Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH:15]1[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]2[N:22]=[CH:23][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])=[N:25][CH:26]=2)[CH2:16]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(Cl)(Cl)Cl.O>[C:1]1([CH2:11][N:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]3[N:22]=[CH:23][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])=[N:25][CH:26]=3)[CH2:16]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: COC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3cccc4ccccc34)C2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-naphthaldehyde (143 μl), methyl (2E)-3-{5-[(3R)-3-pyrrolidinylamino]-2-pyrazinyl}acrylate dihydrochloride (260 mg) and DIEA (282 μl) in dichloromethane (20 mL) was stirred at ambient temperature for 1 hour. After then, sodium triacetoxyborohydride (515 mg) was added and stirred overnight. Water and chloroform was added to the reaction mixture, and organic layer was separated. Aqueous layer was extracted twice with chloroform and combined organic layer was washed twice with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel to give methyl (2E)-3-(5-{[(3R)-1-(1-naphthylmethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (480 mg).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[OH-].[Na+].[Cl:7][CH2:8][CH2:9][N:10]([CH2:34][CH2:35][Cl:36])[P:11]([N:27]([CH2:31][CH2:32][Cl:33])[CH2:28][CH2:29][Cl:30])(=[O:26])[O:12][CH2:13][CH2:14]OS(C1C=CC(Br)=CC=1)(=O)=O>CO>[Cl:36][CH2:35][CH2:34][N:10]([CH2:9][CH2:8][Cl:7])[P:11]([N:27]([CH2:28][CH2:29][Cl:30])[CH2:31][CH2:32][Cl:33])(=[O:26])[O:12][CH2:13][CH2:14][S:1][CH2:2][CH2:3][OH:4]
Reactant: O=P(OCCOS(=O)(=O)c1ccc(Br)cc1)(N(CCCl)CCCl)N(CCCl)CCCl
Reactant: OCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=P(OCCSCCO)(N(CCCl)CCCl)N(CCCl)CCCl
Temperature: 0 °C
Reaction time: 12 h
Yield: 54.9 %

Procedure:
2-mercaptoethanol (400 μL, 5.7 mmol) was dissolved in methanol (8 mL), and NaOH in methanol, (3.56 mL of 4M, 14.25 mmol) was added. The solution was cooled to 0° C. and 2-(4-bromobenzenesulfonyloxy)ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate (8.35 mL of 0.82M solution in toluene, 6.84 mmol) was added, and the reaction mixture allowed to warm to room temperature. After 12 hours, the mixture was filtered, neutralized to pH 7 with 1M aqueous H3PO4, and concentrated under vacuum to a thick syrup. This syrup was diluted with isopropyl acetate (200 mL), and washed with water (3×200 mL). The isopropyl acetate layer was dried over MgSO4, filtered, and concentrated under vacuum to give a clear oil. This oil was purified on a 30 mm×150 mm silica gel column using a gradient of 70:30 ethyl acetate/hexanes to 100% ethyl acetate to give 2-{[2-(hydroxy)ethyl]thio}ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate as a clear oil (1.41 g, 55% yield). 1H NMR (CDCl3): δ 1.64 (bs, 1H), 2.76 (t, 2H, J=5.9 Hz), 2.84 (t, 2H, J=6.3 Hz), 3.40-3.47 (m, 8H), 3.62-3.69 (m, 8H), 3.76 (t, 2H, J=5.9 Hz), 4.18-4.23 (m, 2H); 31P NMR (CDCl3): δ 17.58.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([Br:13])[CH:5]=1)(=[O:3])[CH3:2].[B-](F)(F)(F)F.[CH3:19][CH2:20][O:21][C:22]([C:24](C#N)=[N:25]OC(N(C)C)=[N+](C)C)=O.N1CCOCC1.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(OCC)(=O)C>[Br:13][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:12]=[CH:11][C:7]=1[C:8]([N:25]1[CH2:19][CH2:20][O:21][CH2:22][CH2:24]1)=[O:10]
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: CC(=O)c1ccc(C(=O)O)c(Br)c1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C(=O)N2CCOCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of the product obtained in step 3 (230 mg, 0.95 mmol) and TOTU (310 mg, 0.95 mmol) in DMF (2 mL) was added morpholine (83 μL, 0.95 mmol) and DIPEA (162 μL, 0.95 mmol). The reaction mixture was stirred for 2 h at RT. Ethyl acetate (20 ml) and water (20 ml) was added, the organic phase was separated and washed with hydrochloric acid (1 M, 20 ml), water (20 ml), brine (2×20 ml) and dried over Na2SO4. After evaporation and flash-chromatography the product was obtained as oil (160 mg, 54%).
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH2:9]([C:11](=[CH2:14])[CH:12]=O)[CH3:10].[NH2:15][C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)(C)C>[CH2:9]([C:11]1[CH:12]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:15][CH:14]=1)[CH3:10]
Reactant: C=C(C=O)CC
Reactant: CCOC(=O)C=C(N)C(=O)OCC
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)O
Product: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Temperature: 70 °C
Yield: 37.3 %

Procedure:
Isopropyl alcohol 150 ml and maleic acid 30.7 g (0 264 mol) were placed in 200 ml four-neck flask equipped with a reflux condenser. After heating the content to 70° C., a mixture of 22.2 g (0.264 mol) of 2-ethyl-2-propenal and 32.9 g (0.176 mol) of ethyl β-amino-β-ethoxycarbonylacrylate were added dropwise thereto with air-bubbling and refluxed for 10 hours. After removal of isopropyl alcohol, 100 ml of water was added thereto and the reaction mixture was neutralized with sodium carbonate. Oil layer was separated and concentrated under reduced pressure to obtain 16.5 g of 5-ethyl-2,3-diethoxycarbonylpyridine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8]Br)[CH3:2].NC(N)=[S:15].[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][SH:15])[CH3:2]
Reactant: CCOC(=O)C(C)(C)CCCBr
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)(C)CCCS
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of 5-bromo-2,2-dimethylpentanoic acid ethyl ester (2.41 g, 10 mmol) in ethyl alcohol (5 mL) was added thiourea (0.77 g, 10 mmol) and the mixture was refluxed for 3 h under a nitrogen atmosphere. A solution of sodium hydroxide (0.62 g, 15 mmol) in deionized water (2.5 mL) was added and stirring was continued for another 2 h at reflux temperature. The mixture was cooled to rt and the ethanol was distilled off under reduced pressure. Diethyl ether (20 mL) was added and the layers were separated. The organic phase was washed with saturated sodium chloride solution (5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 5-mercapto-2,2-dimethylpentanoic acid ethyl ester (1.41 g, 74%) as a yellow oil. 1H NMR (300 MHz, CDCl3/TMS): d (ppm): 4.12 (q, J=7.0 Hz, 2H), 2.57-2.43 (m, 2H), 1.69-1.45 (t, 4H), 1.25 (t, J=7.0 Hz, 3H), 1.17 (s, 7H). 13C NMR(75 MHz, CDCl3/TMS): d (ppm): 177.55, 41.0, 39.24, 25.07, 24.90, 14.18.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4](=[O:14])[N:3]1[CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22]>O1CCOCC1.[Pd]>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4](=[O:14])[N:3]1[CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22]
Reactant: O=C1CCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)C(=O)N1
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 6.5 h
Yield: 69 %

Procedure:
A mixture of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline {alternatively named as N-(2,6-dioxopiperidin-3-yl)-4-nitrophthalimide} (1 g, 3.3 mmol) and 10% Pd/C (0.13 g) in 1,4-dioxane (200 mL) was hydrogenated at 50 psi for 6.5 hours. The catalyst was filtered through Celite and the filtrate concentrated in vacuo. The residue was crystallized from ethyl acetate (20 mL) to give 0.62 g (69%) of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline {alternatively named as N-2,6-dioxopiperidin-3-yl)-4-aminophthalimide} as an orange solid. Recrystallization from dioxane/ethyl acetate gave 0.32 g of yellow solid: mp 318.5-320.5° C.; HPLC (nova Pak C18, 15/85 acetonitrile/0.1% H3PO4) 3.97 min (98.22%): 1H NMR (DMSO-d6) δ 11.08(s, 1H), 7.53-7.50 (d, J=8.3 Hz, 1H), 6.94(s, 1H), 6.84-6.81(d, J=8.3 Hz, 1H), 6.55(s, 2H), 5.05-4.98(m, 1H), 2.87-1.99(m, 4H); 13C NMR (DMSO-d6) δ 172.79, 170.16, 167.65, 167.14, 155.23, 134.21, 125.22, 116.92, 116.17, 107.05, 48.58, 30.97, 22.22; Anal. Calcd for C13H11N3O4: C, 57.14; H, 4.06; N, 15.38. Found: C, 56.52; H, 4.17; N, 14.60.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10](O)[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2C=CC=C3C=2CCC3O)C=CC=CC=1>>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10]=[CH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Agent: OC1CCc2c(-c3ccccc3)cccc21
Product: C1=Cc2cccc(-c3ccccc3)c2C1

Procedure:
Under a dry nitrogen atmosphere, a solution of 5.45 g (0.04 mole) of (+)-α-pinene in 15 ml of tetrahydrofuran was stirred and cooled to 0° C. Twenty ml of a 1 M solution of boranetetrahydrofuran complex (0.02 mole) was added slowly, and the reaction mixture was stirred at 0° C. for 1 hour. To this was added dropwise a solution of 3.28 g (0.017 mole) of 7-phenyl-1H-indene in 15 ml of tetrahydrofuran. The reaction mixture was stirred at 0° C. for 2.5 hours, then at room temperature for 2 hours. The mixture was cooled to 0° C., and 6.9 ml of water, 10.3 ml of a 3 N sodium hydroxide solution, and finally 10.3 ml of 30% hydrogen peroxide were added in sequence slowly. The mixture was stirred at room temperature for two days, then poured into water, and extracted with two 100 ml portions of diethyl ether. The ether extracts were washed with 100 ml of water, dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated to give an oil. The oil was distilled using a Kugelrohr distillation apparatus (95° C./2.5 mm) to leave 2.62 g of an oily pot residue. The nmr spectrum of the oily residue indicated a 3:1 ratio of 4-phenyl-2-indanol to 4-phenyl-1-indanol (99% purity by gas chromatography).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6]Br.Cl.[CH2:15]([O:17][NH2:18])[CH3:16]>C(N(C(C)C)C(C)C)C>[ClH:1].[CH2:15]([O:17][NH:18][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:11][C:10]([Cl:12])=[CH:9][C:8]=1[Cl:13])[CH3:16]
Reactant: CCON
Reactant: Clc1cc(Cl)c(OCCBr)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCONCCOc1c(Cl)cc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 96 h
Yield: 105.9 %

Procedure:
30.4 g (0.1 mole) of 2,4,6-trichlorophenoxyethyl bromide were added to a suspension of 48.5 g (0.5 mole) of O-ethylhydroxylamine hydrochloride in 250 ml of ethyldiisopropylamine, and the mixture was stirred for 4 days at 50° C. and then cooled to 15° C. and filtered under suction. The filtrate was evaporated down under reduced pressure, in the final stage at 60° C. and under 0.1 mbar, the residue was dissolved in 300 ml of ether, and the solution was gassed with hydrogen chloride at +3° C. 17 g of O-ethyl-N-(2,4,6-trichlorophenoxy)ethylhydroxylamine hydrochloride of melting point 173°-175° C. were obtained.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][OH:29])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:29][CH2:28][C:26]1[N:27]=[C:23]([N:21]2[CH2:22][CH:19]([OH:18])[CH2:20]2)[S:24][CH:25]=1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CO)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 95.7 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-hydroxymethyl-1,3-thiazol-2-yl)azetidine (548.5 mg, 1.29 mmol) (obtained as described in Reference Example 2(2)) in anhydrous tetrahydrofuran (28 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (1.56 ml, 1.56 mmol) in an ice bath, and the mixture was then stirred in the ice bath for 1 hour. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 1-(4-hydroxymethyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (230 mg, yield 96%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:14][N:15]([CH3:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[S:10][C:9]1=[S:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:14][N:15]([CH3:24])[C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)[S:10][C:9]1=[S:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N(C)C=C2SC(=S)N(Cc3ccccc3)C2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN(C=C1SC(=S)N(Cc2ccccc2)C1=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a stirred solution of 3-benzyl-5-{[N-(4-methoxyphenyl)-methylamino]-methylene}-2-thioxothiazolidin-4-one (0.25 g, 0.67 mmol) in DCM (6 mL, anhyd) chilled to −78° C. was added dropwise a 1.0 M solution of boron tribromide in DCM (4.0 mL, 4.0 mmol). The reaction flask was removed from the dry-ice bath and allowed to warm to ambient temperature. After 4 h the reaction flask was chilled again to −78° C., and the reaction mixture was quenched by addition of MeOH (30 mL). The reaction mixture then was concentrated under reduced pressure and chromatographed (silica gel, DCM) to afford 3-benzyl-5-{[N-(4-hydroxyphenyl)-methylamino]-methylene}-2-thioxothiazolidin-4-one (0.16 g, 67%) as a yellow solid. 1H-NMR (CDCl3): δ 7.73 (1H, s), 7.44 (2H, d), 7.23-7.31 (3H, m), 7.07 (2H, m), 6.89 (2H, m), 5.30 (1H, s), 5.24 (2H, s), 3.49 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][CH2:9][CH2:10][CH3:11])=[N:4][C:3]=1[CH2:12][CH2:13][OH:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(OCC)(=O)C>C(Cl)Cl>[CH3:22][S:23]([O:14][CH2:13][CH2:12][C:3]1[N:4]=[C:5](/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH3:11])[O:6][C:2]=1[CH3:1])(=[O:25])=[O:24]
Reactant: CCCC=Cc1nc(CCO)c(C)o1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC/C=C/c1nc(CCOS(C)(=O)=O)c(C)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-[5-Methyl-2-(1-penten-1-yl)oxazol-4-yl]ethanol (1.03 g) was dissolved in methylene chloride (10 ml), and triethylamine (1.03 ml) was added. Methanesulfonyl chloride (0.41 ml) was added dropwise at 0° C., and the mixture was stirred at room temperature for 30 min. Ethyl acetate (100 ml) was added, and the mixture was washed with 10% aqueous citric acid solution (100 ml) and then with saturated brine (100 ml), and dried (Na2SO4). The solvent was evaporated under reduced pressure to give the title compound (1.1 g).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[OH:9][C:10]1[C:11]([C:26]2[O:30][N:29]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:27]=2)=[C:12]([O:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[C:13]2[C:14]([N:19]=1)=[N:15][CH:16]=[CH:17][N:18]=2>C(#N)C.C(OCC)(=O)C.O>[CH3:1][N:19]1[C:14]2=[N:15][CH:16]=[CH:17][N:18]=[C:13]2[C:12]([O:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[C:11]([C:26]2[O:30][N:29]=[C:28]([C:31]([F:33])([F:32])[F:34])[CH:27]=2)[C:10]1=[O:9]
Reactant: CC(C)C(=O)Oc1c(-c2cc(C(F)(F)F)no2)c(O)nc2nccnc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: CC(C)C(=O)Oc1c(-c2cc(C(F)(F)F)no2)c(=O)n(C)c2nccnc12
Temperature: 100 °C

Procedure:
Potassium carbonate (0.023 g) and methyl iodide (0.01 ml) were added to isobutyric acid 6-hydroxy-7-(3-trifluoromethyl-isoxazol-5-yl)-pyrido[2,3-b]pyrazin-8-yl ester (Example 6.6) (0.030 g) in acetonitrile (1.5 ml). The reaction mixture was heated in a microwave to 100° C. for 10 minutes. The reaction mixture was diluted with ethyl acetate and water. The phases were separated. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:2 to 1:1) to give Compound No. B8 of Table B (0.025 g) as a colourless oil that solidified on standing.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[C:14]([Si:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)Cl)([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1>CN(C=O)C>[C:14]([Si:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[O:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]c2ccc(O)cc2c(=O)o1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc2[nH]c(=O)oc(=O)c2c1)(c1ccccc1)c1ccccc1
Yield: 57.7 %

Procedure:
6-Hydroxy-1H-benzo[d][1,3]oxazine-2,4-dione (9.7 g, 54 mmol), tert-butyldiphenylchlorosilane (15.2 mL, 59 mmol) and imidazole (4 g, 59 mmol) were stirred in DMF (100 mL) for 24 h at rt. The reaction mixture was extracted with ethyl acetate (400 mL) and water 300 mL). The product in the organic layer was purified by chromatography on silica gel in hexane/ethyl acetate 2:1 and then crystallized from hot ethyl acetate/hexane, affording white crystals (13 g, 58%), mp. 185° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][C:12]3[C:8]4[C:9](=[N:24][CH:25]=[CH:26][C:7]=4[C:6]=2[CH:27]=1)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=3I.CC1(C)C(C)(C)OB([C:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=2)O1.C(=O)(O)[O-].[Na+]>CN(C)C=O.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>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][C:12]3[C:8]4[C:9](=[N:24][CH:25]=[CH:26][C:7]=4[C:6]=2[CH:27]=1)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=3[C:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=1
Reactant: C[Si](C)(C)CCOCn1c(I)c2c3c(ccnc31)-c1cc(F)ccc1OC2
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2c3c4c(ccnc4n2COCC[Si](C)(C)C)-c2cc(F)ccc2OC3)CC1
Temperature: 80 °C

Procedure:
A mixture of Example 14H (200 mg, 0.403 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (137 mg, 0.443 mmol), tetrakis(triphenylphosphine)palladium(0) (23.28 mg, 0.020 mmol), and sodium bicarbonate solution (1.5 mL, 0.403 mmol) in N,N-dimethylformamide (6 mL) was degassed and heated at 80° C. for 5 hours. After cooling, the mixture was filtered, treated with water and brine and extracted with ethyl acetate (twice). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated, and purified on silica using the ISCO Companion flash system eluting with ethyl acetate/heptanes (15:85 to 20:80) to provide the title compound. MS (ESI+) m/z 552.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[Na].Cl[C:13]1[N:18]=[C:17]([NH2:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:13]2[N:18]=[C:17]([NH2:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1ccc(CO)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: COc1ccc(COc2ccc([N+](=O)[O-])c(N)n2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 60.3 %

Procedure:
4-Methoxybenzyl alcohol (4.8 g, 34.7 mmol) was added to sodium (0.8 g, 34.7 mmol) in toluene (100 mL). After most of the sodium has dissolved 6-chloro-3-nitro-2-pyridineamine (5 g, 28.9 mmol) was added and the reaction was heated at 120° C. for 4 h. As there was still some starting material left, more anion of the 4-methoxybenzyl alcohol was prepared in a separate flask (0.6 g of sodium in 30 mL of toluene and 4 g of 4-methoxybenzyl alcohol were used) and added to the reaction at room temperature. The reaction was then stirred at room temperature for 5 h then water (250 mL) was added and the volume reduced to 200 mL. Diethyl ether was then added and the aqueous phase was extracted (3×500 mL). The combined organic phases were dried (MgSO4), filtered and evaporated. The residue was then chromatographed on silica gel, eluting with DCM to afford 4.8 g of the title compound (60%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:17]([N:18]([CH2:21][CH3:22])[CH2:19][CH2:20][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:16]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 13.6 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.5 mmol) in DMF (10 mL) was added (2-chloroethyl)diethylamine (Compound 175B, 0.6 g, 4 mmol) and K2CO3 (1.38 g, 10 mmol). The reaction mixture was stirred at 140° C. for 1.5 h in a microwave reactor, then concentrated, residue was purified by HPLC to afford 100 mg of the title compound (yield: 12%). 1H NMR (DMSO-d6, 400 MHz): δ=1.1-1.2 (m, 9 H), 1.25 (s, 12
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.Cl>O.CO>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:6]2[CH2:7][CH2:8][C:4]([CH3:3])([C:10]([O:12][CH3:13])=[O:11])[C:5]2=[O:9])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)C1(C)CCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C1(C)CCC(=Cc2ccc(Cl)cc2)C1=O

Procedure:
To a solution of 3.4 g of sodium hydroxide in 770 ml of water were added 15 g of methyl 1-methyl-2-oxocylopentanecarboxylate (prepared in Reference Example 1 hereinafter) and a solution of 13.5 g of 4-chlorobenzaldehyde in 800 ml of methanol, and the mixture was stirred for 5 hours at room temperature. The reaction mixture was neutralized with diluted hydrochloric acid and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed with water and dried. Ethyl acetate was evaporated under reduced pressure to obtain 25 g of an oily matter.
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.[OH-].[Na+].[Rh]>[NH2:1][CH:2]([CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:10]([OH:12])=[O:11]
Reactant: NC(Cc1ccccc1)C(=O)O
Agent: [Rh]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(CC1CCCCC1)C(=O)O
Reaction time: 8 h

Procedure:
(RS)-phenylalanine (500.2 mg) was dissolved in H2O (50 ml) and 2N NaOH (1.5 ml). Rh/Al2O3 catalyst (500.5 mg) was added, and the whole was stirred overnight under a hydrogen atmosphere at atmospheric pressure. After the reaction was completed, Rh/Al2O3 was separated by filtration. The filtrate was concentrated to give crude (RS)-2-amino-3-cyclohexylpropanoic acid. Then, the crude (RS)-2-amino-3-cyclohexylpropanoic acid was dissolved in 2N NaOH (15.08 ml). THF (15 ml) and then 4-chlorobenzenesulfonyl chloride (3.196 g) were added, and the whole was stirred at room temperature overnight under argon. The reaction mixture was diluted with water, washed with ethyl acetate, acidified with 2N HCl and extracted 3 times with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution, and dried over Na2SO4. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 80 g, ethyl acetate) and then by preparative TLC to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexylpropanoic acid (200.9 mg).