Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([OH:23])=[CH:15][C:14]=1[CH2:13][C@H:12]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])(=[O:3])[CH3:2].[O:33]1[CH:38]=[CH:37][CH2:36][CH2:35][CH2:34]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>O1CCCC1.C(OCC)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([O:23][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][O:33]2)=[CH:15][C:14]=1[CH2:13][C@H:12]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12

Procedure:
A solution of 21.3 g of 17β-acetoxy-7α-(5-acetoxypentyl)-estra-1,3,5(10)-trien-3-ol in 213 ml of tetrahydrofuran is allowed to stand with 21.3 ml of 3,4-dihydro-2H-pyran and 1.065 g of p-toluenesulfonic acid for 8 hours at room temperature. The reaction solution is mixed with 3 ml of pyridine, then diluted with diethyl ether, washed with water and dried. The residue that is obtained after the concentration by evaporation is chromatographed on silica gel, and 24.3 g of 17β-acetoxy-7α-(5-acetoxypentyl)-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene is obtained as an oil. [α]D22=+31.5° (c=0.535% in chloroform)
Reaction SMILES: [N:1]#[C:2]Cl.[CH:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([CH3:11])[CH:5]=1.C1(O)C=CC=CC=1>>[OH:10][C:9]1[CH:4]=[CH:5][C:6]([CH2:11][C:2]#[N:1])=[CH:7][CH:8]=1
Reactant: N#CCl
Reactant: Cc1ccc(O)cc1
Solvent: Oc1ccccc1
Product: N#CCc1ccc(O)cc1
Yield: 55 %

Procedure:
There were fed into the 1 meter heated reactor having a diameter of 55 mm and an average temperature of 720° C. via line 1 per hour 46.1 grams (0.75 mole) of gaseous cyanogen chloride and via line 2 313.6 grams (2.9 moles) of gaseous p-cresol as well as 1-2 liters of gaseous nitrogen. From the reactor 3 the nitrile containing gas entered into column 5 via the cooled line 4. The column 5 consisted of a "Sambay-Evaporator" having an inner surface area of 0.1 m and an erect packed column 20 cm long. At the foot of the column there were fed in per hour 2-3 liters of gaseous nitrogen, the temperature of the oil in the double jacket of the column is so regulated that the crude product condensing in the column and having a temperature of about 180° C. can be withdrawn via line 8, while at the head of the column 5 the waste gas having a temperature of about 160° C. is led via line 7 into the fractionating column 8. The column 8 has a length of 50 cm, a diameter of 2 cm and is filled with Raschig rings. At the foot of column 8 per hour there were led in about 2-3 liters of gaseous nitrogen. The cooling over the double jacket is so regulated that at the foot of the column there prevails a sump temperature of up to 120° C. and at the column head a temperature of 20°-40° C. The p-cresol condensing in the column 8 contains 5-6% phenol. Only after distillation separation of the phenol can be recovered p-cresol mixed with fresh p-cresol for replacement of material consumed be returned into the reactor 3. The residual gas leaving the column 8 is led via line 10 into the separator 11 at -30° C., as well as to the activated carbon filter (not shown) and thereupon led into the washing column 14 in which there takes place the washing of the residual gas with water. There are obtained in the column 5 per hour 91.6 grams of crude product from which there is obtained by distillation in the column 18 at 160° C./l Torr 54.9 grams of p-hydroxyphenylacetonitrile. This corresponds to a yield of 55% based on the cyanogen chloride employed.
Reaction SMILES: O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]([NH:35][NH:36][C:37](=O)[CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]1[O:34][C:37]([CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[N:36][N:35]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
(CF3SO2)2O (1.0 mL) was slowly added to a −10° C. solution of tert-butyl (3-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-3-oxopropyl)carbamate (1.0 g, 2.17 mmol) and pyridine (1.0 mL) in dry DCM (10 mL). The reaction mixture was allowed to warm to rt and then was stirred at rt for 1 h. Then saturated NaHCO3 was added at 0° C. very slowly. The organic layer was separated and the aqueous layer was exacted with EtOAc (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 10:1 to 4:1 petroleum ether/EtOAc) to give tert-butyl (2-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)ethyl)carbamate (0.40 g, 42%) as a slight yellow solid. ESI-MS (EI+, m/z): 444 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 7.48-7.46 (m, 2H), 7.45-7.37 (m, 3H), 6.99 (t, J=5.5 Hz, 1H), 4.99-4.94 (m, 2H), 4.59 (d, J=7.0 Hz, 1H), 3.73 (br s, 1H), 3.32-3.26 (m, 2H), 2.96-2.92 (m, 2H), 2.85-2.81 (m, 2H), 2.19-2.15 (m, 1H), 2.05-1.99 (m, 2H), 1.86-1.83 (m, 1H), 1.34 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15](OCC)=[O:16])=[N:10]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[C:12]([CH3:14])[C:11]([CH:15]=[O:16])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)cc1C
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(-n2cc(C)c(C=O)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
A solution (10 mL) of ethyl 1-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylate (2.7 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (20 mL) of lithium aluminum hydride (0.40 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr. The mixture was ice-cooled again, and water (1.0 mL), 1N aqueous sodium hydroxide solution (5.0 mL) and water (1.0 mL) were successively added dropwise to quench the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (1.38 g) of 1-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-methanol as a pale-yellow oil. This was dissolved in toluene (30 mL), manganese dioxide (2.0 g) was added, and the mixture was heated under reflux with a Dean-Stark trap for 1 hr. The reaction mixture was allowed to cool to room temperature, and manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title object compound (0.96 g, 43%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[F:14][C:15]1[C:16]([O:24][CH3:25])=[C:17]([C:20]([F:23])=[CH:21][CH:22]=1)[CH:18]=O>>[F:14][C:15]1[C:16]([O:24][CH3:25])=[C:17]([CH:18]2[N:11]([CH2:10][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=3)[C:16](=[O:24])[CH:15]([F:14])[CH2:22]2)[C:20]([F:23])=[CH:21][CH:22]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COc1c(F)ccc(F)c1C=O
Product: COc1c(F)ccc(F)c1C1CC(F)C(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedures 10A2 (GP10A2), 10B (GP10B), 10F (GP10F), and 10I (GP10I) using commercially available (4-(trifluoromethoxy)phenyl)methanamine and synthesized 3,6-difluoro-2-methoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 419.85 g/mol.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CC(C(=O)Cl)c1ccc2c(c1)CCc1ccccc1C2=O
Reactant: CN1CCNCC1
Product: CC(C(=O)N1CCN(C)CC1)c1ccc2c(c1)CCc1ccccc1C2=O
Yield: 103 %

Procedure:
Following the procedure of Example 6 but starting with 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionyl chloride (8 g.) and 1-methylpiperazine (8.2 g.), 4-[2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionyl]-1-methylpiperazine (10 g.) is obtained in the form of an oil.
Reaction SMILES: [H-].[Na+].[Br-].[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:6])=[O:5].[O:30]([CH2:38][C@H:39]1[C@@H:44]([CH2:45][CH:46]=O)[CH2:43][O:42][C@@H:41]([CH3:48])[O:40]1)[Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].[Cl-].[NH4+].C(O)(=O)C(O)=O>CS(C)=O>[O:30]([CH2:38][C@H:39]1[C@@H:44]([CH2:45]/[CH:46]=[CH:10]\[CH2:9][CH2:8][CH2:7][C:4]([OH:6])=[O:5])[CH2:43][O:42][C@@H:41]([CH3:48])[O:40]1)[Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@H]1OC[C@H](CC=O)[C@H](CO[Si](C)(C)C(C)(C)C)O1
Agent: O=C(O)C(=O)O
Agent: [Br-]
Agent: [Cl-]
Solvent: CS(C)=O
Product: C[C@@H]1OC[C@H](C/C=C\CCCC(=O)O)[C@H](CO[Si](C)(C)C(C)(C)C)O1
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
A suspension of sodium hydride (3.49 g, 60% in oil) in dimethylsulfoxide (75 ml) was heated at 75° C. for 1 hour and the resulting solution was cooled to room temperature. To the solution was added dropwise (4-carboxybutyl)triphenylphosphonium bromide (32.2 g) in dimethylsulfoxide (100 ml). After being stirred at room temperature for 15 minutes, to the mixture was added (2R,4R,5S)-4-t-butyldimethylsiloxymethyl-5-formylmethyl-2-methyl-1,3-dioxane (6.3 g) in dimethylsulfoxide (10 ml) and the solution was stirred at room temperature for 1.5 hour. To the reaction mixture was added aqueous ammonium chloride (100 ml) and the mixture was adjusted to pH 4 with oxalic acid. The mixture was extracted with ethyl acetate and the organic layer was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column (150 g) with a mixture of n-hexane and ethyl acetate (10:1 - 1:1) as an eluent to give (2R,4R,5S)-4-t-butyldimethylsiloxymethyl-5-[(Z)-6-carboxy-2-hexenyl]-2-methyl-1,3-dioxane (5.50 g) as a colorless oil.
Reaction SMILES: [ClH:1].O1CCOCC1.[Br:8][C:9]1[CH:10]=[C:11]2[N:27]([CH3:28])[CH:26]=[CH:25][C:12]2=[N:13][C:14]=1[C@H:15]([NH:17]C(=O)OC(C)(C)C)[CH3:16]>>[ClH:1].[Br:8][C:9]1[CH:10]=[C:11]2[N:27]([CH3:28])[CH:26]=[CH:25][C:12]2=[N:13][C:14]=1[C@H:15]([NH2:17])[CH3:16]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1Br
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](N)c1nc2ccn(C)c2cc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 100 mL pear flask was charged with 4.0M hydrogen chloride in dioxane (2.117 mL, 8.47 mmol) and cooled in an ice-bath. To the beige solution was added (R)-tert-butyl (1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (3 g, 8.47 mmol) in one portion. The ice-bath was removed and the mixture was stirred at RT for 90 minutes. Ethoxyethane was added (80 mL) and the mixture was cooled in an ice-bath. A resulting white precipitate was collected on a fritted glass funnel to give an HCl salt of the title compound, which was used without further purification.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[N:7]=[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CS(C)=O>[C:17]1([C:8]2[O:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]([CH2:5][C:1]#[N:2])[N:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1nc(-c2ccccc2)oc1-c1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1nc(-c2ccccc2)oc1-c1ccccc1
Temperature: 45 °C
Reaction time: 3 h
Yield: 103.7 %

Procedure:
To a suspension of potassium cyanide (67.1 mg, 0.999 mmol) in DMSO (2 mL) was added dropwise at RT a solution of 4-(chloromethyl)-2,5-diphenyloxazole (245 mg, 908 μmol) in DMSO (3 mL) over a period of 5 min. The reaction mixture was stirred at RT for 2 h and at 45° C. for another 3 h. The reaction mixture was cooled to RT, poured into water (25 mL) and extracted with ethyl acetate (2×75 mL). The organic phases were washed with water (2×20 mL) and brine (1×20 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 245 mg crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light yellow solid (189 mg, 726 μmol, 79.9%).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][C:32]([NH2:39])([CH3:38])[C:33]1[O:37][CH:36]=[CH:35][CH:34]=1>>[CH3:31][C:32]([NH:39][C:22]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)=[O:30])([CH3:38])[C:33]1[O:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(N)c1ccco1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: CC(C)(NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C)c1ccco1
Yield: 71 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and α,α-dimethylfurfurylamine (prepared as described in Preparation 11c) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 71%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[PH:10](=O)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>C(N(CC)CC)C>[CH2:12]([O:11][P:10]([CH:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[CH:3]=1)[OH:6])[O:14][CH2:15][CH3:16])[CH3:13]
Reactant: CCO[PH](=O)OCC
Reactant: O=Cc1cccc(Br)c1
Solvent: CCN(CC)CC
Product: CCOP(OCC)C(O)c1cccc(Br)c1
Temperature: 40 °C
Reaction time: 72 h
Yield: 98.3 %

Procedure:
Into a mixture of 3-bromobenzaldehyde (20 g, 108.1 mmol) and diethyl phosphonate (14.2 g, 108.1 mmol) was added triethylamine (0.44 g, 4.32 mmol) and the mixture was stirred at 40° C. for 72 hours. Purification by ISCO (hexane/EtOAc 1/1) gave diethyl[(3-bromophenyl)(hydroxy)methyl]phosphonite (32.62 g); MS m/e (M)+ 322.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])[CH2:2]1
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=S(=O)(NC1CNc2ccccc2C1)c1ccccc1
Product: O=S(=O)(NC1Cc2ccccc2N(Cc2cccc(Cl)c2)C1)c1ccccc1

Procedure:
The title compound was prepared from 162B and 3-chlorobenzaldehyde by procedures analogous to those described in Example 22A. HPLC: 99% at 3.94 min (retention time) (Conditions: Phenom Prime S5, C18 (4.6×50 mm); Eluted with 0% to 100% B, 4 min gradient (A=90% H2O−10% MeOH−0.1% TFA and B=10% H2O−90% MeOH−0.1% TFA); Flow rate at 4.0 mL/min, UV detection at 220 nm). MS (ES): m/z 413 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[C:17]=1[N+:23]([O-:25])=[O:24]>CN(C=O)C>[NH2:5][C:4]1[CH:3]=[C:2]([CH:8]=[CH:7][CH:6]=1)[O:1][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[C:17]=1[N+:23]([O-:25])=[O:24]
Reactant: Nc1cccc(O)c1
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cccc(Oc2ccnc(N)c2[N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
3-Hydroxyaniline (2.07 g, 19.0 mmol) was dissolved in dry DMF (65 mL) and the solution was degassed by argon bubbling for 10 minutes. Potassium tert-butoxide (2.13 g, 19.0 mmol) was added and the stirring was continued for 1 hour at room temperature. 4-Chloro-3-nitropyridin-2-amine (3.0 g, 17.3 mmol) was added as a solid in one portion and the reaction mixture was subsequently heated at 80° C. for 20 hours. The solvent was evaporated in vacuo and the brown oily residue was taken up in 1M HCl (aq) (50 mL). This layer was washed with EtOAc (3×50 mL) and subsequently basified to pH ˜10 with 1M NaOH (aq). The brown precipitate was collected, washed with H2O (3×25 mL) and dried in vacuo, to afford 4-(3-aminophenoxy)-3-nitropyridin-2-amine (3.50 g, 80%). 1H-NMR (δ, ppm, DMSO-d6): 5.39 (s, 2H, NH2), 6.02 (d, 1H, HPy,5, J=5.7 Hz), 6.23-6.30 (m, 2H, Harom,Ph′), 6.47 (d, 1H, Harom,Ph′, J=8.0 Hz), 7.04-7.24 (m, 3H, NH2+Harom,Ph′), 7.48 (m, 2H, Harom), 7.98 (d, 1H, HPy,5); LC-MS (m/z): 247 (M+H, 100).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:39]=[C:38]([CH3:40])[C:37]([O:41]CC4C=CC=CC=4)=[C:36](Cl)[CH:35]=3)[C:19](=[O:32])[N:20]3[CH2:25][CH2:24][N:23]([CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:50]=[CH:51][CH:52]=[CH:53][C:4]=2[NH:3]1.[H][H]>CO.C(N(CC)CC)C.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:35]=[CH:36][C:37]([OH:41])=[C:38]([CH3:40])[CH:39]=3)[C:19](=[O:32])[N:20]3[CH2:21][CH2:22][N:23]([CH:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[CH2:24][CH2:25]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:50]=[CH:51][CH:52]=[CH:53][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(Cl)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)ccc1O

Procedure:
A suspension of 108 mg (0.15 mmol) (R)-1-(4-benzyloxy-3-chloro-5-methyl-benzyl)-2-oxo-2-[4-(tetrahydropyran-4-yl)-piperazin-1-yl]-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 30 mg 10% Pd/C in 10 mL MeOH and 0.5 mL triethylamine was hydrogenated at RT and 3000 hPa hydrogen pressure until the theoretical amount of hydrogen had been taken up. The catalyst was filtered off, the residue was dissolved in 1 mL DMF and purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.O=P(Cl)(Cl)Cl.CN([CH:25]=[O:26])C>>[F:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:25]=[O:26])=[C:12]([OH:16])[CH:11]=2)[CH2:8][CH2:9]1
Reactant: CN(C)C=O
Reactant: Oc1cccc(N2CCN(CCF)CC2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N2CCN(CCF)CC2)cc1O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
600 mg (2.675 mmol) 3-[4-(2-Fluoro-ethyl)-piperazin-1-yl]-phenol are dissolved in 8 mL DMF and cooled to 0° C. 0.27 mL (1.1 eq) POCl3 is added dropwise within 2 min. and the reaction mixture stirred for an additional 5 min. before being allowed to reach room temperature, and then heated and stirred for 3 h at 90° C. The reaction mixture is evaporated and the residue extracted with water and ethyl acetate. The organic phases are washed with brine, dried over sodium sulphate and evaporated. The residue is column chromatographed (silica gel, ethyl acetate followed by ethyl acetate/MeOH 85:15) to yield the desired product as a yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12](=O)[NH:13]N2CCCCC2)=[CH:6][C:5]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27]>O1CCCC1>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]2[CH2:8][CH2:9][CH2:4][CH2:5][CH2:6]2)=[CH:6][C:5]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27]
Reactant: COCCCCOc1cc(OCC(=O)NN2CCCCC2)ccc1C(=O)OC
Solvent: C1CCOC1
Product: COCCCCOc1cc(OCCN2CCCCC2)ccc1C(=O)OC
Reaction time: 4 h

Procedure:
A solution of 2-(4-methoxybutoxy)-4-(piperidin-1-ylcarbamoylmethoxy)-benzoic acid methyl ester (2.29 g) in tetrahydrofuran (10 ml) is added dropwise at 0°-5° C. over a period of 15 minutes to a 1M borane THF complex solution in tetrahydrofuran (10.0 ml). The mixture is then heated to reflux temperature and stirred for 4 hours. A further 2.0 ml of a 1M borane THF complex solution are added. After one hour under reflux, the mixture is allowed to cool, the solvent is removed, and anhydrous methanol (0.97 ml) and 3.75N hydrochloric acid solution in diethyl ether (1.61 ml) are added to the residue. After stirring overnight at room temperature, the mixture is concentrated and the crude product is purified by FC (eluant gradient from P to N). 2-(4-Methoxybutoxy)-4-(piperidin-1-ylethoxy)-benzoic acid methyl ester, Rf (L)=0.38, is obtained in the form of a brown oil (1.39 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 70 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 70%). 1H NMR (300 MHz, CDCl3): δ 2.43-2.49 (m, 3H), 3.13-3.21 (m, 4H), 3.77 (s, 3H), 4.11-4.13 (m, 4H), 6.88-6.99 (m, 4H), 7.13 (m, 1H), 7.25 (m, 1H), 7.48-7.65 (m, 2H).