Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][C:5]=2[N:6]=1.[CH3:14][Mg]Cl.Cl>O1CCCC1.O>[C:11]([C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([Cl:1])=[N:6][C:5]=2[CH:7]=1)(=[O:12])[CH3:14]
Reactant: O=C(Cl)c1ccc2sc(Cl)nc2c1
Reactant: C[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc2sc(Cl)nc2c1
Reaction time: 0.5 h

Procedure:
A solution of 2-chloro-5-(chlorocarbonyl)benzothiazole (321 mg, 1.38 mmol, prepared according to U.S. Pat. No. 3,654,296) and ferric acetylacetonate (14.7 mg, 0.042 mmol) in anhydrous tetrahydrofuran (13.8 mL) was cooled in an ice-methanol bath (−20° C.), stirred under a nitrogen atmosphere, and treated dropwise over 5 minutes with 1M methyl magnesium chloride in tetrahydrofuran (1.38 mL). The resulting mixture was stirred at −15° C. for 15 minutes then at room temperature for 30 minutes. The mixture was treated with 2N hydrochloric acid (1.38 mL), diluted with water, and extracted with ethyl acetate. The extracts were washed with 5% aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to white solid (299 mg). The crude product was purified by flash chromatography on silica gel (25 g, loaded as a dichloromethane solution and eluted with 2% ethyl acetate in dichlormethane) to afford 5-acetyl-2-chlorobenzothiazole (201 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.Cl.O([NH2:20])C.O.[OH-].[Na+]>N1C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH2:20])[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: O=C(Cc1ccncc1)c1ccccc1Cl
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: NC(Cc1ccncc1)c1ccccc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a solution of 1-(2-chlorophenyl)-2-(pyridin-4-yl)ethanone (22) (2.0 g, 8.7 mmol) in pyridine (24 mL) was added methoxyl amine hydrochloride (1.45 g, 17.4 mmol) in one portion at room temperature. The resulting mixture was stirred at 50° C. for one hour. The pyridine was removed under vacuum, and residue was added water and extracted with ethyl acetate. Ethyl acetate phase was washed with brine, dried over magnesium sulfate and concentrated. Purification by chromatography on silica gel gave a mixture of geometrical oxime isomers (1.77 g, 78%) as a yellow oil. To a solution of above mixture of syn- and anti-oximes, (1.77 g, 6.8 mmol) in THF (32 mL) at room temperature was added borane-THF complex (1M, 17 mL). The resulting solution was refluxed for 3 hours, and cooled to 0° C. Water (28 mL) was carefully added followed by 20% NaOH (28 mL). The resulting biphasic mixture was refluxed overnight, and allowed to cool to room temperature. The mixture was extracted with ethyl acetate. Combined ethyl acetate phase was washed with brine, dried over magnesium sulfate and concentrated to give 1-(2-chlorophenyl)-2-(pyridin-4-yl)ethanamine (23) (1.2 g 76%) as yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH:19]=[CH:18]1>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:19]2[CH2:18][C:17](=[O:23])[O:22][C:20]2=[O:21])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SC2CC(=O)OC2=O)cc(C(C)(C)C)c1O
Yield: 56.5 %

Procedure:
The procedure of Example 1 is repeated using 23.84 grams of 2,6-di-tert-butyl-4-mercaptophenol, 9.8 grams of maleic anhydride, and 0.51 grams of triethylamine. The residue is recrystallized once from hexane:toluene mixture and once from cyclohexane to give 19.0 grams of a light yellow solid, m.p. 92°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1>C(O)(=O)C.Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OCC2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ccc(OCC2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
In a manner similar to Preparation 3, hydrogenate 1[2-(4-chlorophenyl)ethyl]-4-[(4-nitrophenoxy)methyl]piperidine in acetic acid and hydrochloric acid over palladium on carbon to obtain the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][O:16][Si](C(C)(C)C)(C)C)=[CH:10][CH:9]=1)([O-:7])=[O:6].O1CCOCC1.O>CO>[CH3:2][O:3][N:4]=[C:14]([C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][CH:12]=1)[CH2:15][OH:16]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CON
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CON=C(CO)c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
69 mg of O-methylhydroxylamine hydrochloride were added to a solution of 0.12 g (0.41 mmol) of 4'-nitro-2-t-butyldimethylsilyloxyacetophenone (obtained above) in a mixture of methanol (1.2 ml), 1,4-dioxane (2.0 ml) and water (2.0 ml). The resulting mixture was stirred for 1.5 hours at 80° C., then poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography, eluted with a stepwise gradient of ethyl acetate (10-40%) in hexane, to give 58 mg (67% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:10][C:5]2=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][CH2:23][CH2:24][CH2:25][F:26].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]([CH2:22][CH2:23][CH2:24][CH2:25][F:26])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2nc(Cl)ccc2[nH]1
Reactant: FCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2nc(Cl)ccc2n1CCCCF
Temperature: 60 °C

Procedure:
To a solution of methyl 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate 11-c (2.9 g, 12.2 mmol) in DMF (50 mL) were added successively cesium carbonate (4 g, 12.2 mmol) and 1-bromo-4-fluorobutane (1.3 mL, 12.2 mmol). The resulting mixture was heated at 60° C. overnight. The reaction mixture was allowed to cool down to room temperature then poured into iced water and the product was extracted 3 times with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to give the targeted product 11-d as a yellowish solid. The product was used as such in the next step. m/z=313 (M+H)+, Cl pattern.
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[O:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:20][C:10]1[C:11](=[O:13])[NH:12][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][C:9]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(-c2ccncc2)nc(-c2ccccc2)[nH]1
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccccc2)nc(-c2ccncc2)c1Br
Temperature: 90 °C
Yield: 92.1 %

Procedure:
2-Phenyl-6-(4-pyridyl)pyrimidin-4-one (0.61 g) obtained in Example 12 was dissolved in 3 ml of acetic acid, and then the mixture was added with 0.48 g of N-bromosuccinimide and heated at 90° C. for 1 hour. Water was added to the reaction mixture, and solid mass was separated by filtration. The solid was washed with water, acetone, and ethyl acetate, and dried to obtain 0.74 g of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C@H:34]([CH:37]([CH3:39])[CH3:38])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C@@H:34]([CH2:35][OH:36])[CH:37]([CH3:39])[CH3:38])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: CC(C)[C@@H](N)CO
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN[C@@H](CO)C(C)C)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and (R)-2-amino-3-methyl-1-butanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C25H38N6O5SF [(M+H)+]553.2603, observed 553.2600.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.OS([O-])=O.[Na+]>ClCCl>[CH3:16][CH:12]([CH2:13][CH2:14][CH3:15])[CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C@@H:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH:2]=[O:1])=[CH:9][CH:8]=1
Reactant: CCCC(C)COc1ccc([C@H](CO)NC(=O)OC(C)(C)C)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])O
Solvent: ClCCl
Product: CCCC(C)COc1ccc([C@H](C=O)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
A solution of t-butyl (1R)-2-hydroxy-1-(4-(2-methylpentyloxy)phenyl)ethylcarbamate (500 mg, 1.48 mmol) prepared according to the procedure described in example 1, in dichloromethane (10 mL) was treated with sodium bicarbonate (622 mg, 7.41 mmol) and Dess-Martin Periodinane (1.26 g, 2.96 mmol) at room temperature. The mixture was stirred at room temperature under N2 for 1.5 h. The reaction mixture was placed in an ice-water bath and a 1:1 mixture of saturated aqueous NaHCO3 solution and saturated NaHSO3 solution (4 mL) was added and the cooling bath was removed and the mixture was stirred for 5 min at room temperature. The reaction mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (20 mL). The aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (10%→15% ethyl acetate in hexanes, 25 g column) to afford t-butyl (1R)-1-(4-(2-methylpentyloxy)phenyl)-2-oxoethylcarbamate (318 mg, 64% yield) as a colorless oil which was stored in the freezer until used in the next step: 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.23 (d, J=8.6 Hz, 2H), 6.93 (d, J=8.6 Hz, 2H), 5.11 (d, J=7.6 Hz, 1H), 3.82 (dd, J=9.6, 6.0 Hz, 1H), 3.73 (dd, J=9.3, 6.5 Hz, 1H), 1.82-1.92 (m, 1H), 1.40 (s, 9H), 1.25-1.49 (m, 3H), 1.11-1.22 (m, 1H), 0.96 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.1 Hz, 3H); LRMS (ESI) m/e 279.2 [(M-t-Bu)+, calcd for C15H21NO4 279.1].
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([Cl:11])[O:8][C:7]=1[CH3:12])=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:11][C:9]1[O:8][C:7]([CH3:12])=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(Cl)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(Cl)cc1C(=O)O
Yield: 64.6 %

Procedure:
2-Methyl-3-furancarboxylic acid ethyl ester (10.5 g) was dissolved in acetonitrile (50 ml), and sulfuryl chloride (5.6 ml) was added under ice-cooling. The mixture was stirred at 10° C. for 30 minutes, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours, and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-chloro-2-methyl-3-furancarboxylic acid ethyl ester (10 g) as oil. 5-Chloro-2-methyl-3-furancarboxylic acid ethyl ester (10 g) was dissolved in ethanol (100 ml), and 1N aqueous sodium hydroxide (60 ml) was added. The mixture was stirred under reflux for 30 minutes and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were recrystallized from acetone-hexane to give 5-chloro-2-methyl-3-furancarboxylic acid (5.5 g) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=O)[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:4]=1[CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32].[OH-:34].[K+].Cl>CO>[C:25]([CH2:24][O:23][C:5]1[C:4]([CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1[CH2:11][C:12](=[O:34])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)([OH:27])=[O:26]
Reactant: COC(=O)COc1c(CC=C(C)C)c(OC)cc(OC)c1C(=O)CCc1ccc(OC)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COc1ccc(CC(=O)Cc2c(OC)cc(OC)c(CC=C(C)C)c2OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
Then, 1.9 g of 1-[4,6-dimethoxy-2-methoxycarbonylmethoxy-3-(3-methyl-2-butenyl)phenyl]-3-(4-methoxyphenyl)-1-propanone was dissolved in 20 ml of methanol, and 20 ml of a 5% aqueous solution of potassium hydroxide was added to the solution and the mixture was stirred at room temperature for 30 minutes to effect a reaction. After the reaction, the reaction mixture was made acidic by dilute hydrochloric acid, extracted with diethyl ether and filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and diethyl ether to obtain 1.7 g (yield=92.4%) of 1-[2-carboxymethoxy-4,6-dimethoxy-3-(3-methyl-2-butenyl)phenyl]-3-(4-methoxyphenyl)-propanone in the form of a colorless prism.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[C:5]([N:10]=[C:11]=[O:12])(=[O:9])[C:6]([CH3:8])=[CH2:7]>ClCCCl>[C:5]([NH:10][C:11]([NH:4][C:1](=[O:3])[CH3:2])=[O:12])(=[O:9])[C:6]([CH3:8])=[CH2:7]
Reactant: C=C(C)C(=O)N=C=O
Reactant: CC(N)=O
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)NC(C)=O
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 95.8 %

Procedure:
To a solution of acetamide (0.59 g; 10 mmol) in 1,2-dichloroethane (20 ml), a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (5 ml) was dropwise added at room temperature, and the reaction mixture was stirred at 80° C. for 3.5 hours. After cooling, 1,2-dichloroethane was evaporated under reduced pressure to give 1-methacryloyl-3-acetylurea (1.63 g), which was recrystallized from a mixture of benzene and hexane to give colorless needles. M.P., 92°-94° C.
Reaction SMILES: Br[C:2]1[C:12]2[N:11]3[CH2:13][CH2:14][CH2:15][C@@H:16]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[C@H:10]3[C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:28][O-:29].[Na+].[NH4+].[Cl-]>CN(C=O)C.CO.[Cu]I>[CH3:28][O:29][C:2]1[C:12]2[N:11]3[CH2:13][CH2:14][CH2:15][C@@H:16]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[C@H:10]3[C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CCCN2c3c(Br)cccc3Oc3ccccc3[C@H]12)C(F)(F)F
Reactant: C[O-]
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cccc2c1N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Reaction time: 4 h

Procedure:
Copper(I) iodide (21 mg, 0.11 mmol) was added to a stirring solution of trans-N-(6-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (100 mg, 0.22 mmol) in DMF (1.5 mL) in a Dean-Stark apparatus. Subsequently a solution of NaOMe (1.2 mL, 1.2 mmol) in methanol was added and stirring was continued at 135° C. for 4 h. After cooling down, the reaction mixture was poured into sat (aq) NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. After purification on a SPE-column and by HPLC the title compound (11 mg, 13%) was obtained. Data: 1H-NMR (400 MHz, CDCl3) 1.50 (m, 1H), 1.76 (m, 1H), 1.87 (m, 1H), 1.94 (m, 1H), 2.87 (m, 1H), 3.29 (dt, J=12, 3.2, 1H), 3.86 (s, 3H), 4.28 (d, J=3.2, 1H), 4.81 (m, 1H), (Ar) 6.66 (d, J=12, 1H), 6.78 (d, J=12, 1H), 7.10 (m, 1H), 7.20-7.31 (m, 4H), 8.18 (m, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:10][CH2:11][O:12][CH2:13][CH2:14]Br.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: BrCCOCCBr
Reactant: Nc1cccc(Br)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cccc(N2CCOCC2)c1
Temperature: 100 °C
Yield: 16.4 %

Procedure:
To a solution of 3-bromoaniline (1.00 g, 5.81 mmol) in anhydrous DMF (20 mL) was added 1-bromo-2-(2-bromoethoxy)ethane (1.62 g, 6.18 mmol) and DIPEA (2.25 g, 17.4 mmol). The solution was heated to 100° C. for 16 h, cooled and concentrated. The residue was purified by preparative HPLC purification. (230 mg, yield 16.4%) MS (ESI+) e/z: 242.0 [M+1]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[C:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:5].[C:16]([O:20][C:21](=[O:33])[NH:22][C@H:23]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1)[CH3:24])([CH3:19])([CH3:18])[CH3:17].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:2][O:3][C:4]([C:6]1[C:7]2[CH2:8][CH2:9][N:10]([CH2:31][C:28]3[CH:27]=[CH:26][C:25]([C@@H:23]([NH:22][C:21]([O:20][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:33])[CH3:24])=[CH:30][CH:29]=3)[CH2:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:5]
Reactant: COC(=O)c1cccc2c1CCNC2
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1cccc2c1CCN(Cc1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 600 mg (2.64 mmol) 1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid methyl ester hydrochloride and 657 mg (2.64 mmol) [(S)-1-(4-formyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (example II) in 5 mL THF are added 452 μL (7.91 mmol) AcOH and the mixture is stirred at r.t. for 10 min. After that time, the resulting mixture is cooled to 0° C., 838 mg (3.95 mmol) sodium triacetoxyborohydride are added and the reaction mixture is stirred at r.t. for 2 h. The reaction is quenched by the addition of 500 μl water and purified by HPLC (ACN/H2O/NH3).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](Cl)=[O:24]>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)=[O:24]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)CCc1ccc(CN)cc1
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)NCc1ccc(CCC(=O)O)cc1

Procedure:
By reaction of ethyl β-[4-(aminomethyl)-phenyl]-propionate hydrochloride (m.p. 192°-193° C.) with 5-chloro-2-methoxybenzoyl chloride, there is obtained β-[4-(5-chloro-2-methoxybenzamidomethyl)-phenyl]-propionic acid; m.p. 152°-153° C., after recrystallization from isopropanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][C:8]2=[O:17])[CH2:3][CH2:2]1.Cl[C:19]1[CH:35]=[CH:34][C:22]([C:23]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:24])=[CH:21][C:20]=1[N+:36]([O-:38])=[O:37]>>[N+:36]([C:20]1[CH:21]=[C:22]([C:23]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:24])[CH:34]=[CH:35][C:19]=1[N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][C:8]2=[O:17])[CH2:3][CH2:2]1)([O-:38])=[O:37]
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(O)c1ccccc1C(=O)c1ccc(N2CCC(N3C(=O)CCc4ccccc43)CC2)c([N+](=O)[O-])c1

Procedure:
The product was prepared from 1-piperidin-4-yl-3,4-dihydroquinolin-2(1H)-one (Chem. Pharm. Bull. (1996), 44(4), 725-33) (0.45 g) and 2-(4-chloro-3-nitrobenzoyl)benzoic acid (0.6 g) using the method of example 1. Used crude.
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4].Br[C:46]1[S:47][CH:48]=[CH:49][N:50]=1>>[CH3:44][C:2]([CH3:1])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:46]3[S:47][CH:48]=[CH:49][N:50]=3)=[CH:17][CH:18]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)O
Reactant: Brc1nccs1
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(-c2nccs2)cc1)C(=O)O

Procedure:
The title compound was prepared with similar methods to those in Example 147 using 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazol-2-yl)propanoic acid and 2-bromothiazole. MS (ESI): mass calcd. for C32H28N4O3S, 548.19; m/z found, 549.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.85 (d, J=8.5, 1H), 8.35 (d, J=8.6, 1H), 8.20 (d, J=8.0, 1H), 8.07-7.86 (m, 5H), 7.85-7.77 (m, 2H), 7.62 (d, J=9.1, 1H), 7.50 (d, J=2.3, 1H), 7.40 (d, J=8.3, 2H), 7.34 (dd, J=9.1, 2.3, 1H), 5.89 (s, 2H), 5.72 (s, 2H), 3.55 (s, 2H), 1.33 (s, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]2=[O:13])[CH:2]=1.I[C:15]1[CH:23]=[CH:22][C:18]2[S:19][CH:20]=[CH:21][C:17]=2[CH:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:19]1[CH:20]=[CH:21][C:17]2[CH:16]=[C:15]([N:9]3[CH2:10][CH2:11][CH2:12][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[C:8]3=[O:13])[CH:23]=[CH:22][C:18]1=2
Reactant: O=C1NCCCN1c1cccnc1
Reactant: Ic1ccc2sccc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cccnc2)CCCN1c1ccc2sccc2c1
Yield: 12.7 %

Procedure:
Using the same reaction conditions as in Example 1, 1-pyridin-3-yl-tetrahydro-pyrimidin-2-one (I-10b: 67.8 mg, 0.3831 mmol) was reacted with 5-iodo-benzo[b]thiophene (100 mg, 0.3831 mmol), 1,4-dioxane (5 mL), copper iodide (7.29 mg, 0.03831 mmol), trans-1,2-diamino cyclohexane (13.15 mg, 0.1149 mmol) and potassium carbonate (106.1 mg, 0.7662 mmol) to afford 15 mg of the product (17.5% yield).