Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:38](I)[CH3:39]>CN(C)C=O>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[CH2:38][CH3:39]
Reactant: CCI
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(C)C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.7 %

Procedure:
5-Methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1 g) is dissolved in dimethylformamide (10 ml) and thereto are added potassium carbonate (0.5 g) and ethyl iodide (0.45 g). The mixture is stirred at room temperature overnight. After completion of the reaction, the reaction solution is poured into ice-water and the precipitated crystal is collected by filtration, and purified by silica gel column chromatography (eluent; dichloromethane:methanol=90:1), and recrystallized from diisopropyl alcohol/petroleum ether to give 5-(N-methyl-N-ethylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (50 mg) as white powder, m. p. 192°-193° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][OH:23])[CH:16]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>N1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][O:23][S:26]([CH3:25])(=[O:28])=[O:27])[CH:16]=1
Reactant: Nc1c(C(=O)c2cccc(CCO)c2)cnn1-c1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of 5-amino-1-(4-fluorophenyl)-4-[3-(2-hydroxyethyl)benzoyl]pyrazole (0.8 g, 2.5 mmol) in pyridine (10 ml) was added methanesulfonyl chloride (0.29 ml, 3.7 mmol). After 2 h, the reaction mixture was poured into 2 N hydrochloric acid (40 ml) and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 40-100% ethyl acetate/hexane) to give 5-amino-1-(4-fluorophenyl)-4-[3-(2-methanesulfonyloxyethyl)benzoyl]pyrazole (0.87 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C([Li])CCC.CON(C)[C:24](=[O:26])[CH3:25]>C1COCC1.CCCCCC>[F:15][C:14]1[CH:13]=[CH:12][C:4]([CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)=[CH:3][C:2]=1[C:24](=[O:26])[CH3:25]
Reactant: Fc1ccc(CN2CCOCC2)cc1Br
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)c1cc(CN2CCOCC2)ccc1F
Temperature: -75 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
4-(3-Bromo-4-fluorobenzyl)morpholine (Preparation 4, 35.5 g) is dissolved in THF (400 mL) and cooled to −75° C. A solution of n-butyllithium in hexane (2.5 M, 57.0 mL) is added via addition funnel, maintaining the temperature below −68° C. A solution of N-methoxy-N-methylacetamide (16.0 g) in THF (50 mL) is added via addition funnel, maintaining the temperature below −65° C. The reaction is stirred at −75° C. for 1 h and allowed to warm to rt overnight. The reaction is quenched with 1 N HCl (150 mL) and poured into ethyl acetate (400 mL). The aqueous layer is separated, basified with sat. aq. NaHCO3, and extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with sat. NaHCO3 (2×100 mL) and brine (50 mL). The combined aqueous washes are back-extracted with ethyl acetate (100 mL). The organic layers are combined, dried (Na2SO4), and concentrated in vacuo to a yellow oil. The crude product is distilled (135° C., 0.3 Torr) to afford 19.7 g (64%) of the title compound as a clear, colorless oil. Physical characteristics: Bp 135° C. (0.3 Torr); 1H NMR (300 MHz, DMSO-d6) δ 7.72, 7.61-7.56, 7.31, 3.56, 3.48, 2.58, 2.34; IR (liq.) 1996, 1979, 1919, 1688, 1612, 1492, 1417, 1361, 1291, 1281, 1212, 1118, 865 cm−; MS (ESI+) m/z 238 (M+H)+. Anal. Calcd for C13H16FNO2: C, 65.81; H, 6.80; N, 5.90. Found: C, 65.43; H, 6.75; N, 5.84.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])[CH2:2][CH3:3].C(=O)(O)[O-].[Na+].Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CCOCC>[CH3:21][O:20][C:18](=[O:19])[CH2:17][NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:5]=1
Reactant: COC(=O)CCl
Reactant: CCCc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCCc1cccc(NCC(=O)OC)c1
Reaction time: 24 h

Procedure:
3-n-Propyl-aniline (20 g, 148 mmol), sodium bicarbonate (24.9 g, 296 mmol) and methyl chloroacetate (24.0 g, 221 mmol) were mixed under nitrogen and stirred at 80°-90° C. for 24 h. The cooled reaction was poured into ether (100 ml) and filtered. The filtrate was washed with water (100 ml), dilute hydrochloric acid (100 ml) and water (100 ml), then dried and concentrated in vacuo. The oily product (21.2 g) was distilled on the Kugelrohr collecting the fraction boiling at 160°/0.35 mmHg to give the title compound (Intermediate 32) as a colourless liquid which solidified into a pale yellow, low melting solid (16.1 g, 53%).
Reaction SMILES: [C:1]1([P:7](=[O:10])([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O.[Ru]>[CH:1]1([P:7](=[O:8])([OH:10])[OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=P(O)(O)c1ccccc1
Agent: [Ru]
Solvent: O
Product: O=P(O)(O)C1CCCCC1
Yield: 95 %

Procedure:
A cycloalkyl phosphorus compound is obtained by the catalytic hydrogenation of a substituted or unsubstituted aryl phosphonic acid using a heterogeneous catalyst which is a Group VIII metal on carbon. The hydrogenation is preferably effected in water. The catalyst can be ruthenium or carbon. When phenylphosphonic acid is used as the starting material, a yield of about 95% of essentially pure cyclohexylphosphonic acid can be obtained.
Reaction SMILES: O[C@@H]([C@@H](CCCC1C=CC=CC=1)C(O)=O)C(N1CCOCC1)=O.C[O:25][C:26](=[O:48])[C@@H:27]([CH:37]([O:46][CH3:47])[C:38]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[O:39])[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:47][O:46][CH:37]([C@@H:27]([CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:26]([OH:48])=[O:25])[C:38]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[O:39]
Reactant: COC(=O)[C@H](CCCc1ccccc1)C(OC)C(=O)N1CCOCC1
Agent: O=C(O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1
Product: COC(C(=O)N1CCOCC1)[C@@H](CCCc1ccccc1)C(=O)O

Procedure:
It is similarly prepared according to the procedure of (22), but using (R)-2-(1-Methoxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid methyl ester (6b).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.C(N(CC)C(C)C)(C)C.Cl.[NH2:44][C:45]([CH3:51])([CH3:50])[C:46]([O:48][CH3:49])=[O:47]>CN(C=O)C>[CH3:49][O:48][C:46](=[O:47])[C:45]([NH:44][C:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[OH:1])=[O:14])([CH3:51])[CH3:50]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: COC(=O)C(C)(C)N
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1O
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a solution of 4.70 g 1-hydroxy-2-naphthalene carboxylic acid in 40 ml abs. DMF under inert atmosphere 3.72 g 1-hydroxybenzotriazole and 8.89 g N,N′-diisopropyl carbodiimide and 7 ml of N,N-diisopropylethylamine were added at 0° C. After 30 minutes at 0° C. 4.22 g of methyl 2-aminoisobutyrate hydrochloride, followed by 5 ml of N,N-diisopropylethylamine were added. After 16 h at room temperature the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl and brine. The organic layer was dried over magnesium sulphate, and concentrated and the resulting residue was crystallized from toluene to yield 4.18 g of 2-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester.
Reaction SMILES: NCCC[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:8]#[N:9].N1C=CC(C2C=CC(C(O)=O)=CC=2)=CC=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:19][O:18][CH2:17][CH2:16][O:15][CH2:14][O:13][C:12]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[CH:10][CH:11]=1
Reactant: COCCOCOc1ccc(C#N)cc1CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)c1ccc(-c2ccncc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCOCOc1ccc(C#N)cc1
Temperature: 35 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
3-(3-Aminopropyl)-4-(2-methoxyethoxymethoxy)benzonitrile (88 mg, 0.33 mmol) in DMF (0.5 mL) is added to a mixture of 4-pyridin-4-yl benzoic acid (60 mg, 0.3 mmol), TBTU (106 mg, 0.33 mmol), and Et3N (0.043 mL, 0.033 mmol) in DMF (1 mL). The mixture is stirred at 35° C. for 4 hours. The solution is diluted with EtOAc (20 mL), washed with saturated NaHCO3 (3×17 mL) and brine (3×17 mL), dried over MgSO4, filtered and concentrated. The residue is chromatographed (4% MeOH/CH2Cl2) to give 3-[4-(pyridin-4-yl)-benzamido]propyl)-4-(2-methoxyethoxymethoxy)-benzonitrile (0.09 g, 0.20 mmol), contaminated with an unknown byproduct. The crude material (0.08 g, 0.18 mmol) is dissolved in CH2Cl2 (5 mL), treated with MCPBA (57-86%, 92 mg) at 0° C., a room temperature for 2 hours. The residue from aqueous workup and concentration is treated with anhydrous HCl/EtOH followed by ammonolysis as described in Example 307, part D. HPLC purification (10% MeCN/0.1% TFA in H2O to 100% MeCN) gave the title compound (0.007 g, 0.01 mmol). 1H NMR (CD3OD, 300 MHz) δ8.94 (bs, 1H), 8.65 (bs, 1H), 8.40 (m, 3H), 7.90 (m, 6H), 7.64 (d, 1H), 7.57 (dd, 1H), 6.93 (d, 1H), 3.43 (t, 2H), 2.77 (t, 2H), 1.97 (m, 2H). Ion spray MS [M+1]=391, [M+2]2+=196.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[N+:28]([O-])=O)[C:19]2=[O:31])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(OCC)(=O)C.CCCCCC.CCOCC>C(OCC)(=O)C.CC(C)=O.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH2:28])[C:19]2=[O:31])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Agent: [Pd]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Reaction time: 5 h
Yield: 83.2 %

Procedure:
A mixture of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-nitroisoindoline-1,3-dione (710 mg, 1.58 mmol) and Pd/C (200 mg) in ethyl acetate/acetone (40 mL each) was shaken under H2 (50 psi) in a Parr Type Shaker for 5 hours. The suspension was filtered through a pad of magnesium sulfate. The filtrate was concentrated in vacuo to give an oil. The oil was stirred with ethyl acetate (a mL), hexane (2 mL) and ether (2 ML)for 1 h. The resulting suspension was filtered and the solid was dried in a vacuum oven to give 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-aminoisoindoline-1,3-dione as a yellow solid (550 mg, 83% yield): mp, 135.0-137.5° C.; 1H NMR (DMSO-d6); δ 1.32 (t, J=6.9 Hz, 3H, CH3), 3.00 (s, 3H, CH3), 3.73 (s, 3H, CH3), 4.00 (q, J=6.9 Hz, 2H, CH2), 4.08 (dd, J=4.2, 14.5 Hz, 1H, CHH), 4.36 (dd, J=10.8, 14.2 Hz, 1H, CHH), 5.72 (dd, J=4.1, 10.3 Hz, 1H, NCH), 6.51(br s, SH, NH2), 6.89-7.07 (m, 5H, Ar), 7.43 (t, J=7.4, Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.68, 41.55, 48.62, 55.23, 55.93, 64.48, 110.70, 111.42, 112.52, 112.96, 120.38, 121.30, 129.95, 132.23, 135.37, 145.56, 148.56, 149.56, 168.19, 169.43; Anal Calcd for C20H22NO6S: C, 57.41; H, 5.30; N, 6.69. Found C, 57.11; H, 5.23; N, 6.43.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11](=[O:28])[N:12]([C:16]1[S:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:20]=1)[CH2:13][CH2:14][OH:15])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([O:10][C:11]([N:12]([C:16]1[S:17][CH:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[N:20]=1)[CH2:13][CH2:14][O:15][S:2]([CH3:1])(=[O:4])=[O:3])=[O:28])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N(CCO)c1nc(-c2ccc(F)cc2)cs1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCOS(C)(=O)=O)c1nc(-c2ccc(F)cc2)cs1
Reaction time: 4 h

Procedure:
98.7 mg (0.86 mmol) of methanesulfonyl chloride were added dropwise with cooling to 265 mg (0.78 mmol) of (4-(4-fluorophenyl)thiazol-2-yl)-(2-hydroxyethyl)-carbamic acid tert-butyl ester and 237.7 mg (2.35 mmol) of triethylamine in 25 ml of methylene chloride. After 4 h at room temperature, the mixture was extracted with water and the organic phase was concentrated. Yield: 241 mg (74%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[Br-:20].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:20][C:11]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:3]2[CH2:4][CH2:5][O:1][N:2]=2)[C:12]=1[CH3:13]
Reactant: Cc1cccc(N)c1C1=NOCC1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(Br)ccc(N)c1C1=NOCC1

Procedure:
30 g (170 mmol) of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline are dissolved in 400 ml of acetonitrile, and 94 g (0.68 mol) of potassium carbonate are added. At temperatures <30° C., 84 g (174 mmol) of tetrabutylammonium tribromide are then added a little at a time, with vigorous stirring. For work-up, the solid is filtered off with suction and the solution is diluted with methylene chloride and extracted with water. The solvent is stripped off and the residue is then taken up again in methyl tert-butyl ether and washed twice with water. The organic phase is dried and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(N3CCN(C)CC3)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 60.4 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (17 mg, 0.034 mmol) in DCM (2 mL) was added 1-methylpiperazine (0.011 mL, 0.10 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (11 mg, 60%). LC-MS m/z 536 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 3H), 1.66 (m, 2 H), 2.28 (s, 3H), 2.31 (s, 3H), 2.42 (m, 4H), 3.37 (m, 2H), 3.57 (m, 4H), 4.13 (m, 2H), 7.16 (m, 2H), 7.46 (m, 1H), 7.51 (m, 1H), 7.68 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:23]C(=O)C1C=CC(F)=C(Br)C=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])NCCC(C)(C)C)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]1[C:43]([N:44]2[CH2:48][CH2:47][CH2:46][C:45]2=[O:49])=[CH:42][C:41]([N:50]2[CH2:54][CH2:53][CH2:52][C:51]2=[O:55])=[CH:40][C:36]=1[C:37](O)=[O:38].N[C@H]([C@H]1OC(=O)[C@H](C)C1)CC1C=CC=CC=1>>[F:34][C:35]1[C:43]([N:44]2[CH2:48][CH2:47][CH2:46][C:45]2=[O:49])=[CH:42][C:41]([N:50]2[CH2:54][CH2:53][CH2:52][C:51]2=[O:55])=[CH:40][C:36]=1[C:37]([NH:23][C@H:8]([C@@H:9]1[CH2:10][C@@H:11]([CH3:12])[C:13](=[O:21])[O:22]1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:38]
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1ccc(F)c(Br)c1)C(=O)NCCC(C)(C)C
Reactant: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1F
Agent: C[C@@H]1C[C@@H]([C@@H](N)Cc2ccccc2)OC1=O
Product: C[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)c2cc(N3CCCC3=O)cc(N3CCCC3=O)c2F)OC1=O

Procedure:
Prepared in an analogous manner to D3 from 2-fluoro-3,5-bis-(2-oxopyrrolidin-1-yl)benzoic acid (D40) and (3R,5S)-5-((S)-1-amino-2-phenylethyl)-3-methyldihydrofuran-2-one (D48).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[F:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][C:30](=[O:36])[NH:31]3)[CH:24]=[CH:25][CH:26]=1>>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13](/[CH:16]=[C:29]3\[C:30](=[O:36])[NH:31][C:32]4[C:28]\3=[C:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[CH:22]=3)[CH:35]=[CH:34][CH:33]=4)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Yield: 38.9 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-5-(2-dimethylamino-ethyl)-2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 41 (37 mg, yield 38.9%) as a yellow solid.
Reaction SMILES: [NH2:1][OH:2].Cl.NO.C[O-].[Na+].[N+:9]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH:14]=[CH:15][C:16]#[N:17])([O-:11])=[O:10]>CO>[N+:9]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH:14]=[CH:15][C:16](=[N:1][OH:2])[NH2:17])([O-:11])=[O:10]
Reactant: N#CC=Cc1ccccc1[N+](=O)[O-]
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(C=Cc1ccccc1[N+](=O)[O-])=NO

Procedure:
A solution of hydroxylamine prepared from hydroxylamine hydrochloride (8.34 g.) in methanol (150 ml.) by neutralisation with sodium methoxide was added to o-nitrocinnamonitrile (6.96 g.) (S. Malinowski, Roczniki Chem., 1952, 26, 85) and the mixture was refluxed for 2 hr., then evaporated to ca. 15 ml. under reduced pressure. Ethyl acetate (150 ml.) was added, and the solution was extracted with 2N-hydrochloric acid (2 × 150 ml.). The acid extracts were neutralised with solid sodium hydrogen carbonate, giving a solid (3.3 g., 40%). Recrystallisation from aqueous methanol gave o-nitrocinnamamidoxime, m.p. 173°, λmax. 236, 265 nm, (ε 17150, 14700) (Found: C, 52.4; H, 4.5; N, 20.05. C9H9N3O3 requires C, 52.2; H, 4.4; N, 20.3%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[C:16]=2[CH:30]=1.CC(C1C=C(C(C)C)C(S([N:46]=[N+:47]=[N-:48])(=O)=O)=C(C(C)C)C=1)C.C(O)(=O)C>>[N:46]([CH:19]1[N:18]=[C:17]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:16]2[CH:30]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[N:21]([CH3:22])[C:20]1=[O:23])=[N+:47]=[N-:48]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: CN1C(=O)CN=C(c2cccnc2)c2cc(Cl)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Product: CN1C(=O)C(N=[N+]=[N-])N=C(c2cccnc2)c2cc(Cl)ccc21
Yield: 90.2 %

Procedure:
As illustrated in the scheme above and following General Procedure 6, KHMDS (10.5 mL of 0.5 M in toluene, 5.25 mmol), 7-chloro-1,3-dihydro-1-methyl-5-(3-pyridinyl)-2H-1,4-benzodiazepin-2-one (1.43 g, 4.99 mmol), trisyl azide (3.86 g, 12.5 mmol) and acetic acid (1.26 mL, 22.0 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (1:1 CH2Cl2:EtOAc) provided the title compound as a yellow foam (1.47 g, 90%). 1H-NMR (CDCl3): δ 8.80 (s, 1H), 8.76 (d, J=3.6 Hz, 1H), 8.14 (dt, J=1.6 Hz, J=8.0 Hz, 1H), 7.61 (dd, J=2.0 Hz, J=8.4 Hz, 1H), 7.44 (ddd, J=0.8 Hz, J=4.8 Hz, J=8.0 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H), 4.56 (s, 1H), 3.48 (s, 3H). MS (ESI) (M+H)+=327.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[N:12]=[C:11]([C:21]([OH:23])=O)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[N:12]=[C:11]([C:21]([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=[O:23])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: Cc1ccc(-n2nc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)cn1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: Cc1ccc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2cc(F)cc(Cl)c2)cn1

Procedure:
57 mg (0.17 mmol) of the compound of Example 24A is reacted analogously to the synthesis of the compound of Example 1 with 23 mg (0.19 mmol) of 4-imidazolinone-hydrochloride. 58 mg (84% of theory) of the title compound is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C@@H:12]2[CH2:17][C@H:16]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])[CH2:15][CH2:14][C@@H:13]2[NH:23][C:24](=[O:39])[CH2:25][C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:38])([F:37])[F:36])[C:28]=3[N:27]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[C:41]([N:43](C)C)=O>[C-]#N.[C-]#N.[Zn+2].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.[Pd].[Pd].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.[Fe+2].[Zn]>[C:41]([C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][C@@H:12]2[CH2:17][C@H:16]([N:18]([CH:20]([CH3:21])[CH3:22])[CH3:19])[CH2:15][CH2:14][C@@H:13]2[NH:23][C:24](=[O:39])[CH2:25][C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:36])([F:37])[F:38])[C:28]=3[N:27]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1)#[N:43]
Reactant: CC(=O)N(C)C
Reactant: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)Cc2nc3c(C(F)(F)F)cccc3[nH]2)[C@H](CS(=O)(=O)c2ccc(Br)cc2)C1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)Cc2nc3c(C(F)(F)F)cccc3[nH]2)[C@H](CS(=O)(=O)c2ccc(C#N)cc2)C1
Temperature: 105 °C

Procedure:
(1S,2R,4R)—N-[2-(4-Bromo-benzenesulfonylmethyl)-4-(isopropyl-methyl-amino)-cyclohexyl]-2-(4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetamide, Example 3, (30 mg) was dissolved in DMA (1 ml) prior to the addition of Zn(CN)2 (34 mg), Pd2(dba)3 (10 mg), dppf (11 mg) and Zn powder (4 mg). The resulting solution was heated at 105° C. oil bath for over night. After cooling, the solution was concentrated. EtOAc and 10% amminum hydroxide (aq) were added. The organic layer was dried, filtered, and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (8 mg). MS found: (M+H)+=576.5.