Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[N:10][CH:9]=[C:8]2[N:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:13]=[CH:14][C:7]=12)=[O:5])C>CCOC(C)=O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[C:8]3=[CH:9][N:10]=[N:11][C:6]([C:4]([OH:5])=[O:3])=[C:7]3[CH:14]=[N:13]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1nncc2c1cnn2-c1ccc(F)cc1
Solvent: CCOC(C)=O
Product: O=C(O)c1nncc2c1cnn2-c1ccc(F)cc1

Procedure:
The title product is prepared from 1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyridazine-4-carboxylic acid ethyl ester (520 mg, 1.82 mmol) according to the procedure described in Example 1, with the exception that the reaction progress is monitored for the disappearance of the starting material by TLC (EtOAc:hexanes; 1:1) prior to work up.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([O:15]CC)=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+:19]>C(O)C.O>[CH2:1]([N:8]1[C:12]([C:13]([O-:15])=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[K+:19]
Reactant: CCOC(=O)c1nnnn1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C([O-])c1nnnn1Cc1ccccc1

Procedure:
To a solution of 1-benzyl-5-carboethoxy tetrazole prepared in Example 1, in warm absolute ethanol is added a stoichiometric excess of KOH in water to precipitate crystalline 1-benzyl-1H-tetrazole-5-carboxylic acid potassium salt.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:45](COCC[Si](C)(C)C)[C:25]4[N:26]=[CH:27][N:28]=[C:29]([O:30][C:31]5[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:40][CH:41]6[CH2:43][CH2:42]6)=[O:39])=[C:33]([Cl:44])[CH:32]=5)[C:24]=4[CH:23]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[Cl:44][C:33]1[CH:32]=[C:31]([O:30][C:29]2[C:24]3[CH:23]=[C:22]([C:19]4[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:17][CH:18]=4)[NH:45][C:25]=3[N:26]=[CH:27][N:28]=2)[CH:36]=[CH:35][C:34]=1[NH:37][C:38]([NH:40][CH:41]1[CH2:42][CH2:43]1)=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3cc4c(Oc5ccc(NC(=O)NC6CC6)c(Cl)c5)ncnc4n3COCC[Si](C)(C)C)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccc(OCC5CCNCC5)cc4)cc23)cc1Cl)NC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
After dissolving 37 mg of 4-(4-(4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxymethyl)piperidine-1-carboxylic acid tert-butyl ester in 1 ml of trifluoroacetic acid, the mixture was stirred at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, saturated sodium bicarnobate water was added to alkalinity and liquid separation and extraction were performed with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to dryness to obtain the 25 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:37])([CH3:36])[CH2:23][CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:38][C:39]1[NH:40][CH:41]=[C:42]([N+:44]([O-:46])=[O:45])[N:43]=1.C(=O)([O-])O.[Na+].CN(C)C=O>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:37])([CH3:36])[CH2:23][CH2:24][N:40]3[CH:41]=[C:42]([N+:44]([O-:46])=[O:45])[N:43]=[C:39]3[Cl:38])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(O)COc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)(CCn1cc([N+](=O)[O-])nc1Cl)COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
4-{4-[2-Hydroxy-2-methyl-4-(toluene-4-sulfonyloxy)butoxy]phenyl}piperazine-1-carboxylic acid tert-butyl ester (4.69 g, 8.77 mmol), 2-chloro-4-nitro-1H-imidazole (1.55 g, 10.52 mmol), sodium hydrogen carbonate (0.88 g) and dimethylformamide (47 ml) were mixed, and the mixture was stirred at 90 to 100° C. overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. After filtering under reduced pressure, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→3:7) to afford the title compound as a yellow amorphous solid (2.12 g).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[N:32][CH:33]=1>C(#N)C.O>[CH3:18][O:17][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:2]=1[O:1][CH2:27][C:28]1[CH:33]=[N:32][C:31]([CH3:34])=[CH:30][CH:29]=1)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1ccc(CCl)cn1
Reactant: COc1cc(CNC(=O)OC(C)(C)C)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(CNC(=O)OC(C)(C)C)ccc1OCc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 63 h
Yield: 106.2 %

Procedure:
To a stirred solution of tert-butyl 4-hydroxy-3-methoxybenzylcarbamate (21.02 g, 82.99 mmol) in acetonitrile (250 mL) was added potassium carbonate (30.61 g, 221.5 mmol) and 5-(chloromethyl)-2-methylpyridine hydrochloride (16.25 g, 91.29 mmol). The resulting mixture was heated to reflux. After 63 h, the brown suspension was allowed to cool to room temperature and was diluted with water (1000 mL). The mixture was extracted with dichloromethane (3×250 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 31.59 g (>100%) of tert-butyl 3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzylcarbamate as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:15])[CH:14]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][O:8][CH2:7]1.[Li]CCCC.C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:15])[C:14]=1[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][O:8][CH2:7]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc(F)cc(OC2CCCOC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2c(F)cc(OC3CCCOC3)cc2F)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(3,5-difluorophenoxy)tetrahydro-2H-pyran (1.42 g, 6.63 mmol) in THF (26 mL) at −78° C., a solution of n-BuLi in hexanes (1.6 M; 10.4 mL, 16.6 mmol) was added slowly through a dripping funnel. When addition was complete, the mixture was kept at −78° C. for 1 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.06 mL, 19.9 mmol) was then added in one portion. The mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was quenched with NaHCO3 solution and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give sub-title compound as a colorless oil. LCMS calc. for C17H24BF2O4 (M+H)+ m/z=341.2. found: 341.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:15][C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:14])[C:8]=2[C:7]=1[OH:16])=[O:5])C.[H-].[Na+].[CH3:19]I>O1CCCC1>[CH3:1][O:3][C:4]([C:6]1[S:15][C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:14])[C:8]=2[C:7]=1[O:16][CH3:19])=[O:5]
Reactant: CI
Reactant: CCOC(=O)c1sc2ncnc(Cl)c2c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sc2ncnc(Cl)c2c1OC
Reaction time: 1 h

Procedure:
4-Chloro-5-hydroxy-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.4 g, 1.5 mmol) in tetrahydrofuran (10 mL) was slowly added to a slurry of sodium hydride (60 percent in mineral oil, 0.1 g 2.5 mmol) in tetrahydrofuran (30 mL) and stirred for one hour. Methyl iodide (2 mL) was added and the solution warmed to reflux for two hours. After cooling the reaction was quenched with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine, dried (NaSO4) and concentrated. The residue was purified by chromatography over silica (40 percent ethyl acetate/hexane) affording product as a yellow solid. (0.2 g, 50 percent) yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(O)c1
Product: O=C(Nc1cccc(O)c1)c1ccccc1
Yield: 58.7 %

Procedure:
By using 3-aminophenol (1.0 g) and benzoyl chloride (644 mg) as starting materials, the title compound (573 mg) was obtained in the same manner as that of Reference Example 18.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([C:9]1[C:14]([OH:15])=[CH:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:11][N:10]=1)=[O:8])C.[OH-].[Na+].Cl>C1COCC1>[F:22][C:18]1[CH:17]=[C:16]([C:12]2[CH:13]=[C:14]([OH:15])[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:23])=[O:3])=[O:8])=[N:10][CH:11]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CNC(=O)c1ncc(-c2cccc(F)c2)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ncc(-c2cccc(F)c2)cc1O
Reaction time: 0.42 h
Yield: 55.8 %

Procedure:
To a slurry of {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid ethyl ester, 5, (226 g, 0.71 mol) in THF (1 L) at room temperature was added an aqueous solution of sodium hydroxide (1 M, 2 L) while maintaining the internal reaction temperature below 25° C. The progress of the reaction was monitored by TLC. After 20-30 minutes, the reaction was completed. The pH of the reaction solution was adjusted using concentrated HCl to 5-5.5 while maintaining the internal temperature below 25° C. The reaction mixture was filtered to remove insoluble matter and the filtrate was concentrated by rotary evaporation at up to 40° C. bath temperature until all THF was removed. The resulting solid was collected by vacuum filtration and washed with water (1 L). The solid was then dissolved in a mixture of water (1.5 L) and THF (1.5 L) at room temperature. The pH was adjusted from approximately 5 to approximately 2-2.25 with concentrated HCl. The resulting mixture was stirred for 30 minutes, after which time the pH was confirmed in the range of 2-2.5. The biphasic mixture was concentrated by rotary evaporation at up to 40° C. bath temperature until the removal of THF ceased. The resulting solid was filtered, washed with water (2×1 L), and dried to afford 115 g (55.8% yield) of the desired product as a white solid. MP: 182-184° C.; MS (ESI−): m/z 289 (M−1); 1H NMR (300 MHz, DMSO-d6) δ 12.90 (s, 1H), 12.38 (s, 1H), 9.39-9.37 (t, J=6.3 Hz, 1H), 8.55 (s, 1H), 7.80-7.67 (m, 2H), 7.59-7.52 (m, 1H), 7.34-7.27 (m, 1H), 4.02-3.99 (m, 2H), 3.51 (s, 1H).
Reaction SMILES: [OH-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH:12]=[CH:13][C:14]1[CH:48]=[CH:47][C:17]([C:18]([NH:20][C:21]2[CH:33]=[C:32]([CH2:34][CH2:35][CH2:36][S:37]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH:31]=[CH:30][C:22]=2[O:23][CH2:24][C:25]([O:27]CC)=[O:26])=[O:19])=[CH:16][CH:15]=1>O1CCCC1>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH:12]=[CH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][C:21]2[CH:33]=[C:32]([CH2:34][CH2:35][CH2:36][S:37]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH:31]=[CH:30][C:22]=2[O:23][CH2:24][C:25]([OH:27])=[O:26])=[O:19])=[CH:47][CH:48]=1
Reactant: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1ccc(C=Cc2nc3ccccc3s2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1ccc(C=Cc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
10% Sodium hydroxide aqueous solution (6 ml) was added at room temperature to a mixture of ethyl 2-[4-[2-(2-benzothiazolyl)vinyl]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (196 mg, 0.29 mmol) and tetrahydrofuran (10 ml), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, water was added the resulting residue, and then the solution was adjusted to pH 1 by adding concentrated hydrochloric acid. Thereafter, the solid material formed was collected by filtration, washed with water and ether in that order, dried under reduced pressure and then recrystallized from ethanol (50 ml) to give 2-[4-[2-(2-benzothiazolyl)vinyl]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetic acid (156 mg, 0.24 mmol, 83%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH2:8][CH3:9])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].[F:27][C:28]([F:38])([F:37])[CH2:29][CH2:30][S:31][CH2:32][CH2:33][C:34](Cl)=[O:35]>O>[Cl:1][C:2]1[C:6]([N:7]([CH2:8][CH3:9])[C:34](=[O:35])[CH2:33][CH2:32][S:31][CH2:30][CH2:29][C:28]([F:38])([F:37])[F:27])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: O=C(Cl)CCSCCC(F)(F)F
Reactant: CCNc1cn(-c2cccnc2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(C(=O)CCSCCC(F)(F)F)c1cn(-c2cccnc2)nc1Cl

Procedure:
A 100 mL three-neck round bottom flask was charged with 3-chloro-N-ethyl-1-(pyridine-3-yl)-1H-pyrazol-4-amine (5.00 g, 22.5 mmol) and ethyl acetate (50 mL). Sodium bicarbonate (4.72 g, 56.1 mmol) was added, followed by dropwise addition of 3-((3,3,3-trifluoropropyl)thio)propanoyl chloride (5.95 g, 26.9 mmol) at <20° C. for 2 hours, at which point HPLC analysis indicated that the reaction was complete. The reaction was diluted with water (50 mL) (off-gassing) and the layers separated. The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were concentrated to dryness to afford a light brown solid (10.1 g, quantitative). A small sample of crude product was purified by flash column chromatography using ethyl acetate as eluent to obtain an analytical sample: mp 79-81° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J=2.7 Hz, 1H), 8.97 (s, 1H), 8.60 (dd, J=4.8, 1.4 Hz, 1H), 8.24 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.60 (ddd, J=8.4, 4.7, 0.8 Hz, 1H), 3.62 (q, J=7.2 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H), 2.66-2.57 (m 2H), 2.57-2.44 (m, 2H), 2.41 (t, J=7.0 Hz, 2H), 1.08 (t, J=7.1 Hz, 3H). EIMS m/z 406 ([M]+).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]1[CH:7]=[C:8]([CH2:13][C@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:15]2[CH2:17][O:16]2)[CH:9]=[C:10]([F:12])[CH:11]=1>O1CCCC1>[F:5][C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([F:12])[CH:11]=1)[CH2:13][C@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:15]([OH:16])[CH2:17][CH:1]=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Solvent: C1CCOC1
Product: C=CC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C

Procedure:
Vinylmagnesium bromide was added to copper (I) bromide-dimethyl sulfide complex in tetrahydrofuran at low temperature. Tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate (12) in tetrahydrofuran was added. At room temperature, the reaction was quenched with saturated ammonium chloride, extracted, and dried over sodium sulfate. A white solid (13) was obtained upon concentration.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH3:3].[Cl:24][C:25]1[CH:30]=[C:29]([NH2:31])[C:28]([NH2:32])=[C:27]([CH3:33])[CH:26]=1>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH3:33])[C:28]2[N:32]=[C:7]([C:6]3[CH:9]=[CH:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:12][C:5]=3[CH2:4][N:2]([CH3:3])[CH3:1])[NH:31][C:29]=2[CH:30]=1
Reactant: CN(C)Cc1cc(OCCCC2CCN(C)CC2)ccc1C=O
Reactant: Cc1cc(Cl)cc(N)c1N
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cc2[nH]c(-c3ccc(OCCCC4CCN(C)CC4)cc3CN(C)C)nc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 9.8 %

Procedure:
{2-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzyl}-dimethyl-amine. To a solution of {2-bromo-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzyl}-dimethyl-amine (801 mg, 2.2 mmol, 1.0 equiv) in THF (10 mL) at −78° C., 1.7 M tert-butyllithium in pentane (3.83 mL, 6.5 mmol, 3.0 equiv) was added and the solution was stirred for 15 min. The solution was then warmed to 0° C., stirred for 5 min, and then re-cooled to −78° C. DMF (1.68 mL, 21.7 mmol, 10.0 equiv) was added and the mixture was stirred for 30 min. Water (1.0 mL) was added and the mixture was poured into satd. aq. NaHCO3. The aqueous mixture was extracted three times with ethyl acetate and the combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was partially purified by Method 2 to afford 221 mg of a mixture of 2-dimethylaminomethyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde and several other unidentified products. The crude dimethylaminomethyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde (110 mg) was dissolved in DMF and 5-chloro-3-methyl-benzene-1,2-diamine (54 mg, 0.34 mmol) and Na2S2O5 (85 mg, 0.45 mmol) were added. The mixture was warmed to 90° C. and stirred for 3 h. The reaction mixture was purified by Method 2 to afford 15.2 mg of the title compound. MS (electrospray): mass calculated for C26H35ClN4O, 454.25; m/z found, 455.5 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.07 (d, J=8.6 Hz, 1H), 7.47-7.42 (m, 1H), 7.07-6.97 (m, 3H), 4.04 (t, J=6.4 Hz, 2H), 3.58 (s, 2H), 2.93-2.82 (m, 2H), 2.56 (s, 3H), 2.43 (s, 6H), 2.27 (s, 3H), 2.06-1.93 (m, 2H), 1.87-1.70 (m, 4H), 1.49-1.40 (m, 2H), 1.36-1.21 (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][S:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:10]([OH:11])[CH2:9][S:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=O)CSCc2ccncc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(O)CSCc2ccncc2)cc1

Procedure:
Under a nitrogen atmosphere, alpha-(4-picolylthio)p-methoxyacetophenone (1.99 g., 7.3 mmoles) was dissolved in 25 ml. of stirring ethanol. Sodium borohydride (0.45 g., 11.7 mmoles) was added portionwise and the mixture then refluxed gently for 30 minutes. The mixture was partially cooled and evaporated to dryness. Water (50 ml.) was added to the residue, which was then acidified with excess 1N hydrochloric acid. The acid solution was made basic with solid sodium bicarbonate and product extracted into ethyl acetate. The ethyl acetate was dried over anhydrous sodium sulfate and concentrated to an oil, which crystallized on standing. Trituration with diethyl ether and filtration gave purified 4-[2-(4-methoxyphenyl)-2-hydroxyethylthiomethyl]pyridine (1.50 g.; m.p. 70°-72.5° C.; pnmr/CDCl3 /TMS/delta: 7.2 (d, 2H), 6.4 (s, 2H), 6.3 (1H, exchanges with D2O), 6.2 (d, 3H), 5.3 (t, 1H), 3.2 (broad doublet, 2H), 2.7 (d and s, 4H), 1.5 (d, 2H); ir (KBr): 3.25, 6.25, 6.65, 8.05, 8.6, 12.5μ].
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:27]=[C:28]([NH:32][C:33](=[N:42][C:43]#[N:44])OOC3C=CC=CC=3)[CH:29]=[C:30]([CH3:31])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH:45]([NH:48][CH:49]([CH3:51])[CH3:50])([CH3:47])[CH3:46]>C(O)(C)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[CH:27]=[C:28]([NH:32][C:33]([N:48]([CH:49]([CH3:51])[CH3:50])[CH:45]([CH3:47])[CH3:46])=[N:42][C:43]#[N:44])[CH:29]=[C:30]([CH3:31])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(NC(=NC#N)OOc3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CC(C)NC(C)C
Solvent: CC(C)O
Product: CCCc1nc2c(C)cc(NC(=NC#N)N(C(C)C)C(C)C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 1c from 4'-[[2-n-propyl-4-methyl-6-(2-phenoxy-3-cyano-isoureido)-1H-benzimidazol -1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl and diisopropylamine in boiling isopropanol.
Reaction SMILES: [OH-].[Na+].C([N:6]([C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([Br:21])=[C:16]([CH3:22])[CH:15]=1)[CH2:7][CH2:8][O:9]C(=O)CBr)(=O)C>CCO.C(OCC)(=O)C>[Br:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([NH:6][CH2:7][CH2:8][OH:9])=[CH:15][C:16]=1[CH3:22]
Reactant: CC(=O)N(CCOC(=O)CBr)c1cc(C)c(Br)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(NCCO)cc(C)c1Br
Temperature: 25 °C
Yield: 100.2 %

Procedure:
6 N NaOH (1.5 ml) was added to a solution of bromo-acetic acid 2-[acetyl-(4-bromo-3,5-dimethyl-phenyl)-amino]-ethyl ester (302 mg, 0.74 mmol) in EtOH (6 ml). The reaction solution was heated under reflux overnight, cooled to room temperature and then diluted with ethyl acetate. The organic phase was sequentially washed with water and saturated brine and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-(4-bromo-3,5-dimethyl-phenylamino)-ethanol (181 mg, 68%).
Reaction SMILES: C([O:9][C:10]1[C:11]([C:21]([O:23]C)=O)=[N:12][C:13]([Br:20])=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=O)C1C=CC=CC=1.[CH3:25][O:26][C:27]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>C1(C)C=CC=CC=1>[Br:20][C:13]1[N:12]=[C:11]([C:21]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:27]=2[O:26][CH3:25])=[O:23])[C:10]([OH:9])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2
Reactant: COC(=O)c1nc(Br)c2cccnc2c1OC(=O)c1ccccc1
Reactant: COc1cccc(CN)c1OC
Solvent: Cc1ccccc1
Product: COc1cccc(CNC(=O)c2nc(Br)c3cccnc3c2O)c1OC

Procedure:
Into a round bottom flask fitted with a gas inlet, condenser and a magnetic stirring bar was placed methyl 8-(benzoyloxy)-5-bromo-1,6-naphthyridine-7-carboxylate (0.4 g, 1.03 mmol), 2,3-dimethoxybenzylamine (0.432 g, 0.38 mL, 2.58 mmol) and 10 mL toluene. This mixture was refluxed for 18 hours, after which the reaction was cooled and the solvent removed in vacuo. The resulting residue was triturated with diethyl ether and filtered to yield 5-bromo-N-(2,3-dimethoxybenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide as a light yellow solid.