Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[OH:32])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH2:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[CH:42]=[N:41][CH:40]=[CH:39]2>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH:20]2[O:32][CH2:35][C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[CH:42]=[N:41][CH:40]=[CH:39]3)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccc2cnccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(O)C1
Agent: Br
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3cnccc3c2)C1

Procedure:
By alkylating tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxy-piperidine-1-carboxylate [Example 86(n)] with 6-bromomethyl-isoquinoline hydrobromide (Example 4) analogously to Example 1(g) there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(isoquinolin-6-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 583 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[NH:9][C:8](=[S:12])[C:7]([C:13]#[N:14])=[CH:6][C:5]=2[C:4](=[O:15])[CH2:3]1.[OH-].[K+].Br[CH2:20][CH2:21][CH2:22][CH3:23].O>CN(C=O)C>[CH2:20]([S:12][C:8]1[C:7]([C:13]#[N:14])=[CH:6][C:5]2[C:4](=[O:15])[CH2:3][C:2]([CH3:16])([CH3:1])[CH2:11][C:10]=2[N:9]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CC1(C)CC(=O)c2cc(C#N)c(=S)[nH]c2C1
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCSc1nc2c(cc1C#N)C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.6 %

Procedure:
To a solution of 7,7-dimethyl-5-oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (0.5 g, 2.2 mmol) in DMF (4 ml) was added 10% aqueous potassium hydroxide (1.23 ml), followed by dropwise addition of 1-bromobutane (0.24 ml, 2.2 mmol). The mixture was stirred at room temperature for 12 h, then water (12 ml) was added. The product was extracted with diethyl ether. The extract was washed with water and dried over sodium sulfate. Filtration and concentration under reduced pressure afforded the residue which was purified by flash chromatography on silica gel (petroleum ether-ethyl acetate, 10:1) to give the title compound (0.41 g, 59%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[N:6](C)[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].F[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>CS(C)=O>[F:25][C:23]1[CH:24]=[CH:19][C:20]([N+:26]([O-:28])=[O:27])=[C:21]([O:1][C:2]2[NH:6][N:5]([CH3:12])[CH:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)[CH:22]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Cn1nc(C(F)(F)F)cc1O
Agent: [K+]
Solvent: CS(C)=O
Product: CN1NC(Oc2cc(F)ccc2[N+](=O)[O-])=CC1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 15 %

Procedure:
5-Hydroxy-1-methyl-3-trifluoromethylpyrazole (8.3 g, 50 mmol) and powdered potassium carbonate (8.3 g, 60 mmol) were stirred together in dimethylsulfoxide (40 ml) for 30 minutes. 2,4-Difluoronitrobenzene (7.9 g, 50 mmol) was added and the mixture stirred at room temperature for 18 h. The mixture was partitioned between diethyl ether and water, the ethereal extract washed with water and brine, dried over magnesium sulfate, filtered and the filtrate evaporated. The residue was further purified by flash column chromatography over silica gel, to give the desired product (2.3 g) as a solid. m.p. 68°-70° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#[N:2].[CH2:29](N)[CH2:30][NH2:31]>P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>[NH:2]1[CH2:29][CH2:30][N:31]=[C:1]1[C:3]1[CH:4]=[C:5]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C#N)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Reactant: NCCN
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=NCCN3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Temperature: 120 °C
Yield: 86.7 %

Procedure:
To a 10-mL microwave tube were added 6-cyano-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (33 mg, 0.088 mmol), ethylenediamine (1 mL, 14.81 mmol), and phosphorus pentasulfide (0.585 mg, 2.63 μmol), and the mixture was degassed for 5 min. The tube was sealed and the mixture was heated at 120° C. in a microwave. The mixture was concentrated and the residue was purified using reverse-phase HPLC under acidic conditions to give 32 mg of product as off-white solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.46 (m, 6H), 2.11 (s, 3H), 2.17 (s, 3H), 2.24 (s, 3H), 4.35 (d, J=5.05 Hz, 2H), 4.75 (quin, J=6.69 Hz, 1H), 5.87 (s, 1H), 7.49-7.60 (m, 2H), 8.16-8.26 (m, 2H), 8.39 (s, 1H). MS: (M+H)+=419.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[C:3]=1[O:10][CH3:11].CN(C=O)C.S(Cl)([Cl:19])=O>C(Cl)Cl>[Cl-:1].[Cl:1][C:2]1[CH:7]=[CH:6][NH+:5]=[C:4]([CH2:8][Cl:19])[C:3]=1[O:10][CH3:11]
Reactant: COc1c(Cl)ccnc1CO
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(Cl)cc[nH+]c1CCl
Product: [Cl-]
Reaction time: 1.5 h

Procedure:
The resulting solution of 4-chloro-2-hydroxymethyl-3-methoxypyridine (−30% strength) was diluted with CH2Cl2 (48 L). DMF (65.5 g, 0.896 mol) was added in one portion and, then, thionyl chloride (11.1 kg, 93.2 mol) over 3-5 h at 15-30° C. After stirring for additional 1.5 h, about 45 L of solvents were distilled off. Toluene (20 L) was added and 20 L of solvents were again removed by distillation. Then, ethanol (1.5 L) was added to the resulting thick slurry. The solids were filtered off at 10-15° C., washed with toluene (17 L) and dried in vacuo at 30° C. to give 4-chloro-2-chloromethyl-3-methoxypyridinium chloride as an off-white solid (m. p. 132° C.); yield 15.0 kg (59%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13]C)[CH:8]=1)=[O:5].Br.O>C(O)(=O)C>[F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5]
Reactant: COc1cc(NC(=O)c2cc(F)ccc2F)ccn1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1cc[nH]c(=O)c1)c1cc(F)ccc1F
Temperature: 90 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
To 2,5-difluoro-N-(2-methoxy-4-pyridyl)benzamide (2.60 g, 9.84 mmol) in acetic acid (15.60 mL) was added HBr 33% in acetic acid (12.1 mL of 33% w/v, 49.20 mmol) and the mixture was stirred at 90° C. for 5 h. Additional HBr (10 mL, 33% in acetic acid) was added and the mixture was stirred at 90° C. overnight. The mixture was cooled to room temperature and was poured into water (200 mL). The mixture was stirred and the solid was collected by filtration. The solid was washed with water (2×50 mL). The solid was slurried in hexanes (2×50 mL) and filtered to give 2,5-difluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (2.30 g, 9.19 mmol, 93%). ESI-MS m/z calc. 250.05. found 251.3 (M+1)+; Retention time: 1.16 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 10.59 (s, 1H), 7.56 (ddd, J=8.2, 5.4, 3.0 Hz, 1H), 7.46 (pd, J=9.1, 4.4 Hz, 2H), 7.33 (d, J=7.2 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.42 (dd, J=7.2, 2.1 Hz, 1H) ppm.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:2].S([O-])(O[O-])(=O)=[O:14].[K+].[K+].[OH2:21]>CO>[CH2:1]([S:3]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:14])=[O:21])[CH3:2]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CCSc1ccc(C(=O)O)cc1
Reactant: O
Agent: [K+]
Solvent: CO
Product: CCS(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirring solution of 4-(ethylthio)benzoic acid (1 g, 5.5 mmol) in methanol (30 mL) at 0° C. under argon was added a solution of potassium peroxymonosulfate (6.8 g, 11 mmol) in water (30 mL). The resulted suspension was stirred at room temperature for 15 h. Methanol was evaporated under vacuum, the reaction mixture was diluted with water (30 mL), and the product was extracted with EtOAc (2×30 mL). The combined organic phase was washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated under reduced pressure to obtain 910 mg of title compound as a white solid. HPLC/MS: retention time=1.695 min, [M+H]+=215.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:31])/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])[NH2:3].C1C=CC2[N:40]([OH:41])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1>CN(C=O)C>[OH:41][NH:40][C:28](/[CH:27]=[CH:26]/[C:23]1[CH:24]=[CH:25][C:20](/[CH:19]=[CH:18]/[C:17]([C:14]2[CH:15]=[CH:16][C:11]([N:8]3[CH2:9][CH2:10][N:5]([C:2]([NH2:3])=[O:4])[CH2:6][CH2:7]3)=[CH:12][CH:13]=2)=[O:31])=[CH:21][CH:22]=1)=[O:29]
Reactant: On1nnc2ccccc21
Reactant: NC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)cc2)CC1
Agent: Cl
Agent: NOC1CCCCO1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)NO)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.2 %

Procedure:
(E)-3-(4-{(E)-3-[4-(4-Carbamoyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid hydrochloride (316 mg, 0.716 mmol) was suspended in DMF (5 ml). HOBT (193 mg, 1.43 mmol), EDC (273 mg, 1.43 mmol), TEA (0.200 ml, 1.43 mmol) and NH2OTHP (100 mg, 0.86 mmol) were added. The mixture was stirred at room temperature for 72 h and then partitioned between water and hot AcOEt. The organic extract was dried over Na2SO4, evaporated in vacuo and the crude product was crystallized from DCM/Et2O. The resulting solid was suspended in DCM and treated with HCl/Et2O for 1 h. The precipitate was filtered off, giving 103 mg of 4-(4-{(E)-3-[4-((E)-2-hydroxycarbamoyl-vinyl)-phenyl]-acryloyl}-phenyl)-piperazine-1-carboxylic acid amide as its hydrochloride salt.
Reaction SMILES: C[C@H](NC)C(N[C@H:6]([C:13]([N:15]1[C@H:19]([C:20]([NH:22][C:23]2[C:28]([C:29]3N=CC=CN=3)=[CH:27][CH:26]=[CH:25][CH:24]=2)=O)C[CH2:17][CH2:16]1)=O)[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=O.C[C@@H]1[C@@H](C(N[C:46]2[C:51](C3N=CC=CN=3)=[CH:50][CH:49]=[CH:48][CH:47]=2)=O)N(C([C@@H](NC([C@@H](NC)C)=O)C2CCCCC2)=O)CC1.[CH3:74][C:75]([O:77][CH2:78][C@H:79]([C@H:103]([OH:114])[CH2:104][C@@H:105]([O:110][C:111]([CH3:113])=[O:112])[C:106]([OH:109])([CH3:108])[CH3:107])[C@@H:80]1[C@@:84]2([CH3:101])[CH2:85][CH2:86][C:87]3[C@@:92]4([CH3:100])[CH2:93][CH2:94][C@H:95]([OH:99])[C:96]([CH3:98])([CH3:97])[C@@H:91]4[CH2:90][CH2:89][C:88]=3[C@:83]2([CH3:102])[CH2:82][CH2:81]1)=[O:76]>>[CH3:74][C:75]([O:77][CH2:78][C@H:79]([C@H:103]([OH:114])[CH2:104][C@@H:105]([O:110][C:111]([CH3:113])=[O:112])[C:106]([OH:109])([CH3:108])[CH3:107])[C@@H:80]1[C@@:84]2([CH3:101])[CH2:85][CH2:86][C:87]3[C@@:92]4([CH3:100])[CH2:93][CH2:94][C@H:95]([OH:99])[C:96]([CH3:97])([CH3:98])[C@@H:91]4[CH2:90][CH2:89][C:88]=3[C@:83]2([CH3:102])[CH2:82][CH2:81]1)=[O:76].[CH2:26]1[CH2:25][CH2:24][CH:23]([N:22]2[CH2:17][CH2:16][N:15]([CH:13]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:19][CH2:20]2)[CH2:28][CH2:29][CH2:27]1
Reactant: CN[C@@H](C)C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1-c1ncccn1)C1CCCCC1
Reactant: CN[C@@H](C)C(=O)N[C@H](C(=O)N1CC[C@H](C)[C@H]1C(=O)Nc1ccccc1-c1ncccn1)C1CCCCC1
Agent: CC(=O)OC[C@H]([C@H](O)C[C@@H](OC(C)=O)C(C)(C)O)[C@H]1CC[C@@]2(C)C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Product: c1ccc(CC(c2ccccc2)N2CCN(C3CCCCCC3)CC2)cc1

Procedure:
Dispersion 3 containing comparison solvents CS-2 and CS-3 and comparison stabilizer CST-1 has a high number of crystals. Use of the solvent of the invention with CST-1 reduces the number of crystals, as in Dispersion 4, but further improvement is achieved through the use of the solvent of the invention S-1 combined with stabilizer of the invention ST-1 as in Dispersions 5, 6, 7, and 9. The use of solvent S-3 with ST-1 and IC-7 also provided a dispersion with low crystals, as in Dispersion 10. The combination of the coupler of the invention and the solvent of the invention also provided a low crystal dispersion, as in Dispersion 9.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:17])[CH2:11][C:12](OCC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[CH2:1]([O:8][CH2:9][C@@H:10]([OH:17])[CH2:11][C:12]([NH:19][NH2:20])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)C[C@H](O)COCc1ccccc1
Solvent: CCO
Solvent: O
Product: NNC(=O)C[C@H](O)COCc1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
In a 100 ml flask were put 4.15 g (17.4 mmol) of ethyl (S)-4-benzyloxy-3-hydroxybutyrate (optical purity: 89%e.e.) prepared in Reference Example 2, 20 ml of ethanol, and 2.62 g (52.2 mmol) of hydrazine monohydrate in a nitrogen stream, and the mixture was heated under reflux for 20 hours. The reaction mixture was cooled to room temperature (22 to 24° C.), and ethanol was removed by evaporation under reduced pressure. To the residue was added 40 ml of diethyl ether, followed by heating under reflux to dissolve the crude crystals. The solution was cooled to 5° C., followed by stirring for 1 hour. The crystals thus precipitated were collected by filtration and washed with 10 ml of diethyl ether to give 2.90 g (74%) of the title compound. Melting point: 96.9° C. Optical purity: >99.9%e.e.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(OCC)(OCC)[CH3:2].Cl.[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([OH:24])[C:22]=1[OH:23])[C:17]([OH:19])=[O:18].[CH3:25]CCCCC>>[CH3:25][O:18][C:17]([C:16]1[CH:20]=[C:21]([OH:24])[C:22]2[O:23][C:1]([CH3:2])=[N:13][C:14]=2[CH:15]=1)=[O:19].[O:9]1[C:10]2[CH:11]=[CH:20][CH:21]=[CH:22][C:14]=2[N:13]=[CH:1]1
Reactant: CCOC(C)(OCC)OCC
Reactant: CCCCCC
Reactant: Nc1cc(C(=O)O)cc(O)c1O
Agent: Cl
Product: COC(=O)c1cc(O)c2oc(C)nc2c1
Product: c1ccc2ocnc2c1
Temperature: 25 °C
Yield: 88 %

Procedure:
To stirred triethyl orthoacetate (35.0 mL, 190 mmol), 3-amino-4,5-dihydroxybenzoate hydrochloride (6.00 g, 27.3 mmol) was added. The stirred suspension was refluxed for 20 minutes and cooled to room temperature. The reaction mixture was poured into hexane (200 mL). The formed precipitate was separated by filtration and vacuum-dried to afford benzoxazole methyl 7-hydroxy-2-methyl-1,3-benzoxazole-5-carboxylate (4.98 g, 24.04 mmol, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.74 (br. s, 1H), 7.66 (d, J=1.4 Hz, 1H), 7.43 (d, J=1.4 Hz, 1H), 3.85 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]([CH2:32][O:33][CH:34]([CH3:36])[CH3:35])[CH2:20][NH:21]C(=O)OCC3C=CC=CC=3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1>C(O)C.[Pd]>[NH2:21][CH2:20][CH:19]([NH:18][C:16]([C:12]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:37]([F:41])=[CH:38][CH:39]=[CH:40][C:2]=3[F:1])[C:7]2=[N:14][C:13]=1[CH3:15])=[O:17])[CH2:32][O:33][CH:34]([CH3:36])[CH3:35]
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CNC(=O)OCc1ccccc1)COC(C)C
Agent: [Pd]
Solvent: CCO
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CN)COC(C)C

Procedure:
305 mg of rac-benzyl {2-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-carbonyl)amino]-3-isopropoxypropyl}carbamate (intermediate 116A; 0.54 mmol) were initially charged in 46 ml of ethanol, 44 mg of 10% palladium on activated carbon were added and the mixture was hydrogenated under hydrogen standard pressure for 4 hours. The reaction mixture was filtered and concentrated and the residue was purified by preparative HPLC (column: Macherey-Nagel VP 50/21 Nucleodur 100-5 C18 HTEC, 50×21 mm; mobile phase: gradient with 0.1% strength aqueous ammonia solution and methanol). This gave 127 mg of the title compound (54% of theory).
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH3:22])[CH:16]=3)=[N:10][CH2:11][C:12](=S)[NH:13][C:7]=2[CH:6]=[C:5]([CH2:23][CH3:24])[CH:4]=1)[CH3:2].[C:25]1([CH2:31][C:32]([NH:34][NH2:35])=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:1]([C:3]1[C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH3:22])[CH:16]=3)=[N:10][CH2:11][C:12]3[N:13]([C:32]([CH2:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:34][N:35]=3)[C:7]=2[CH:6]=[C:5]([CH2:23][CH3:24])[CH:4]=1)[CH3:2]
Reactant: NNC(=O)Cc1ccccc1
Reactant: CCc1cccc(C2=NCC(=S)Nc3cc(CC)cc(CC)c32)c1
Solvent: CCO
Product: CCc1cccc(C2=NCc3nnc(Cc4ccccc4)n3-c3cc(CC)cc(CC)c32)c1
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 6,8-diethyl-1,3-dihydro-5-(m-ethylphenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with phenylacetic acid hydrazide and the resulting product heated to 250° C. to give 7,9-diethyl-1-benzyl-6-(m-ethylphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl.O=C1C2(CCN([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:26](=[O:27])[C:25]4[CH:28]=[CH:29][CH:30]=[C:23]5[C:24]=4[C:19](=[CH:20][CH:21]=[CH:22]5)[C:18]3=[O:31])CC2)N(C2C=CC=CC=2)CN1.[Br:38][CH2:39][CH2:40]CCCCBr.BrCCCCBr>>[Br:38][CH2:39][CH2:40][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:26](=[O:27])[C:25]2[CH:28]=[CH:29][CH:30]=[C:23]3[C:24]=2[C:19](=[CH:20][CH:21]=[CH:22]3)[C:18]1=[O:31]
Reactant: BrCCCCCCBr
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: Cl
Solvent: BrCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr

Procedure:
Following the procedure of part (a) of example 26 but substituting 1,6-dibromohexane for the 1,4-dibromobutane, one obtains 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 95°-96°.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:12][CH2:13][Mg+].[Br-].[NH4+].[Cl-]>CCOCC>[OH:9][C:3]([C:2]([F:10])([F:11])[F:1])([CH2:12][CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC[Mg+]
Reactant: CCOC(=O)C(=O)C(F)(F)F
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)C(O)(CC)C(F)(F)F

Procedure:
To a −78° C. solution of ethyl trifluoropyruvate (129.0 g 758 mmol) in ether was added dropwise within 90 min a solution of EtMgBr 3.0 M in ether (252 mL). The solution was brought over one 1 h to ca. −10° C. and poured over 2 L of saturated NH4Cl. The layers were separated and the aqueous phase extracted with ether (3×500 mL). The organic phases were combined, dried over MgSO4 and the solvent removed. Distillation at 50-65° C. (30 mm Hg) gave the title compound. 1H NMR (400 MHz, acetone-d6): δ 5.4 (s, 1H), 4.35 (q, 2H), 2.07 (m, 1H), 1.83 (m, 1H), 1.3 (t, 3H) and 0.93 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.[Cl:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][O:29][C:28]1=[O:32]>>[ClH:1].[ClH:24].[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][N:14]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCCl
Reactant: Clc1ccc2c(c1)CC(N1CCNCC1)c1cc(Cl)ccc1O2
Product: Cl
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Cl)ccc3Oc3ccc(Cl)cc32)CC1

Procedure:
1-[2,8-dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine is reacted with 3-(2-chloro-ethyl)-2-oxazolidinone in the manner described in Example 1, and there is obtained 3-[2-{4-[2,8-dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone dihydrochloride having a melting point of 187°-188° C (with decomposition).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]1>CN1CCCC1=O>[CH3:8][C:6]1[CH:7]=[C:2]([N:18]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc(N2CCC(O)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
In a three necked flask, 38.78 g of 5-fluoro-2-nitrotoluene (0.25 mol), 41.4 g of potassium carbonate (0.3 mol) and 200 ml of N-methylpyrrolidinone were mixed. 26.13 g of 3-pyrrolidinol (0.3 mol) were added to this mixture. The heterogeneous mixture was agitated at ambient temperature for 12 hours. The reacting mixture was then poured on ice water. A yellow powder was then obtained. The powder was then filtered off and rinsed with water. After drying under vacuum with P2O5, 55.56 g of a yellow solid were obtained (yield) (95%).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=2)[CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:15]=3[S:14][C:13]2=[O:25])=[N:6][CH:7]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.O>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:2]2[CH:3]=[N:4][C:5]([C:8]3[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=3)[CH2:11][N:12]3[C:16]4[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:15]=4[S:14][C:13]3=[O:25])=[N:6][CH:7]=2)[CH2:32][CH2:31]1
Reactant: O=c1sc2ccc(C(F)(F)F)cc2n1Cc1cccc(-c2ncc(I)cn2)c1
Reactant: CN1CCNCC1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCN(c2cnc(-c3cccc(Cn4c(=O)sc5ccc(C(F)(F)F)cc54)c3)nc2)CC1
Temperature: 100 °C

Procedure:
513 mg (1 mmol) of 3-[3-(5-iodopyrimidin-2-yl)benzyl]-5-trifluoromethyl-3H-benzothiazol-2-one is suspended in toluene, briefly heated to 100° C. and cooled to room temperature. 134 μl (1.2 mmol) of methylpiperazine, 297 mg (1.4 mmol) of potassium phosphate trihydrate, and 33 mg (0.08 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and 18 mg (0.02 mmol) of tris(benzylideneacetone)dipalladium are subsequently added and stirred at 100° C. under an argon atmosphere. 33 mg (0.08 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and 18 mg (0.02 mmol) of tris(benzylideneacetone)dipalladium are subsequently again added and stirred at 100° C. for a further 24 h under an argon atmosphere. Water is added to the reaction mixture, which is then extracted with ethyl acetate and dried. The crude product is purified by means of preparative HPLC. The product is in the form of the trifluoroacetate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=O)=[CH:5][CH:4]=1)#[N:2].[Cl:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH3:22])=C(Cl)[N:14]=1>>[Cl:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH3:22])=[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:14]=1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Reactant: N#Cc1ccc(NC=O)cc1
Product: Cn1cnc2c(Nc3ccc(C#N)cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(4-cyano-phenyl)-formamide and 2,6-dichloro-9-methyl-9H-purine.