Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:14])[CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1.C(OCC)(=O)C>C(Cl)Cl>[Cl:1][CH2:2][CH:3]([O:14][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][O:32]1)[CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6]
Reactant: CCOC(=O)CNC(=O)CC(O)CCl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CC(CCl)OC1CCCCO1
Reaction time: 7 h

Procedure:
1 g Ethyl 2-(4-chloro-3-hydroxybutanamido)acetate is dissolved in 10 ml CH2Cl2. 100 mg pyridine p-toluenesulphonate and 0.5 ml dihydropyran are added. The mixture is stirred for 7 h. The solvent is evaporated and the residue chromatographed, eluting with ethyl acetate. A colourless oil is obtained, Rf 0.5 (silica gel plates, thickness 0.25 mm, eluent ethyl acetate).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]CCCC)=[O:15])[CH:12]=2)[C:7]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[CH:6]1)[CH2:2][CH2:3][CH3:4].O[Li].O.C1COCC1.O>CO>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[C:7]([C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1ccc2c(C(=O)C(F)(F)F)cn(CCCC)c2c1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCn1cc(C(=O)C(F)(F)F)c2ccc(C(=O)O)cc21
Yield: 70.7 %

Procedure:
Butyl 1-butyl-3-(trifluoroacetyl)-1H-indole-6-carboxylate (0.277 g), LiOH.H2O (0.040 g), THF (1.5 mL), water (0.5 mL), and methanol (0.5 mL) were stirred overnight at room temperature. The solvents were then removed under reduced pressure and HCl (2N, 0.5 mL) was added to the residue. The residue was extracted with ethyl acetate, dried over magnesium sulfate, filtered, and concentrated. Chromatography on silica gel using methanol/dichloromethane (6/94) gave 1-butyl-3-(trifluoroacetyl)-1H-indole-6-carboxylic acid (0.166 g). MS (ESI+) for C15H14F3N1O3+H1 m/z 314.10 (M+H)+.
Reaction SMILES: COC([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=O.[OH-].[Na+].C(O)(=O)C>C(O)C.O.[Au]>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: COC(=O)NCCCCCCCCCCC(=O)O
Agent: [Au]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: NCCCCCCCCCCC(=O)O
Yield: 33.1 %

Procedure:
1.0 g (3.9×10-3 mol) of 11-(methoxycarbonylamino) undecanoic acid, is dissolved in 20 mL ethanol and added to 2.0 g (5.0×10-2 mol) sodium hydroxide in 2 mL water. The mixture is refluxed for 17 hours, and the resulting gold-colored solution is cooled and neutralized with acetic acid to a pH of 7. The neutralized solution is filtered to remove any salt and the filtrate is stripped to yield crude amino acid. The crude acid is dissolved in 50 mL of water, cooled in ice and filtered to yield 0.41 g (53%). Recrystallizion from 16 mL ethanol/water (3:1) resulted in 0.26 g (34% yield) 11-aminoundecanoic acid (mp. 189°-192° C., Lit. mp. 190°-192° C).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=[O:15])[C@@H:12]2[CH2:17][CH2:18][C@H:9]1[CH2:10][C@H:11]2[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[C:25]([NH2:27])=[O:26].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[NH2:27][C:25]([C@@H:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:14]([C@@H:13]1[C@@H:12]2[CH2:17][CH2:18][C@@H:9]([CH2:10][C@H:11]2[OH:19])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])=[O:26]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1[C@H]2CC[C@H]([C@H](O)C2)[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H]2CC[C@H]([C@H](O)C2)[C@H]1C(=O)N1CCC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid obtained in Example 2-5 (4.05 g), (2S)-2-pyrrolidinecarboxamide (1.77 g) and 1-hydroxybenzotriazole hydrate (1.68 g), were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.15 g) and N,N-diisopropylethylamine (5.2 mL) with cooling on an ice bath. After 5 minutes, the ice bath was removed and the mixture was stirred overnight at room temperature.
Reaction SMILES: N.[Na].[C:3]([CH2:6][C:7](=[O:9])[CH3:8])(=[O:5])[CH3:4].[CH2:10](Br)[CH2:11][CH3:12]>C(OCC)C.O.[N+]([O-])([O-])=O.[Fe+2].[N+]([O-])([O-])=O.[Na]>[CH3:8][C:7](=[O:9])[CH2:6][C:3](=[O:5])[CH2:4][CH2:10][CH2:11][CH3:12]
Reactant: CCCBr
Reactant: CC(=O)CC(C)=O
Agent: [Fe+2]
Agent: N
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CCOCC
Product: CCCCC(=O)CC(C)=O
Reaction time: 0.33 h
Yield: 77.6 %

Procedure:
Metallic sodium (0.3 g, 13 mmol) was added to a liquid ammonia solution (400 ml). After the mixture was dyed blue, iron nitrate hydrate (0.13 g, 0.3 mmol) was added and then again metallic sodium (12.6 g, 0.55 mol) was added. After completion of the NaNH2 formation, a solution of acetylacetone (30 g, 299 mmol) in ethyl ether (20 ml) was added within 10 minutes at -78° C. After 20 minutes, propyl bromide (28.2 g, 299.6 mmol) was added by instillation within 25 minutes. After further stirring for 50 minutes, ethyl ether (100 ml) was added and the ammonia was evaporated. After about 12 hours, the mixture was extracted with ethyl ether 3 times (50 ml each) and the combined organic phases were washed twice with an NaCl solution (50 ml each) and dried on Na2SO4. After removal of the solvent, 33 g of 2,4-octanedion was obtained. After vacuum distillation (13.5 mbars, 78° C.), 22.59 g of 2,4-octanedion, corresponding to a yield of 52.9 percent, was obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[O:4][C:3]1=O.[NH2:14][CH2:15]C(O)=O.O.C(N(CC)CC)C>COCCOC.C(O)(=O)C.CCOCC>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[NH:14][CH2:15][C:3]1=[O:4]
Reactant: NCC(=O)O
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CN1C(=O)CNC(=O)c2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
1-Methyl-1H-benzo[d][1,3]oxazine-2,4-dione (11.0 g, 62.1 mmol) and 2-aminoacetic acid (5.13 g, 68.3 mmol) were dissolved in DME (60 mL) and water (20 mL) and triethylamine was added. The reaction mixture was stirred at 60° C. for 4 hours. The mixture was concentrated in vacuo to get a light tan heavy oily residue that was dissolved in acetic acid (75 mL). This mixture was refluxed 4 hours then cooled down to room temperature. The solvent was evaporated to get a tan heavy oil. The oil was allowed to stand at room temperature overnight in ether (50 mL). The beige crystalline solid was filtered and washed with ether. The solid was then triturated in ether to afford title compound 467 (7.95 g, 67%) as a beige crystalline solid. 1H NMR (DMSO-d6) δ (ppm): 8.70 (s, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.60 (t, J=7.2 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 3.75-3.72 (m, 1H), 3.51-3.46 (m, 1H), 3.28 (s, 3H). MS (ESI): 190.90 (MH)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[C:10]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:24][CH:23]=1)=[O:21].[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C.S(Cl)(Cl)(=O)=O>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:20](=[O:21])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([O:19][S:38]([CH3:37])(=[O:40])=[O:39])[CH:13]=[CH:12]2
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(F)cc2F)ccc2cc(O)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)cc3F)ccc2c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 69 %

Procedure:
Dissolve [2-(2,4-difluoro-phenyl)-6-hydroxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (540 mg, 1.11 mmoles), and methane sulfonyl chloride (254 mg, 2.22 mmoles) in 10 ml acetonitrile and add triethylamine (224 mg, 2.22 mmoles). Stir the mixture for 5 days at room temp. Add equivalent amounts of the sulfonyl chloride and triethylamine and stir for 30 minutes. Evaporate the mixture to dryness, dissolve in methanol and pass through an SCX column. Wash the column with methanol and elute the product with 2 N ammonia/methanol to yield 433 mg (69%) of the title compound: mass spectrum (ion spray) m/z=566 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>ClCCl>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][S:7]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[O:14][CH3:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=S(=O)(Cl)Cc1ccc(Br)cc1
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)Cc2ccc(Br)cc2)c(OC)c1
Reaction time: 2 h

Procedure:
While cooling with ice, 20.0 g of 4-bromobenzylsulfonyl chloride were initially charged in 200 ml of dichloromethane, and a solution of 24 ml of 2,4-dimethoxybenzylamine in 100 ml of dichloromethane was slowly added dropwise. For improved stirrability, a further 100 ml of dichloromethane were added, and the reaction mixture was allowed to come to room temperature. After stirring for 2 hours, the reaction mixture was washed with 100 ml of water, with 100 ml of 0.2 N aqueous hydrochloric acid, with 100 ml of saturated aqueous sodium hydrogencarbonate solution and finally once more with 100 ml of water. The organic phase was dried over Na2SO4, concentrated by rotary evaporation and dried under high vacuum. The residue (30 g) was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2]C(Cl)Cl.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[OH:15])[CH3:7]>[Ti](Cl)(Cl)(Cl)Cl>[CH2:6]([C:8]1[C:9]([OH:15])=[CH:10][C:11]([CH3:14])=[C:12]([CH:13]=1)[CH:1]=[O:2])[CH3:7]
Reactant: CCc1ccc(C)cc1O
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: CCc1cc(C=O)c(C)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
Titanium(IV) chloride (11 mL, 11 mmol, 1M in CH2Cl2) followed by dichloromethyl methyl ether (1.04 g, 9.1 mmol) was added to a cooled 0° C. solution of 2-ethyl-5-methyl-phenol (0.75 g, 5.5 mmol) The reaction mixture was stirred for 30 mins and then warmed up to rt and stirred for another 30 mins. The mixture was poured into ice and extracted with EtOAc. The organic layers were washed with satd NaHCO3, brine, dried over Na2SO4 and concentrated to a purple oil. Purification by flash column chromatography (0% to 10% EtOAc in hexanes) gave the title compound as an oil (0.45 g, 50%). 1H NMR (400 MHz, CDCl3): δ 1.26 (t, J=7.6 Hz, 3H), 2.60 (s, 3H), 2.65 (q, J=7.6 Hz, 2H), 5.37 (s, 1H), 6.62 (s, 1H), 7.62 (s, 1H), 10.11 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([NH2:13])[CH:12]=[C:6]2[CH2:5]1.Br[C:17]1[C:18](=[O:25])[N:19]([CH3:24])[CH:20]=[C:21]([Br:23])[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:23][C:21]1[CH:22]=[C:17]([NH:13][C:11]2[CH:12]=[C:6]3[CH2:5][N:4]([CH2:3][C:2]([F:1])([F:14])[F:15])[CH2:9][CH2:8][N:7]3[N:10]=2)[C:18](=[O:25])[N:19]([CH3:24])[CH:20]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Nc1cc2n(n1)CCN(CC(F)(F)F)C2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(CC(F)(F)F)C3)c1=O
Temperature: 25 °C
Yield: 76 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 134b (300 mg, 1.36 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (364 mg, 1.36 mmol), cesium carbonate (887 mg, 2.7 mmol), and 1,4-dioxane (20 mL). After bubbling nitrogen through the suspension for 10 minutes, xantphos (78 mg, 0.136 mmol) and Pd2(dba)3 (62 mg, 0.068 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and heated at reflux for 5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (30 mL). The combined filtrate was concentrated under reduced pressure. The solid residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 134c (420 mg, 76%) as a yellow solid. MS-ESI: [M+H]+ 406.0
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:5]=[C:4]([OH:18])[CH:3]=1.Cl[C:20]([S:22]Cl)=[O:21]>O1CCCC1>[NH2:1][C:2]1[C:3]2[S:22][C:20](=[O:21])[O:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1
Reactant: O=C(Cl)SCl
Reactant: Nc1cc(O)nc(SCc2cccc(F)c2F)n1
Solvent: C1CCOC1
Product: Nc1nc(SCc2cccc(F)c2F)nc2oc(=O)sc12
Reaction time: 0.67 h
Yield: 97.1 %

Procedure:
To a stirred suspension of 6-amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinol (9.58 g) in tetrahydrofuran (96 ml) was added chlorocarbonylsulfenyl chloride (4.89 g) over 7 minutes, followed by tetrahydrofuran (2 ml). The reaction mixture was stirred for 40 minutes and the resulting precipitate collected by filtration, washing twice with tetrahydrofuran (19 ml), to afford the title compound as a pale yellow solid (11.31 g).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].[Mn]([O-])(=O)(=O)=[O:23].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[C:16]([F:17])([F:19])[F:18])[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:23]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=C(O)c1ccc(N2CCOCC2)c(C(F)(F)F)c1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(N2CCOCC2=O)c(C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
1.00 g (3.63 mmol) 4-(morpholin-4-yl)-3-trifluoromethyl-benzoic acid (prepared by synthesis sequence analogously to Example 13a and 13b) is suspended in 40 ml of water and 150 mg (3.75 mmol) sodium hydroxide are added. Then 1.73 g (10.92 mmol) potassium permanganate are added and the mixture is stirred for 1.5 hours at 45° C. Then the reaction mixture is cooled in the ice bath and sodium thiosulphate is added until total decolorisation is obtained. After extraction 3 times with ethyl acetate the combined organic phases are dried over sodium sulphate evaporated down i. vac. After application of the residue to silica gel it is purified by chromatography on silica gel (eluant: dichloromethane/methanol 95:5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[Mg]Br.FC1C=C(F)C=CC=1Br.[Mg].[C:21]([O:24][CH2:25][C:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])=[O:27])(=[O:23])[CH3:22].Cl>C1COCC1>[C:30]([O:29][CH2:28][C:26]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:27])[CH2:25][O:24][C:21](=[O:23])[CH3:22])(=[O:32])[CH3:31]
Reactant: CC(=O)OCC(=O)COC(C)=O
Reactant: Fc1ccc([Mg]Br)c(F)c1
Agent: Cl
Agent: Fc1ccc(Br)c(F)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)OCC(O)(COC(C)=O)c1ccc(F)cc1F
Temperature: -30 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, 850 ml of THF solution of 2,4-difluorophenylmagnesium bromide prepared from 202.6 g (1.05 mol) of 2,4-difluorobromobenzene and 26.7 g (1.1 mol) of magnesium turnings was added dropwise at -30° C. to 1.7 l of THF solution of 174 g (1.00 mol) of 1,3-diacetoxyacetone which was previously cooled to -30° C. After the resulting liquid was stirred at -60° C. for 2 hours, a temperature thereof was gradually raised to room temperature. Then, to the reaction mixture was added 1 l of 1.2 N aqueous solution of hydrochloric acid at 5° C. or below, and an aqueous layer was extracted twice with 1 l of ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried and concentrated under reduced pressure to give 302 g of crude oil. The obtained oil was purified by means of column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 125 g of the desired compound. The compound was recrystallized from toluene/hexane
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[NH2:14][CH2:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cccc(O)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(O)c3)ccc12
Yield: 6.9 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (100 mg, 0.385 mmol), 3-(aminomethyl)phenol (59 mg, 0.479 mmol), Pd2(dba)3 (40 mg, 0.044 mmol), rac-BINAP (79 mg, 0.127 mmol) and NaOt-Bu (92 mg, 0.963 mmol) in DMA (6 mL) was heated at 80° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3-hydroxy-benzylamino)-2H-phthalazin-1-one (8 mg) as a brown solid, 1H (400 MHz, CDCl3) δ: 4.48 (s, 2H), 6.77 (dd, 1H), 6.83 (m, 2H), 6.92 (d, 1H), 7.02 (m, 1H), 7.17 (t, 1H), 8.15 (d, 1H), 10.34 (s, 1H) ppm. m/z (M+1) 301.99.
Reaction SMILES: [C:1]1([B-:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].O.Cl.[C:29]([P:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[C:20]1([B-:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1.[C:38]([PH+:33]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:39])([CH3:40])[CH3:41]
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: c1ccc([B-](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Temperature: 25 °C

Procedure:
A 300-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 15.1 g (44 mmol) of sodium tetraphenylborate and 60 ml of water were weighed in the flask, followed by stirring to dissolve sodium tetraphenylborate. While the stirring was continuously carried out, the aqueous solution of tri-tert-butylphosphine hydrochloride was added to the solution, and the mixture was stirred at 25° C. for 3 hours. After the completion of the reaction, the precipitated product was filtered off. The so obtained crystal was suspended in 100 ml of toluene at 50° C., and the suspension was cooled to 25° C. and filtered. The product filtered off was washed with 100 ml of toluene. The crystal was then suspended in 100 ml of methanol at 50° C., and the suspension was cooled to 25° C. and filtered. The product filtered off was washed with 100 ml of methanol. The crystal obtained was dried to give 18.2 g of objective tri-tert-butylphosphonium tetraphenylborate as white crystal. The yield (mol %) was 87% based on tri-tert-butylphosphine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@H:10]([CH2:11][CH2:12][CH:13]=O)[CH2:9][CH2:8][N:7]1[C@@H:15]([CH3:22])/[C:16](/[CH3:21])=[CH:17]/[CH:18]=[CH:19]\[CH3:20])=[O:5])[CH3:2].[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[BH3-]C#N.[Na+]>CCO.CCOCC>[CH2:1]([O:3][C:4]([C@@H:6]1[C@H:10]([CH2:11][CH2:12][CH2:13][NH:31][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][CH2:8][N:7]1[C@H:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:22])=[O:5])[CH3:2]
Reactant: NCCc1ccccc1
Reactant: C/C=C\C=C(/C)[C@H](C)N1CC[C@@H](CCC=O)[C@H]1C(=O)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)[C@@H]1[C@H](CCCNCCc2ccccc2)CCN1[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of (2S,3R)-1-((2E,4Z)-(S)-1,2-Dimethyl-hexa-2,4-dienyl)-3-(3-oxo-propyl) pyrrolidine-2-carboxylic acid ethyl ester(1. g, crude) in EtOH(10 mL) is added phenethylamine(0.44 g, 3.65 mmol) at r.t. After stirring at r.t. for 30 min, NaBH3CN(0.3 g, 4.87 mmol) is added in one portion, After stirring at r.t. for 1.5 Hrs, the reaction solution is diluted with 50 mL of ether and washed with 20 mL of brine. The ether layer is concentrated and the crude product is purified by chromatography (CH2Cl2/MeOH: 97/3) to give a pale liquid (405 mg, 30.0%). (NMR and MS data confirmed, U-4117-52-20).
Reaction SMILES: C([N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:16])[CH:12]=2)[NH:7][C:6]1=[O:17])(C)(C)C.O([CH2:26][C:27]([F:30])([F:29])[F:28])S(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:26][C:27]([F:30])([F:29])[F:28])[C:6](=[O:17])[NH:5][C:14]2=[O:15]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)n1c(=O)[nH]c2ccc(Cl)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1[nH]c(=O)n(CC(F)(F)F)c2ccc(Cl)cc12
Temperature: 50 °C
Reaction time: 48 h
Yield: 99.4 %

Procedure:
To a solution of 3-tert-butyl-6-chloro-1H-quinazoline-2,4-dione (1.0 g, 3.97 mmol) in acetonitrile (40 mL) was added trifluoroethyl triflate (0.736 mL, 4.76 mmol) and potassium carbonate (821 mg, 5.95 mmol). The reaction was heated to 50° C. and stirred 48 hrs. The solution was cooled, concentrated, and dissolved in ethyl acetate. The solution was washed with sodium bicarbonate, brine, dried over Na2SO4, filtered, and concentrated. The crude residue was dissolved in acetic acid and treated with 4 mL HBr solution (30 weight % in AcOH). The reaction was stirred for 3 hours at room temperature, and concentrated to provide 1.1 g of yellow solid. 1H NMR (300 MHz, CD3OD) δ ppm 4.96 (q, J=8.7 Hz, 2H), 7.53 (d, J=9.0 Hz, 1H), 7.75 (dd, J=2.6, 9.1 Hz, 1H), 8.07 (d, J=2.7 Hz, 1H); MS (ESI+Q1MS) m/z 279 [M+H]+