Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](F)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][OH:17].C[O-].[Na+]>>[CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:17][CH3:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: Fc1cccc(SCc2ccccc2)n1
Agent: C[O-]
Agent: [Na+]
Product: COc1cccc(SCc2ccccc2)n1
Yield: 86 %

Procedure:
2-(Benzylthio)-6-fluoropyridine (199 mg) and 28% sodium methoxide methanol solution (2 mL) were stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 182 mg, 86%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:9][S:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]1=[O:16].Cl[CH2:18][C:19](=[O:37])[C@@H:20]([NH:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:29]([NH:28][CH:20]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:19](=[O:37])[CH2:18][NH:2][CH:3]1[CH2:9][S:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]1=[O:16])(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)c1ccccc1
Reactant: CCOC(=O)CN1CCSCC(N)C1=O
Agent: Cl
Product: CCOC(=O)CN1CCSCC(NCC(=O)C(Cc2ccccc2)NC(=O)c2ccccc2)C1=O

Procedure:
6-Amino-tetrahydro-5-oxo-1,4-thiazepine-4(5H)-acetic acid, ethyl ester, hydrochloride is reacted with (S)-N-[3-chloro-2-oxo-1-(phenylmethyl)propyl]benzamide according to the procedure of Example 1(h) to give tetrahydro-6-[[3-(benzoylamino)-2-oxo-4-phenylbutyl]amino]-5-oxo-1,4-thiazepine-4(5H)-acetic acid, ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)=[O:9])[C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(-c2ccn(C)n2)c(C(=O)O)c1
Product: Cc1ccc(-c2ccn(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using 5-methyl-2-(1-methyl-1H-pyrazol-3-yl)benzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 472 [M+1]+.
Reaction SMILES: [NH2-].[Na+].[C:3]1([C:9]2[N:10]=[C:11]([CH2:14][C:15]#[N:16])[S:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:19][CH2:20][N:21]([CH2:23][CH2:24]Cl)[CH3:22].N>C1(C)C=CC=CC=1.O>[CH3:22][N:21]1[CH2:23][CH2:24][C:14]([C:11]2[S:12][CH:13]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:10]=2)([C:15]#[N:16])[CH2:19][CH2:20]1
Reactant: N#CCc1nc(-c2ccccc2)cs1
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: N
Agent: [NH2-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCC(C#N)(c2nc(-c3ccccc3)cs2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 16.7 %

Procedure:
Sodium amide (878 mg, 22.4 mmol) was suspended in toluene (15 mL) and cooled to 0° C. To this suspension was added dropwise a solution of (4-phenyl-thiazol-2-yl)-acetonitrile (1.5 g, 7.4 mmol) in toluene (10 mL) while maintaining the temperature at 0° C. The reaction mixture was stirred for 20 min. Separately the bis-(2-chloroethyl)methylamine hydrochloride (1.45 g, 7.4 mmol) was taken in water (8 mL), cooled to 0° C., and basified with aqueous ammonia solution (adjusted to pH of the solution to ˜8). The oily layer was separated out from the aqueous layer and the organic product was extracted with toluene. The toluene layer was dried over sodium hydroxide pellets. The dry toluene solution of bis-(2-chloroethyl)methylamine was added to the reaction mixture at 0° C. The reaction mixture was allowed to warm up to room temperature and further heated to 110° C. for 3 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 5% MeOH in CH2Cl2) to afford 1-methyl-4-(4-phenylthiazol-2-yl)piperidine-4-carbonitrile (350 mg, yield 17%). 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.99-7.97 (m, 2H), 7.49-7.44 (m, 2H), 7.40-7.36 (m, 1H), 2.92-2.90 (m, 2H), 2.40-2.37 (m, 2H), 2.31-2.16 (m, 7H). MS (ESI) m/z: Calculated for C16H17N3S: 283.11. found: 284.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[I-].[Na+].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(Cl)(Cl)Cl.O.C(O)C>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][N:5]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:4]=1
Reactant: CCOC(=O)CBr
Reactant: FC(F)(F)c1cc[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1ccc(C(F)(F)F)n1

Procedure:
To a chloroform solution (2 mL) of 3-(trifluoromethyl)-1H-pyrazole (68 mg, 0.50 mmol), potassium carbonate (104 mg, 0.75 mmol) and ethyl bromoacetate (100 mg, 0.60 mmol) were added and the resultant mixture was stirred at 70° C. for 2 hours. To the reaction solution, adequate amount of sodium iodide was added and the resultant mixture was further stirred for 1 day. To the reaction solution, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (147 mg, 0.77 mmol), 1-hydroxybenzotriazole (catalytic amount) and ethanol (500 μL) were added and the resultant mixture was stirred for 2 hours. After completion of the reaction, water was added to the reaction solution and extraction with chloroform from the resultant mixture was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of the title compound. The crude product was used in the next reaction as it was.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]3[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[H][H]>CO.[Pd]>[NH2:24][C:23]1[C:18]([NH:17][CH:14]2[CH2:15][CH2:16][N:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]3)[CH2:12][CH2:13]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)N1CCC(N2CCC(Nc3ncccc3[N+](=O)[O-])CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)N1CCC(N2CCC(Nc3ncccc3N)CC2)CC1

Procedure:
Seventy (70) mg of 2-[1-(1-methoxycarbonylpiperidin-4-yl)-piperidin-4-yl]amino-3-nitropyridine was dissolved in 5 ml of methanol, and to which 20 mg of 10% palladium/carbon catalyst was added to effect catalytic reduction at room temperature under atmospheric pressure of hydrogen. After filtering the catalyst off and drying the filtrate to solid, the resulting residue was purified by silica gel column chromatography (chloroform/methanol=95/5) to give 20 mg of 3-amino-2-[1-(1-methoxycarbonylpiperidin-4-yl)-piperidin-4-yl]aminopyridin.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13].BrCCOC.BrCC(C)C.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:37]([NH:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][C:42]=1[CH2:50][CH3:51])(=[O:39])[CH3:38]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13].[C:37]([NH:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](=[O:46])[CH2:13][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:14])=[CH:43][C:42]=1[CH2:50][CH3:51])(=[O:39])[CH3:38]
Reactant: CCc1cc(C(=O)O)ccc1NC(C)=O
Agent: COCCBr
Agent: COCCOc1ccccc1C(C)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CC(C)CBr
Product: CCc1cc(C(=O)CC(=O)c2ccccc2OCCOC)ccc1NC(C)=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A separated flask was charged with 1-(2-(2-methoxyethoxy)phenyl)ethanone (11.2 g, 57 mmol). (1-(2-(2-Methoxyethoxy)phenyl)ethanone was prepared by a procedure analogous to Example 1, in which commercially 1-bromo-2-methoxyethane was substituted for 1-bromo-2-methyl propane). The 1-bromo-2-methoxyethane was added to anhydrous THF (50 mL) and cooled to −78° C. To this solution was added commercially available lithium hexamethyl-silylamide (1M in hexanes, 172 mL, 172 mmol, Aldrich) over a 3 hour period at −78° C. The mixture was stirred for an additional 2 hours at −78° C. To the resulting mixture were added dropwise a solution of CDI and 4-acetamido-3-ethylbenzoic acid (above) at −78° C. The resulting mixture was stirred at −78° C. for an additional 30 min and subsequently allowed to warm up to room temperature over 12 h. The reaction was quenched with 1 N HCl and extracted with EtOAc and water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give 1-(4-acetamido-3-ethylphenyl)-3-(2-(2-methoxyethoxy)phenyl)propane-1,3-dione as a white solid (11 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[C:5]([F:11])=[CH:4][C:3]=1[N+:12]([O-])=O.[H][H]>CO.[Pd]>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[C:5]([F:11])=[CH:4][C:3]=1[NH2:12]
Reactant: COc1c(Cl)c(F)cc([N+](=O)[O-])c1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1c(Cl)c(N)cc(F)c1Cl
Temperature: 25 °C
Yield: 93 %

Procedure:
72.0 g of 2,4-dichloro-5-fluoro-3-methoxynitrobenzene (0.30 mol) and 2.65 g of Pd/C in 500 ml of methanol were hydrogenated under 3 Mpa (hydrogen pressure) at 60° C. for 3 hours. The reactant was cooled to room temperature. The catalyst was filtered out, and the solvent was evaporated to give 58.5 g of 2,4-dichloro-5-fluoro-3-methoxyaniline (0.279 mol) in 92.9% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([CH2:13][C:14]([N:16]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:17]CC2C=CC=CC=2)=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1>CO.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([CH2:13][C:14]([N:16]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[OH:17])=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(CC(CC(=O)N(Cc2ccccc2)OCc2ccccc2)C(=O)O)cn1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CC(CC(=O)N(O)Cc2ccccc2)C(=O)O)cn1
Yield: 22 %

Procedure:
A solution of 2-(6-Amino-pyridin-3-ylmethyl)-N-benzyl-N-benzyloxy-succinamic acid (0.9 g, 1.7 mmol) and palladium (0.5 g, 5% on charcoal) in methanol (100 mL) was hydrogenated at 1 bar for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (CHCl3/MeOH/H2O, 10:5:1) to give the title compound (123 mg, 22%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][O:41][CH:40]([CH2:44]O)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][O:41][CH:40]([CH2:44][N:24]2[C:20](=[O:30])[C:21]3=[CH:29][CH:28]=[CH:27][CH:26]=[C:22]3[C:23]2=[O:25])[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(CN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97 %

Procedure:
Triphenylphosphine (506 mg, 1.87 mmol) and phthalimide (275 mg, 1.87 mmol) were added to 4-(tert-butoxycarbonyl)morpholin-2-yl methanol (340 mg, 1.56 mmol) in tetrahydrofuran (3 mL). The mixture was stirred at room temperature for 5 min, followed by addition of a 40% diethyl azodicarboxylate/toluene solution (1.06 mL, 2.34 mmol) and stirring at room temperature for 4 hours. Subsequently, ethyl acetate was added and the mixture washed sequentially with tap water and brine. The mixture was then dried over magnesium sulfate and the solvent was evaporated. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=10:1->3:1) gave 524 mg (97%) of the desired compound as a colorless powder.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([C:23](=[O:29])[N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25])[CH:17]=2)=[C:10]([CH3:30])[CH:9]=1)=[O:6])C.S([O-])([O-])(=O)=O.[Mg+2].[NH3:38]>CCO.C(Cl)Cl>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:11]2[C:10]([CH3:30])=[CH:9][C:8]([NH:7][C:5]([C:4]([NH2:38])=[O:3])=[O:6])=[CH:13][C:12]=2[CH3:14])=[CH:17][C:18]=1[C:23](=[O:29])[N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25]
Reactant: N
Reactant: CCOC(=O)C(=O)Nc1cc(C)c(Oc2ccc(O)c(C(=O)N(C)C(C)C)c2)c(C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(NC(=O)C(N)=O)cc(C)c1Oc1ccc(O)c(C(=O)N(C)C(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-{4-[4-hydroxy-3-(isopropylmethylcarbamoyl)-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid ethyl ester (7.1 mg, 0.017 mmol) in 1 mL of EtOH in the presence of magnesium sulfate (10 mg) at 0° C. was bubbled in NH3 gas for 10 min. The solution was allowed to warm to RT. After stirring at RT for 0.5 h, the solution was diluted with 2 mL of CH2Cl2 and filtered. The filtrate was concentrated to give the title compound as a white solid. MS Calc.: 399.5 Found: 398.4 (M−1).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.[C:21](OCC)(=[O:23])C.O1CCCC1>C(O)(=O)C>[Cl:1][C:2]1[N:7]2[C:8]([CH:21]=[O:23])=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: Clc1cccc2nccn12
Agent: C1N2CN3CN1CN(C2)C3
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=Cc1cnc2cccc(Cl)n12
Yield: 37 %

Procedure:
A solution of 5-chloroimidazo[1,2-a]pyridine (997 mg) and hexamethylenetetramine (1.8 g) in acetic acid (10 ml) was stirred at 90° C. for 5 hours. After the reaction mixture was allowed to cool, ethyl acetate-tetrahydrofuran (4/1; 200 ml) was added and the mixture was washed with saturated aqueous solution of sodium chloride. The organic layer was neutralized with 2N-aqueous solution of sodium hydroxide, dried over MgSO4, and concentrated. The resulting crystals were rinsed with diethyl ether to provide the title compound (440 mg, 37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:35]=[C:36]([Cl:38])[N:37]=2)[C:31]([O:33]C)=[O:32])[CH2:24][CH:23]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:35]=[C:36]([Cl:38])[N:37]=2)[C:31]([OH:33])=[O:32])[CH2:24][CH:23]1[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(Cl)nc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2cc(C(=O)O)cc(Cl)n2)CC1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 105.4 %

Procedure:
To a solution of 66 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-6-chloroisonicotinate in 2.0 ml of THF and 1.0 mL of methanol was added 1.00 mL of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring overnight. It was neutralized by addition of 1.00 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 68 mg of 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-6-chloroisonicotinic acid as a pale yellow resinous compound. ESI+: 600
Reaction SMILES: [CH3:1][CH:2]([NH:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH3:5]>C1COCC1>[CH3:1][CH:2]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(C)NC(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCCC(C)NCc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
In a manner analogous to Example 1 a solution of N-(1-methylbutyl)-4-chlorobenzamide (2.26 g; 0.01 mol) in dry THF (25 ml) was reacted with an ice-cooled solution of 1.0 M.B2H6 -THF complex (45 ml; 0.045 mol) under a nitrogen blanket to give the title compound as an oil.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[NH:8][C:7](=[O:14])[C:6]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH3:4].[CH3:30][CH:31]([O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[CH3:32].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:30][CH:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N:8]2[C:7](=[O:14])[C:6]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:10]3[N:11]=[CH:12][N:13]=[C:9]23)=[CH:36][CH:35]=1)[CH3:32]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)C)cc2)c2ncnn12
Reaction time: 16 h
Yield: 102.2 %

Procedure:
To a suspension (15 mL) of 4′-[(7-butyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), [4-(1-methylethoxy)phenyl]boronic acid (0.47 g), triethylamine (0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane was added copper(II) acetate (0.47 g), and the mixture was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.69 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](Cl)=[O:12])=[CH:3]1.Cl.[CH2:15]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([Br:38])[CH:31]=2)=[CH:26][CH:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:15]([N:22]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([Br:38])[CH:31]=2)=[CH:26][CH:25]=1)[C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)=[O:12])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cn1cc(C(=O)Cl)c2ccccc21
Reactant: COc1ccc(-c2ccc(CNCc3ccccc3)cc2)cc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2ccc(CN(Cc3ccccc3)C(=O)c3cn(C)c4ccccc34)cc2)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
1-methyl-1H-indole-3-carbonyl chloride (16.3 mmol), prepared in step 1 of Example 9, in 60 mL of methylene chloride was added under nitrogen dropwise over 15 minutes to a solution of the HCl salt of N-benzyl-N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]amine (5.0 g, 11.9 mmol), prepared in step 2 of Example 11, and triethylamine (4.6 mL, 33 mmol) in 100 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature for 16 h. The reaction was extracted with 1 N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give N-benzyl-N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-1-methyl-1H-indole-3-carboxamide (6.1 g, 95%) as a white solid, MS (ESI) m/z 539 [M+H]+. Elemental Analysis for C31H27BrN2O2: Calc'd: C, 69.02; H, 5.04; N, 5.19; Found: C, 68.55; H, 5.32; N, 4.99.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([C:20]3[S:24][C:23]([NH:25][C:26]4[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=4)=[N:22][C:21]=3[NH2:38])[S:18][CH:19]=2)[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1.CN(C=O)C>C1COCC1>[NH2:38][C:21]1[N:22]=[C:23]([NH:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)[S:24][C:20]=1[C:17]1[S:18][CH:19]=[C:15]([C:11]2[CH:10]=[C:9]([NH:8][C:1](=[O:3])[CH3:2])[CH:14]=[CH:13][CH:12]=2)[N:16]=1
Reactant: COc1cc(Nc2nc(N)c(-c3nc(-c4cccc(N)c4)cs3)s2)cc(OC)c1OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(N)c(-c3nc(-c4cccc(NC(C)=O)c4)cs3)s2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
Acetic anhydride (21.3 μL, 0.2250 mmol) was added to a solution of 4-(3-aminophenyl)-N2′-(3,4,5-trimethoxyphenyl)-[2,5′]bithiazolyl-2′,4′-diamine (50.0 mg, 0.1125 mmol), prepared as described in Example C(1), dissolved in pyridine (28.5 μL, 0.352 mmol), DMF (70 μL), and THF (700 μL) at −15° C. (bath temperature). After 30 minutes, the reaction was quenched with MeOH (0.5 mL), concentrated, and purified by preparative C-18 reverse-phase HPLC (gradient elution, 95% H2O/0.1% TFA/CH3CN to 5% H2O/0.1% TFA/CH3CN), giving 46 mg (82% yield) of N-{3-[4′-amino-2′-(3,4,5-trimethoxy-phenylamino)-[2,5′]bithiazolyl-4-yl]-phenyl}acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:19])[C:15]=1[C:16](O)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2.S(Cl)(C)(=O)=O.[CH2:32]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:26][O:25][C:21]1[CH:20]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:22]=1[O:23][CH3:24])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:19])[C:15]=1[C:16]([N:42]1[CH2:43][CH2:44][N:39]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:40][CH2:41]1)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)O)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)N2CCN(Cc3ccccc3)CC2)cc(OC)c1OC

Procedure:
Under the conditions given in Example 1 (a), 6 g of 3',4',5'-trimethoxy-flavone-3-carboxylic acid with 4.1 g 4-dimethylaminopyridine and 1.6 ml mesylchloride in absolute dichloromethane were converted into the mixed anhydride. This was reacted with 3.3 ml 1-benzylpiperazine analogously to Example 1 (b). The reaction mixture was worked up analogously to Example 1 (b). 7.0 g of pure 3',4',5'-trimethoxy-3-[(4-benzylpiperazin-1-yl)-carbonyl]flavone were obtained.