Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[C:3]=1[CH3:12].[CH3:13][CH2:14]O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:13]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[C:3]=1[CH3:12])=[CH2:14]
Reactant: CCO
Reactant: COc1c(C#N)ccc(Br)c1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: C=Cc1ccc(C#N)c(OC)c1C

Procedure:
The mixture of 4-bromo-3-methyl-2-(methyloxy)benzonitrile (8.10 g, 35.8 mmol), potassium vinyl trifluoroborate (6.24 g, 46.6 mmol) and PdCl2(dppf)2 (0.55 g, 0.70 mmol) in 160 mL of EtOH and 40 mL of TEA was refluxed under Ar for 4 hours. The mixture was concentrated, and the residue was purified by column chromatography (PE:EtOAc=20:1) to afford 4-ethenyl-3-methyl-2-(methyloxy)benzonitrile.
Reaction SMILES: CC([N:5]([C@H:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:28]3[CH2:27][O:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:25]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:19][C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:29])[NH2:5])=[CH:18][CH:17]=3)[C:28]=2[CH2:27][O:26]1
Reactant: C[C@H](C(=O)Nc1ccc(Oc2cccc3c2COC3)cc1)N(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2COC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A solution of 1,1-dimethylethyl((1R)-2-{[4-(1,3-dihydro-2-benzofuran-4-yloxy)phenyl]amino}-1-methyl-2-oxoethyl)carbamate (Intermediate 6, 108 mg) and TFA (1 ml) in dichloromethane (4 ml) was stirred under argon at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was purified by SCX to afford the title compound (81 mg).
Reaction SMILES: N#N.[C:3]([C:6]1[O:10][C:9]([CH2:11][N:12]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[N:21]=[CH:22][O:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]O)[CH:26]=3)=[O:19])=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].C[CH2:34][N:35](C(C)C)[CH:36](C)C.CS(Cl)(=O)=O.CNC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.CC(=O)OCC>[C:3]([C:6]1[O:10][C:9]([CH2:11][N:12]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[N:21]=[CH:22][O:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][N:35]([CH3:36])[CH3:34])[CH:26]=3)=[O:19])=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(CO)c3)n2)o1
Agent: CNC
Agent: CS(=O)(=O)Cl
Agent: N#N
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(CN(C)C)c3)n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(3-hydroxymethyl-phenyl)-oxazole-4-carboxylic acid [1-(5-acetyl-furan-2-ylmethyl)-1H-pyrazol-3-yl]-amide (75 mg, 0.19 mmol) in CH2Cl2 (2.0 mL) was treated with DIPEA (0.05 mL, 0.28 mmol) followed by methanesulfonyl chloride (0.02 mL, 0.22 mmol). The reaction mixture was stirred for at rt 2.5 h before dimethylamine (0.9 mL of a 2N solution in THF, 1.8 mmol) was added and the reaction mixture was further stirred at rt for 8 h. EA (10 mL) and sat. aq. NaHCO3 (10 mL) were added and the aqueous layer was extracted with EA (10 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (93:7 CH2Cl2-MeOH) gave the title compound as a pale yellow oil. TLC: rf (93:7 CH2Cl2-MeOH)=0.27. LC-MS-conditions 02: tR=0.74 min; [M+H]+=434.14.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:12]1[N:17]=[C:16]([Cl:18])[N:15]=[C:14]2[N:19]([CH3:22])[N:20]=[CH:21][C:13]=12>>[Cl:18][C:16]1[N:15]=[C:14]2[N:19]([CH3:22])[N:20]=[CH:21][C:13]2=[C:12]([N:8]2[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]2)[N:17]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Product: Cn1ncc2c(N3CCN(S(C)(=O)=O)CC3)nc(Cl)nc21

Procedure:
Reaction of 1-methanesulfonyl-piperazine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave 6-chloro-4-(4-methanesulfonyl-piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:12])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cccc(Oc2ccccc2)c1
Temperature: -78 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
To a stirred solution of 3-phenoxybenzaldehyde (2 g, 10.09 mmol) in THF (15 mL) at −78° C. was added phenyllithium (6.73 mL, 1.8M solution in cyclohexane-ether) dropwise. After stirring under argon at −78° C. for 4 hrs, the reaction was quenched with water and extracted with diethyl ether. The organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude mixture was purified via flash SiO2 chromatography (ethyl acetate/hexanes (10%/90%) to (20%/80%)) to give 128 (2.79 g, 86% yield): 1H-NMR (400 MHz, chloroform-d) δ 6.87-7.38 (m, 10H), 7.09 (m, 1H), 6.99 (app d, J=7.3 Hz, 1H), 6.88 (m, J=8.6, 2.2 Hz, 1H), 5.81 (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>C(Cl)Cl>[Cl:14][CH:6]1[NH:7][C:2]([NH2:1])=[N:3][CH:4]=[C:5]1[N+:9]([O-:11])=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1ncc([N+](=O)[O-])c(=O)[nH]1
Solvent: ClCCl
Product: NC1=NC=C([N+](=O)[O-])C(Cl)N1
Temperature: 100 °C

Procedure:
A suspension mixture of 2-amino-5-nitro-3,4-dihydropyrimidin-4-one (1.5 g, 9.61 mmol) and phosphorus oxychloride (27 mL, 0.29 mol) was heated under reflux (100° C.) for 18 hr. The reaction mixture turned into a yellow solution. The mixture was cooled to RT before being concentrated in vacuo. DCM (10 mL) was added and concentrated in vacuo was repeated. Ice (ca 5 g) was added, resulted in a sticky solid. DCM (20 mL) was added and the mixture was quenched by addition to an ice-cold saturated aqueous NaHCO3 solution (150 mL). The pH of mixture was adjusted to basic by final addition of 2M aq K2CO3. Attempt to extract product with DCM resulted in emulsion formation. Emulsion was removed by suction filtration. The aqueous layer was extracted with EtOAc (3×50 mL). The EtOAc extracts were combined with the DCM extract, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a yellow powder: 1H NMR (500 MHz, DMSO) δ 8.40-8.48 (2H, m), 9.02 (1H, s). LC-MS: m/z=+174.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13]>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12](=[O:13])/[CH:14]=[CH:8]/[C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(C)nc1
Yield: 84.5 %

Procedure:
A mixture of 6-methylpyridine-3-carboxaldehyde (2 g, 16.5 mmol) and methyl (triphenylphosphoranylidene) acetate (6.1 g, 1.1 eq.) in toluene (100 mL) was stirred at reflux for 18 hours. The solvent was removed in vacuo, the residue washed with diethyl ether (100 mL) and filtered. The crude product was purified by chromatography eluting with CH2Cl2/MeOH (99/1) to give the title compound as a white solid (2.47 g, 85%). 1H NMR (CDCl3, 250 MHZ) δ(ppm); 8.60 (d, 1H); 7.70 (dd, 1H); 7.65 (d, J=15 Hz, 1H); 7.20 (d, 1H); 6.50 (d, J=15 Hz, 1H); 3.85 (s, 3H); 2.60 (s, 3H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([O:9]C)=[O:8].Cl>O>[CH3:3][O:4][C:5]([F:13])([F:14])[C:6]([F:11])([F:12])[C:7]([OH:9])=[O:8]
Reactant: COC(=O)C(F)(F)C(F)(F)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(F)(F)C(F)(F)C(=O)O
Temperature: 25 °C
Yield: 73.4 %

Procedure:
A mixture of 32 g sodium hydroxide, 400 g water and 152 g methyl 3-methoxytetrafluoropropionate was stirred at room temperature until a single liquid layer was obtained. The product was acidified with 37% aqueous HCl and the lower layer separated. The aqueous layer was extracted four times with 50 ml ethyl ether and the combined ether extracts and lower layer distilled to give 103.3 g (73.4%) 3-methoxytetrafluoropropionic acid, b.p. 85°-86° at 20 mm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[CH:16]1[CH2:18][CH2:17]1.[H-].[Na+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:6]=1[CH:16]1[CH2:17][CH2:18]1
Reactant: ClCc1ccccc1
Reactant: COC(=O)Cc1c(C2CC2)[nH]c2ccc(OC)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1c(C2CC2)n(Cc2ccccc2)c2ccc(OC)cc12
Reaction time: 0.5 h
Yield: 4 %

Procedure:
A solution of 3.8 g (146 mmol) of 2-cyclopropyl-5-methoxyl-1H-indole-3-acetic acid methyl ester in 50 mL of DMF was treated with 0.59 g (0146 mol) of 60% NaH/mineral oil, stirred 0.5 hour, and 1.69 mL (146 mmol) of benzyl chloride added. After 20 hours, the reaction mixture was diluted with water, extracted with EtOAc, the EtOAc solution was washed four times with water and dried over Na2SO4. After concentrating at reduced pressure, the product was purified by chromatography on silica, eluting with a gradient, 5% EtOAc/toluene→15% EtOAc/toluene, to give 2.05 g (40% yield) of 2-cyclopropyl-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetic acid methyl ester as an oil.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[N:17]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=[N:15][C:14]=1[C:30]([NH2:32])=[O:31])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:35]I>C(O)(=O)C>[C:1]([NH:9][C:10]([NH:12][C:13]1[N:17]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:16]=[N:15][C:14]=1[C:30]([NH2:32])=[O:31])=[SH:11][CH3:35])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: NC(=O)c1ncn(OCCCOCc2ccccc2)c1NC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C[SH]=C(NC(=O)c1ccccc1)Nc1c(C(N)=O)ncn1OCCCOCc1ccccc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
A mixture of 5-(N'-benzoylthiocarbamoyl)amino-1-(3-benzyloxyprop-1-oxy)imidazole-4-carboxamide (2.9 g, 6.4 mmol), 0.1N sodium hydroxide solution (100 ml) and methyl iodide (0.64 ml; 10.3 mmol) was stirred at 20° C. for 16 hours and then the solution adjusted to pH 5 with glacial acetic acid. After several extractions with chloroform, the combined extracts were dried (magnesium sulphate) and evaporated to a syrup. Column chromatography on silica gel (eluted with chloroformethanol, 30:1) afforded the title compound (2.7 g, 88.7%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[N:12]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:13]2[C:18]([N:19]=1)=[C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:16]=[C:15]([C:26]1[C:27]([CH3:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1)[N:14]=2>CS(C)=O>[NH2:32][C:29]1[N:28]=[C:27]([CH3:33])[C:26]([C:15]2[N:14]=[C:13]3[C:18]([N:19]=[C:11]([NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:12]3[CH2:34][CH:35]3[CH2:37][CH2:36]3)=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:16]=2)=[CH:31][N:30]=1
Reactant: NCCN1CCOCC1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Solvent: CS(C)=O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(NCCN3CCOCC3)n(CC3CC3)c2n1
Temperature: 150 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
2-Morpholin-4-yl-ethylamine (162 mg, 1.25 mmol) and dimethyl sulfoxide (700 μl) were added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and the resulting mixture was stirred at 150° C. for 3 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was concentrated, and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (101 mg, 75%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH:45]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:43]=[N:42]2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(#N)C.C(=O)([O-])[O-].[K+].[K+]>O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[C:28]([O:32][C:33]([N:35]1[CH2:36][CH2:37][CH:38]([N:41]2[CH:45]=[C:44]([C:2]3[CH:3]=[C:4]4[C:10]([C:11](=[O:12])[C:13]5[C:18]([F:19])=[CH:17][CH:16]=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[C:14]=5[F:27])=[CH:9][NH:8][C:5]4=[N:6][CH:7]=3)[CH:43]=[N:42]2)[CH2:39][CH2:40]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cc23)c1F
Temperature: 160 °C
Yield: 67.4 %

Procedure:
In a 10 mL microwave vial, propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (9, 51.0 mg, 0.111 mmol) and 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (34, 84.2 mg, 0.223 mmol) are combined with 0.680 mL of acetonitrile and potassium carbonate (0.34 mL, 1.00 M in water). 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.3 mg, 0.011 mmol) is added and the mixture is heated at 160° C. in the microwave for 5 minutes, then diluted with water and extracted with ethyl acetate. The organic layer is washed with water, brine, and dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-1001, 47 mg). MS (ESI) [M+H+]+=629.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: CCCCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1cc(C(=O)O)cc(C(=O)OC)c1
Yield: 52.9 %

Procedure:
A suspension of 5-butoxy-isophthalic acid dimethyl ester (2.0 g, 7.5 mmol) in THF/MeOH/water (5.0 mL each) is treated with lithium hydroxide (0.22 g, 9.0 mmol) at room temperature for 1.0 h. The reaction mixture is acidified with 1.0 M HCl and the product is extracted with EtOAc (30 mL), washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to afford the title compound as solid (1.0 g, 53%). LC-ES/MS m/e 270.3 (M+18), 251.3 (M−1).
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[C:53]2[CH:54]=[C:55]([C:57]([CH3:60])([CH3:59])[CH3:58])[O:56][C:52]=2[C:51]([C:61]#[N:62])=[CH:50][C:49]=1[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.[CH3:69][N:70]([CH3:76])[C@H:71]1[CH2:75][CH2:74][NH:73][CH2:72]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:57]([C:55]1[O:56][C:52]2[C:51]([C:61]#[N:62])=[CH:50][C:49]([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[C:48]([N:73]3[CH2:74][CH2:75][C@H:71]([N:70]([CH3:76])[CH3:69])[CH2:72]3)[C:53]=2[CH:54]=1)([CH3:60])([CH3:59])[CH3:58]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CC(C)(C)c1cc2c(Br)c(-c3ccccc3)cc(C#N)c2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)[C@H]1CCN(c2c(-c3ccccc3)cc(C#N)c3oc(C(C)(C)C)cc23)C1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 32.9 %

Procedure:
(R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (65.9 mg, 106 μmol) was dissolved under heat in toluene (1.5 ml), then cooled to room temperature, and palladium(II) acetate (15.8 mg, 70.6 μmol) was added, followed by stirring for 1 minute. 4-Bromo-2-tert-butyl-7-cyano-5-phenyl-1-benzofuran (I-258) (500 mg, 1.41 mmol), (3S)-3-(dimethylamino)pyrrolidine (215 μl, 1.69 mmol), sodium tert-butoxide (190 mg, 1.98 mmol) and toluene (1.5 ml) were successively put into it, followed by stirring at 80° C. for 14 hours. Water (30 ml) was added to the reaction liquid, the product was extracted with chloroform (50 ml×3). The organic layer was washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified twice by silica gel column chromatography (chloroform:methanol=200:1) to obtain the entitled compound (180 mg, 33%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[BH4-].[Na+].CC(O)=O>CO>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([OH:12])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: O=C1CCCc2c(Br)cncc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC1CCCc2c(Br)cncc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
4-Bromo-6,7-dihydroisoquinolin-8(5H)-one (2.135 g, 9.44 mmol) was suspended in MeOH (18.9 mL), cooled to 0° C. and treated with NaBH4 (357 mg, 9.44 mmol) in 5 portions over 30 min; then, the reaction was stirred for ¾ h at 0° C. (TLC after 30 min showed no more starting material). AcOH was then added dropwise until pH˜5-6 and the reaction mixture was evaporated. The residue was diluted with water and poured on aq. sat. NaHCO3-sol. followed by extraction with EtOAc (3×). The organic layers were washed once with aq. sat. NaHCO3-sol. and aq. 10% NaCl-sol., dried over Na2SO4 and concentrated in vacuo. The residue was re-dissolved in CH2Cl2, evaporated with n-pentane (3×) to around 20 ml each time, while the product precipitates; then, the solvent was decanted and the residue washed with n-pentane and dried in high vacuum to afford the title compound (1.98 g, 92%) as dark brown viscous oil. MS: 227 (M+, 1Br).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:10]1=[O:22])=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:10]1=[O:22]
Reactant: COC(=O)CCN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CCN1CCCC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
To a round bottom flask was added (S)-methyl 3-(3-(tert-butoxycarbonylamino)-2-oxoazepan-1-yl)propanoate (15 mg, 0.048 mmol) and a solution of 4 N HCl (119 μL, 0.477 mmol) in dioxane. The reaction was stirred at rt for 3 hr. The reaction was concentrated and the residue was dried over vacuum pump for 5 hr to give (S)-methyl 3-(3-amino-2-oxoazepan-1-yl)propanoate (10 mg, 0.047 mmol, 98% yield) as a white semi-solid.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15](SSC2SC3C=C(C)C=CC=3N=2)[N:14]([CH:28]([C:42]([CH3:44])=[CH2:43])[C:29]([O:31][CH2:32][C:33]([C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=2)=[O:34])=[O:30])[C:13]1=[O:45])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:46]1([S:52](=[S:65])([O:54]C2SC3C=C(C)C=CC=3N=2)=[O:53])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.O.C1(S([O-])=O)C=CC=CC=1.[Na+]>CC(C)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:54][S:52]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)(=[O:65])=[O:53])[N:14]([CH:28]([C:42]([CH3:44])=[CH2:43])[C:29]([O:31][CH2:32][C:33]([C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=2)=[O:34])=[O:30])[C:13]1=[O:45])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2nc(OS(=O)(=S)c3ccccc3)sc2c1
Reactant: C=C(C)C(C(=O)OCC(=O)c1ccc(Br)cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccc(C)cc2s1
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)C(C(=O)OCC(=O)c1ccc(Br)cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
A 1.23 g quantity of p-bromophenacyl 2-[3-phenoxyacetamido-4-(6-methylbenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 572 mg of 6-methylbenzothiazol-2-yl benzenethiosulfonate were dissolved in 10 ml of acetone. To the solution were added 2 ml of water and then 3 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 5 hours. The precipitated 6-methylbenzothiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving p-bromophenacyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 94%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below shows the data thereof.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].C(N(CC)CC)C.[C:17](Cl)(=[O:26])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:26])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccccc1)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
3,4-Dichloroaniline (5.41 g, 33.6 mmol) and triethylamine (1.5 ML) were dissolved in 160 mL of THF and treated with trans-cinnamoyl chloride (6.71 g, 40.3 mmol) with vigorous stirring at room temperature for 2 h, and then quenched with 10 mL of H2O. The reaction mixture was extracted with EtOAc (3×100 mL). The combined organics were washed with saturated solution of Na2CO3, brine, dried over MgSO4 and then concentrated in vacuo to yield the title compound as a white crystalline solid (6.2 g, 63%), MS (ES) m/e 293 [M+H]+.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8]CN2CCN(C3C(OC)=CC=CN=3)CC2C)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:40][O:41][C:42]1[C:43]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH:49]2[CH3:54])=[N:44][CH:45]=[N:46][CH:47]=1>>[ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][N:51]2[CH2:52][CH2:53][N:48]([C:43]3[C:42]([O:41][CH3:40])=[CH:47][N:46]=[CH:45][N:44]=3)[CH:49]([CH3:54])[CH2:50]2)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2
Reactant: COc1cccnc1N1CCN(CCCc2csc3ccccc23)C(C)C1
Reactant: COc1cncnc1N1CCNCC1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: COc1cncnc1N1CCN(CCc2csc3ccccc23)CC1C

Procedure:
The title compound was prepared (0.20 g, 24%, mp 140°-144° C.) in a manner analogous to the preparation of 1-[3-(benzo[b]thien-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)-2-methylpiperazine hydrochloride (Example 41) by the reaction of 3-benzo[b]thieneethanol tosylate (Example 47) with 1-(5-methoxy-4-pyrimidinyl)-2-methylpiperazine.