Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(=O)(O)(O)O.[CH2:6]([O:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:22][C@@H:21]3[C@H:17]2[CH2:18][CH2:19][N:20]3C(OC(C)(C)C)=O)=[N:13][C:12]=1[CH3:30])=[O:10])[CH3:7].O>ClCCl>[C@@H:21]12[CH2:22][N:16]([C:14]3[S:15][C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])=[C:12]([CH3:30])[N:13]=3)[C@@H:17]1[CH2:18][CH2:19][NH:20]2
Reactant: CCOC(=O)c1sc(N2C[C@@H]3[C@H]2CCN3C(=O)OC(C)(C)C)nc1C
Agent: O=P(O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1sc(N2C[C@H]3NCC[C@H]32)nc1C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
85% phosphoric acid (0.44 mL, 3.78 mmol) was added to a solution of tert-butyl (1R,5R)-6-[5-(ethoxycarbonyl)-4-methyl-1,3-thiazol-2-yl]-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate obtained in Example (236b) (278 mg, 0.76 mmol) in dichloromethane (1 mL) at room temperature, followed by stirring for two hours. Water was added to the reaction solution, and the mixture was washed with ethyl acetate. Then, a 1 N aqueous sodium hydroxide solution was added to the aqueous layer, followed by extraction with an ethyl acetate/methanol mixed solvent. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. Thereafter, the solvent was evaporated under reduced pressure to obtain 175 mg of the title compound as a pale yellow oily substance (87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:27]([O-])=O)[CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][C:18]2[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH:10]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][C:18]2[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH:10]=1)[NH2:27]
Reactant: COc1ccc(Cc2cc(Sc3c(Cl)cc([N+](=O)[O-])cc3Cl)ccc2OC)cn1
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc(Cc2cc(Sc3c(Cl)cc(N)cc3Cl)ccc2OC)cn1

Procedure:
3,5-Dichloro-4-(4'-methoxy-3'-(6-methoxy-3-pyridylmethyl)phenylthio)-nitrobenzene (28.60 g) and iron powder (35 g) were stirred with heating in glacial acetic acid (250 ml) at 90° for 40 minutes. The mixture was cooled, filtered, then evaporated to dryness and the resulting gum redissolved in chloroform, washed with water (twice), dried over anhydrous magnesium sulphate and evaporated to give the crude product as a light brown gum (27.17 g). This gum was chromatographed on silica gel using ethyl acetate-petroleum spirit (60°-80°, gradient elution) as eluant. 3,5-Dichloro-4-(4'-methoxy-3'-(6-methoxy-3-pyridylmethyl)phenylthio) aniline was isolated as a pale yellow solid (21.29 g, 79%), m.p. 114°-115°.
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:26][CH2:25]3)=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1)=[O:21]
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCN(Cc2ccc(F)cc2)CC1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: NCC(=O)NCC1CCN(Cc2ccc(F)cc2)CC1
Yield: 46 %

Procedure:
A solution of the 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]-1-(4-fluorobenzyl)piperidine and piperidine (5 mL) in DMF (5 mL) was stirred at room temperature for 17 h. Concentration and column chromatography (SiO2, Et3N:CH3OH:CH2Cl2=0.5:2:8) afforded 4-{(glycylamino)methyl}-1-(4-fluorobenzyl)piperidine (453 mg, 46%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH:5]1[C:18](=O)[CH2:17][CH:16]2[N:7]([CH2:8][CH2:9][C:10]3[C:15]2=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:6]1)[CH3:3].C(O)(=O)C.[NH3:28].[BH4-].[Na+]>CO>[CH2:4]([CH:5]1[CH2:6][N:7]2[CH2:8][CH2:9][C:10]3[C:15]([CH:16]2[CH2:17][CH:18]1[NH2:28])=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH:2]([CH3:3])[CH3:1]
Reactant: COc1cc2c(cc1OC)C1CC(=O)C(CC(C)C)CN1CC2
Reactant: N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)C1CC(N)C(CC(C)C)CN1CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
With reference to FIG. 11, tetrabenazine (317 mg, 1 mmol) was dissolved in methanol (MeOH, 10 ml) and cooled with ice-water. To this solution, ammonia acetate (500 mg) was added, followed by the addition of sodium borohydride (50 mg) in portion. The reaction was stirred at room temperature for 24 hours and quenched with water. The aqueous solution was extracted with methylene chloride (10 ml) twice. The combined organic phase was washed with brine and dried with sodium sulfate. After removing the solvent, the residue was purified by chromatography. One hundred and fifty milligrams of (HG-6) (3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-amine) was obtained as white solid (yield: 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(Br)cn1
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2)cn1
Yield: 810.6 %

Procedure:
Prepared from commercially available 2-amino-5-bromopyridine (5.0 g, 29 mmol) and commercially available 4-trifluoromethylphenylboronic acid (6 g, 32 mmol) as described in example C.20 step 2. Obtained the title compound as an off-white solid (56 g, 56%). MS (ISP) 239.2 [(M+H)+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28]>CC(=O)CC.[I-].[K+]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCC1Cl
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1CCCC1Oc1ccc(OCc2ccccc2)cc1
Yield: 34 %

Procedure:
To a mixture of 4-benzyloxyphenol (5 g, 25 mmol), potassium iodide (125 mg), and potassium carbonate (4.48 g, 32.5 mmol) in 2-butanone (30 ml) was added 2-chlorocyclopentanone (5.9 g, 50 mmol). The mixture was heated at reflux for 5 h, filtered and concentrated in vacuo. The residue was dissolved in diethyl ether and washed successively with 10% aqueous sodium hydroxide, water and brine. After drying over magnesium sulfate, solvents were removed in vacuo and the residue subjected to flash chromatography on silica gel eluting with 30% diethyl ether in hexanes to afford the title compound as a pale orange solid (2.4 g).
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4]C.[C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])(=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:2](/[O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:6](=[O:8])[CH3:7])=[CH:3]\[CH3:4]
Reactant: CC=CCCl
Reactant: CC(=O)Nc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C/C=C/Oc1ccccc1NC(C)=O

Procedure:
A heterogenic mixture of commercially available 1-chloro-2-butene (Aldrich, predominantly trans) (453 mg, 0.49 mL, 5.00 mmol), 2-acetamidophenol (756 mg, 5.00 mmol) and potassium carbonate (691 mg, 5.00 mmol) in aceton (10 ml) was heated to reflux over night. After evaporation of the solvent the residue was taken up by ethylacetate and water. Washing of the organic phase with water, 5-proz. sodium hyroxide and brine and evaporation of the solvent afforded the crude which was purified by flash chromatography on silica gel (heptane/EtOAc=3:2). Yield: 732 mg (71%) of a brownish yellow solid. Trans:cis=81:19 (ratio determined by 1H-NMR; 400 MHz, CDCl3):
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([OH:9])=[N:7][CH:8]=1.C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C>[Br:17][C:5]1[C:6]([OH:9])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1
Reactant: BrBr
Reactant: Oc1ccc(C(F)(F)F)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ncc(C(F)(F)F)cc1Br
Temperature: 80 °C
Yield: 100.6 %

Procedure:
To a solution of 5-(trifluoromethyl)pyridin-2-ol (10.52 g, 62 mmol) and sodium acetate (5.29 g, 64 mmol) in glacial acetic acid (38 mL) was added bromine (3.36 mL, 65 mmol) at room temperature. The white cloudy solution slowly turned into a clear brown solution, which was heated at 80° C. for 2.5 h. The mixture was allowed to cool to room temperature and then evaporated under reduced pressure. The residue was neutralized with saturated NaHCO3 solution to pH=8. The resulting solution was extracted with EtOAc three times. The combined extracts were dried over MgSO4, filtered, and evaporated in vacuo to yield 15.1 g (99.8%) of the crude product (15.1 g, 98.8%) as a white solid. LC-MS calculated for C6H3BrF3NO: (M+H)+241.9; found 241.9/243.9.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([C:13]3[O:17][C:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]4)=[N:15][C:14]=3[C:25]([F:28])([F:27])[F:26])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43](=[O:46])[CH:44]=[CH2:45]>C(#N)C>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43](=[O:46])[CH2:44][CH2:45][N:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([C:13]3[O:17][C:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]4)=[N:15][C:14]=3[C:25]([F:27])([F:28])[F:26])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C=CC(=O)Nc1ccccc1F
Reactant: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4[nH]ccc4c3)o2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4c(ccn4CCC(=O)Nc4ccccc4F)c3)o2)C1
Temperature: 25 °C
Reaction time: 30 h
Yield: 7.6 %

Procedure:
To a solution of compound 44 (0.080 g, 0.204 mmol) and cesium carbonate (0.133 g, 0.408 mmol) in anhydrous acetonitrile (1.0 mL) at room temperature was added N-(2-fluorophenyl)acrylamide (C-4) (0.101 g, 0.612 mmol) in one portion. The reaction mixture was stirred at room temperature for 30 h, then additional N-(2-fluorophenyl)acrylamide (C-4) (0.168 g, 1.02 mmol) was added, and the reaction mixture was heated at 50° C. for 24 h. The reaction mixture was filtered over a celite pad, washed with methylene chloride (50 mL) and concentrated. Purification of the crude residue by silica gel chromatography (eluant gradient: 100% methylene chloride to 100% EtOAc) followed by C18 reverse phase chromatography (H2O:CH3CN eluant gradient) gave 8.7 mg (6.8% yield) of N-[1-(3-(2-fluorophenylamino)-3-oxopropyl)-1H-indol-5-yl]-2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (71) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 10.05 (br s, 1H), 10.05 (br s, 1H), 9.82 (br s, 1H), 7.88 (m, 1H), 7.85 (m, 1H), 7.53 (d, 1H, J=9.1 Hz), 7.37 (m, 1H), 7.24 (m, 1H), 7.15 (m, 2H), 6.42 (m, 1H), 4.49 (br t, 2H, J=6.6 Hz), 4.12 (m, 2H), 3.05 (t, 1H, J=11.5 Hz), 2.92 (t, 2H, J=6.6 Hz), 2.74 (t, 1H, J=11.9 Hz), 1.78 (m, 3H), 1.54 (m, 1H), 1.16 (m, 1H), 0.94 (d, 3H, J=6.3 Hz). MS (M+1): 558.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1.FC(F)(F)S(O[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[N:32][C:33]([N:36]([CH3:47])[CH:37]3[CH2:42][C:41]([CH3:44])([CH3:43])[NH:40][C:39]([CH3:46])([CH3:45])[CH2:38]3)=[CH:34][CH:35]=2)=[C:26]([OH:48])[CH:25]=1)(=O)=O.C(=O)(O)[O-].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:31]=[N:32][C:33]([N:36]([CH3:47])[CH:37]4[CH2:42][C:41]([CH3:43])([CH3:44])[NH:40][C:39]([CH3:46])([CH3:45])[CH2:38]4)=[CH:34][CH:35]=3)=[C:26]([OH:48])[CH:25]=2)[CH:6]=[N:5][CH:4]=1
Reactant: CN(c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cncc(-c2ccc(-c3ccc(N(C)C4CC(C)(C)NC(C)(C)C4)nn3)c(O)c2)c1
Temperature: 100 °C
Yield: 60 %

Procedure:
Following GENERAL METHOD 1-3 for Suzuki Coupling, to a 25 mL microwave vial, was added 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (94 mg, 0.400 mmol), 3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl trifluoromethanesulfonate (Intermediate 9-2, 105 mg, 0.2 mmol), sodium bicarbonate (50.4 mg, 0.600 mmol) and Pd(PPh3)4 (11.56 mg, 10.00 μmol), followed by dioxane (2 mL) and water (0.5 mL). The reaction mixture was purged with N2 for 10 minutes, and heated in a microwave at 100° C. for 1 h, then diluted with EtOAc and filtered through celite. The filtrate was acidified to pH ˜3 with 1N HCl, and loaded onto an SCX column. The column was washed with MeOH, and eluted with 2N NH3 in MeOH. After concentration, the residue was purified by preparative HPLC to provide 5-(5-methoxypyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol (55 mg, 0.120 mmol, 60% yield), LCMS: Rt=0.50 min [Method Q]; MS (M+1)=448.4; 1H NMR (METHANOL-d4) δ 8.17 (d, J=5.1 Hz, 1H), 8.11 (d, J=9.1 Hz, 1H), 7.85 (d, J=7.1 Hz, 1H), 7.22-7.33 (m, 4H), 7.06 (s, 1H), 5.10 (m, 1H), 3.97 (s, 3H), 3.03 (s, 3H), 1.74 (dd, J=12.6, 3.0 Hz, 2H), 1.59 (t, J=12.4 Hz, 2H), 1.42 (s, 6H), 1.26 (s, 6H).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)[CH:9]=1)(=[O:5])=[O:4].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:46]([C:48]1[N:49]=[C:50]([C:61]([O-])=[O:62])[N:51]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:52]=1)#[N:47].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:15]1([C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][S:3](=[O:4])(=[O:5])[NH:2][CH3:1])[CH:13]=[CH:12][C:11]=2[NH:14][C:61]([C:50]2[N:51]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:52]=[C:48]([C:46]#[N:47])[N:49]=2)=[O:62])[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: CNS(=O)(=O)CCc1ccc(N)c(C2=CCCCC2)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNS(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 123 mg (0.418 mmol) of 2-(4-amino-3-cyclohex-1-enyl-phenyl)-ethanesulfonic acid methylamide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 292 mg (0.627 mmol) of PyBroP, 140 mg (0.460 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 218 μL (1.25 mmol) of DIEA. The mixture was stirred at RT for 2 h, diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3 (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 177 (71%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C26H37N5O4SSi, 544.2 (M+H). found 543.9.
Reaction SMILES: [CH3:1][Mg+].[Br-].[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=[O:13])[CH2:7][CH2:6]1>C1COCC1>[OH:4][C:5]1([CH3:1])[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=[O:13])[CH2:7][CH2:6]1
Reactant: O=C(O)CC1CCC(=O)CC1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1(O)CCC(CC(=O)O)CC1

Procedure:
Prepared using an excess of MeMgBr (26 mmol) in THF (20 ml) with (4-Oxo-cyclohexyl)-acetic acid (13 mmol) as described on Journal of American Society 93 (1), 1971, 121-129.
Reaction SMILES: [O:1]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][C:30]1[C:31]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:32][C:33]([N+:38]([O-])=O)=[C:34]([CH:37]=1)[C:35]#[N:36])[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:10][C:11]([N+:16]([O-])=O)=[C:12]([CH:15]=1)[C:13]#[N:14]>CC(O)=O.CC(O)C.[Fe]>[O:1]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:10][C:11]([NH2:16])=[C:12]([CH:15]=1)[C:13]#[N:14])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][C:30]1[C:31]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:32][C:33]([NH2:38])=[C:34]([CH:37]=1)[C:35]#[N:36]
Reactant: COCCOc1cc([N+](=O)[O-])c(C#N)cc1OCCOCCOCCOCCOc1cc(C#N)c([N+](=O)[O-])cc1OCCOC
Agent: [Fe]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COCCOc1cc(N)c(C#N)cc1OCCOCCOCCOCCOc1cc(C#N)c(N)cc1OCCOC
Temperature: 25 °C
Yield: 82.8 %

Procedure:
To a solution of 5,5′-((((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(4-(2-methoxyethoxy)-2-nitrobenzonitrile) (0.2 g) in AcOH (10 mL) and i-PrOH (10 mL) was added iron powder (0.5 g). The resulting mixture was heated to reflux for 1 h. After reaction finished, the mixture was cooled to room temperature, filtered, the precipitate washed with EA (10 mL). The combined washings and filtrate were concentrated under reduced pressure and purification by silica chromatography to give 0.15 g of 5,5′-((((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(2-amino-4-(2-methoxyethoxy)benzonitrile). 1H-NMR (400 MHz, CDCl3): δ: 6.90 (s, 2H), 6.25 (s, 2H), 4.20-4.16 (br, 4H), 4.15-4.02 (m, 8H), 3.82-3.79 (m, 4H), 3.77-3.75 (m, 4H), 3.72-3.70 (m, 4H), 3.68-3.66 (m, 4H), 3.43 (s, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH:2]=1.[CH3:12][N:13]([C:15]1C=CC=C[N:16]=1)C>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:9][CH2:10][NH:11][C:12]2=[N:13][C:15]#[N:16])[CH:2]=1
Reactant: CN(C)c1ccccn1
Reactant: NCCNCc1cccnc1
Solvent: CC#N
Product: N#CN=C1NCCN1Cc1cccnc1

Procedure:
7.56 g of N-pyrid-3-ylmethylethylenediamine, 7.31 g of dimethyl-N-cyanothioiminocarbonate and 20 mg of dimethylaminopyridine in 50 ml of acetonitrile are heated at reflux for 3 hours. The product crystallises out when the mixture has cooled. The resulting crystals are filtered off and washed with ether, yielding the title compound of formula ##STR6## having a melting point of 126.5°-128.5° C. (compound No. 1).
Reaction SMILES: [CH2:1]([O:8][CH:9]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][C:11](OCC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>CCOCC>[CH2:1]([O:8][CH:9]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(OCc1ccccc1)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: O=CCC(OCc1ccccc1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a 1000 mL round-bottomed flask was added ethyl 3,3-dibenzyloxypropionate (9, 15 g, 0.0477 mole) and ether (300 mL). The solution was cooled to -78° C. under a dry argon atmosphere and diisobutylaluminum hydride (47.7 mL of 1M solution in hexanes, 0.0477 mole) was added dropwise. The mixture was stirred for 0.5 h at -78° C. followed by quench with methanol (20 mL). The mixture was allowed to warm to 0° C. and washed 2 times with potassium sodium tartrate, tetrahydrate 20% solution in water (2@250 mL), brine (200 mL) and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give 3,3-dibenzyloxypropanal as a colorless oil (12.1 g, 94% yield): 1H NMR d 2.83 (dd, 2H, J=2, 5.3 Hz), 4.61 (d, 2H, J =11.6 Hz), 4.69 (d, 2H, J=11.6 Hz), 5.20 (t, 1H, J=5.5 Hz), 7.27-7.36 (m, 10H), 9.74 (s, 1H); IR (Neat) 3100, 3080, 3045, 2940, 2895, 1735, 1500, 1460, 1390, 1360, 1210, 1110, 1060, 1030, 740, 700. ##STR11##
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18](O)=O)[CH3:15].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH2:14]([C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1)[CH3:15]
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: CCc1cnccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: CCc1cnccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 15.6 %

Procedure:
A mixture of 0.40 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 0.41 g of 3-ethylisonicotinic acid, 0.44 g of WSC and 10 ml of pyridine was stirred for 2.5 hours at 120° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. To the residue was added a mixture of 0.60 g of p-toluenesulfonic acid monohydrate and 10 ml of toluene, and the mixture was stirred for 7 hours at 120° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.10 g of 2-(3-ethylpyridin-4-yl-)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as present active compound 217).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([Li])CCC>CCCCCC.O1CCCC1>[CH3:22][CH:23]1[CH2:28][CH2:27][N:26]([C:17]([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:16]=2)=[O:19])[CH2:25][CH2:24]1
Reactant: CC1CCNCC1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1CCN(C(=O)c2nc(-c3ccccc3)nc3ccccc23)CC1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), 4-methylpiperidine (2.95 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethanol, 4-methyl-1-[(2-phenylquinazolin-4-yl)-carbonyl]-piperidine (1 g), melting at 138° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:21]([NH2:23])=[O:22].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:31](C)=O.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:31])[CH2:17][CH2:16]3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:21]([NH2:23])=[O:22]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)c1cc2c(C3CCNCC3)cccc2n1Cc1cccc(F)c1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN1CCC(c2cccc3c2cc(C(N)=O)n3Cc2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(3-Fluoro-benzyl)-4-piperidin-4-yl-1H-indole-2-carboxylic acid amide (50 mg, 0.14 mmol) in CH2Cl2 (5 ml) were added formaldehyde (20 μl, 0.24 mmol, 37% in H2O solution) and NaBH(OAc)3 (74 mg, 0.35 mmol). After stirring at room temperature for 4 hours, the reaction mixture was added to a saturated solution of sodium bicarbonate, followed by a mixture of CH2Cl2/H2O. The organic fraction was separated, washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo to give 1-(3-Fluoro-benzyl)-4-(1-methyl-piperidin-4-yl)-1H-indole-2-carboxylic acid amide as a brown oil. This oil was dissolved in 4 ml ethanol, and 2 M ethanolic hydrochloric acid solution (1 ml) was added. The reaction mixture is heated at 100° C. for 20 minutes, then cooled to room temperature, and 14 mg of 1-(3-Fluoro-benzyl)-4-(1-methyl-piperidin-4-yl)-1H-indole-2-carboxylic acid amide hydrochloride salt was collected. MS: 366 (M+H)+.