Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:22][C:23]1[O:24][C:25]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1>CN(C=O)C.O>[C:28]1([C:26]2[N:27]=[C:23]([CH2:22][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7]3[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=3)[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[O:24][C:25]=2[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)Nc1cccc(OCC(=O)OC)c1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1cccc(OCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 19.3 %

Procedure:
A solution of methyl [3-[(ethoxycarbonyl) amino]phenoxy]acetate (4.10 g, 16 mmol) was dissolved in DMF (40 mL), NaH (0.94 g of a 50% dispersion in mineral oil, 19 mmol) added and the mixture stirred at room temperature for about 20 minutes. 2 -Bromomethyl-4,5-diphenyl-oxazole (5.10 g, 16 mmol) in DMF (15 mL) was added dropwise and the mixture stirred at room temperature for about 3 hours. The mixture was diluted with H2O, extracted with Et2O and the combined extracts washed with H2O. After drying over MgSO4, the solvent was evaporated and the residue chromatographed twice on a column of silica gel using hexane/EtOAc (4:1) for the first column and CH2Cl2 /MeOH (24:1) for the second to give methyl [3-[[(4,5-diphenyl-2-oxazolyl)methyl](ethoxycarbonyl)amino]phenoxy]acetate (1.50 g, 19%). IR (film) 1765, 1710 cm-1 ; 1H NMR (CDCl3) δ1.22 (3H, t, J=8 Hz, OCH2CH3), 3.75 (3H, s, CO2CH3), 4.21 (2H, q, J=8 Hz, OCH2CH3), 4.47 (2H, s, OCH2CO2CH3), 5.00 (2H, s, CH2 -oxazole), 5.28 (0.2H, s, CH2Cl2), 6.79 (1H, dd, J=9 Hz, J'=2 Hz, aromatic H), 7.05 (2H, m, aromatic H), 7.20 to 7.40 (7H, m, aromatic H) , 7.50 to 7.70 (4H, m, aromatic H); MS m/z 487 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:10])=[O:9].[Li]C(C)(C)C.[CH3:32][C:33]1[CH:40]=[C:39]2[O:41][CH2:42][O:43][C:38]2=[CH:37][C:34]=1[CH:35]=[O:36]>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:35]([OH:36])[C:34]1[CH:37]=[C:38]2[O:43][CH2:42][O:41][C:39]2=[CH:40][C:33]=1[CH3:32])(=[O:9])=[O:10]
Reactant: Cc1cc2c(cc1C=O)OCO2
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2C)OCO3)sc2ncccc12
Yield: 36.7 %

Procedure:
The title compound was prepared by the method of Example 4(B) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxy-methyl)thieno[2,3-b]pyridine-3-sulfonamide (0.31 g, 0.75 mmoles)[Example 4(A)], THF (4 ml), t-BuLi (1.7 M, 0.53 ml, 0.90 mmoles) and 2-methyl-4,5-(methylenedioxy)benzaldehyde (0.15 g, 0.90 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 0.16 g (38%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH2:20][OH:21].[H-].[Na+].[CH2:24](I)[CH3:25]>CN(C=O)C.CCOC(C)=O>[CH2:24]([O:21][CH2:20][C:11]1[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])[CH3:25]
Reactant: CCI
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCc1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 66.63A (0.200 g, 0.689 mmol) in DMF (5 mL), was added NaH (0.0198 g, 0.827 mmol). The reaction was stirred at room temperature for 10 minutes. Ethyl iodide was then added and the reaction was stirred at room temperatures for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, and dried over anhydrous Na2SO4. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:1 EtOAc/hexane) and gave 67.23A in 79% yield. MS ESI (pos.) m/e: 336 (M+18)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[O:23][CH3:24])[C:7]2[CH:25]=[CH:26][C:27]([C:29]#[N:30])=[CH:28][C:6]=2[NH:5][CH2:4]1.[N:31]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])([CH3:37])[C@H:32]([C:34](O)=[O:35])[CH3:33].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:41]([O:40][C:38](=[O:39])[N:31]([C@H:32]([C:34](=[O:35])[NH:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[O:23][CH3:24])[C:7]2[CH:25]=[CH:26][C:27]([C:29]#[N:30])=[CH:28][C:6]=2[NH:5][CH2:4]1)[CH3:33])[CH3:37])([CH3:42])([CH3:43])[CH3:44]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](N)CNc2cc(C#N)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
To a solution of (S)-3-amino-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1Hbenzo[b][1,4]diazepine-7-carbonitrile hydrochloride (510 mg, 1.047 mmol) in DMF (10 mL) were added Boc-N-Me-Ala-OH (234 mg, 1.15 mmol), HOBT (155.62 mg, 1.15 mmol) and DIPEA (0.943 mL, 5.236 mmol). After 10 min, the mixture was cooled to 0° C. and HBTU (436.7 mg, 1.152 mmol) was added portion wise. The resulting mixture was stirred for 2 h. The mixture was diluted with water and extracted with EtOAc. The extracts were washed with 1 M aqueous citric acid solution, brine, saturated aqueous sodium carbonate solution, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to afford the title compound (570 mg, 85.58%) as an off-white solid. LC-MS: 636.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[N+:20]([O-:22])=[O:21])[C:13]([NH:15][NH2:16])=[O:14])=[CH:5][CH:4]=1.[F:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][C:32](O)=O)[CH:27]=[CH:28][CH:29]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>>[F:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][C:32]2[O:14][C:13]([C:12]3[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:10]([CH:11]=3)[NH:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[N:15][N:16]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)CCc1cccc(F)c1
Reactant: COc1ccc(Nc2cc(C(=O)NN)ccc2[N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2cc(-c3nnc(CCc4cccc(F)c4)o3)ccc2[N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
A mixture of 3-[(4-methoxyphenyl)amino]-4-nitrobenzohydrazide (1.60 g, 5.29 mmol), 3-(3-fluorophenyl)propionic acid (0.89 g, 5.29 mmol) and phosphorus oxychloride (5.29 mL) was stirred at 100° C. for 2 hr. The reaction mixture was cooled to 0° C., neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=3/1) to give the title compound (1.51 g, yield 69%) as orange crystals.
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[NH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[N:52][O:53][C:54](C(O)=O)(C)C)[C:23]([NH:25][CH:26]2[C:50](=[O:51])[N:28]3[C:29]([C:47]([OH:49])=[O:48])=[C:30]([CH:33]=[CH:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=4[N+]([O-])=O)[CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1>>[NH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[N:52][O:53][CH3:54])[C:23]([NH:25][CH:26]2[C:50](=[O:51])[N:28]3[C:29]([C:47]([OH:49])=[O:48])=[C:30]([CH:33]=[CH:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)[CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1
Reactant: CC(C)(ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=Cc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])CS[C@H]12)c1csc(N)n1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=Cc3ccc([N+](=O)[O-])cc3)CS[C@H]12)c1csc(N)n1
Yield: 70 %

Procedure:
This compound (210 mg, 0.22 mmol), anisole (0.5 ml, 4.5 mmol) and trifluoro acetic acid (2.5 ml, 33.8 mmol) were used to conduct the procedure similar to that shown in (2) of Example 1 to obtain 100 mg (yield: 70%) of the titled compound as yellow powder.
Reaction SMILES: OS(O)(=O)=O.[C:6]([O:9][CH:10]=[CH2:11])(=O)[CH3:7].OCC[N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[NH:17][C:16]1=[O:23]>C([O-])(=O)C.[Hg+]>[CH:10]([O:9][CH2:6][CH2:7][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[NH:17][C:16]1=[O:23])=[CH2:11]
Reactant: C=COC(C)=O
Reactant: CC1(C)NC(=O)N(CCO)C1=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Hg+]
Product: C=COCCN1C(=O)NC(C)(C)C1=O
Yield: 57.5 %

Procedure:
The same compound may also be obtained as follows: 0.3 g of H2SO4 is added dropwise, with vigorous stirring, to 400 ml of freshly distilled vinyl acetate, 0.002 g of Cu resinate and 0.96 g of mercury acetate, at -25° C., in a 1 liter round-bottomed flask. 41.4 g of 3-hydroxyethyl-5,5-dimethyl-hydantoin are then added, with brief stirring, under conditions such that the temperature in the flask does not rise above -20°. The resulting dispersion is kept at a temperature between -20° C. and -30° C., with slow stirring, and after 16 hours the undissolved alcohol (5.2 g) is filtered off, the solution is poured into ice water which contains sufficient sodium carbonate that the pH value resulting after addition of the solution is 8 or above, and finally the organic phase is separated from the aqueous phase, washed twice with water, dried over sodium sulphate and concentrated on a rotary evaporator. 27.4 g (= 57.5% of theory) of 3-vinyloxyethyl-5,5-dimethyl-hydantoin are obtained.
Reaction SMILES: N[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.O.[ClH:12].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=O>C(O)(C)C>[ClH:12].[CH:8]1[CH:7]=[CH:6][C:5]2[CH2:4][CH2:3][N:2]3[C:10]=2[C:9]=1[C:17]1[CH2:18][NH:13][CH2:14][CH2:15][C:16]=13
Reactant: O=C1CCCCN1
Reactant: NN1CCc2ccccc21
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: c1cc2c3c(c1)c1c(n3CC2)CCNC1
Yield: 72.9 %

Procedure:
A mixture of 1-amino-2,3-dihydroindole (1.0 g, 5.9 mmol), piperidone hydrochloride monohydrate (0.91 g, 5.9 mmol) and isopropanol (29 mL) was brought to reflux for 4 hours. The resulting brown solid was filtered and washed with cold diethylether (20 mL) and dried under vacuum, affording the title compound (1.01 g, 74%). 1H NMR (CD3OD, 300 MHz) δ 7.15 (d, 1H, J=7.7 Hz), 6.85–6.96 (m, 2H), 4.39–4.50 (m, 4H), 3.75 (t, 2H, J=7.3 Hz), 3.57 (t, 2H, J=6.2 Hz), 3.15 (t, 2H, J=6.2 Hz) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)[CH2:11][C:10]([NH2:24])=[N:9]2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:23])[F:22])[CH:14]=3)=[CH:11][C:10]([NH2:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC1=NN(c2ccc(F)cc2)C(c2cccc(OC(F)(F)F)c2)C1
Solvent: Cc1ccccc1
Product: Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-pyrazol-3-ylamine (1.29 g) in toluene (10 ml) was added activated carbon (pH5 to 8, 0.64 g), and the mixture was stirred for 2 hours under oxygen atmosphere under cooling to reflux. After cooling to room temperature, the activated carbon was filtered off through Celite eluting with ethyl acetate. This filtrate was concentrated under reduced pressure. To the resulting residue, a mixed solvent of diisopropyl ether/n-hexane was added and the mixture was stirred at room temperature. The insoluble substance was collected by filtration, and then dried under reduced pressure to give the titled compound (652 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:5]2[CH2:6][CH2:7][CH:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[CH2:3][CH2:4]2)=[N:9][CH:10]=1)#[N:13]
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: N#Cc1ccc(N2CCC(N)CC2)nc1
Product: N#Cc1ccc(N2CCC(NC(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)CC2)nc1
Yield: 41 %

Procedure:
This compound was synthesized from 6-(4-aminopiperidin-1-yl)nicotinonitrile and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (70 mg, yield 41%). 1H NMR (400 MHz, CDCl3) δ 8.42 (m, 2H), 8.27 (d, J=7.8 Hz, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.66-7.61 (m, 2H), 6.67 (d, J=9.0 Hz, 1H), 6.14 (d, J=7.8 Hz, 1H), 4.51-4.48 (m, 2H), 4.39-4.29 (m, 1H), 3.20-3.13 (m, 2H), 2.24-2.20 (dd, J=12.3 Hz, 2.3 Hz, 2H), 1.62-1.52 (m, 2H). MS (ESI) m/z: Calculated for C21H17F3N6O2: 442.14. found: 443.2 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][C:4]1[O:5][C:6]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](SC)=[CH:16][N+:17]([O-:19])=[O:18])=[CH:7][CH:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][S:30][CH2:31][CH2:32][NH2:33])[CH:24]=1>>[CH3:22][N:2]([CH2:3][C:4]1[O:5][C:6]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:33][CH2:32][CH2:31][S:30][CH2:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[CH:16][N+:17]([O-:19])=[O:18])=[CH:7][CH:8]=1)[CH3:1]
Reactant: CSC(=C[N+](=O)[O-])NCCCOCc1ccc(CN(C)C)o1
Reactant: NCCSCc1cccnc1
Product: CN(C)Cc1ccc(COCCCNC(=C[N+](=O)[O-])NCCSCc2cccnc2)o1

Procedure:
A mixture of N,N-dimethyl-5-[[3-[(1-methylthio-2-nitroethenyl)amino]propoxy]methyl]-2-furanmethanamine (0.7 g) and 2-[(3-pyridinylmethyl)thio]ethanamine (0.36 g) was heated at 98°-100° for 3 hr. The oily residue was chromatographed (silica/methanol-0.88 ammonia 79:1) and the appropriate eluate evaporated to dryness to give the title compound as a hemihydrate as an oil (0.52 g).
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=1)=[O:17])(=[O:14])=[O:13].Cl.[N-:29]=[N+:30]=[N-].[Na+]>O>[N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=1)=[O:17])(=[O:14])=[O:13])=[N+:29]=[N-:30]
Reactant: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2N)n1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2N=[N+]=[N-])n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
A solution of 1 g of sodium nitrite in 4 ml of water is slowly added dropwise at 0°-5° C. to a mixture of 3.4 g of N-(2-aminophenylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea, 10 g of ice and 4 ml of 36% hydrochloric acid. After the reaction mixture has been stirred for 2 hours at 0° C., a solution of 1 g of sodium azide in 4 ml of water is added dropwise and the temperature is allowed to rise to 20° C. The reaction mixture is extracted with three 20 ml portions of methylene chloride. The combined organic phases are dried and concentrated. Recrystallisation of the residue yields 1.0 g of N-(2-azidophenylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea which decomposes at 175° C.
Reaction SMILES: ClC1N=C(C)N([CH2:8][C:9]2[S:24][C:12]3[N:13]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:14](=[O:19])[N:15]([CH3:18])[C:16](=[O:17])[C:11]=3[C:10]=2[C:25]([N:27]2[CH2:31][C@H:30]([OH:32])[CH2:29][O:28]2)=[O:26])C=1Cl.[N:34]1[CH:35]=[CH:36][N:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=12.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[OH:32][C@@H:30]1[CH2:29][O:28][N:27]([C:25]([C:10]2[C:11]3[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[N:13]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:12]=3[S:24][C:9]=2[CH2:8][C:36]2[N:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]3=[N:34][CH:35]=2)=[O:26])[CH2:31]1
Reactant: Cc1nc(Cl)c(Cl)n1Cc1sc2c(c1C(=O)N1C[C@H](O)CO1)c(=O)n(C)c(=O)n2CC(C)C
Reactant: c1ccn2ccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)N3C[C@H](O)CO3)c(Cc3cnc4ccccn34)sc21

Procedure:
The product of example 3 part b (1 g), imidazolo[1,2-a]pyridine (0.4 ml), potassium carbonate (0.35 g) and THF (20 ml) were stirred under nitrogen for 1 h. Warer was added to the reaction and extracted with ethyl acetate (×2). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (SiO2/9:1 ethyl acetate-hexane and the ethyl acetate) to give the sub-title compound as a colourless oil. LCMS(ESI) 4275 [M+H]+
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10](OS(C(F)(F)F)(=O)=O)=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:5]=1)([CH3:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3c(C(C)C)n2)n[nH]1
Reactant: C1COCCN1
Product: Cc1cc(Nc2cc3cc(N4CCOCC4)ccc3c(C(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in the example 363 was used, starting from Trifluoro-methanesulfonic acid 1-isopropyl-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl ester and morpholine to give 5 mg of (1-Isopropyl-6-morpholin-4-yl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine as a yellow solid. LC-MS m/e 352 (MH+).
Reaction SMILES: [CH:1]1([N:9]=[C:10]=[S:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOC(C)=O.CCCCCC.CC#[N:26]>>[CH:1]1([NH:9][C:10]([NH2:26])=[S:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC#N
Reactant: S=C=NC1CCCCCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: NC(=S)NC1CCCCCCC1
Reaction time: 72 h
Yield: 78.2 %

Procedure:
To a stirred solution of cyclooctyl isothiocyanate (7.26 g, 42.9 mmol) in 70 ml of CH3CN was added 8.5 ml of 15N NH4OH (130 mmol). The reaction progress was monitored by thin layer chromatography (TLC); 1/1 EtOAc/hexane. After 3 days, the reaction solution was concentrated, dissolved in 50 ml of ethyl acetate and washed with water (25 ml) and brine (aqueous saturated NaCl) (3×25 ml ea.). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica gel, 3/7 EtOAc/hexane) to yield 6.25 g (78.2%) of the desired thiourea. PMR(CDCl3)ppm 6.5 (bs, 1H), 6.00 (s, 2H), 4.35 (bs, 1/2H), 3.45 (bs, 1/2H), 2.1-1.3 (m, 14H). The melting point (MP) was 93°-95° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH2:11])=[CH:2]1.[CH2:12]([C:19]1([N:26]([CH3:28])[CH3:27])[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH2:12]([C:19]1([N:26]([CH3:27])[CH3:28])[CH2:24][CH2:23][CH:22]([NH:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Reactant: NCc1c[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CN(C)C1(Cc2ccccc2)CCC(NCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.5 %

Procedure:
292 mg C-(1H-Indol-3-yl)-methylamine were partly dissolved in dry 1,2-dichloroethane (10 ml) under argon. After addition of 463 mg 4-benzyl-4-dimethylamino-cyclohexanone (see example 3), glacial acetic acid (4 mmol) and sodium triacetoxyborohydride (550 mg), the suspension was stirred for 72 hours at room temperature. For working up, water (10 ml) was added to the reaction mixture. The organic phase was separated off and the aqueous phase was extracted twice with ether and then rendered strongly alkaline with sodium hydroxide solution. It was extracted again with ethyl acetate (4×10 ml). A pale precipitate precipitated out of the combined ethyl acetate phases even during the processing. After cooling, this was filtered off with suction, washed twice with cold ethyl acetate and dried. 235 mg 1-benzyl-N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-cyclohexane-1,4-diamine were obtained as a cis/trans mixture (m.p. 194-198° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2.[Cl-].[Al+3].[Cl-].[Cl-].[C:17]1(=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[O:18]1.O>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:17]([OH:27])=[O:18])=[O:26])[C:5]([CH3:12])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2
Reactant: Cc1ccc(F)c2c1CCCO2
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: Cc1c(C(=O)c2ccccc2C(=O)O)cc(F)c2c1CCCO2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
An ice cold mixture of 8-fluoro-5-methylchroman (0.955 g, 5.75 mmol) in 1,2-Dichloroethane (DCE) (10 mL) was treated with aluminum chloride (1.532 g, 11.49 mmol) followed by isobenzofuran-1,3-dione (0.809 g, 5.46 mmol). The mixture was allowed to warm to ambient temperature and stirred for 90 minutes. Water was then added and the mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.92-2.05 (m, 2 H), 2.34 (s, 3 H), 2.62-2.79 (m, 2 H), 4.15-4.30 (m, 2 H), 6.68 (d, J=11.73 Hz, 1 H), 7.40 (d, J=7.43 Hz, 1 H), 7.51-7.76 (m, 2 H), 7.88 (d, J=7.43 Hz, 1 H), 13.15 (br. s., 1 H); LC/MS (m/z) ES+=315 (M+1).
Reaction SMILES: [NH2:1][C:2](=[N:8][O:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OCC)C>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[CH2:6]([O:5][C:3]([C:2]1[N:1]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])[O:9][N:8]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(N)=NOC(=O)c1cnccc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1noc(-c2cnccc2C(F)(F)F)n1

Procedure:
20 g of ethyl 2-amino-2-(4-trifluormethyl-3-pyridinecarbonyloxyimino)-acetate are dissolved in 200 ml of a mixture of xylene and toluene and admixed with 5 g of Amberlyst 15. The mixture is boiled at 125-130° C. for 6 h using a Dean-Stark apparatus. After the reaction has ended, the mixture is cooled and admixed with a small amount of diethyl ether. The mixture is filtered with suction through a glass filter frit, and the solution is then concentrated. This gives 15.8 g of the product as a yellow oil.
Reaction SMILES: O1C=CC2C=C(C3CO3)C=CC1=2.N1C=CC=C(CO)C=1.[S:21]1[CH:25]=[CH:24][C:23]2[CH:26]=[C:27]([CH:30]3[CH2:32][O:31]3)[CH:28]=[CH:29][C:22]1=2.[CH:33]([N:35]1[CH2:40][CH2:39][N:38]([CH:41]=[O:42])[CH2:37][CH:36]1[CH2:43][OH:44])=[O:34]>>[S:21]1[CH:25]=[CH:24][C:23]2[CH:26]=[C:27]([CH:30]([OH:31])[CH2:32][O:44][CH2:43][CH:36]3[CH2:37][N:38]([CH:41]=[O:42])[CH2:39][CH2:40][N:35]3[CH:33]=[O:34])[CH:28]=[CH:29][C:22]1=2
Reactant: O=CN1CCN(C=O)C(CO)C1
Reactant: c1cc2cc(C3CO3)ccc2s1
Agent: OCc1cccnc1
Agent: c1cc2cc(C3CO3)ccc2o1
Product: O=CN1CCN(C=O)C(COCC(O)c2ccc3sccc3c2)C1

Procedure:
The same procedure as in Production Example 43 was repeated, except that the 2-(benzo[b]furan-5-yl)oxirane and the 3-pyridinemethanol were replaced by 2-(benzo[b]thiophen-5-yl)oxirane and 1,4-diformyl-2-piperazinemethanol, respectively, to obtain oily 1-(benzo[b]thiophen-5-yl)-2-[(1,4-diformylpiperazin-2-yl)methoxy]ethanol (compound No. 354).