Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.C(O)(=O)C.[CH2:23]([O:25][C:26](=[O:78])[CH2:27][CH2:28][CH2:29][C:30](=[O:77])[CH2:31][C@H:32]([OH:76])/[CH:33]=[CH:34]\[C@H:35]([CH3:75])[C@H:36]([O:67][Si:68]([C:71]([CH3:74])([CH3:73])[CH3:72])([CH3:70])[CH3:69])[C@@H:37]([CH3:66])/[CH:38]=[C:39](/[CH3:65])\[CH2:40][C@H:41]([CH3:64])[C@@H:42]([O:56][Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:59])[CH3:58])[C@H:43]([CH3:55])[C@@H:44]([O:51][C:52]([NH2:54])=[O:53])[C@@H:45]([CH3:50])/[CH:46]=[CH:47]\[CH:48]=[CH2:49])[CH3:24]>C(#N)C>[CH2:23]([O:25][C:26](=[O:78])[CH2:27][CH2:28][CH2:29][C@@H:30]([OH:77])[CH2:31][C@H:32]([OH:76])/[CH:33]=[CH:34]\[C@H:35]([CH3:75])[C@H:36]([O:67][Si:68]([C:71]([CH3:72])([CH3:73])[CH3:74])([CH3:69])[CH3:70])[C@@H:37]([CH3:66])/[CH:38]=[C:39](/[CH3:65])\[CH2:40][C@H:41]([CH3:64])[C@@H:42]([O:56][Si:57]([C:60]([CH3:61])([CH3:62])[CH3:63])([CH3:58])[CH3:59])[C@H:43]([CH3:55])[C@@H:44]([O:51][C:52]([NH2:54])=[O:53])[C@@H:45]([CH3:50])/[CH:46]=[CH:47]\[CH:48]=[CH2:49])[CH3:24]
Reactant: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@@H](O)CC(=O)CCCC(=O)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: CC(=O)O
Solvent: CC#N
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@@H](O)C[C@H](O)CCCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.4 %

Procedure:
To a solution of 250 mg (0.95 mmol) of tetramethylammonium triacetoxyborohydride in 0.52 mL of anhydrous acetonitrile is added 0.52 mL of anhydrous acetic acid and the mixture is stirred at ambient temperature for 30 minutes. The mixture is cooled to −29° C., and a solution of 50 mg (0.453 mmol) of (7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-11,17-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-7-hydroxy-10,12,14,16,18,20-hexamethyl-5-oxo-8,13,21,23-tetracosatetraenoic acid ethyl ester in 0.5 mL anhydrous acetonitrile is added. The mixture is stirred at −29° C. for 18 hours. The reaction is quenched with 1 mL of 0.5N aqueous sodium potassium tartrate and the mixture is allowed to warm slowly to ambient temperature. The mixture is diluted with CH2Cl2 and washed with aqueous saturated NaHCO3. The aqueous layer is back extracted with CH2Cl2 four times. The combined organic layers are washed with brine, dried with Na2SO4 and concentrated in vacuo to give the crude product as a white solid (50 mg, 99%). m/z (ESI+) 846 (100 (M+Na+)).
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)=[O:22])[CH2:11][CH2:10]2)[N:5]=[CH:4]1.[N:33]1([C:39]([Cl:41])=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[ClH:41].[ClH:1].[NH:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([NH:20][C:39]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:40])[CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)=[O:22])[CH2:11][CH2:10]2)[N:5]=[CH:4]1
Reactant: Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Product: O=C(Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2)N1CCOCC1

Procedure:
Example 91 was prepared as a light yellow solid from Example 26 and morpholine N-carbonyl chloride as described for Example 27.
Reaction SMILES: NC1[C:3]([F:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.IC.[CH3:12][N:13]([CH:15]=O)[CH3:14]>[H-].[Na+].CCOC(C)=O>[Br:8][C:6]1[CH:7]=[C:15]([N:13]([CH3:14])[CH3:12])[C:3]([F:9])=[N:4][CH:5]=1
Reactant: CN(C)C=O
Reactant: Nc1cc(Br)cnc1F
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-amino-5-bromo-2-fluoropyridine (Matrix Scientific, Columbia, S.C., USA, 1.571 mmol) in DMF (3 ml) and 55% NaH in oil (1.571 mmol) was stirred for 15 min at rt. Was added iodomethane (Aldrich, Buchs, Switzerland, 1.571 mmol) and the RM was stirred for 13 h at rt. The RM was diluted with EtOAc, washed with brine (4×), dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 40%). The fraction containing the first eluting product were evaporated to give (5-bromo-2-fluoro-pyridin-3-yl)-dimethyl-amine as an orange oil (HPLC: tR 3.15 min (Method A); M+H=219, 221 MS-ES) and the fraction containing the second eluting product were evaporated to give the title compound as a red solid (HPLC: tR 2.90 min (Method A); M+H=205, 207 MS-ES).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1c(Cl)nc2ccc(F)cc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2ccc(F)cc2c1Cl
Temperature: 110 °C

Procedure:
Prepared according to general Procedure E using 2,4-dichloro-6-fluoro-3-methylquinoline (250 mg, 1.1 mmol), 2-(tributylstannyl)pyridine (400 mg, 1.1 mmol), tetrakis(triphenylphosphine)palladium(0) (63 mg, 0.05 mmol) in toluene (5 mL) and heating at 110° C. overnight. After purification 4-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)quinoline was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[CH2:9]([N:16]1[C:20]([CH:21]=[O:22])=[CH:19][N:18]=[CH:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([N:16]1[C:20]([CH:21]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)[OH:22])=[CH:19][N:18]=[CH:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1cncn1Cc1ccccc1
Reactant: Fc1ccc(Br)cc1
Product: OC(c1ccc(F)cc1)c1cncn1Cc1ccccc1
Yield: 94 %

Procedure:
Grignard reaction of 4-bromofluorobenzene and 1-benzyl-5-imidazolecarbaldehyde is performed analogously to Example 7 a). The product is crystallized as hydrochloride salt from ethylacetate. Yield 94%.
Reaction SMILES: C([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]2[N:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:31]([N:18]([C:19]1[N:20]=[CH:21][C:22]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[CH:23][N:24]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:38])=[O:5])[S:12][CH:13]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(N2CCOCC2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 46.9 %

Procedure:
2-[(4-{2-[Heptyl(5-morpholin-4-ylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (710 mg) obtained in Example 442-2 was dissolved in dichloromethane (4 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (at this time point, the object product had been extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (300 mg) as a white solid.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:23])[C:14]=2[N:24]=1)C1C=CC=CC=1.Cl>CO.[Pd].C(O)C>[NH2:23][C:15]1[C:14]2[N:24]=[C:11]([CH2:10][CH2:9][OH:8])[N:12]([CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:13]=2[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CC(C)(F)Cn1c(CCOCc2ccccc2)nc2c(N)nc3cccnc3c21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC(C)(F)Cn1c(CCO)nc2c(N)nc3cccnc3c21
Reaction time: 8 h
Yield: 46 %

Procedure:
A solution of 2-[2-(benzyloxy)ethyl]-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (0.78 g, 1.98 mmol) dissolved in 20 mL of methanol was treated with 10% palladium on carbon (200 mg) and 0.68 mL of 3 M HCl in ethanol. The mixture was shaken under H2 at 50 PSI (3.4×105 Pa) overnight. Additional 10% palladium on carbon (200 mg) and 3 M HCl in ethanol (0.33 mL) were added and shaking was continued for 24 hours. The reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with methanol and the combined filtrates were concentrated under reduced pressure. The resulting material was treated with 20 mL of H2O and 2 mL of concentrated NH4OH solution and extracted into CHCl3 (3×25 mL). The combined organic layers were concentrated under reduced pressure. Chromatography (SiO2, 15-30% CMA/CHCl3) gave a white powder. Crystallization from ethanol/H2O gave 276 mg of 2-[4-amino-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]ethanol as white needles, mp 224-225° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.N1C=CC=CC=1.[N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[NH:41][C:40]=1[S:48](Cl)(=[O:50])=[O:49]>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:48]([C:40]3[NH:39][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)(=[O:49])=[O:50])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: O=S(=O)(Cl)c1nc2ccccc2[nH]1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4nc5ccccc5[nH]4)ccc3N2)=C(O)c2ccccc21
Yield: 45 %

Procedure:
A mixture of Example 39H (47.6 mg, 0.10 mmol), pyridine (64 mg, 0.80 mmol), and 2-benzimidazole sulfonyl chloride (87 mg, 0.40 mmol, prepared according to the procedure reported by S. M. Deshpande et al, J. Med. Chem. 1970, 13, 143-144) in acetone (2 mL) was stirred at rt for 16 h. The reaction mixture was evaporated in vacuo and partitioned between ethyl acetate and water. The organic phase was separated, dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with 99:1 dichloromethane/methanol to provide the title compound (28.0 mg, 45% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.39 m, 1 H) 0.67 (d, J=6.62 Hz, 3 H) 0.70 (d, J=6.62 Hz, 3H) 0.77 m, 1 H) 1.29 m, 1 H) 1.54 (s, 3 H) 2.04 m, 1 H) 2.19 m, 1 H) 7.35 (dd, J=6.25, 2.94 Hz, 2 H) 7.51 m, 1 H) 7.64 m, 8 H) 8.13 (d, J=7.72 Hz, 1 H) 11.51 (s, 1 H) 13.77 (s, 1H). MS (ESI+) m/z 620.0 (M+H)+, 641.9 (M+H—Na)+, (ESI−) m/z 618.0 (M−H)−.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.C(N(CC)CC)C.[C:25]([O:29][C:30](=[O:48])[NH:31][CH2:32][CH2:33][C:34](=[O:47])[NH:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=[CH:38][CH:37]=1)([CH3:28])([CH3:27])[CH3:26]>C(O)C>[C:25]([O:29][C:30](=[O:48])[NH:31][CH2:32][CH2:33][C:34](=[O:47])[NH:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:14]([NH2:17])=[N:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[CH:38][CH:37]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc(CCCCN)cc1
Agent: I
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
1-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (0.32 g, 0.82 mmol) and triethylamine (0.42 mL) were added to a solution of {2-[4-(4-amino-butyl)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester 340 (0.25 g, 0.74 mmol) in ethanol (6 mL). The reaction mixture was stirred at 65° C. for 3 hours, and cooled to room temperature. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 10:1:0.1 to 5:1:0.1, v/v chloroform/methanol/concentrated ammonium hydroxide). The product was washed with water (2×25 mL) and dried in a vacuum oven overnight to provide 350 (0.32 g, 78%) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 1.44 (s, 9H), 1.69 (m, 4H), 2.57 (t, 2H), 2.66 (t, 2H), 3.27 (t, 2H), 3.40 (m, 2H), 7.15 (d, 2H), 7.47 (d, 2H).
Reaction SMILES: C([CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]([S:18][CH2:19][CH2:20][CH3:21])=[N:7][CH:6]=1)(O)=O.[O:22]1CCCC1>C1(C)C=CC=CC=1>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:5]([CH2:4][OH:22])=[CH:6][N:7]=[C:8]1[S:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Reactant: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCSc1ncc(CO)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-carboxymethyl-1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazole (3.74 g, 11.5 mmol) in dry tetrahydrofuran (50 ml) was cooled to 78° C. under argon, and a solution of diisobutyl-alumninum hydride in toluene (30 ml of 1M) was added dropwise. The mixture was stirred at -78° C. for 1.5 hours, then allowed to slowly warm to room temperature. The reation was quenched by pouring onto iced dilute acetic acid, the product was extracted into methylene chloride and the organic extracts were washed with water, 5% sodium carbonate solution and brine. The dried, concentrated product was a light tan solid (3.32 g). Crystallization from ethanol/water gave 1-(2-chlorophenyl)methyl-5-hydroxymethyl-2-propylthio-1H-imidazole; mp 98°-101° C. The title compound is prepared by the procedure of Example 1 [(iii) Method A (i-vi)] using 1-(2-chlorophenyl)methyl-5-hydroxymethyl-2-propylthio-1H-imidazole in place of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH:12]=O)[CH:5]=1.[CH2:15]([O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[O:29][CH2:28][CH2:27][C:26]2=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1CCCC1>CO>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH:12]=[C:27]2[C:26](=[O:33])[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([O:22][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:24]=3)[O:29][CH2:28]2)[CH:5]=1
Reactant: COC(=O)c1ccc(OC)c(C=O)c1
Reactant: O=C1CCOc2ccc(OCc3ccccc3)cc21
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)c1ccc(OC)c(C=C2COc3ccc(OCc4ccccc4)cc3C2=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
19.1 g (98.3 mmol) of 3-formyl-4-methoxybenzoic acid methyl ester (from Example 37) were added to a room temperature suspension of 25.0 g (98.3 mmol) of 6-benzyloxychroman-4-one and 8.21 mL (98.3 mmol) of pyrrolidine in 350 mL CH3OH. After stirring 20 hours at room temperature, the reaction mixture was filtered, washed two times with CH3OH and the precipitate dried under vacuum to give 33.93 of the title product as a yellow powder. Mp: 167°-169° C. 80% yield. 1H NMR (300 m Hz, CDCl3): δ3.93 (s, 3H); 3.91 (s, 3H); 12 aromatic resonances δ6.8→8.1.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:29]=O)=[N:18][CH:19]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@H:23]2[CH3:28])[N:21]=1.[CH2:31]([NH:38][CH2:39][CH2:40][OH:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:31]([N:38]([CH2:29][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@H:23]2[CH3:28])=[CH:19][N:18]=1)[CH2:39][CH2:40][OH:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C[C@@H]1COCCN1c1cnc(C=O)c(Cl)n1
Reactant: OCCNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: C[C@@H]1COCCN1c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
Sodium triacetoxyborohydride (1.37 g) was added to a solution of 3-chloro-5-[(3R)-3-methylmorpholin-4-yl]pyrazine-2-carbaldehyde (1.04 g), N-benzylethanolamine (0.78 g) and acetic acid (0.74 mL) in acetonitrile (20 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by basic silica gel column chromatography (solvent gradient: 5→40% ethyl acetate/hexane) to give the title compound (1.65 g, quantitative) as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[S:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=O.[CH2:18]([NH2:23])[CH2:19][CH:20]([CH3:22])[CH3:21].[BH4-].[Na+]>CO>[CH3:21][CH:20]([CH3:22])[CH2:19][CH2:18][NH:23][CH2:1][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[S:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CC(C)CCN
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(Oc2ccc(C(N)=O)s2)cc1
Reaction time: 8 h

Procedure:
Place 5-(4-formylphenoxy)thiophene-2-carboxamide (0.235 g, 0.948 mmol), isoamylamine (0.087 g, 0.996 mmol) and 3 Å molecular sieves in a vial. Add methanol (4.7 mL), cap and stir overnight. Add NaBH4 (0.0359 g, 0.948 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes to give the title compound: TOF MS ES+ 319.1 (M+H)+, HRMS calcd for C17H23N2O2S 319.1480 (M+H)+, found 319.1488, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=10.8 min, 100% purity.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[CH:37]=O>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:37][C:28]3[CH:29]=[CH:30][C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:27]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc3ccccc3c2)CC1
Yield: 73 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.98 g) as starting compound and 2-naphthaldehyde (0.74 g) were reacted and treated in the same manner as in Example 121 to give 1.81 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(2-naphthylmethylamino)pentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)=O.[N:16]1([C:22]2[CH:23]=[CH:24][C:25]3[N:26]([C:28]([C:31]([F:34])([F:33])[F:32])=[N:29][N:30]=3)[N:27]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[F:34][C:31]([F:32])([F:33])[C:28]1[N:26]2[N:27]=[C:22]([N:16]3[CH2:21][CH2:20][N:19]([CH2:1][C:3]4[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=4)[CH2:18][CH2:17]3)[CH:23]=[CH:24][C:25]2=[N:30][N:29]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CCOC(=O)/C=C/c1ccc(C=O)cc1
Product: CCOC(=O)/C=C/c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Yield: 59 %

Procedure:
A mixture of ethyl (E)-3-(4-formylphenyl)prop-2-enoate and 6-(piperazin-1-yl)-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 7 to give ethyl (2E)-3-[4-([4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl)phenyl]prop-2-enoate in 59% yield.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C([Li])(C)(C)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][C:15]=1[CH:26]=[O:27].[Cl-].[NH4+]>C1COCC1.CCCCC>[NH:5]1[CH:6]=[C:2]([CH:26]([C:15]2[CH:16]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=[CH:19][C:14]=2[O:13][CH3:12])[OH:27])[N:3]=[CH:4]1
Reactant: Brc1c[nH]cn1
Reactant: COc1ccc(-c2ccccc2)cc1C=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)cc1C(O)c1c[nH]cn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 34.3 %

Procedure:
4-Bromo-1H-imidazole (5.20 g) was dissolved in THF (50 ml) and the mixture was cooled to −78° C. A solution (1.7 M; 50 ml) of t-butyllithium in pentane was added. The mixture was stirred at 0° C. for 1.5 h and cooled to −78° C. again. A solution (30 ml) of 4-methoxy[1,1′-biphenyl]-3-carbaldehyde (2.54 g) in THF was added, and the mixture was heated from −78° C. to room temperature and further stirred at room temperature for 24 h. Aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by silica gel column chomatography (eluent, dichloromethane:methanol=15:1) and recrystallized from ethyl acetate to give the title compound (1.15 g) as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33](O)=[O:34])[CH:31]=2)[NH:26][CH:25]=1.O>CN(C)C=O>[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]([O:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:34])[CH:31]=2)[NH:26][CH:25]=1
Reactant: O=C(O)c1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 61.2 %

Procedure:
Polyphosphoric acid ethyl ester (40 ml) and 4-nitrophenol (6.3 g) were added to a solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-carboxylic acid (15 g) in dimethylformamide (70 ml) and the mixture was stirred at 80° C. for 24 hours. More polyphosphoric acid ethyl ester (20 ml) was added and the mixture stirred at 80° C. for 3 hours. The mixture was cooled, poured into ice and water (900 ml) and stirred for 1 hour with ice cooling. The resulting solid was filtered off and washed with boiling ethanol (1500 ml) and hot water (600 ml) to give the title compound (12.5 g) as pale yellow crystals m.p. 248°-251° C. T.L.C. Silica, ethyl acetate:2-propanol:water:ammonia (25:15:8:2) Rf 0.9.