Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.O>C1COCC1>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(CCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CCCn2cncn2)cc1
Temperature: 50 °C
Reaction time: 60 h
Yield: 45.3 %

Procedure:
1,2,4-triazole (0.68 g) was dissolved in THF (8.0 ml), potassium carbonate (2.7 g) was added to the mixture, a solution of 1-(3-bromopropyl)-4-nitrobenzene (1.6 g) in. THF (8.0 ml) was added dropwise to the solution, and the mixture was stirred for 60 hours at 50° C. After cooling to room temperature, the reaction solution was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 1-[3-(4-nitrophenyl)propyl]-1,2,4-triazole (0.69 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]([I:20])[CH:12]=[C:13]2[C:18]=1[NH:17][CH:16]=[CH:15][C:14]2=O)=[O:8])[CH3:2].[Cl:23]C1C2C(=CC=C(I)C=2)N=CC=1C(NCCN(CC)CC)=O>>[Cl:23][C:14]1[C:13]2[C:18](=[C:9]([C:7]([NH:6][CH2:5][CH2:4][N:3]([CH2:21][CH3:22])[CH2:1][CH3:2])=[O:8])[CH:10]=[C:11]([I:20])[CH:12]=2)[N:17]=[CH:16][CH:15]=1
Reactant: CCN(CC)CCNC(=O)c1cc(I)cc2c(=O)cc[nH]c12
Reactant: CCN(CC)CCNC(=O)c1cnc2ccc(I)cc2c1Cl
Product: CCN(CC)CCNC(=O)c1cc(I)cc2c(Cl)ccnc12
Yield: 73 %

Procedure:
This compound was prepared, starting from compound 100 (2.00 g, 4.84 mmol), according to the procedure developed for compound 95. Reaction time at 100° C.: 15 min; the purification was performed using column chromatography (Al2O3, AcOEt/cyclohexane, 9/1, v/v) to give compound 101 (1.52 g, 3.52 mmol) as a beige solid. Yield 73%; Rf (Al2O3, AcOEt/cyclohexane, 9/1, v/v) 0.49; mp 76-78° C.; IR (KBr) ν 1555, 1654, 2962 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.09 (t, 6H, J=7.1 Hz), 2.64 (q, 4H, J=7.1 Hz), 2.75 (t, 2H, J=6.4 Hz), 3.66 (q, 2H, J=6.4 Hz), 7.54 (d. 1H, J=4.7 Hz), 8.68 (d, 1H, J=2.1 Hz), 8.76 (d, 1H, J=4.7 Hz), 9.07 (d, 1H, J=2.1 Hz), 11.01 (m, 1H); MS m/z 433 (M+2, 1), 431 (M+, 1), 360 (1), 358 (1), 317 (1), 315 (3), 289 (1), 287 (1), 191 (1), 189 (2), 161 (3), 126 (2), 99 (9), 86 (100), 71 (2), 58 (9).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8](N)=[C:7](N)[CH:6]=1)C.[B:14]1(B2OC(C)(C)C(C)(C)O2)[O:18]C(C)(C)C(C)(C)[O:15]1.C([O-])(=O)C.[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([B:14]([OH:18])[OH:15])=[CH:7][CH:6]=1)=[O:13]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(B(O)O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 228.9 %

Procedure:
Referring to Scheme 11-1, to a solution of the bromide 1 (2.0 g, 4.2 mmol, prepared according to published conditions) in dioxane (60 mL) was added bis(pinacolato)diboron (4.32 g, 17 mmol), Pd(PPh3)4 (0.49 g, 0.42 mmol) and potassium acetate (2.06 g, 21 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 5 h, and then diluted with ethyl acetate (150 mL). The organic phase was washed with H2O (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was further purified by silica gel column chromatography (haxanes/ethyl acetate=1/4 to 0/1 (v/v)) to give 2 (1.73 g, 79% yield). LC-MS (ESI): m/z 523.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].[C:13](=O)([O-])O.[Na+].CI.Cl>CN(C)C=O>[CH3:13][O:4][C:3](=[O:5])[C:2]([CH3:1])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6]
Reactant: O=C([O-])O
Reactant: CC(C)(C(=O)O)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 74.9 %

Procedure:
9.00 g (55 mmol) 2-methyl-2-phenyl-propionic acid was dissolved in 90 ml N,N-dimethylformamide, 11.51 g (2.5 eq.) of sodium hydrogencarbonate was added followed by 6.89 mL (15.72 g 2 eq.) of methyl iodide. The mixture was stirred at rt for 40 hours, then poured into ice water, the pH was adjusted to ˜3.0 with aq. HCl (1N) and the mixture extracted 3 times with ether; the organic phases were washed with water, dried over MgSO4, filtered and evaporated to give 7.34 g of the crude title compound as yellow oil. MS: 178.1 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][OH:11])C)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[NH2:35][C:36]1[N:44]=[CH:43][N:42]=[C:41]2[C:37]=1[N:38]=[CH:39][N:40]2[C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52]([NH:54][C:55]2[CH:60]=[CH:59][C:58]([Cl:61])=[C:57]([C:62]([F:65])([F:64])[F:63])[CH:56]=2)=[O:53])=[CH:47][CH:46]=1>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:7][CH2:9][CH2:10][O:11][C:23](=[O:25])[NH:35][C:36]1[N:44]=[CH:43][N:42]=[C:41]2[C:37]=1[N:38]=[CH:39][N:40]2[C:45]1[CH:46]=[CH:47][C:48]([NH:51][C:52]([NH:54][C:55]2[CH:60]=[CH:59][C:58]([Cl:61])=[C:57]([C:62]([F:64])([F:65])[F:63])[CH:56]=2)=[O:53])=[CH:49][CH:50]=1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reaction time: 0.25 h
Yield: 33 %

Procedure:
In 3 mL of methylene chloride, 110 mg (0.62 mmol) of (2-hydroxyethyl)-methylcarbamic acid tert-butyl ester and 108 μL (0.62 mol) of Hunig's base were dissolved, and 74 mg (0.248 mmol) of triphosgene was added thereto at one time, and the mixture solution was stirred for 15 minutes. To the obtained solution, a solution obtained by dissolving 30 mg (0.062 mmol) of 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride in 3 mL of pyridine was added and the mixture solution was stirred at room temperature for three hours. The reaction solution was concentrated under reduced pressure, and then the residue was partitioned between ethyl acetate and water, and the organic layer was washed with a saturated sodium chloride solution, dried and concentrated. The residue was purified by Megabond Elute Silica Gel (1 g, methanol:ethyl acetate=1:30) to obtain 13 mg (33%) of (9-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purin-6-yl]carbamic acid 2-(tert-butoxycarbonylamino)ethyl ester as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][O:10][CH2:9]2)=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH:16]1[CH2:19][CH:18]([N:20]([CH2:22][C@@H:23]2[C@@H:30]3[C@@H:26]([O:27][C:28]([CH3:32])([CH3:31])[O:29]3)[C@H:25]([N:33]3[CH:41]=[N:40][C:39]4[C:34]3=[N:35][CH:36]=[N:37][C:38]=4[NH2:42])[O:24]2)[CH3:21])[CH2:17]1.C(O)(=O)C>C(Cl)Cl>[CH3:31][C:28]1([CH3:32])[O:29][C@@H:30]2[C@@H:23]([CH2:22][N:20]([CH3:21])[CH:18]3[CH2:17][CH:16]([CH2:15][CH2:14][C:13]4[NH:1][C:2]5[CH:7]=[CH:6][C:5]([CH:8]6[CH2:9][O:10][CH2:11]6)=[CH:4][C:3]=5[N:12]=4)[CH2:19]3)[O:24][C@@H:25]([N:33]3[CH:41]=[N:40][C:39]4[C:34]3=[N:35][CH:36]=[N:37][C:38]=4[NH2:42])[C@@H:26]2[O:27]1
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)Nc2cc(C3COC3)ccc2N)C1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCc2nc3cc(C4COC4)ccc3[nH]2)C1
Temperature: 65 °C
Yield: 64.8 %

Procedure:
N-(2-amino-5-(oxetan-3-yl)phenyl)-3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamide (0.446 g, 0.752 mmol) was taken up in acetic acid (7.7 mL, 140 mmol) and heated at 65° C. for 3.5 h; HPLC/LC MS indicated complete conversion. At 3.75 h the acetic acid was removed by distillation with minimal warming to afford an orange oil, which was taken up in CH2Cl2 (45 mL) and washed with saturated aqueous NaHCO3 (2×30 mL). The aqueous layer was treated with NaCl until saturated and extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford a light orange oil. Purification by column chromatography (2×8 cm silica; 0-5% 7 N methanolic NH3/CH2Cl2) afforded the title compound (0.28 g, 65%) as a light orange foam:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([CH3:29])[C:14]=1[CH2:15]C(Br)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(#N)C.O>[CH3:12][C:13]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([CH3:29])[C:14]=1[CH2:15][NH:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(F)cc(C)c1CC(Br)c1ccccc1
Reactant: Cc1nc2cccc(N)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: Cc1nc2cccc(NCc3c(C)cc(F)cc3C)c2[nH]1
Temperature: 75 °C
Yield: 22.4 %

Procedure:
4-amino-2-methylbenzimidazole (0.6 g, 4,1 mmol) was dissolved in acetonitrile (10 ml). To the solution were added 2,6-dimethyl-4-fluoro-benzylbenzylbromide (0.89 g, 4,1 mol) and potassium carbonate (0.68 g, 4.9 mmol) and the mixture was warmed at 70-80° C. for 3 h. The reaction mixture was cooled to room temperature and methylene chloride (25 ml) and water (25 ml) was added. The organic layer was separated, dried over sodium sulfate and was evaporated under reduced pressure. The residue was crystallized twice from ethyl acetate and was purified by column chromatography on silica gel, using methylene chloride containing 10% methanol as eluent. There was obtained 0.26 g (22%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](O)=[O:5].S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClCCl.CN(C=O)C>[CH3:1][CH:2]([CH3:7])[CH2:3][C:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: CC(C)CC(=O)O
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.6 %

Procedure:
A mixture of 3-methylbutanoic acid (20.4 g, 0.2 mol), thionyl chloride (35.7 g, 0.3 mol) and DMF (0.5 ml) was heated at reflux for 2 h. The mixture was carefully concentrated in vacuo to give the crude acid chloride. A suspension of anhydrous aluminium chloride (15.4 g, 115 mmol) in dichloromethane (100 ml) was cooled to 0° C. and a solution of the above acid chloride in dichloromethane (50 ml) was added dropwise. The mixture was stirred for 15 min and a solution of benzene (17.9 g, 0.23 mol) in dichloromethane (50 ml) was added dropwise and the resulting mixture stirred at room temperature for 16 h. The reaction mixture was poured into cold 0.05N hydrochloric acid (300 ml) and the resulting mixture extracted with dichloromethane (3×100 ml). The combined organic phases were washed with 1 hydrochloric acid (300 ml), water (300 ml) and saturated sodium hydrogen-carbonate solution (300 ml) and dried (MgSO4). The solvent was evaporated in vacuo to give 21.6 g of 3-methylbutyrophenone.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:9][C:8](=[O:18])[NH:7]1.C[O:21][C:22](=[O:38])[CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:25]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26]1.Cl>[OH-].[Na+]>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([CH:24]([CH:25]2[CH2:29][CH2:28][C:27](=[O:30])[NH:26]2)[CH2:23][C:22]([OH:38])=[O:21])=[CH:36][CH:35]=1.[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH:10]2[CH2:9][C:8](=[O:18])[NH:7][CH:6]2[CH2:5][CH2:4][C:3]([OH:19])=[O:2])=[CH:16][CH:15]=1
Reactant: COC(=O)CCC1NC(=O)CC1c1ccc(Cl)cc1
Reactant: COC(=O)CC(c1ccc(Cl)cc1)C1CCC(=O)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC(c1ccc(Cl)cc1)C1CCC(=O)N1
Product: O=C(O)CCC1NC(=O)CC1c1ccc(Cl)cc1

Procedure:
A solution of 36.7 g of 3-(4-chlorophenyl)-5-oxo-2-pyrrolidinepropanoic acid methyl ester and β-(4-chlorophenyl)-5-oxo-2-pyrrolidinepropanoic acid methyl ester in 130 ml of 1 N aqueous sodium hydroxide solution is heated to 60° C. for four hours. Excess aqueous hydrochloric acid (1 N, 140 ml) is added and the solution concentrated under reduced pressure to give β-(4-chlorophenyl)-5-oxo-2-pyrrolidinepropanoic acid and 3-(4-chlorophenyl)-5-oxo-2-pyrrolidinepropanoic acid. The acids are dissolved in 100 ml of acetic anhydride and the solution heated to 90° C. The solution is filtered hot and the filtrate concentrated in vacuo. The oil is chromatographed on silica gel (200-400 mesh) (elution with chloroform) to yield cis-and trans-dihydro-1-(4-chlorophenyl)-1H-pyrrolizine-3,5(2H,6H)diones as a white solid with mp 153°-58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([CH2:28][C:29]([O:31]C)=O)=[N:9]1.[CH2:33]([NH2:35])[CH3:34].Cl.C(N)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([CH2:28][C:29]([NH:35][CH2:33][CH3:34])=[O:31])=[N:9]1
Reactant: CCN
Reactant: COC(=O)Cc1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Agent: Cl
Product: CCNC(=O)Cc1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of the methyl [1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]acetate (100 mg, 0.2 mmol), EtNH2 (2.0M in THF, 5 mL) and ethylamine hydrochloride (200 mg) was stirred at 70° C. in a sealed vial for 8 h. The solvent was removed in vacuo, another EtNH2/THF (2.0M, 5 mL) was added, the mixture was stirred at 78° C. for another 24 h. Another 3 mL of EtNH2/THF was added, and the mixture was stirred at 78° C. for another 20 h. The solvent was removed in vacuo, and the crude product was purified by flash chromatography (0-30% 20% MeOH/DCM) to give the title compound as a white solid (85 mg, 83%). 1HNMR (CDCl3): δ 8.04 (m, 1H), 7.84-7.82 (m, 1H), 7.74-7.71 (m, 1H), 7.60-7.46 (m, 5H), 7.21 (d, 1H), 6.78 (d, 1H), 6.61 (s, 1H), 6.45 (brs, 1H), 3.69 (s, 2H), 3.30 (q, 2H), 3.07 (s, 3H), 1.14 (t, 3H). MS(ES): 500 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18]CC)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:21]1([CH:27]([NH2:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(C(O)=O)(F)(F)F.Cl.O.C(Cl)Cl>[C:21]1([CH:27]([NH:29][C:16]([CH2:15][CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:14][CH2:13]2)=[O:18])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(N)c1ccccc1
Reactant: CCOC(=O)CC1CCN(Cc2ccc(F)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(NC(=O)CC1CCN(Cc2ccc(F)cc2)CC1)c1ccccc1
Yield: 50 %

Procedure:
1-[(4-fluorophenyl)methyl]-4-[(ethoxycarbonyl)methyl]piperidine (0.55 g, 1.97 mmol) was refluxed in CF3CO2H/HCl/H2O (1:1:1) 10 ml to give the corresponding acid, which was then reacted with 1-phenylethylamine (0.29 g, 2.40 mmol), EDCI (0.56 g, 2.97 mmol) and HOBT (0.40 g, 2.96 mmol) in CH2Cl2 (10 ml) to produce a solid, 0.33 g (50% yield) (procedure D). 1H NMR (CD3Cl) δ 7.35-7.23 (7H, m, Ar—H), 7.00-6.94 (2H, t, J=8.4 Hz, Ar—H), 5.83-5.80 (1H, bd, J=7.5 Hz, NH), 5.15-5.10 (m, 1H, PhCHMe), 3.42 (s, 2H, p-PhCH2N), 2.83-2.78 (m, 2H, N(CH)2), 2.07-2.05 (2H, d, J=7.2 Hz, CH2CO), 1.99-1.89 (2H, m), 1.86-1.78 (1H, m), 1.71-1.61 (2H, t, J=15 Hz), 1.48-1.45 (3H, d, J=6.9 Hz, Me), 1.33-1.21 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=3[CH3:13])[CH2:22][CH2:23]2)=[O:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)ccc1C(=O)O
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: COc1cc(Br)ccc1C(=O)N1CCN(c2ccc(C)cc2C)CC1
Yield: 81.3 %

Procedure:
Methyl 4-bromo-2-methoxybenzoate (10 g) was dissolved in methanol (80 mL), 1N aqueous sodium hydroxide solution (80 mL) was added, and the mixture was refluxed for 3 hr. After cooling, 1N hydrochloric acid (80 mL) was added, and the mixture was filtered to give 4-bromo-2-methoxybenzoic acid (9.2 g). By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-methoxybenzoic acid (3.1 g) and 1-(2,4-dimethylphenyl)piperazine (2.7 g), the title compound (4.4 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10]Cl)[C:3]=1[O:12][CH3:13].[C-:14]#[N:15].[K+].O>CS(C)=O>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH2:10][C:14]#[N:15])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)c(OC)c(CCl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(Br)c(OC)c(CC#N)c1
Reaction time: 2 h
Yield: 76.9 %

Procedure:
A solution of 1-Bromo-3-chloromethyl-2,5-dimethoxy-benzene 53 (7.0 g, 26.4 mmol) and KCN (1.7 g, 26.4 mmol) in DMSO (50 ml) was heated to 75° C. After 2 hr, the reaction was cooled and poured into water. The aqueous layer was extracted with EtOAc and the organic layer was dried and concentrated. The product was purified by column chromatography on silica gel (20% EtOac/Hex) to give 54 as an oil (5.2 g, 77%): 1H NMR (DMSO-d6) δ 7.20 (d, 1 H, J=3.0 Hz), 6.99 (d, 1 H, J=3.0 Hz), 4.00 (s, 2 H), 3.75 (s, 6 H)
Reaction SMILES: Cl.[N:2]([CH2:5][C@H:6]([NH2:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:3]=[N-:4].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>ClCCl>[N:2]([CH2:5][C@H:6]([NH:12][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:3]=[N-:4]
Reactant: CCOC(=O)[C@@H](N)CN=[N+]=[N-]
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)[C@H](CN=[N+]=[N-])NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
To a solution of ethyl 3 azido-2(S)-aminopropionate hydrochloride (0.3 g) in dichloromethane (3 ml) was added triethylamine (0.47 ml) and benzoyl chloride (0.2 ml) under stirring at 0° C. After stirring at ambient temperature for 2 hours, the mixture was poured into water and extracted with dichloromethane. The extract was washed with water, saturated aq. NaHCO3, water and brine, and dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from diethyl ether to give ethyl 3 azido-2(S)-(benzoylamino)propionate (0.35 g).
Reaction SMILES: I[CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[N:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=1>>[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:3]1[CH2:2][N:12]1[CH2:13][CH:14]=[C:15]([C:18]2[NH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:17]1
Reactant: ICC1Cc2ccccc2C1
Reactant: c1ccc2[nH]c(-c3ccncc3)cc2c1
Product: C1=C(c2cc3ccccc3[nH]2)CCN(CC2Cc3ccccc3C2)C1

Procedure:
From 22c and 27a. 1H NMR (CDCl3) d 2.50-2.55 (m, 2H), 2.65 (broad s, 2H), 2.70-2.85 (m, 5H), 3.00-3.15 (m, 2H), 3.25 (d, 2H), 6.05 (broad s, 1H), 6.45 (s, 1H), 7.05 (t, 1H), 7.10-7.25 (m, 5H), 7.30 (d, 1H), 7.55 (d, 1H), 8.10 (broad s, 1H). MS m/z (%): 329 (MH+, 5%), 160 (4%), 131 (4%), 91 (6%), 44 (100%).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][Si:10](C#C)([CH3:12])[CH3:11].[CH:15](N(CC)C(C)C)(C)[CH3:16].O>CN1CCCC1=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:9][Si:10]([CH3:12])([CH3:11])[C:7]1[C:2]([NH:1][C:15]#[CH:16])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1Br
Reactant: C#C[Si](C)(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: C#CNc1ncccc1[Si](C)(C)C
Temperature: 70 °C
Reaction time: 6 h
Yield: 94.3 %

Procedure:
To a solution of 2-amino-3-bromopyridine (5.72 g, 33.1 mmol) in N-methylpyrrolidinone (120 mL) were added trimethylsilyl acetylene (9.36 mL, 66.2 mmol), tetrakis(triphenyl phosphine) palladium (0) (1.91 g, 1.66 mmol), copper (I) iodide (630 mg, 3.31 mmol) and N,N-diisopropyl ethyl amine (11.5 mL, 66.2 mmol) at room temperature, which was stirred at 70° C for 6 hours under a nitrogen atmosphere. To the reaction solution was added water, and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride water, dried over anhydrous magnesium sulfate, and the solvent thereof was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (5.94 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.Br[C:14]1[S:15][CH:16]=[C:17]([Br:19])[N:18]=1.[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[C@H:28]([CH2:37][CH2:38][CH:39]=[CH2:40])/[CH:29]=[N:30]/[S@@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32].CO>O1CCCC1>[Br:19][C:17]1[N:18]=[CH:14][S:15][C:16]=1[C@@H:29]([NH:30][S@@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[C@H:28]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=1[F:20])[CH2:37][CH2:38][CH:39]=[CH2:40]
Reactant: C=CCC[C@H](/C=N/[S@](=O)C(C)(C)C)c1cccc(F)c1F
Reactant: Brc1csc(Br)n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: C=CCC[C@@H](c1cccc(F)c1F)[C@H](N[S@](=O)C(C)(C)C)c1scnc1Br
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
To a 250 mL round bottom flask was added tetrahydrofuran (10 mL) and diisopropylamine (1.04 mL, 7.33 mmol) under nitrogen. The flask was cooled down to −20° C. before addition of n-BuLi (2.93 mL, 7.33 mmol). The reaction was stirred at this temperature for 5 min before being cooled to −78° C. 2,4-dibromothiazole (1.782 g, 7.33 mmol) was added at once to the reaction mixture. After stirring at −78° C. for 10 min, (R,E)-N-((S)-2-(2,3-difluorophenyl)hex-5-enylidene)-2-methylpropane-2-sulfinamide (1.1494 g, 3.67 mmol) in 5 mL tetrahydrofuran was added to the reaction mixture via cannula. The reaction was allowed to continue to stir while it was gradually warmed up to −60° C. (4 h). The reaction was cooled down to −78° C. and n-BuLi (2.93 mL, 7.33 mmol) was added at −78° C. The reaction was stirred for 20 min. Methanol (0.44 mL, 11.0 mmol)l was added to quench the reaction. The reaction was stirred at rt for 0.5 h. The solvent was removed under vacuum and the crude mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried (sodium sulfate), filtered and concentrated. Flash chromatography using ethyl acetate in hexane from 0 to 50% to 85% gave the desired product (1.08 g, 62%) as a brown oil, which was solidified upon standing at room temperature overnight: MS (ESI)[M+H+]=479.12. 1H NMR showed a mixture of two diastereomers with a ratio of 3/1 (epimerized 1 from previous reactions).