:33][C:32]4[CH:31]=[N:30][N:29]([CH3:28])[C:38]=4[NH:37][C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][C:35]3=4)=[O:20])=[CH:17][C:16]=2[CH3:24])[CH2:7][CH2:6]1
Reactant: Cc1cc(C(=O)O)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Yield: 5 %

Procedure:
4-{4-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid from Example E43 (139 mg, 0.37 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (75 mg, 0.37 mmol) were dissolved in dichloromethane (5 ml) and DIEA (0.195 ml, 1.11 mmol). WSCD (93 mg, 0.48 mmol) and DMAP (9 mg, 0.07 mmol) were added and the mixture was heated at reflux for 3 days, then washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (11 mg, 5%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring 0° C. suspension of NaH (18.3 g, 763 mmol) in THF (195 mL) was added by addition funnel azepan-2-one (75.0 g, 667 mmol) in THF. An additional 2L of solvent was added as the reaction progressed in order to maintain agitation of the very viscous reaction suspension. Following addition, the reaction was allowed to warm to room temperature, and when the evolution of H2 gas ceased after stirring overnight, benzyl bromide was added dropwise by addition funnel and the reaction was stirred overnight. The crude product was filtered through Celite and concentrated in vacuo. Recrystallization from hexanes and ethyl acetate provided pure 1-benzyl-azepan-2-one as a white fluffy solid. 1H NMR (CDCl3, 300 MHz) 7.38-7.24 (5H, m), 4.61 (2H, s), 3.33-3.29 (2H, m), 2.65-2.61 (2H, m), 1.77-1.66 (4H, m), 1.56-1.46 (2H, m) ppm. 13C NMR (CDCl3, 75 MHz) 176.13, 138.06, 128.67, 128.31, 127.43, 51.20, 49.04, 37.33, 30.12, 28.26, 23.58 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ccc(Cl)nc1
Product: O=C(Nc1ccc(Cl)nc1)c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 5-amino-2-chloropyridine as a white solid as described in Example 1. 1H NMR (CDCl3): 8.89-8.84 (m, 1H), 8.52 (d, J=2.1, 1H), 8.27-8.23 (m, 1H), 8.21-8.17 (m, 1H), 7.83 (s, 1H), 7.53-7.50 (m, 1H), 7.39 (d, J=8.7, 1H).