Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][CH:12]=[C:13]([Sn](CCCC)(CCCC)CCCC)[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[C:29]1[S:30][C:31]2[C:37]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)=[C:36]([C@H:45]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:46]([O:48][CH3:49])=[O:47])[C:35]([CH3:55])=[CH:34][C:32]=2[N:33]=1.O1CCOCC1>C(OCC)(=O)C.[F-].[Na+].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.[Cu]I>[C:51]([O:50][C@@H:45]([C:36]1[C:35]([CH3:55])=[CH:34][C:32]2[N:33]=[C:29]([C:13]3[N:14]=[C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]4)[S:11][CH:12]=3)[S:30][C:31]=2[C:37]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:46]([O:48][CH3:49])=[O:47])([CH3:54])([CH3:52])[CH3:53]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc(N2CCN(C(C)C)CC2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3csc(N4CCN(C(C)C)CC4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A 5 mL microwave reaction tube was charged with 2-(4-isopropylpiperazin-1-yl)-4-(tributylstannyl)thiazole (33 mg, 0.066 mmol), (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (40 mg, 1.2 eq.), Pd(PPh3)4 (15 mg, 15 mol %), CuI (5 mg, 30 mol %) and dioxane (1 mL). The reaction was heated to 110° C. in oil bath for 1 hour. Reaction mixture was diluted with ethyl acetate and saturated NaF aqueous solution was added and stirred for 30 minutes. Extracted with ethyl acetate and the organic layer was concentrated and purified via Combiflash (0-100% ethyl acetate in hexane) to give desired compound. LCMS-ESI+: calc'd for C31H38ClN4O3S2: 613.2 (M+H+); Found: 613.4 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][S:5][CH3:6].[NH2:10][CH2:11][C:12]([OH:14])=[O:13]>O>[NH2:1][C@H:2]([C:7]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: NCC(=O)O
Solvent: O
Product: CSCC[C@H](N)C(=O)NCC(=O)O

Procedure:
The title compound was prepared according to the procedures of Example 1A and B above by replacing DL-methionine with L-methionine (Aldrich Chemical Co., Beil. 4(2),938). The title compound had a melting point of 188° to 190° C (d). The compound was found to be water soluble. The product thus obtained was subjected to amino acid analysis and found to contain 49.42 mole percent glycine and 50.58 mole percent methionine.
Reaction SMILES: [C:1]([OH:11])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>[Br-].C([N+](CC)(CC)CC)C.O>[C:1]([O:11][CH2:12][CH:14]1[O:16][CH2:15]1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: ClCC1CO1
Reactant: O=C(O)/C=C/c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: O
Product: O=C(C=Cc1ccccc1)OCC1CO1
Temperature: 110 °C

Procedure:
To 7.5 g of trans-cinnamic acid (manufactured by Wako Pure Chemical) were added 3 g of tetraethylammonium bromide (manufactured by Wako Pure Chemical) and 100 ml of epichlorohydrin (manufactured by Wako Pure Chemical), the mixture was heated to reflux at 110° C. for 3 hours, 50 ml of distilled water was added thereto, an organic layer was separated, concentrated in vacuo at 80° C. and distilled under reduced pressure of 6 mmHg and the fraction of 130 to 160° C. was recovered to give 12 g of glycidyl cinnamate. An epoxy equivalent of this glycidyl cinnamate was 240.3.
Reaction SMILES: Br[C:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[O:4][C:3]=1[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.CC1(C)C(C)(C)OB([C:26]2[CH:43]=[CH:42][C:29]([O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)=[CH:28][CH:27]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.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]>[CH3:8][C:5]1([CH3:9])[O:4][C:3]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[C:2]([C:26]2[CH:27]=[CH:28][C:29]([O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)=[CH:42][CH:43]=2)[C:6]1=[O:7]
Reactant: CC1(C)OC(c2ccc(C#N)cc2)=C(Br)C1=O
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OC(c2ccc(C#N)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Yield: 60.9 %

Procedure:
A solution of 4-(3-bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (0.3 g, 1.03 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (0.374 g, 1.03 mmol), and Cs2CO3 (1.70 g, 5.14 mmol) in toluene (7 mL) and water (2.5 mL) was degassed. Then, Pd(dppf)Cl2(0.17 g, 0.20 mmol) was added under an inert atmosphere and the solution was again degassed. Then the reaction was refluxed for 2 h, The reaction mixture was then filtered through a pad of Celite® and the filtrate was diluted with EtOAc (40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)benzonitrile (280 mg, 61%) as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO): δ 8.42 (d, J=8.5 Hz, 1 H), 8.01 (t, J=7.9 Hz, 2 H), 7.90 (d, J=8.4 Hz, 2 H), 7.78 (t, J=8.3 Hz, 1 H), 7.72-7.67 (m, 3 H), 7.62 (t, J=8.3 Hz, 1 H), 7.16 (d, J=8.8 Hz, 2 H), 7.10 (d, J=8.8 Hz, 2 H), 5.38 (s, 2 H), 1.46 (s, 6 H). MS: [M+H]: m/z=447.5. HPLC: 98%, Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([C:8](=[O:10])[C:7]2[CH:11]=[C:12]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:13]([OH:14])=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=2)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)N2CCN(Cc3ccccc3)CC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under nitrogen atmosphere, 3,5-di-t-butyl-4-hydroxy-benzoic acid (3.10 g, 12.4 mmol.) and 1-benzylpiperazine (2.00 g, 11.3 mmol.) were dissolved in dichloromethane. Under chilling with ice, to this solution was portionwise added 1-(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.87 g, 15.0 mmol.), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1), to give the desired compound as an amorphous product (5.08 g, yield: 100%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:25])[C@@H:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:16])[CH2:9]1)C1C=CC=CC=1.O.[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:21]([O:20][C:18]([NH:17][C@@H:15]([CH3:16])[C:14]([NH:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)=[O:25])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CCNC1
Yield: 92.6 %

Procedure:
1 Benzyl-3-(S)-[2-(S)-(tert-butoxycarbonylamino)propionylamino]pyrrolidine (21.3 g) was dissolved in methanol (250 mL), and hydrogenated over 20% palladium hydroxide on charcoal, 50% water wet (5.0 g) at 50 psig and 25° to 40° C. until the uptake of hydrogen ceased. The reaction was then filtered through celite to remove the catalyst and the residue rinsed with methanol (100 mL) and the combined filtrates concentrated under vacuum to give 3-(S)-[2-(S)-(tert-butoxycarbonylamino)propionylamino]pyrrolidine (14.6 g) as a colorless oil which crystallized on standing: HPLC: 99% S,S isomer. A portion was recrystallized from methyl tert-butyl ether: mp 137°-138° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[S:31][C:30]([NH:32]C(=O)C)=[N:29][CH:28]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[S:31][C:30]([NH2:32])=[N:29][CH:28]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ncc(-c2ccc3c(c2)CN(c2ncnc(C)c2Cc2ccc(F)cc2)CCO3)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ncnc(N2CCOc3ccc(-c4cnc(N)s4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
A solution of N-[5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidine-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,3-thiazol-2-yl]acetamide (75 mg, 0.15 mmol) in 6 N hydrochloric acid (4 mL) was stirred at 95° C. for 15 h. After cooling to room temperature the mixture was neutralized with 50% aqueous sodium hydroxide, concentrated to dryness, and the solid residue extracted with ethanol (3×10 mL). Evaporation of the solvent and purification of the residue by preparative HPLC afforded 5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,3-thiazol-2-amine (43 mg, 62% yield) as a colorless solid. 1H NMR (400 MHz, CD3OD): 8.46 (s, 1H), 7.21 (m, 1H), 7.11 (m, 4H), 6.98 (s, 1H), 6.90 (d, 1H), 6.61 (m, 1H), 4.46 (s, 2H), 4.26 (ms, 2H), 3.97 (s, 2H), 3.87 (m, 2H), 2.21 (s, 3H); MS (EI) C24H22FN5OS: 448 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[OH:25][C:19]1([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:24][CH2:23][CH2:22][N:21]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:7])[CH2:20]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc(C)cc3)C2)c1

Procedure:
The compound of Example 9 was prepared according to the general preparation protocol A from 4-methylbenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:28][NH:29][O:30][CH3:31].C(N(CC)CC)C>O1CCCC1.C(#N)C>[CH3:31][O:30][N:29]([CH3:28])[C:12]([CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 120.3 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (5.00 g) in tetrahydrofuran (62.1 mL), 1,1′-carbonyldiimidazole (6.05 g) was added and the mixture was stirred at room temperature for an hour. To the reaction mixture, a solution of N,O-dimethylhydroxylamine hydrochloride (3.64 g) and triethylamine (4.02 g) in acetonitrile (62.1 mL) was added and the mixture was stirred at the same temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and water was added to the resulting residue. Extraction was conducted with ethyl acetate and the combined organic layers were washed with an aqueous solution of 5% citric acid and saturated brine. The washed organic layers were dried over anhydrous sodium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate as a pale yellow oil (7.30 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14]([OH:16])=O.Cl.CN.O[N:21]1[C:25]2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:25][NH:21][C:14]([C:2]1[CH:1]=[C:10]2[C:5](=[CH:4][CH:3]=1)[CH:6]=[C:7]([C:11]([OH:13])=[O:12])[CH:8]=[CH:9]2)=[O:16]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2cc(C(=O)O)ccc2c1
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a mixture of naphthalene-2,6-dicarboxylic acid (5 g), methylamine hydrochloride (1.64 g) and 1-hydroxybenzotriazole (3.75 g) in dimethylformamide (50 ml) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (3.79 g) under ice-cooling. The mixture was stirred for 1 hour at the same temperature and then at ambient temperature overnight. The mixture was diluted with water, and the precipitates were collected by filtration to give 6-(methylcarbamoyl)naphthalene-2-carboxylic acid (4.07 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:13]1[N:18]=[C:17]2[O:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH:22]([NH2:23])[C:16]2=[CH:15][C:14]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1.[F:33][C:34]([F:41])([F:40])[CH:35]([OH:39])[C:36](O)=[O:37].CCN(CC)CC.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CC(O)C.CCO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:13]1[N:18]=[C:17]2[O:19][C:20]([CH3:24])([CH3:25])[CH2:21][CH:22]([NH:23][C:36](=[O:37])[CH:35]([OH:39])[C:34]([F:41])([F:40])[F:33])[C:16]2=[CH:15][C:14]=1[C:26]1[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: CC1(C)CC(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(-c4ncon4)cc3Cl)nc2O1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CC(NC(=O)C(O)C(F)(F)F)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(-c4ncon4)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product of Step B (107 mg, 0.23 mmol), 3,3,3-trifluoro-2-hydroxypropionic acid (39 mg, 0.27 mmol), and NEt3 (63 μL, 0.45 mmol) in 10 mL of CH2Cl2 was added PyBOP (140 mg, 0.27 mmol). After stirring at rt for 16 h, the mixture was concentrated. Chromatography on a Biotage 25+M cartridge using 1:1 v/v EtOAc/hexanes as the eluant afforded two enantiomeric mixtures, which were subsequently resolved (the one having higher Rf value on TLC was resolved by AD using 13% EtOH/hex, and the other by AD using 20% IPA/hept) to afford the title compounds.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9](=O)[NH:8][C:7]=1[CH:16]([CH3:18])[CH3:17])=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH:16]([CH3:18])[CH3:17])=[N:8][C:9]([Cl:21])=[CH:10][C:11]=1[CH:12]([CH3:14])[CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C(C)C)cc(=O)[nH]c1C(C)C
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C(C)C)cc(Cl)nc1C(C)C
Yield: 85 %

Procedure:
A solution of 2.2 g (8.76 mmol) 2,4-diisopropyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester in POCl3 (43.8 ml) was stirred at 120° C. for 2 h. Then excess POCl3 was evaporated. The residue was dissolved in EtOAc (60 ml) and the solution was washed with a sat. NaHCO3 sol, water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification of this residue by CC (hexane/EtOAc 97:3) provided 2.0 g (7.43 mmol, 85%) 6-chloro-2,4-diisopropyl-pyridine-3-carboxylic acid ethylester.
Reaction SMILES: Cl.C(OCC)(=O)C.C([O:12][C:13]1[C:14]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:36])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[CH2:22][CH2:21]2)=[N:15][CH:16]=[CH:17][N:18]=1)(C)(C)C.[OH-].[Na+]>ClCCl>[CH3:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][C:26]([CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][C:14]2[C:13](=[O:12])[NH:18][CH:17]=[CH:16][N:15]=2)[CH2:25][CH2:24]1)=[O:36]
Reactant: COc1ccccc1CC(=O)C1CCN(Cc2nccnc2OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccccc1CC(=O)C1CCN(Cc2ncc[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
After adding 2 ml of 4N hydrogen chloride/ethyl acetate to the obtained 1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-methoxyphenyl)ethanone, the mixture was stirred overnight at room temperature. Aqueous 1N sodium hydroxide was added to the reaction solution for adjustment to pH 8, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added and the precipitate was filtered out to obtain the title compound (89 mg, 34% yield, 3 steps).
Reaction SMILES: [NH2:1][C:2](=[O:30])[C@H:3]([NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([NH:23][C:24]2[S:28][N:27]=[C:26]([CH3:29])[CH:25]=2)[CH:15]=1)[CH2:4][O:5]CC1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2](=[O:30])[C@H:3]([NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([NH:23][C:24]2[S:28][N:27]=[C:26]([CH3:29])[CH:25]=2)[CH:15]=1)[CH2:4][OH:5]
Reactant: Cc1cc(Nc2cc(N[C@H](COCc3ccccc3)C(N)=O)ccc2C(N)=O)sn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(Nc2cc(N[C@H](CO)C(N)=O)ccc2C(N)=O)sn1
Reaction time: 1 h
Yield: 33.1 %

Procedure:
To a suspension of (R)-4-(1-amino-3-(benzyloxy)-1-oxopropan-2-ylamino)-2-(3-methylisothiazol-5-ylamino)benzamide (4 mg, 0.009 mmol) in CH2Cl2 (1 mL), BBr3 (0.050 mL, 0.53 mmol) was added. After being stirred and swirled for 1 h, the mixture was purified by HPLC to give the titled compound (1 mg). MS 336.3 (M+H); UV 202.9, 294.6 nm
Reaction SMILES: [Cl:1][C:2]([Cl:57])([Cl:56])[C:3]([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:34](=[O:48])[N:35]([CH:45]3[CH2:47][CH2:46]3)[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=3[Cl:44])=[C:16]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25][O:26][Si](C(C)(C)C)(C)C)[CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:13]2)=[O:8])([CH3:5])[CH3:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[Cl:56][C:2]([Cl:1])([Cl:57])[C:3]([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:34](=[O:48])[N:35]([CH:45]3[CH2:47][CH2:46]3)[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=3[Cl:44])=[C:16]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:13]2)=[O:8])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3cc(CCCO[Si](C)(C)C(C)(C)C)no3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC(c3cc(CCCO)no3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Yield: 160.4 %

Procedure:
A sol. of compound E5 (728 mg, 0.800 mmol) and TBAF (1.0 M in THF, 1.00 mL, 1.00 mmol) in THF (20 mL) was stirred at 0° C. for 3.5 h. The mixture was diluted with EtOAc and was washed with brine (4×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:4→1:2→1.1→EtOAc) yielded the title compound (1.02 g, 96%). LC-MS: tR=1.17 min, ES+: 795.31.
Reaction SMILES: C(C1CC1)=C.[CH2:6](Cl)/[CH:7]=[CH:8]/[CH2:9]Cl.[C:12]([O:21][CH:22]([CH3:24])[CH3:23])(=[O:20])[CH2:13][C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15].[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC.[OH-].[K+]>O>[CH:7]([CH:8]1[CH2:9][C:13]1([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[C:12]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[CH2:6]
Reactant: ClC/C=C/CCl
Reactant: CC(C)OC(=O)CC(=O)OC(C)C
Agent: C=CC1CC1
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Solvent: O
Product: C=CC1CC1(C(=O)OC(C)C)C(=O)OC(C)C
Yield: 153.1 %

Procedure:
To illustrate the preparation of vinylcyclopropane derivatives via malonic ester condensation in an aqueous medium, the following experiment was conducted: To a flask provided with a stirrer and containing 125 g (1.0 mol) trans 1,4-dichlorobutene-2, 94 g (0.50 mol) diisopropyl malonate and 3.2 g (1.63 mol percent based on the malonate ester) tricaprylylmethylammonium chloride were added dropwise over a 30-minute perid with vigorous stirring 168 g 50% aqueous potassium hydroxide solution. Cooling was provided to maintain the reaction temperature at 25°-30° C. After five hours the reaction mixture was poured into water and extracted three times with ethyl ether. The combined etheral layers were dried over magnesium sulfate, filtered and concentrated to afford 184 g (67.2% yield) diisopropyl 2-vinylcyclopropane-1,1-dicarboxylate. Bp 77°-78° C.(0.5 mm); nD24° 1.4482. Infrared and proton nmr spectra were consistent with the desired structure. Similar results were obtained using other quaternary ammonium compounds, however, when the onium compound was omitted the reaction did not proceed.
Reaction SMILES: [C:1]([O:4][CH:5]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:41]([NH:43][CH3:44])[CH3:42])[CH:38]=[CH:39][CH:40]=1>ClCCl>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]([N:43]([CH3:44])[CH:41]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH3:33])[CH:36]=2)[CH3:42])=[O:8])[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: CNC(C)c1cccc(OC)c1
Reactant: COc1cc(C(OC(C)=O)C(=O)O)cc(OC)c1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1cccc(C(C)N(C)C(=O)C(OC(C)=O)c2cc(OC)c(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
A solution of α-acetoxy-3,4,5-trimethoxyphenyl-acetic acid (7.1 g) in dichloromethane (50 ml) was reacted with 1,1′-carbonyldiimidazole (4.06 g) at room temperature for 30 minutes. The solution was refluxed for 30 minutes, after which 1-(3-methoxyphenyl)-N-methylethylamine (4.13 g) dissolved in dichloromethane (10 ml) was added. The mixture was stirred at room temperature for 2 hours, after which it was washed with aqueous hydrochloric acid (20 ml, 1M) followed by aqueous sodium hydrogen carbonate (20 ml, 0.5 M). The organic phase was dried and concentrated to dryness, leaving crude 2-(3,4,5-trimethoxyphenyl)-2-acetoxy-N-methyl-N-[1-(3-methoxyphenyl)ethyl]acetamide (7.27 g).