Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[N:12]=[CH:11][C:10]([C@H:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:14])=[CH:9][CH:8]=1.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>C1COCC1>[C:24]([O:23][C:21]([N:18]1[CH2:17][CH2:16][N:15]([C@@H:13]([C:10]2[CH:9]=[C:8]([B:28]([OH:33])[OH:29])[C:7]([F:6])=[N:12][CH:11]=2)[CH3:14])[CH2:20][CH2:19]1)=[O:22])([CH3:26])([CH3:25])[CH3:27]
Reactant: C[C@H](c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
n-Butyllithium (2.5 M in hexanes, Aldrich; 20.0 mL, 50.0 mmol) was added (dropwise over 20 min) to a solution of (R)-tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (10.0 g, 32.3 mmol) in THF (150 mL) at −78° C., and the resulting mixture was stirred at −78° C. for 20 min. Triisopropyl borate (15.0 mL, 65.2 mmol) was then added (dropwise over 10 min), followed by additional THF (20 mL) to rinse solidified triisopropyl borate from the side of the flask. The resulting mixture was stirred at −78° C. for min, and the cooling bath was then removed. The reaction mixture was stirred for 1 h, and 1 N aq. NaOH (100 mL) and water (40 mL) were then sequentially added. The resulting mixture was stirred for 10 min, and the organic layer was separated. The organic layer was extracted with 1 N aq. NaOH (40 mL), and the aqueous layers were then combined and pH-adjusted with N aqueous HCl to a final pH of about 5. The resulting mixture was extracted with EtOAc (3×200 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide (R)-5-(1-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (9.27 g, 81% yield) as a white solid. 1H NMR (400 MHz, d4-MeOH) δ 8.39 (br. s., 1H), 8.26 (d, J=6.5 Hz, 1H), 4.54-4.63 (m, 1H), 3.31 (br. s., 4H; masked by MeOH), 3.13 (br. s., 4H), 1.80 (d, J=6.8 Hz, 3H), 1.45 (s, 9H). 19F NMR (377 MHz, d4-MeOH) δ −60.93 (br. s., 1F). m/z (ESI, +ve) 354.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:52][C:51]4[CH:53]=[CH:54][C:48]([F:47])=[CH:49][CH:50]=4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Nc1ccc(F)cc1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2ccc(F)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 4-fluoroaniline (Aldrich) to give the title product. LC-MS (ES+) 758 [(M+H)+].
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:25]=[C:26]([C:29]3[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=3)[CH:27]=[CH:28][C:5]=2[N:4]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:25]=[C:26]([C:29]3[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=3)[CH:27]=[CH:28][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(C3=NNC(=O)CC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nc2ccc(C3=NNC(=O)CC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 64 from methyl 4'-[[2-ethyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and sodium hydroxide solution in ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH2:13]([NH2:16])[CH2:14][CH3:15].[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH2:13]([NH:16][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH3:15]
Reactant: O=C1CCc2cccc(Cl)c2C1
Reactant: CCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCNC1CCc2cccc(Cl)c2C1

Procedure:
8-Chloro-2-tetralone (500 mg, 2.78 mMol) in toluene (25 mL) was reacted with propylamine (1.14 mL, 13.9 mMol) and sodium borohydride (500 rag) as described in Example2 to give after purification by flash chromatography (5% methanol in dichloromethane+tr. NH4OH) the title compound as a dark oil (340 mg, 55%). The hydrochloride was formed, and recrystallization (ethanol/diethyl ether) gave a colorless, crystalline solid (m.p.=213°-215° C.).
Reaction SMILES: [O-]CC.[Na+].[N+:5]([C:8]1[CH:22]=[CH:21][C:11]([CH2:12]P(=O)(OCC)OCC)=[CH:10][CH:9]=1)([O-:7])=[O:6].[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:27]=O>C(O)C>[CH3:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:12][C:11]2[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:22][CH:21]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: COc1ccc(C=O)cc1C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
Sodium ethoxide (prepared from 0.70 g of Na and 30 mL of ethanol) was added to an ice-cold mixture of diethyl p-nitrobenzylphosphonate (9.09 g, 0.033 mole) and 3-methyl-p-anisaldehyde (5.0 g, 0.033 mole) in ethanol (about 100 mL). The resulting mixture was stirred overnight. The solid product was filtered, washed with ethanol and vacuum dried to give MMONS, 3-methyl-4-methoxy-4'-nitrostilbene (4.946 g, 0.0157 mole, 47.6% yield, m.p. 109°-111° C.). Recrystallization of MMONS from chloroform/ethanol gave crystals suitable for x-ray analysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(c2cccc(Br)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2cccc(Br)c2)CC1
Temperature: 50 °C
Yield: 86 %

Procedure:
To a solution of ethyl 1-(3-bromophenyl)piperidine-4-carboxylate (5.6 g, 18 mmol) in THF/MeOH (360 mL, 1:1), was added a solution of NaOH (1M, 90 mL) at rt. The mixture was heated at 50° C. for 30 min and organic solvent was removed under reduced pressure. The water solution was mixed with ice and 1M HCl (90 mL) and extracted with dichloromethane/methanol. The combined organic phase was dried over unhydrous Na2SO4 and evaporated. The residue was solidified with dichloromethane/hexane to give the titled compound (4.4 g, 85%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1.N1C2C(=C(C3C=C(NC4C=NC=CC=4)C=C(OC)C=3)C=CC=2)C=C1>>[Br:10][C:4]1[CH:3]=[C:2]([NH:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: Nc1cccnc1
Reactant: COc1cc(Br)cc(Br)c1
Agent: COc1cc(Nc2cccnc2)cc(-c2cccc3[nH]ccc23)c1
Product: COc1cc(Br)cc(Nc2cccnc2)c1

Procedure:
(3-Bromo-5-methoxy-phenyl)-pyridin-3-yl-amine was prepared from 1,3-dibromo-5-methoxy-benzene and pyridin-3-ylamine as described for Example 36. This material was converted to [3-(1H-indol-4-yl)-5-methoxy-phenyl]-pyridin-3-yl-amine by the method of Example 35. 1H NMR (400 MHz, CDCl3): δ 8.44 (d, J=2.7 Hz, 1H), 8.34 (br s, 1H), 8.17 (dd, J=4.7, 1.2 Hz, 1H), 7.50 (ddd, J=8.2, 2.7, 1.4 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.27-7.23 (m, 2H), 7.19-7.15 (m, 2H), 6.98 (t, J=1.7 Hz, 1H), 6.89 (dd, J=2.2, 1.4 Hz, 1H), 6.73 (t, J=2.1 Hz, 1H), 6.64 (t, J=2.2 Hz, 1H), 5.81 (s, 1H), 3.84 (s, 3H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:16]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:15])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:6]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([N:38]3[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]3)[CH:35]=[CH:36][CH:37]=2)O1>>[NH2:16][C:4]1[S:3][C:2]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N:38]3[CH2:39][CH2:40][NH:41][CH2:42][CH2:43]3)[CH:33]=2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=1)=[O:15]
Reactant: Cn1cc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)cn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Product: Cn1cc(NC(=O)c2nc(-c3cccc(N4CCNCC4)c3)sc2N)cn1
Yield: 19 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate and tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate gave 274 as a pale brown solid (18 mg, 19% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 9.82 (s, 1H), 7.99 (s, 1H), 7.65 (s, 1H), 7.45 (s, 3H), 7.28 (dd, J=8, 7.5 Hz, 1H), 7.19 (d, J=7.5 Hz, 1H), 6.96 (dd, J=8, 2.5 Hz, 1H), 3.82 (s, 3H), 3.14 (t, J=5 Hz, 4H), 2.86 (t, J=5 Hz, 4H). Alkyl NH not seen. LCMS (ES+) m/z 384 (M+1)
Reaction SMILES: [C:1]1([C@@H:7]2[O:11][N:10]=[C:9]([C:12]([C:14](=O)C)=[O:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]Br>ClCCCl.ClC(Cl)C.O>[Br:17][CH2:14][C:12]([C:9]1[CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:11][N:10]=1)=[O:13]
Reactant: CC(=O)C(=O)C1=NO[C@@H](c2ccccc2)C1
Reactant: BrBr
Solvent: CC(Cl)Cl
Solvent: O
Solvent: ClCCCl
Product: O=C(CBr)C1=NO[C@@H](c2ccccc2)C1
Temperature: 30 °C
Yield: 72.9 %

Procedure:
1-[(5R)-4,5-dihydro-5-phenyl-3-isoxazoyl]ethanone (3.2 g, 16.7 mmol) was dissolved in 1,2-dichloroethane (15 mL), and a solution of bromine (2.13 g, 13.3 mmol) in dichloroethane (5 mL) was added over 30 minutes while maintaining the temperature of the reaction mixture at about 30° C. The reaction mixture was diluted with water (10 mL), and the organic layer was concentrated under reduced pressure and purified by medium-pressure liquid chromatography using 35% of dichloromethane in hexanes as eluant to give 2.6 g of the title compound as a white solid, melting at 31-33° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([OH:31])=[O:30])[CH3:25])[C:16]=1[CH3:35])=[O:14].[CH3:36]O>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([O:31][CH3:36])=[O:30])[CH3:25])[C:16]=1[CH3:35])=[O:14]
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)c2cccc(C(=O)O)c2)c2ncccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C(C)n2c(C)c(C(=O)NCc3c(OC)cc(C)[nH]c3=O)c3cccnc32)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 3-(1-(3-(((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl)benzoic acid (20 mg, 0.042 mmol) in MeOH (6 mL) was added 2-3 drops of sulfuric acid. The mixture was stirred at 70° C. for 1 hour. The solvent was evaporated. The residue was dissolved in water (3 mL), quenched by saturated NaHCO, solution, extracted with EA (10×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated to give the title compound (20 mg, yield: 97%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH2:17]([SH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[C:18]1([CH2:17][S:24][C:8]2[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1SCc1ccccc1
Temperature: 140 °C
Yield: 71.49 %

Procedure:
In a stirred suspension of 96.37 g potassium carbonate in 700 gm dimethyl formamide, 100 gm 2-chloro nicotinic acid was charged. A solution of 82.38 g benzyl mercaptan in 300 gm dimethyl formamide was added in a period of two hours maintaining reaction temperature 80-90° C. The temperature of the reaction was raised up to 140° C. and then maintained for another three hours. 500 g water was added after completion of the reaction and solvent recovery. Product precipitation achieved by lowering the pH of the reaction mass by using dilute HCl. Product 2-(Phenyl methyl thio)-3-pyridine carboxylic acid precipitated completely till pH 4.5. After filtration and washing, cake was dried to get 110 g white to off white solid product 2-(Phenyl methyl thio)-3-pyridine carboxylic acid with 71.49% yield (Assay by HPLC 99.23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]2[NH:11][C:12]3[C:13]([N:18]=2)=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:6]=[CH:7][C:8]=1[OH:9].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]2[NH:11][C:12]3[C:13]([N:18]=2)=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:6]=[CH:7][C:8]=1[O:9][S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: COc1cc(-c2nc3ncccc3[nH]2)ccc1O
Reactant: CS(=O)(=O)Cl
Product: COc1cc(-c2nc3ncccc3[nH]2)ccc1OS(C)(=O)=O

Procedure:
Prepared analogously to Example 1 from 2-(3'-methoxy-4'-hydroxy-phenyl)-imidazo[4,5-b]pyridine and methanesulfonic acid chloride.
Reaction SMILES: C([N:8]([CH2:23][CH:24]([OH:34])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33])[C:9]([CH3:22])([CH3:21])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[NH2:19])=[CH:14][N:13]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:9]([NH:8][CH2:23][CH:24]([OH:34])[CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])([CH3:21])[CH3:22])=[N:13][CH:14]=1)(=[O:20])[NH2:19]
Reactant: Cc1ccccc1OCC(O)CN(Cc1ccccc1)C(C)(C)COc1ccc(C(N)=O)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccccc1OCC(O)CNC(C)(C)COc1ccc(C(N)=O)cn1

Procedure:
A solution of 22 g of crude 1-[N-benzyl-N-[2-(5-carbamoyl-2-pyridyloxy)-1,1-dimethyl-ethyl]-amino]-3-(2-methyl-phenoxy)-2-propanol in 220 ml of methanol is hydrogenated analogously to Example 1, a total of 6 g of palladium-on-charcoal catalyst (5% strength) being added in 2 portions in order that the calculated amount of hydrogen should be taken up. Working up gives an oil from which 1-[2-(5-carbamoyl-2-pyridyloxy)-1,1-dimethyl-ethylamino]-3-(2-methyl-phenoxy)-2-propanol of melting point 122°-128° C. is obtained by crystallisation from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:13]([CH3:15])[CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:16][CH:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1>>[CH2:22]([N:19]1[CH2:20][CH2:21][CH:17]([NH:16][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([N:13]([CH3:15])[CH3:14])=[CH:4][C:5]=2[O:11][CH3:12])[CH2:18]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: COc1cc(N(C)C)c(Cl)cc1C(=O)O
Product: COc1cc(N(C)C)c(Cl)cc1C(=O)NC1CCN(Cc2ccccc2)C1

Procedure:
By following general method A using 0.85 g. of 5-chloro-4-dimethylamino-2-methoxybenzoic acid and 0.65 g. of 3-amino-1-benzylpyrrolidine, 0.8 g. of N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-dimethylamino-2-methoxybenzamide was obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.Br[CH2:33][CH2:34][CH2:35][CH2:36]Br.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[N+:16]([C:15]1[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([N:1]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:7][CH2:6]2)=[N:11][C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][C:28]([F:30])([F:31])[F:29])=[N:13][CH:14]=1)([O-:18])=[O:17]
Reactant: BrCCCCBr
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N2CCCC2)CC1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]-pyrimidine-2,4-diamine (86 mg, 0.2 mmol) in DMF (1 mL) were added 1,4-dibromobutane (710 μL, 0.59 mmol) and DIPEA (103 μL, 0.59 mmol). The reaction mixture was stirred at 65° C. for 4 h. The reaction mixture was then diluted with EtOAc and washed with saturated NaHCO3 and water (×4). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 10:1:0.05 CH2Cl2:MeOH:NH4OH as an eluent to afford 60 mg (62%) of the title compound as an off-white solid, m/z 493.3 [M−1]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[N:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[C:17](O)=O.N>>[N:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[C:17]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1cnccn1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3cnccn3)n2)c1

Procedure:
The titled compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and pyrazine-2-carboxylic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.66 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 8.60 (dt, J=8.0, 1.9 Hz, 1H), 8.77 (dd, J=5.0, 1.8 Hz, 1H), 8.86-8.89 (m, 1H), 8.89-8.91 (m, 1H), 9.34 (dd, J=2.4, 0.8 Hz, 1H), 9.56 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 226 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].[OH-].[Na+].Cl>O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(=O)NCCCC(=O)O)cc1
Reaction time: 2 h

Procedure:
10.2 g. of p-methoxybenzoyl chloride are added at 30° C. in one portion while stirring well to 30.9 g. of 4-amino-butyric acid, 24.0 g. of sodium hydroxide and 300 ml. of ion-free water. After 2 hours, the mixture is acidified with 75 ml. of concentrated hydrochloric acid at a temperature below 10° C. The precipitate is filtered off, washed ion-free with water, dried in a drying oven at 65° C. over phosphorus pentoxide and then recrystallized from 45 ml. of acetone/low-boiling petroleum ether (3:1). There is obtained 4-(p-methoxybenzoylamino)butyric acid having a melting point of 120.5°-122° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[N:13][C:12]([NH2:15])=[N:11][C:10]=1[NH2:16].Cl[CH:18]([C:21]1([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[CH:27]3)[CH2:23][CH2:22]1)[CH:19]=O>C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([NH2:16])=[N:11][C:12]2[N:13]([C:18]([C:21]3([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[CH2:23][CH2:22]3)=[CH:19][N:15]=2)[N:14]=1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1
Solvent: CCO
Product: Nc1nc2ncc(C3(c4ccc5ncccc5c4)CC3)n2nc1-c1cccc(Cl)c1Cl
Temperature: 105 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A mixture of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (19 mg, 0.076 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (22 mg, 0.091 mmol) in ethanol (0.50 mL) was stirred at 105° C. overnight. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product (12 mg, 35%). LCMS: (M+H)=447.3/449.2/451.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[NH:14][C:13]=2[CH:12]=[C:11]([Br:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33].O>ClCCl>[CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:13]=2[CH:12]=[C:11]([Br:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2c(OCc3ccccc3)cc(Br)cc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1nc2c(OCc3ccccc3)cc(Br)cc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.5 %

Procedure:
18.6 g (58.6 mmol) 4-Benzyloxy-6-bromo-2-methyl-1H-benzimidazole and 9 ml (70.3 mmol) triethyl-amine were suspended in 370 ml dichloromethane and 13.9 ml (70.3 mmol) (2-chloromethoxy-ethyl)-trimethylsilane were added dropwise. The reaction was stirred at room temperature for 3 h, poured into water (400 ml) and extracted with dichloromethane (3×100 ml). The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (toluene/dioxane=9:1) to afford 5.9 g (23%) of the title compound as a beige solid. m.p. 94°-95° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[NH2:18][C:19](N)=[S:20]>S1(CCCC1)(=O)=O>[NH2:18][C:19]1[S:20][C:2]2[C:3]([C:14]([F:17])([F:16])[F:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[CH:6][C:7]=2[N:8]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: NC(N)=S
Solvent: O=S1(=O)CCCC1
Product: Nc1nc2cc([N+](=O)[O-])cc(C(F)(F)F)c2s1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
13.5 g of 2-chloro-3,5-dinitrobenzotrifluoride is slowly introduced, with stirring, into a solution of 15.2 g of thiourea in 50 ml of sulpholane at 100° C. The mixture is stirred at 100° C. for a further 2.5 hours, cooled and the solid is filtered off with suction and the dry residue is thoroughly stirred with 50 ml of carbon disulphide. The solid is filtered off with suction and 7.5 g of material, which is homogeneous by chromatography and has a melting point of 303°-307° C. (decomposition), are obtained. After recrystallisation from pyridine/water (3/1), the melting point rises to 315°-316° C. (decomposition). me+ : 263
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]([NH:11][CH2:12][CH:13]=[CH2:14])[CH:9]=[CH2:10]>>[CH2:8]([N:11]([CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH:9]=[CH2:10]
Reactant: Clc1ccncc1
Reactant: C=CCNCC=C
Product: C=CCN(CC=C)c1ccncc1
Temperature: 130 °C
Yield: 64.9 %

Procedure:
The title compound was prepared by hydrosilation of 4-diallylaminopyridine with dimethyl(ethoxy)silane, (EtO)Me2SiH. The 4-diallylaminopyridine was obtained by reaction of 4-chloropyridine with diallylamine. Thus, in an experiment similar to that described in Example 1, 4-chloropyridine (11.2 g; 0.10 mol) and diallylamine (14.6 g; 0.15 mol) were combined in an ampoule, degassed under vacuum, sealed and heated for three days at 130° C. The product mixture was dissolved in water, neutralized with 10% NaOH and extracted with several portions of diethyl ether. The ether solution was filtered, the solvent was evaporated, and the residue was distilled to give 4-diallylaminopyridine (11.3 g; 65%; b.p. 92° C.@ 0.25 torr). 4-Diallylaminopyridine (5.2 g; 0.030 mol), (EtO)Me2SiH (8.3g; 0.080 mol), and H2PtCl6 (60 μL; 0.080 mol/L in isopropylalcohol (i-PrOH); 4.6×10-6 mol) were combined as in Example 1 and heated for 10 hours at 130° C. After reaction the product mixture was distilled under vacuum to give Silane 2a, N,N[bis(3-(dimethyl(ethoxy)silyl)propyl)-4-aminopyridine, as a colorless liquid (5.75 g; 50%; b.p. 142°-146° C. @ 0.05 torr), which was also characterized by elemental analysis, infrared, 1H and 13C-NMR spectroscopy, and gas chromatography-mass spectrometry.