Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([O:6][NH:7][C:8](=[NH:42])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:18]3=[N:17][C:16]=2[C:30]#[C:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=2)=[CH:11][N:10]=1)=O)C.N1CCCN2CCCCCC=12.Cl>CC1C=CC=CC=1C>[O:27]1[CH2:26][CH2:25][N:24]([C:23]2[C:18]3[N:19]([C:15]([C:12]4[CH:13]=[CH:14][C:9]([C:8]5[N:42]=[C:4]([OH:3])[O:6][N:7]=5)=[N:10][CH:11]=4)=[C:16]([C:30]#[C:31][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:17]=3)[N:20]=[CH:21][CH:22]=2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)ONC(=N)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: C1CCC2=NCCCN2CC1
Product: Oc1nc(-c2ccc(-c3c(C#Cc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cn2)no1
Temperature: 25 °C

Procedure:
A solution of compound 42b (0.10 g, 0.18 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.10 g, 0.66 mmol) in o-xylene (2 mL) was stirred at 130° C. in an oil bath for 2 h. The reaction mixture was allowed to cool to rt, and the solution was adjusted to pH 7 with 0.5 N HCl. The solids formed were collected by filtration and washed with CH2Cl2/MeOH (1:10) (3×10 mL) to obtain the title compound 26 as a brown solid. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 13.25 (s, 1H), 9.48 (s, 1H), 8.79-8.75 (m, 1H), 8.47 (d, J=8.4 Hz, 1H), 8.33 (d, J=5.7 Hz, 1H), 8.24 (d, J=8.7 Hz, 1H), 8.06-8.01 (m, 2H), 7.87-7.66 (m, 3H), 7.56 (d, J=6.0 Hz, 1H), 4.10-3.98 (m, 4H), 3.91-3.78 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H20N8O3: 517.2 (M+H). Found: 517.1.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](O)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[F:30][C:31]1([F:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:16]=[CH:17][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:19][CH:20]=4)[C:13]([N:34]4[CH2:35][CH2:36][C:31]([F:37])([F:30])[CH2:32][CH2:33]4)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1C=C(O)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C1C=C(N2CCC(F)(F)CC2)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-(4-morpholinophenyl)-1H-pyrrol-2(5H)-one (1.0 g, 2.65 mmol), 4,4-difluoropiperidine hydrochloride (0.800 g, 5.1 mmol) and K2CO3 (0.73 g, 5.3 mmol) in toluene/DMF (2:1; 15 ml) according to method 8a described above.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[O:13]=[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:15]1[CH2:24][CH2:25][CH:26]([C:30]1([CH2:44][CH:45]([CH3:47])[CH3:46])[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]1=[O:43])[C:27](O)=[O:28].Cl.[CH2:49]([O:56][NH2:57])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.CN1CCOCC1>C(Cl)Cl>[CH2:49]([O:56][NH:57][C:27](=[O:28])[CH:26]([CH2:25][CH2:24][N:15]1[C:14](=[O:13])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:23])[C:30]1([CH2:44][CH:45]([CH3:46])[CH3:47])[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]1=[O:43])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)O)CCN(CCc2ccccc2)C1=O
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)NOCc2ccccc2)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
CDI (82 mg, 0.51 mmol) is added to a solution of α-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (202 mg, 0.424 mmol) and CH2Cl2 (3.2 mL) at room temperature, and the solution is stirred for 1 hour at room temperature. O-Benzylhydroxylamine hydrochloride (98 mg, 0.614 mmol) and 4-methylmorpholine (84 uL, 0.76 mmol) are added in succession, and the solution is allowed to stir overnight at room temperature. Aqueous workup (CH2Cl2, MgSO4) and purification by column chromatography (2% acetene/CH2Cl2) gives 120 mg (49%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[C:7]([C:8]([O:10]CC)=[O:9])[CH:6]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cc(CO)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.3 %

Procedure:
Add commercially available 5-hydroxymethyl-isophthalic acid diethyl ester (5 g, 19.8 mmol) and NaOH (0.79 g, 19.8 mmol) to ethanol (100 mL). Stir for 4 h at room temperature. Concentrate and pour the residue into water (100 mL) and diethyl ether (100 mL). Separate the aqueous layer and wash it with diethyl ether (40 mL). Acidify the aqueous layer with 5 N HCl to about pH=1. Extract the acidic solution with ethyl acetate (3×40 mL). Wash the combined organic layers with water, saturated aqueous sodium chloride, dry (sodium sulfate) and concentrate to give the title compound as a solid (3.3 g, 74%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].[NH2:14][OH:15]>CCO>[NH2:2][C:1](=[N:14][OH:15])[C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: NO
Reactant: COC(=O)c1cc(C#N)ccc1O
Solvent: CCO
Product: COC(=O)c1cc(C(N)=NO)ccc1O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a suspension of methyl 5-cyano-2-hydroxy-benzoate (ASTATECH; 63806; 1 g; 5.64 mmol; 1 eq.) in EtOH (10 mL) was added hydroxylamine (50% in water) (1.69 mL; 28.22 mmol; 5 eq.). The reaction mixture was stirred at 60° C. for 30 min. While cooling to RT a white precipitate was formed. Solvents were removed to dryness and the white solids were washed with EtOH to afford title compound pure at 66% as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.12 (d, J=2.2 Hz, 1H), 7.81 (dd, J=8.4, 2.2 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 5.82 (br s, 2H), 5.69 (br s, 1H), 3.91 (s, 3H). LC/MS (Method A): 210.8 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:41])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[CH2:9][CH2:8][N:7]([CH2:19][CH2:20][CH:21]=[C:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[N:32][C:27]=3[CH2:26][O:25][C:24]3[CH:33]=[CH:34][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:36][C:23]2=3)[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2([OH:11])[CH2:9][CH2:8][N:7]([CH2:19][CH2:20][CH:21]=[C:22]3[C:28]4[CH:29]=[CH:30][CH:31]=[N:32][C:27]=4[CH2:26][O:25][C:24]4[CH:33]=[CH:34][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:36][C:23]3=4)[CH2:6][C:5]2([CH2:3][OH:2])[CH3:41])=[CH:13][CH:14]=1
Reactant: COC(=O)C1(C)CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(CO)C1)c1cccnc1CO2
Temperature: 0 °C
Reaction time: 3 h
Yield: 43.6 %

Procedure:
4-(4-Chloro-phenyl)-4-hydroxy-1-{3-[7-(hydroxyl-1-methyl-ethyl)-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene]-propyl}-3-methyl-piperidine-3-carboxylic acid methyl ester (0.250 g, 0.43 mmol) was dissolved in tetrahydrofuran and cooled to 0° C. To the solution was added LiAlH4 (1.3 mL, 1.3 mmol) dropwise and the reaction was allowed to stir at 0° C. for 3 h. The reaction was quenched with ice water slowly and diluted with ethyl acetate. The reaction mixture was allowed to stir at room temperature for 45 min. to break up any aluminum complexes. The organics were separated and the aqueous layer was extracted (2×) more. All of the organics were collected, dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (50% ethyl acetate/50% hexane to 75% ethyl acetate/25% hexane) to yield the title compound (0.103 g, 43%). 1H-NMR (CDCl3): δ 0.53 (s, 3H), 1.55 (d, 6H), 1.62 (m, 1H), 2.40 (q, 2H), 2.55 (q, 3H), 2.72–2.86 (m, 4H), 3.19 (dd, 1H), 3.24 (d, 1H), 3.41 (d, 1H), 5.33 (bs, 2H), 6.17 (t, 1H), 6.44 (bs, 1H), 6.79 (d, 1H), 7.17 (d, 1H), 7.26–7.59 (m, 7H), 8.50 (d, 1H). ESI-MS m/z: 549 (M+1), retention time 1.39.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:23]1([NH:29][C:30](=[O:31])[N:3]([CH2:4][C:5]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:6]=2[CH2:7][N:8]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:9]3=[O:14])[CH3:2])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C=NC1CCCCC1
Reactant: CNCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O)C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a suspension of 3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and cyclohexyl isocyanate (0.28 mL, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with MeOH and extracted with H2O (40 mL), then with 1N HCl (40 mL). The organic layer was washed with brine (40 mL) and concentrated on rota-vap. The resulting oil was purified on silica gel column to give 3-cyclohexyl-1-[2-(2,6-dioxo-piperidin-3-yl) 1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea (0.54 g, 71%): mp 219-221° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 30/70 (CH3CN/H2O): tR=4.61 (99%); 1H NMR (DMSO-d6): δ 1.02-1.30 (m, 5H), 1.54-1.76 (m, 5H), 2.00-2.05 (m, 1H), 2.29-2.36 (m, 1H), 2.58-2.64 (m, 1H), 2.76 (s, 3H), 2.87-3.01 (m, 1H), 3.36-3.42 (m, 1H), 4.28 (d, J=17.3 Hz, 1H), 4.36 (d, J=17.5 Hz, 1H), 4.53 (s, 2H), 5.12-5.19 (dd, J=4.9, 13.1 Hz, 1H), 6.07 (d, J=7.7 Hz, 1H), 7.38 (d, J=7.4 Hz, 1H), 7.50 (t, J=7.4 Hz, 1H), 7.61 (d, J=7.4 Hz, 1H), 11.03 (s, 1H). 13C NMR (DMSO-d6) δ: 22.69, 25.10, 25.35, 31.14, 33.22, 34.00, 46.12, 48.21, 49.34, 51.45, 121.59, 128.30, 130.08, 131.87, 134.41, 139.99, 157.09, 168.02, 170.99, 172.84. Anal Calcd for C22H28N4O4+0.1H2O: C, 63.78; H, 6.86; N, 13.52. Found: C, 63.41; H, 6.93; N, 13.33.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].S(Cl)([Cl:19])=O>N1C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][Cl:19])=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOP(=O)(OCC)c1ccc(CO)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1ccc(CCl)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.3 grams (0.004 mole) of 4-(diethylphosphono)phenylmethanol and two drops of pyridine in 10 mL of methylene chloride was added 0.39 mL (0.005 mole) of thionyl chloride. Upon completion of the addition, the reaction mixture was stirred for 30 minutes, then washed with 10 mL of water and 10 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding the intermediate 4-(diethylphosphono)phenylmethyl chloride. The chloride was not further characterized. A solution of 2.7 grams (0.005 mole) of 4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine (prepared as in Step A of Example 17) in 10 mL of dimethyl sulfoxide was stirred, and 2.5 mL (excess) of diisopropylethylamine was added. To this was then added a solution of the methyl chloride, prepared above, in one mL of dimethyl sulfoxide. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for one hour, then poured into water, and the mixture was extracted with one 150 mL portion of methylene chloride. The extract was washed with one 50 mL portion of an aqueous solution saturated with ammonium chloride and one 50 mL portion of water. The extract was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with pure ethyl acetate as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.6 grams of N-[4-(diethylphosphono)phenylmethyl]-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CN(C=O)C.[C:6]([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([O:8][CH2:9][CH3:10])=[O:7].[CH:18]([S:20]([F:23])(=[O:22])=[O:21])=[CH2:19]>O>[C:6]([C:11]1[CH:12]=[CH:13][C:14]([NH:15][CH:19]=[CH:18][S:20]([F:23])(=[O:22])=[O:21])=[CH:16][CH:17]=1)([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C=CS(=O)(=O)F
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(NC=CS(=O)(=O)F)cc1
Temperature: 110 °C
Yield: 49.8 %

Procedure:
To a 75 mL DMF solution of 4-carboethoxyaniline (3.88 g, 23.5 mmol) was added ethenesulfonyl fluoride (3.3 mL, 30 mmol) under nitrogen. The solution was warmed to 100-120° C. for 6 hours. The cooled solution was slowly Poured into water and chilled in ice. The yellow solid precipitate was collected, dissolved in methylene chloride, washed with brine and dried (Na2SO4). After the solvent had been removed by distillation, the brown solid (5.4 g) was crystallized from methylene chloride/ether/hexane. The title compound (3.2 g, 49% yield) was obtained as a tan solid, mp 109.5°-111.5° C.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH:7]=CC)[OH:3].C1(OC)C(=CC=C(C=1)CC=C)[OH:15]>O>[O:15]=[CH:7][C:6]1[CH:5]=[CH:4][C:2]([OH:3])=[C:1]([O:11][CH3:12])[CH:10]=1
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: CC=Cc1ccc(O)c(OC)c1
Solvent: O
Product: COc1cc(C=O)ccc1O

Procedure:
On the basis of the substrates (a) Benzoe Siam Resin (b) isoeugenol and (c) eugenol, all dispersed in tap water as the reaction medium, the compound vanillin was produced. The substrates were taken up in flasks mounted on a shaking apparatus after which the enzyme lipoxidase (Sigma L8383) in a dose of 0.2% w/w based on the substrate was added. The temperature during the reaction was kept at 25° C. The starting mixture had a initial pH of 8. After an incubation time of 24 hours the reaction was stopped by inactivation of the enzyme (10 min. at 70° C.). The results of the experiments are shown in Table B below.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:11]([OH:18])[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)C#N)=[CH:4][CH:3]=1.N>Br>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: N#CC(=C(O)c1ccncc1)c1ccc(F)cc1
Agent: Br
Agent: N
Product: O=C(Cc1ccc(F)cc1)c1ccncc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(4-Fluorophenyl)-3-hydroxy-3-pyridin-4-ylacrylonitrile (0.15 mol/40.6 g) was dissolved in 290 ml of 48% HBr. With vigorous stirring, the reaction mixture was heated under reflux for 24 h. 500 g of ice were then added to the reaction mixture, and the mixture was stirred for another 2 h. After addition of a further 300 g of ice and neutralization of the mixture to pH 7 using concentrated NH3 and a further 60 min of stirring, the title compound was obtained as an ochre-brown precipitate. The precipitate was filtered off, washed with H2O and dried over P2O5 under reduced pressure. Yield: 16.1 g (50%)
Reaction SMILES: C[N:2](C)/[C:3](=[N:5]/[C:6]([C:8]1[N:17]=[C:16]2[N:10]([CH2:11][CH2:12][O:13][C:14]3[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:15]=32)[CH:9]=1)=O)/[CH3:4].C(O)(=O)C.Cl.[CH:29]([NH:32]N)([CH3:31])[CH3:30]>>[Br:22][C:20]1[CH:19]=[CH:18][C:15]2[C:16]3[N:10]([CH2:11][CH2:12][O:13][C:14]=2[CH:21]=1)[CH:9]=[C:8]([C:6]1[N:32]([CH:29]([CH3:31])[CH3:30])[N:2]=[C:3]([CH3:4])[N:5]=1)[N:17]=3
Reactant: C/C(=N\C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)N(C)C
Reactant: CC(C)NN
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Temperature: 95 °C
Yield: 83.8 %

Procedure:
To a solution of 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid [1-dimethylamino-eth-(E)-ylidene]-amide (0.340 g, 0.000901 mol) in acetic acid (3.0 mL, 0.053 mol) was added isopropylhydrazine hydrochloride (0.1196 g, 0.001082 mol). The reaction was heated to 95° C. for 3 h. The acetic acid was removed in vacuo and the product was loaded as a solid onto silica and purified by flash chromatography (0-10% MeOH in DCM) to give 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (293 mg) as an orange solid. MS (ESI+) 388.1/390.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:4]=1[NH2:5].[Br:11]N1C(=O)CCC1=O>CN(C=O)C.[Cl-].[Na+].O>[Br:11][C:8]1[C:7]([CH3:10])=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1ccc(C)cc1N
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)c(C)cc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a cooled (0° C.) solution of 2-methoxy-5-methylaniline (500 mg, 3.64 mmol) in DMF (5 mL) was added slowly, over 10 minutes, a solution of N-bromosuccinimide (662 mg, 3.72 mmol) in DMF (2.5 mL). The reaction mixture was stirred for 18 hours, whilst slowly warming to room temperature. The reaction mixture was diluted with brine (25 mL) and extracted with EtOAc (25 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-20% EtOAc in cyclohexane to give the title compound (679 mg, 86%). 1H NMR (500 MHz, CDCl3): δ 6.93 (s, 1H), 6.62 (d, J=0.5 Hz, 1H), 3.83 (s, 3H), 3.73 (br s, 2H), 2.26 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2(O)[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][O:16]2)[N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[C:15]2[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][O:16]2)[N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CCOC1(O)C(Cc1ccc(Cl)cc1)n1cncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CCOC1=C(Cc1ccc(Cl)cc1)n1cncn1
Yield: 8.5 %

Procedure:
5 g (0.0155 mole) of 1-(4-chlorophenyl)-2-(3,3-dimethyl-2-hydroxy-tetrahydrofuran-2-yl)-2-(1,2,4-triazol-1-yl)-ethane are dissolved in 100 ml of toluene, 0.5 g of p-toluenesulphonic acid are added and the mixture is heated under reflux for 2 hours, using a water separator. The reaction mixture is cooled, washed with water, dried over sodium sulphate and concentrated in vacuo. The residue is purified by column chromatography (silica gel; ethyl acetate/cyclohexane=3:1). 2.8 g (59.6% of theory) of 1-(4-chlorophenyl)-2-(3,3-dimethyl-tetrahydrofuran-2-ylidene)-2-(1,2,4-triazol-1-yl)-ethane are obtained as form A of melting point 89° C. and 0.4 g (8.5% of theory) of 1-(4-chlorophenyl)-2-(3,3-dimethyl-tetrahydrofuran-2-ylidene)-2-(1,2,4-triazol-1-yl)-ethane are obtained as form B of melting point 175°-177° C.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([O:16][CH3:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][CH:5]([CH2:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])[C:4]1=[O:33])[CH3:2].[OH:34]O.[OH-].[Na+]>C(O)C.O>[CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([O:16][CH3:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][CH:5]([CH2:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]([NH2:29])=[O:34])[C:4]1=[O:33])[CH3:2]
Reactant: OO
Reactant: CCN1C(=O)C(Cc2cccc(C#N)c2)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCN1C(=O)C(Cc2cccc(C(N)=O)c2)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Yield: 59 %

Procedure:
To a solution of 40 mg (0.91 mmol) of 3-[(1-ethyl-7,8-dimethoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)methyl]benzonitrile (IIcp) in 1 ml of ethanol, add under an inert atmosphere 27 μl (0.27 mmol) of 30% (m/m) H2O2 in water, 36 μl (0.018 mmol) of 0.5 M NaOH in water. Stir under reflux for 12 hours. Evaporate to dryness. Take up in a 25 ml of a water-ice mixture. Filter the solid, wash twice with 20 ml of water and once with 5 ml of ether. One obtains 24 mg of the abovenamed product as a white powder. Yield: 59%. M: 111–113° C. 1H-NMR (CDCl3, 200 MHz): d 1.10 (s, 3H, CH3), 3.50–3.75 (m, 6H, 1H —CH2Ph+1H —NCH2+CH+OCH3), 3.98–4.11 (m, 4H, 1H —CH2Ph+OCH3), 4.38–4.49 (m, 1H —NCH2), 5.91 (m, 1H exchangeable CO—NH2), 6.26 (m, 1H exchangeable CO—NH2), 6.66 (s, 1H Ar), 6.85 (s, 1H Ar), 7.30–7.86 (m, 9H Ar).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:23])([F:22])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])=[CH:12][CH:11]=1)=[O:8].[CH3:24][N:25](C=O)[CH3:26]>>[CH3:24][N:25]([CH3:26])[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]([F:23])([F:22])[F:5])=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: O=C(O)CCCc1ccc(NC(=O)C(F)(F)F)cc1
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)CCCc1ccc(NC(=O)C(F)(F)F)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (71 mg, 0.60 mmol) was added slowly to a solution of 4-[4-(2,2,2-Trifluoroacetylamino)phenyl]butanoic acid (Formula 45) (0.15 g, 0.55 mmol) in DMF (5 mL) cooled at −5° C. The mixture was stirred for an additional 1 hour at −5° C. Excess dimethylamine (freshly distilled from its 40% aqueous solution) was added to the reaction medium. The second mixture was stirred for an additional 1 hour. Ethyl acetate (50 mL) was added to the mixture, which was washed with brine (2×50 ml). The organic layer was dried over MgSO4, and concentrated to yield N,N-Dimethyl 4-[4-(2,2,2-Trifluoroacetylamino)phenyl]butanamide (Formula 46) (0.17 g, quant.) as a yellowish solid. 1H NMR 9.70 (br s, 1H), 7.55 (d, 2H, J=8.6 Hz), 7.11 (d, 2H, J=8.6 Hz), 2.91 (s, 3H), 2.89 (s, 3H), 2.60 (t, 2H, J=7.7 Hz), 2.27 (t, 2H, J=7.7 Hz), 1.89 (p, 2H, J=7.7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[CH:13]1[NH:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14]1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1>>[F:30][C:29]([F:31])([F:32])[O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:18]2[CH:13]([C:4]3[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH3:10])=[CH:6][C:5]=3[O:11][CH3:12])[CH2:14][CH2:15][CH2:16][C:17]2=[O:19])=[CH:23][CH:24]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: COc1cc(OC)c(C2CCCC(=O)N2)c(OC)c1
Product: COc1cc(OC)c(C2CCCC(=O)N2Cc2ccc(OC(F)(F)F)cc2)c(OC)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,4,6-trimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.10 min.; [M+H]+: 439.78 g/mol.