Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12](N)=[O:13].S(=O)(=O)(O)O.[OH-].[Na+].[C:22]([O-])(O)=[O:23].[Na+]>CO.O>[CH3:22][O:23][C:12]([C:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[N:8][C:9]=2[CH:10]=[CH:11][C:2]=1[NH2:1])=[O:13]
Reactant: O=C([O-])O
Reactant: NC(=O)c1c(N)ccc2ncccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(N)ccc2ncccc12
Temperature: 140 °C
Reaction time: 0.22 h
Yield: 26 %

Procedure:
To a solution of 2 g (10.68 mmol) of the above 6-amino-quinoline-5-carboxylic acid amide in 10.76 mL of absolute methanol is added 2.34 mL (42.73 mmol) of concentrated sulphuric acid. The reaction is stirred in a microwave during 13 minutes at 140° C. The reaction is repeated 6 times with flask opening after each run because of gas formation. The mixture is then cooled at 0° C. and water is added. The pH of the mixture is increased slowly to 6 with addition of an aqueous 6N NaOH solution. The pH is adjusted to 8 with a saturated aqueous solution of NaHCO3. The product is extracted with ethyl acetate (4 times) and the combined organic layers are dried on Na2SO4, filtrated and evaporated. After flash chromatography purification with heptane and ethyl acetate as eluants, 555 mg (26%) of a yellowish solid are obtained; LC/MS: 203/204 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(Cl)Cl.Cl[Si](C)(C)C>C(OC(=O)C)C>[C:11]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1)([CH:10]=[CH2:9])=[O:12]
Reactant: Nc1ccc(CCCC(=O)O)cc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CC(=O)Nc1ccc(CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
4-(4-aminophenyl)butyric acid (6 g, 3.36 mmol) was added to a 200 mL three-mouthed round flask, and methylene chloride (100 mL) was added and dissolved under the nitrogen atmosphere at 40° C. To the solution was added chlorotrimethyl silane (6.0 mL). The solution was refluxed and agitated for 2 hours and, after reaction, cooled down to the room temperature. While kept at 0 to 5° C. on an ice bath under the nitrogen atmosphere, an acid eliminator (in an excess amount by 10% in concentration relative to the reactant) was added dropwise through a funnel for 10 minutes, where the acid eliminator contained imidazole and tetraethyl amine mixed at the same mole fraction. In the same manner, a solution containing acryloyl chloride (2.8 mL) in methylene chloride (30 mL) was added dropwise for 20 minutes, and the solution was kept for 30 minutes of reaction and then warmed up to the room temperature for 2 more hours of reaction. After the solvent was removed, 2M sodium hydroxide solution (200 mL) was added, and the solution was stirred for 2 hours. The aqueous solution was weak-acidified (pH 5˜6) with a 2M hydrogen chloride solution to form an aqueous solution containing a white precipitate. This solution was added to a separatory funnel along with ethylacetate (200 mL) and shaken up to cause phase separation into aqueous and ethylacetate layers. The solvent in the ethylacetate layer where the product is dissolved was removed on an evaporator, and the residual solid was dried out in a vacuum oven for 24 hours to yield a white 4-(4-acrylaminophenyl)butyric acid (APB) solid (yield 92%). The melting point of the solid was 107° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([S:11][CH3:12])=[C:9]([CH3:13])[NH:8][C:7]=12.[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1>>[CH3:13][C:9]1[NH:8][C:7]2=[C:2]([N:15]3[CH2:16][CH2:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:14]3)[N:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[S:11][CH3:12]
Reactant: CSc1c(C)[nH]c2c(Cl)nccc12
Reactant: c1ccc2c(c1)CCNC2
Product: CSc1c(C)[nH]c2c(N3CCc4ccccc4C3)nccc12
Temperature: 140 °C
Reaction time: 8 h

Procedure:
7-Chloro-2-methyl-3-methylsulfanyl-1H-pyrrolo[2,3-c]pyridine (418 mg) prepared in Step 1 was added to 1,2,3,4-tetrahydroisoquinoline (3 ml). The reaction mixture was stirred overnight at 140° C., cooled to room temperature, and then purified with silica gel column chromatography to give 440 mg of the titled compound as pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:31])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)([O-])=[O:2].C(=O)(O)[O-].[Na+]>C(O)C>[OH:2][NH:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:31])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH:21]=[C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)[C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)n1CCCCN1CC=C(c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c2cc(NO)ccc2c(=O)n1CCCCN1CC=C(c2ccccc2)CC1
Yield: 44 %

Procedure:
To a stirred solution of 7-nitro-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.2 g) in ethanol (10 ml) was added. Stannous chloride (0.46 g) and the mixture was refluxed for 30 minutes. After cooling, an aqueous sodium bicarbonate was added to adjust the pH to 7 and inorganic salts were filtered off through filter cell. The filter cake was washed with hot ethanol. Combined filtrate and washings were evaporated and the crude residue was washed in turn with water and cold ethanol, and then dried to give crystals of 7-hydroxyamino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (85 mg).
Reaction SMILES: [C:1]([N:6]1[C@@:10]2([CH2:14][CH2:13][N:12]([C@@H:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]2=[O:30])[CH2:9][CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].CC=CC(Cl)=O>>[CH3:4][C:2](=[CH2:3])[C:1]([N:6]1[C@@:10]2([CH2:14][CH2:13][N:12]([C@@H:15]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]2=[O:30])[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)C[C@H](C(=O)OCc1ccccc1)N1CC[C@]2(CCCN2C(=O)C(C)C)C1=O
Agent: CC=CC(=O)Cl
Product: C=C(C)C(=O)N1CCC[C@]12CCN([C@H](CC(C)C)C(=O)OCc1ccccc1)C2=O
Yield: 50 %

Procedure:
Following the procedure described for the synthesis of 13, staffing from 11 (200 mg, 0.43 mmol) and methylacryloyl chloride (89 mg, 0.86 mmol), the title compound (70 mg, 50%) was obtained as a colourless oil, after purification by LC (silica gel, hex-EtOAc, 2:1). HPLC [Column Novapack C18 (Waters), 3.9×150 mm, Φ=1 ml/min, λ=214 nm, eluent: ACN/0.05% TFA, (25/75)] Rt==6.38 min. 1H-NMR (200 MHz, CDCl3) δ 0.91 (t, J=6, 6H), 1.44 (m, 1H), 1.64-1.93 (m, 5H), 1.93 (s, 3H), 1.96-2.12 (m, 2H), 2.78 (m, 1H), 3.20 (m, 1H), 3.56-3.68 (m, 3H), 4.80 and 4.77 (2d, J=10, 1H), 5.16 (s, 2H), 5.19 (d, J=9, 2H), 7.32 (m, 5H). 13C-NMR (75 MHz, CDCl3) δ 19.8, 21.4, 23.0, 24.2, 24.9, 29.9, 37.1, 37.7, 41.1, 50.2, 53.2, 66.6, 67.4, 116.9, 128.1, 128.3, 128.4, 135.0, 141.7, 170.7, 174.1. ESI-MS Calcd for C24H32N2O4: 412.24. Found: 413.3 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8](=[O:18])[CH2:9][NH:10]C(=O)OC(C)(C)C)[C@@H:3]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C(Cl)Cl>[NH2:10][CH2:9][C:8]([N:4]1[CH2:5][C@H:6]([OH:7])[C@@H:2]([OH:1])[C@H:3]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:18].[C:30]([OH:32])([C:29]([F:34])([F:33])[F:28])=[O:31]
Reactant: COc1ccc(C[C@@H]2[C@H](O)[C@@H](O)CN2C(=O)CNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C[C@@H]2[C@H](O)[C@@H](O)CN2C(=O)CN)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Following the procedure as described in Example 11, except using material from Example 40 (350 mg, 0,920 mmol), CH2Cl2 (35 mL, trifluoroacetic acid (500 μlit, 6.49 mmol) and stirring at room temp for 45 min, the title compound is isolated (quantitative yield) as a mono TFA salt and is used crude, “as is”, in the next step. LC/MS (Condition A): ret. T=1.54 min, (M+H)+ 281.19.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([O:12][C@@H:13]([C:18]1[C:19]([CH3:60])=[N:20][C:21]2[N:22]([N:36]=[C:37]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:38]=2[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)[CH:40]=2)[C:23]=1[C:24]1[C:25]([CH3:35])=[C:26]2[C:31](=[C:32]([F:34])[CH:33]=1)[O:30][CH2:29][CH2:28][CH2:27]2)[C:14]([O:16]C)=[O:15])([CH3:11])([CH3:10])[CH3:9].[Li+].[OH-]>O1CCOCC1>[C:8]([O:12][C@@H:13]([C:18]1[C:19]([CH3:60])=[N:20][C:21]2[N:22]([N:36]=[C:37]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:38]=2[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)[CH:40]=2)[C:23]=1[C:24]1[C:25]([CH3:35])=[C:26]2[C:31](=[C:32]([F:34])[CH:33]=1)[O:30][CH2:29][CH2:28][CH2:27]2)[C:14]([OH:16])=[O:15])([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(-c3cccc(OCc4ccc(F)cc4)c3)c(-c3ccccc3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1nc2c(-c3cccc(OCc4ccc(F)cc4)c3)c(-c3ccccc3)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 60 °C
Reaction time: 48 h
Yield: 50.7 %

Procedure:
To a solution of (2S)-methyl 2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-3-(3-((4-fluorobenzyl)oxy)phenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate TFA salt (10 mg, 0.014 mmol) in dioxane (0.5 mL) was added 1.0 N LiOH aqueous solution (0.5 mL, 0.5 mmol). The reaction mixture was stirred at 60° C. for 48 h. The reaction mixture was filtered and the filtrate was purified by preparative HPLC to afford (5 mg, 50%) of the title compound as the TFA salt. Preparative HPLC condition: Phenomenex Luna C18 30×100 mm S10, 50 to 100% B over 22 min gradient, 6 min hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA. Flow rate: 40 mL/min. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.087 (9H, br. s.), 1.88 (2H, br. s.), 2.51 (2H, br. s.), 2.71 (3H, br. s.) 2.82-2.96 (2H, m), 4.29 (2H, br. s.), 4.6 (1H, s), 5.02 (2H, s), 6.9 (1H, s), 7.14-7.47 (12H, m), 7.97 (1H, s).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([O:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[N+:39]([O-])=O)[CH:12]([N:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Ni]>[NH2:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[O:31][CH:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:12]([N:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)C(C(CCOCc1ccccc1)Oc1ccc(F)cc1[N+](=O)[O-])N(Cc1ccccc1)Cc1ccccc1
Agent: [Ni]
Solvent: CO
Product: Nc1cc(F)ccc1OC(CCOCc1ccccc1)C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1

Procedure:
6.00 g (11 mmol) racemic (2R,3R and 2S,3S)-5-Benzyloxy-2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-pentanoic acid in 100 ml methanol were hydrogenated with 1.5 g Raney-Nickel. Filtration and removal of the solvent by distillation yielded 5.57 g (98%) (2R,3R and 2S,3S)-3-(2-amino-4-fluoro-phenoxy)-5-benzyloxy-2-dibenzylamino-pentanoic acid as foam, MS m/e (%): 529.5 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[F:18][CH:19]([F:21])Cl>O.O1CCOCC1>[F:18][CH:19]([F:21])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccccc1)c1ccc(OC(F)F)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
100 g of 4-hydroxybenzophenone and 200 g of sodium hydroxide are dissolved in a mixture of 1 l of water and 500 ml of dioxane. The mixture is heated to 70° C. and a vigorous stream of difluorochloromethane (Frigen 22) is introduced. After 2 hours, the mixture is cooled to room temperature and 1 l of water is added to the contents of the flask. The mixture is extracted three times using 1.2 l of chloroform each time, the chloroform phase is extracted by shaking with 1N sodium hydroxide solution, washed with water and the organic phase is dried using potassium carbonate. After stripping off the solvent and subsequent distillation under vacuum, 60 g (48%) of 4-difluoromethoxybenzophenone are obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([NH:12]C(=O)C)=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])[CH3:2].Cl>CO>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])[CH3:2]
Reactant: CCn1c(Cn2ccnc2-c2cc(F)ccc2F)nc2cc(NC(C)=O)ccc21
Agent: Cl
Solvent: CO
Product: CCn1c(Cn2ccnc2-c2cc(F)ccc2F)nc2cc(N)ccc21

Procedure:
Crude N-{1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-1H-benzimidazol-5-yl}acetamide is treated with 10% aqueous HCl (20 mL) in methanol (10 mL) at reflux for 1.5 h. After cooling, the methanol is removed in vacuo, and the aqueous layer washed with ethyl acetate. The aqueous layer is adjusted to pH 10 with 3 N NaOH, then extracted with ethyl acetate (3×), and the combined organic extracts washed with water (2×) then saturated aqueous sodium chloride, dried (MgSO4) and concentrated to give 1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-amino-1H-benzimidazole. LCMS MH+ 354.4.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([C:15]3[N:19]=[C:18]([C:20]4[CH:21]=[N:22][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:24][CH:25]=4)[O:17][N:16]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][CH2:40][O:41][CH3:42]>CN(C=O)C>[CH3:42][O:41][CH2:40][CH2:39][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][C:28]([F:30])([F:29])[F:31])=[CH:24][CH:25]=3)[O:17][N:16]=2)[N:9]=1
Reactant: COCCBr
Reactant: Nc1nc(Nc2ccccc2)nc(-c2noc(-c3ccc(OCC(F)(F)F)nc3)n2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(OCC(F)(F)F)nc3)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.5 %

Procedure:
2-N-Phenyl-6-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-1,3,5-triazine-2,4-diamine (prepared in an analogous manner to Example 41, 0.100 g, 0.232 mmol) was added to cesium carbonate (0.151 g, 0.465 mmol) in DMF (3 mL) at room temperature followed by the addition of 1-bromo-2-methoxyethane (22 μL, 0.232 mmol). The reaction mixture was stirred at room temperature for 1 h and then heated to 50 C for 18 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a brown solid. The solid was purified by preparative HPLC, Method A to afford the title compound (2.8 mg, 2.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:11])[C:9]#[N:10].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:12][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:11])[C:9]#[N:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1N(C)C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C#N)c1ccccc1CBr
Yield: 474.4 %

Procedure:
22.6 g (0.155 mol) of N-(2-methylphenyl)-N-methyl-cyanamide are dissolved in 300 ml of carbon tetrachloride, admixed with about 5 g of N-bromosuccinimide and 0.1 g of azodiisobutyronitrile and radiated using a UV lamp (250 W) for 5 hours with stirring. Over this period, more N-bromosuccinimide (a total of 32.9 g (0.185 mol)) is added a little at a time. The temperature increases during the reaction, until the solution boils at reflux. The reaction mixture is cooled and filtered, and the filtrate is concentrated under reduced pressure. 30 g of N-(2-bromomethyl-phenyl)-N-methyl-cyanamide of a content of 40% (HPLC) are obtained.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:23][NH:24][C:25](=[O:32])[CH:26]([CH2:30][CH3:31])[C:27](O)=[O:28]>>[F:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:23][NH:24][C:25](=[O:32])[CH:26]([CH2:30][CH3:31])[C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28]
Reactant: CCC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: CCC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The tide compound, MS: m/e=478.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-ethyl-malonamic acid.
Reaction SMILES: [Br-].[Li+].[CH3:3][Li].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH3:32])[C:19]2[C:24]([NH:25][C:26]3(OCC)[CH2:28][CH2:27]3)=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH3:32])[C:19]2[C:24]([NH:25][C:26]3([CH3:3])[CH2:27][CH2:28]3)=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC1(Nc2cccnc2N(C)C2CCN(Cc3ccccc3)CC2)CC1
Reactant: [Li]C
Agent: [Br-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CN(c1ncccc1NC1(C)CC1)C1CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixture of methyllithium-lithium bromide (1.5M in ether, 2.28 ml) in dry toluene (6.3 ml) at -78° under nitrogen in a flame-dried flask is added a mixture of 1-benzyl-4-[N-methyl-N-(3-(1-ethoxycyclopropylamino)-2-pyridinyl)amino]piperidine (EXAMPLE 123, 325 mg) in dry toluene (8.5 ml) at -78°. The mixture is stirred at -78° C. for 1 hr, quenched carefully with saturated aqueous ammonium chloride (10 ml) and water (10 ml) and warmed to 20°-25°. The mixture is extracted with ethyl acetate (25 ml) and the organic phase is washed with water (10 ml) and saline (10 ml), dried over magnesium sulfate and concentrated to give the crude product which is chromatographed (silica gel, 230-400 mesh, 35 g; eluting with a gradient of methanol/chloroform (1/99-4/96)) to give the title compound, NMR (CDCl3) 7.72, 7.31, 7.25, 7.17, 6.91, 5.02, 3.50, 3.02, 2.88, 2.59, 2.01, 1.71, 1.32, 0.75 and 0.65δ.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH:13]([OH:26])[CH2:14][NH:15][CH:16]([CH3:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)=O)C.[NH3:29]>C(O)C>[C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH:13]([OH:26])[CH2:14][NH:15][CH:16]([CH3:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)(=[O:3])[NH2:29]
Reactant: CCOC(=O)Cc1ccc(OCC(O)CNC(C)CCc2ccccc2)cc1
Reactant: N
Solvent: CCO
Product: CC(CCc1ccccc1)NCC(O)COc1ccc(CC(N)=O)cc1
Reaction time: 240 h
Yield: 57 %

Procedure:
In this example, 1.7 g of 1-(4-ethoxycarbonylmethylphenoxy)-3-(1-methyl-3-phenylpropylamino)-2-propanol (Compound 14) is dissolved in 100 ml of ethanol and the solution is poured into a pressure tube. Then, 100 ml of liquid ammonia is added thereto. The tube is sealed and is allowed to stand for 10 days at room temperature. After completion of the reaction, ethanol is distilled away from the solution under reduced pressure. The residue is recrystallized from methylisobutylketone to obtain 0.9 g of 1-(4-carbamoylmethylphenoxy)-3-(1-methyl-3-phenylpropylamino)-2-propanol. (Yield: 57%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[CH:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCC=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
A solution of tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (1.00 g, 4.11 mmol) in methylene chloride (20 mL) was cooled to 0° C., and added with the Dess-Martin reagent (2.27 g, 5.34 mmol), and then the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered, and the filtrate was washed with saturated aqueous sodium hydrogencarbonate, and then further washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (0.874 g, 88%).
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16]([Cl:18])[CH:15]=[C:14](Cl)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([Cl:18])[CH:15]=[C:14]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Clc1cc(Cl)nc(NC23CC4CC(CC(C4)C2)C3)n1
Reactant: C1CCNC1
Product: Clc1cc(N2CCCC2)nc(NC23CC4CC(CC(C4)C2)C3)n1
Yield: 86 %

Procedure:
By reacting 2-(1-adamantylamino)-4,6-dichloropyrimidine with pyrrolidine as described in Example 12, the title compound is obtained in a yield of 86%, m.p.: 178°-180° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][CH3:13])=[S:11].C[O:15][CH2:16][CH2:17][O:18]C.C(C=O)=O.NC(N)=S>C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:16]([OH:15])[CH:17]([OH:18])[N:12]([CH3:13])[C:10]1=[S:11]
Reactant: CNC(=S)Nc1ccc(C)cc1C
Reactant: COCCOC
Agent: NC(N)=S
Agent: O=CC=O
Solvent: CCN(CC)CC
Product: Cc1ccc(N2C(=S)N(C)C(O)C2O)c(C)c1
Reaction time: 1 h

Procedure:
30.0 g of N-(2,4-dimethylphenyl)-N'-methyl-thiourea were stirred with 150 ml of 1,2-dimethoxy-ethane and 10 ml of triethylamine, and 36.0 g of a 30% strength aqueous solution of glyoxal was added. After stirring for a short time, the thiourea slowly dissolved, the reaction being exothermic. The temperature was allowed to rise to 50° C. and the solution was kept at this temperature for a further 1 hour. Thereafter, the solvent was distilled off in vacuo and the oily residue was stirred with water, with the addition of a little acetic acid. The reaction product, which solidified in the crystalline form, was filtered off, washed with water and dried. The yield was 37 g. For purification, the product could be recrystallised from isopropyl alcohol.