Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[O:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][N:39]=2)[CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:41]3[CH:40]=[N:39][C:38]([N:35]5[CH2:34][CH2:33][O:32][CH2:37][CH2:36]5)=[CH:43][CH:42]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1ccc(N2CCOCC2)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(N2CCOCC2)nc1)N1CCN(C2CCC2)CC1
Yield: 29 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 2-morpholino-5-pyridineboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (29%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:5][NH:6]2.[Li]C(C)(C)C.[C:27](=[O:29])=[O:28]>C1COCC1.CCOC(C)=O>[C:18]([Si:15]([CH3:17])([CH3:16])[O:14][CH2:13][CH2:12][C:4]1[C:3]2[C:2]([C:27]([OH:29])=[O:28])=[CH:10][CH:9]=[C:8]([CH3:11])[C:7]=2[NH:6][CH:5]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C=O
Reactant: Cc1ccc(Br)c2c(CCO[Si](C)(C)C(C)(C)C)c[nH]c12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)O)c2c(CCO[Si](C)(C)C(C)(C)C)c[nH]c12
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a suspension of KH (1.85 g of 30 wt % in oil, 13.85 mmol) in THF (100 mL) was added a solution of 4-bromo-3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-7-methyl-1H-indole (3.40 g, 9.24 mmol) in THF (10 mL) at 0° C. After stirring for 40 minutes, the solution was cooled to −78° C. and tert-BuLi (10.9 mL of 1.7 M in pentane, 18.47 mmol), precooled to −78° C., was added. After stirring for 1 hour at −78° C., the reaction mixture was transferred to the flask containing anhydrous CO2 (dry ice, 100 g) via cannula under N2 atmosphere at −78° C. The suspension was warmed to room temperature very slowly using cold bath. The mixture was diluted with EtOAc (200 mL) and the organic solution was washed with 1 N HCl (2×200 mL), H2O (200 mL) and brine (200 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 15% EtOAc in hexanes) to give 0.74 g (41% based on the recovered SM) of title compound as a white solid. 1H NMR (CDCl3): 300 MHz δ 8.26 (bs, 1H), 7.84 (d, J=7.56 Hz, 1H), 7.32 (d, J=2.46 Hz, 1H), 7.12 (d, J=7.56 Hz, 1H), 3.98 (t, J=6.39 Hz, 2H), 3.33 (t, J=6.39 Hz, 2H), 2.63 (s, 3H), 0.89 (s, 9H), −0.08 (s, 6H).
Reaction SMILES: C([CH:4]1[C:9](=O)[CH2:8][C:7](=[O:11])[O:6][C:5]1=[O:12])(=O)C.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C(O)(=O)C>[Br:13][C:14]1[CH:15]=[C:16]2[C:18]([C:9]([CH2:4][C:5]([OH:12])=[O:6])=[CH:8][C:7](=[O:11])[NH:17]2)=[CH:19][CH:20]=1
Reactant: CC(=O)C1C(=O)CC(=O)OC1=O
Reactant: Nc1cccc(Br)c1
Solvent: CC(=O)O
Product: O=C(O)Cc1cc(=O)[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a suspension of 3-acetyl-tetrahydropyran-2,4,6-trione (25 g, 0.147 mol) and acetic acid (50 ml) was added a solution of m-bromoaniline (25.3 g, 0.147 mol) in acetic acid (30 ml) at room temperature. The reaction was continuted under the same conditions for 30 minutes. The reaction mixture was poured into ice-water (1 L) and then the separated solid was filtered off by aspiration. The residue was washed with water and dried. The obtained solid (54 g) was added in small portions to concentrated sulfuric acid (250 ml) and stirred at room temperature for 16 hours. The reaction mixture was poured into ice-water and then the separated solid was filtered off by aspiration. The residue was washed with methanol and acetone and then dried to give 7-bromo-l,2-dihydro-2-oxo-4-quinolineacetic acid (19.5 g) as a white solid. The solid (19.5 g) was suspended in methanol 500 ml. Thionyl chloride 15.1 ml (207 mmol) was added dropwise thereto at room temperature and the mixture was refluxed for 0.5 hour. The reaction mixture was poured into ice-water (1 L) and then the separated solid was filtered off by aspiration. The residue was washed with water and recrystallized from methanol to give the entitled compound as white crystals (mp 208°-210 ° C. (from methanol), 13.6 g, yield 31.2 %).
Reaction SMILES: [CH2:1]([C@@H:7]1[CH:12]([OH:13])[CH2:11][CH:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[CH2:1]([C@@H:7]1[C:12](=[O:13])[CH2:11][CH:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCC1CC(O)[C@@H](CCCCCC)C(=O)O1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCC1CC(=O)[C@@H](CCCCCC)C(=O)O1

Procedure:
M)b) 3 g of a diastereomer mixture of tetrahydro-3-hexyl-4-hydroxy-(R)-6-undecyl-2H-pyran-2-one were dissolved in 300 ml of acetone. 3 ml of Jones' reagent were added dropwise while stirring in such a manner that the temperature did not exceed 25° C. After 3 hours the reaction mixture was poured into 700 ml of H2O. The lactone precipitated out and was filtered off. After recrystallization in ether/n-hexane there were obtained 1.7 g of tetrahydro-3-hexyl-4-oxo-(R)-6-undecyl-2H-pyran-2-one, m.p. 112.5°-113.5° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].O=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1c1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OC(C)(C)C)C(c2ccccc2)C1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A suspension of potassium tert-butoxide (1.25 g, 11.1 mmol) and methyltriphenylphosphonium bromide (3.86 g, 1.1 mmol) in tetrahydrofuran (100 mL) was stirred at 40° C. for 30 minutes. The mixture was then cooled to room temperature and a solution of tert-butyl 4-oxo-2-phenylpiperidine-1-carboxylate (2.35 g, 8.5 mmol) in tetrahydrofuran (30 mL) was added slowly. The reaction mixture was stirred at 40° C. for 24 hours. The mixture was cooled to room temperature and quenched by the addition of water and diluted with ethyl acetate (250 mL), The organic layer was separated then washed with water, 10% aqueous citric acid and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography on silica gel (hexane:ethyl acetate 95:5 to 9:1) provided tert-butyl 4-methylene-2-phenylpiperidine-1-carboxylate (2.24 g, 96%). 1H NMR (400 MHz, CDCl3): 7.31 (m, 4H), 7.21 (m, 1H), 5.48 (br d, 1H), 4.84 (dd, 2H), 4.07 (br dd, 1H), 2.85 (br, t, 1H), 2.78 (dtr, 1H), 2.64 (dd, 1H), 2.28 (dtr, 1H), 2.20 (br d, 1H), 1.42 (s, 9H). GC/MS (EI) for C17H23NO2: 273 (M+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[CH3:14][N:15]([CH3:28])[CH2:16][CH2:17][CH2:18][C:19]1[C:20]([CH3:27])=[C:21]([CH:25]=O)[NH:22][C:23]=1[CH3:24]>N1CCCC1.C(O)C>[CH3:28][N:15]([CH3:14])[CH2:16][CH2:17][CH2:18][C:19]1[C:20]([CH3:27])=[C:21]([CH:25]=[C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][CH2:2][OH:1])[NH:8][C:7]2=[O:13])[NH:22][C:23]=1[CH3:24]
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Reactant: O=C1Cc2c(CCO)cccc2N1
Solvent: CCO
Solvent: C1CCNC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(CCO)c32)c(C)c1CCCN(C)C
Temperature: 90 °C
Yield: 98.1 %

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (177 mg, 1.0 mmol), 4-(3-dimethylamino-propyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (208 mg, 1.0 mmol) and 3 drops of pyrrolidine in 2.0 mL of ethanol was refluxed at 90° C. for 4 hours and cooled to room temperature. The precipitate was filtered, washed with cold ethanol and hexane, and dried in a vacuum oven overnight to give 360.6 mg (98%) of 3-[4-(3-dimethylamino-propyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: Cl[C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([Cl:18])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>C1COCC1>[Cl:18][C:11]1[C:3]([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[C:2]([NH:33][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CN2CCCCC2)c1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2c([N+](=O)[O-])ccc(Cl)c2CN2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-(2,6-dichloro-3-nitro-benzyl)-piperidine (21) (0.894 g, 3.09 mmol) and triethylamine (0.606 g, 6 mmol) in anhydrous THF (5 mL), p-methoxy benzylamine (0.823 g, 6 mmol) was added at 0° C. under stirring. The reaction mixture was allowed to warm to room temperature and stirred for additional 12 hours and evaporated to dryness. The product was extracted with EtOAc (100 mL) and washed with water (2×50 mL) and dried (MgSO4). The product was purified by column chromatography (SiO2, hexanes:EtOAc, 95:5 to 9:1) as a yellow oil. Yield: 0.81 g, 67%. 1H-NMR (CDCl3) δ 1.23-1.26 (m, 6H), 2.23 (m, 4H), 3.63 (s, 2H), 3.76 (s, 3H), 3.92 (d, 2H, J=4.4 Hz), 6.65 (d, 1H, J=9.04 Hz), 6.82 (d, 2H, J=8.6 Hz), 7.18 (d, 2H, J=8.6 Hz), 7.18 (d, 2H, J=8.6 Hz) 7.57 (d, 1H, J=9 Hz), 8.29 (bs, 1H). NOE's were observed from H4 to H3, H5, H6. No NOE was observed from H4 to H1, which would have been expected if the other regioisomer was formed. MS (CI) m/z 390 (M+1), 392 (M+2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][C:13]1[N:18]=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:19]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:12])[N:18]=2)(=[O:21])=[O:20])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)n1
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cccc(S(=O)(=O)Nc2cccc3cccnc23)n1
Yield: 22.2 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (250 mg, 1.73 mmol), 6-methyl-pyridine-2-sulfonyl chloride 441 (530 mg, 2.77 mmol), DMAP (cat.), pyridine (3 ml) and DCM (2 ml) gave the title compound (115 mg, 22%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1F)[C:5]([C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].[C-:21]#[N:22].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[C:21]#[N:22])[C:5]([C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: [C-]#N
Reactant: COCOc1cccnc1C(=O)c1ccc(F)c(Br)c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COCOc1cccnc1C(=O)c1ccc(C#N)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a solution of 2-(3-bromo-4-fluorobenzoyl)-3-methoxymethoxypyridine (4.68 g) in dimethyl sulfoxide (50 mL) was added potassium cyanide (2.7 g) at 0° C. The mixture was stirred for 3 hours while raising the temperature to room temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate) and then concentrated. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromo-4-cyanobenzoyl)-3-methoxymethoxypyridine (4.59 g) (compound B-6). Physical properties and spectrum date of the product are shown in Table 3 and Table 4.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[OH-].[Na+].S(OCC)(O[CH2:18][CH3:19])(=O)=O>C(O)C>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10])[CH3:19]
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(=O)c1cc(C)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc(C)cc1C(C)=O
Reaction time: 72 h

Procedure:
The stirred solution of 20.0 g of 1-(2-hydroxy-5-methylphenyl)ethanone in 600 ml of ethanol is admixed with 8.0 g of sodium hydroxide. The resulting solution is admixed with 25.9 ml of diethyl sulphate and the mixture is kept at room temperature over 72 hours. The reaction mixture is concentrated by evaporation, and the residue is admixed with 1M NaOH (300 ml) and extracted with tert-butyl methyl ether (2×500 ml). The organic phases are washed with brine (300 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a brown solid from the residue by means of flash chromatography (SiO2 60F). Rt=4.49.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)=O)[C:5]([O:11]C)=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=1[NH2:21].C([O-])([O-])=O.[Na+].[Na+]>>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[NH:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[C:15]=3[N:21]=2)[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)nc1C(=O)O
Reactant: Nc1cccc(F)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Oc1ccc(Br)nc1-c1nc2c(F)cccc2[nH]1
Temperature: 120 °C
Reaction time: 14 h
Yield: 36.8 %

Procedure:
A mixture of 6-bromo-3-methoxypicolinic acid (1.84 g, 7.93 mmol) and 3-fluorobenzene-1,2-diamine (1.0 g, 7.93 mmol) was stirred in PPA (3 mL) on a pre-heated oil-bath at 120° C. for 14 h. The mixture was poured to ice-water and basified to pH=8 with Na2CO3. Then the mixture was filtrated to collect the brown solid as 6-bromo-2-(4-fluoro-1H-benzo[d]imidazol-2-yl)pyridin-3-ol (900 mg, yield: 37%). The filtrated was extracted with ethyl acetate, and the organic layer was washed with brine and dried over Na2SO4. After concentrated, the residue was purified by column chromatography to give the product of 2-(6-bromo-3-methoxypyridin-2-yl)-4-fluoro-1H-benzo[d]imidazole (350 mg, yield: 14%). 1H-NMR (CDCl3, 400 MHz) δ 10.43˜10.56 (m, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.21˜7.30 (m, 2H), 6.90˜6.98 (m, 1H), 4.05 (s, 3H). MS (M+H)+: 322/324.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][N:3]=1.[CH2:14]([Mg]Br)[CH:15]([CH3:17])[CH3:16]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:12][CH:13]=1
Reactant: CC(C)C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Solvent: C1CCOC1
Product: CC(C)CC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 6-chloro-N-methoxy-N-methylnicotinamide (2 g, 10 mmol) in THF (30 mL) was added the iso-butymagnesium bromide (15 mL of a 1.33M solution in THF, 20 mmol). The reaction mixture was stirred at 25° C. for 2 h. The reaction was quenched by addition of aqueous NH4Cl (30 mL) and extracted with ethyl acetate (30 mL*2). The organic layer was washed with brine (50 mL) and water (50 mL), then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give 1-(6-chloropyridin-3-yl)-3-methylbutan-1-one (1.8 g) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J=2.0 Hz, 1H), 8.12 (dd, J=2.4, 8.4 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 2.75 (d, J=6.8 Hz, 2H), 2.26-2.19 (m, 1H), 0.94 (d, J=6.8 Hz, 6H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([O:10][CH:11]([O:16][CH2:17][CH3:18])[CH2:12][CH2:13][CH2:14][NH2:15])[CH3:9]>C(Cl)Cl>[CH2:17]([O:16][CH:11]([O:10][CH2:8][CH3:9])[CH2:12][CH2:13][CH2:14][NH:15][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])[CH3:18]
Reactant: CCOC(CCCN)OCC
Reactant: O=C1C=CC(=O)O1
Solvent: ClCCl
Product: CCOC(CCCNC(=O)/C=C\C(=O)O)OCC

Procedure:
Maleic anhydride (85 g) of 1300 mL of CH2Cl2 was cooled to 15° C. and treated with 155 g of 4-aminobutyraldehyde diethyl acetal (AmBDA). (Other preparations used the reverse mode of addition with similar results.) Fifteen min after the addition was complete no further AmBDA was detected by glpc. The solvent was removed under reduced pressure (maintained at 0.2 torr for 2 h to assure completion) to give 230 g of slightly orange colored thick oil. On standing for several months at 0° C., this material solidified to an off-white solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH3:20])[CH:13]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH2:19]([O:18][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][C:2]2[N:3]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:20]
Reactant: CC(C)CBr
Reactant: CCOc1cccc(CCc2nc3ccccc3[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(CCc2nc3ccccc3n2CC(C)C)c1
Temperature: 90 °C
Yield: 69.3 %

Procedure:
A 50 mL flask fitted with a stir-bar and septum with an Ar inlet was charged with benzimidazole 70 (800 mg, 3.00 mmol) and K2CO3 (829 mg, 6.00 mmol). DMF (10 mL) was added followed by 1-bromo-2-methylpropane (617 mg, 0.489 mL, 4.50 mmol). The mixture was heated in a 90° C. bath overnight. Another 0.5 mL of 1-bromo-2-methylpropane and 300 mg of K2CO3 were added, and the mixture was heated overnight again. A third addition of 0.5 mL of 1-bromo-2-methylpropane and 300 mg of K2CO3 were added. The mixture was heated another 4 hr until complete as monitored by HPLC. The suspension was cooled, and the solids were filtered off and rinsed with EtOAc (60 mL). The filtrate was washed with saturated aqueous NH4Cl (2×50 mL), H2O (2×50 mL), and brine (30 mL), filtered through phase separation paper, and concentrated in vacuo to an orange-brown oil. The crude oil was filtered through a plug of silica gel with CH2Cl2 (2×100 mL) and 5% EtOAc in CH2Cl2 (3×100 mL). The EtOAc/CH2Cl2 filtrates were concentrated to give 670 mg of Compound #16 as a yellow oil (69%). 1H NMR (300 MHz, CDCl3): δ 7.78 (m, 1H), 7.34-7.19 (m, 4H), 6.87-6.76 (m, 3H), 3.98 (qt, 2H), 3.81 (d, 2H), 3.32-3.22 (m, 2H), 3.21-3.11 (m, 2H), 2.17 (nonet, 1H), 1.40 (t, 3H), 0.93 (d, 6H) ppm. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of 99% with a retention time of 5.1 min.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=O)[NH:17]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:25].Cl.Cl.[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1>>[ClH:25].[ClH:25].[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH:45][C:22]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[C:13]([O:12][CH2:11][C:7]3[C:6]5[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:10]=5[O:9][CH:8]=3)[CH:21]=[CH:20][CH:19]=4)=[O:24])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Reactant: O=C(O)c1cc2c(OCc3coc4c(F)cccc34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4c(F)cccc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(7-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (114) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[S:9][C:5]=2[CH:4]=1.[Se](=O)=[O:14]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH:10]=[O:14])[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(C)sc2c1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: COc1ccc2nc(C=O)sc2c1
Yield: 55.5 %

Procedure:
Oxidation of 6-methoxy-2-methylbenzothiazole (10.0 g, 55.9 mmole) with selenium dioxide (6.2 g, 55.9 mmole) in 300 ml dioxane for six hours by the method of Preparation H gave 6.0 g of 6-methoxy-2-formylbenzothiazole after chromatography of the crude product on silica gel, eluting with chloroform. 1H--NMR(CDCl3)ppm(delta): 3.9 (s, 3H), 7.1-7.5 (m, 2H), 8.0-8.3 (m, 1H), 10.1 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH:20]([CH3:22])[CH3:21])[CH3:2].[C:23]([O:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[CH2:41][O:42][C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:36]Br)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([O:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[CH2:41][O:42][C:43](=[O:50])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:36][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][C:11]=2[CH:20]([CH3:22])[CH3:21])[CH:5]=1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Reactant: CCC(=O)c1ccc(-c2cc(O)ccc2CC)c(C(C)C)c1
Product: CCC(=O)c1ccc(-c2cc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)ccc2CC)c(C(C)C)c1

Procedure:
In a manner similar to that of Example 1(o), by reacting 660 mg (2.2 mmol) of 1-(2′-ethyl-5′-hydroxy-2-isopropylbiphenyl-4-yl)propan-1-one with 1 g (2.3 mmol) of 3,4-bis-(benzoyloxymethyl)benzyl bromide, an oil is obtained, which is used without purification.
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)(O)[O-].[Na+].[C:19](Cl)(=[O:30])[O:20][CH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=1>C(Cl)Cl>[C:4]([O:3][C:1]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:19]([O:20][CH2:21][C:22]2[CH:23]=[C:24]([Cl:29])[CH:25]=[C:26]([Cl:28])[CH:27]=2)=[O:30])[CH2:10]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture comprising of 3-(boc-amino)pyrrolidine (1 g, 5.37 mmol) and saturated sodium bicarbonate (9 mL, 5.37 mmol) in DCM (17.90 mL) was stirred at room temperature for 5 minutes. The resulting mixture was treated with 3,5-dichlorobenzyl carbonochloridate (1.286 g, 5.37 mmol) and stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with DCM. The organic portion was separated and dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cccc(N)c2)n1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(CCc2cccc(N)c2)n1
Yield: 94.3 %

Procedure:
To a mixture of tert-butyl {6-[(3-aminophenyl)ethynyl]pyridin-2-yl}carbamate (70.0 mg, 2.3 mmol) in methanol (25 mL) and was added 10% palladium on carbon (700 mg, 0.60 mmol). The resultant mixture was hydrogenated at 60 psi for 3 hours. The reaction mixture was filtered, washed with MeOH and concentrated to give the desired product (680 mg, 96%). LCMS for C18H24N3O2 (M+H)+: m/z=314.1.