Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29]N(C)C)#[N:2].[NH2:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=1>ClCCl.CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH:33][C:34]4[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=4)=[N:2][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])[CH:14]=1)=[O:20])=[O:23])[CH3:26]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Reactant: Cc1cc(N)ccn1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4ccnc(C)c4)c3cc2OC)c1
Yield: 19 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (100 mg, 0.22 mmol) with 4-amino-2-methylpyridine (28 mg, 0.26 mmol) and chromatography (silica gel, dichloromethane/methanol: 4/1) gives the desired product in 19% yield (21 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=O.[C:11]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1.[Sb](Cl)(Cl)(Cl)(Cl)Cl.[NH3:31]>ClC1C=CC=CC=1>[C:11]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]=[CH:13][C:14]([C:17]2[N:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:12][CH:13]=3)[N:31]=[C:5]([C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[N:18]=2)=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: N
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: Brc1cccc(-c2nc(-c3ccc(-c4ccccc4)cc3)nc(-c3ccc(-c4ccccc4)cc3)n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.9 g of 3-bromobenzoic acid chloride and 3.10 g of 4-biphenylcarbonitrile were dissolved in 50 mL of chlorobenzene in a stream of argon. The thus-obtained solution was cooled to 0° C., and then 2.59 g of antimony pentachloride was dropwise added therein. The mixture was stirred at room temperature for one hour, and then heated at 100° C. for 2 hours. The reaction mixture was left to be cooled to room temperature, and further to −20° C. Aqueous 28% ammonia was added therein to give a white precipitate. The white precipitate-containing suspension was stirred overnight at room temperature. The thus-deposited solid was collected by filtration and washed with methanol. The thus-washed solid was dried and then extracted by a Soxhlet's extractor using chloroform as extraction solvent to give 2.00 g of 2,4-di(4-biphenylyl)-6-(3-bromophenyl)-1,3,5-triazine as a white powder (yield, 43%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]2[S:22][CH:23]([CH2:26][C:27](O)=[O:28])[CH2:24][N:25]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:53][CH2:54][C:55]([CH3:58])([OH:57])[CH3:56]>CN(C)C=O.C(OCC)(=O)C.O>[OH:57][C:55]([CH3:58])([CH3:56])[CH2:54][NH:53][C:27](=[O:28])[CH2:26][CH:23]1[S:22][C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:20][CH:19]=3)=[N:25][CH2:24]1
Reactant: CC(C)(O)CN
Reactant: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)ccc3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
To a solution of [2-(5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (600 mg) in N,N-dimethylformamide (10 mL) were added 1-hydroxybenzotriazole monohydrate (319 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (400 mg), and 1-amino-2-methyl-2-propanol (242 mg), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate) and crystallized from acetonitrile to give the title compound (601 mg, yield 86%) as white crystals.
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]=1>C(OCC)C.Cl[Cu]>[CH2:1]([C:11]1([CH3:10])[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: CC1=CC(=O)CC(C)C1
Agent: Cl[Cu]
Solvent: CCOCC
Product: CC1CC(=O)CC(C)(Cc2ccccc2)C1
Reaction time: 0.08 h
Yield: 53 %

Procedure:
To a cooled (−20° C.) 1M benzylmagnesium bromide solution in diethyl ether (50 ml) under argon was added CuCl (0.52 g, 5.3 mmol) and the mixture was stirred for 5 min. Then a solution of 3,5-dimethyl-2-cyclohexen-1-one (12) (4.4 g, 35.1 mmol) in diethyl ether (15 ml) was added dropwise keeping the temperature below −10° C. The mixture was stirred for 2 h and quenched with 10% aqueous acetic acid (40 ml). The organic layer was separated, washed with water, saturated aqueous NaHCO3 and saturated aqueous NaCl, and dried over MgSO4. Filtration and concentration in vacuo afforded oily residue what was separated by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 10:1). Cyclohexanone 13 (4.0 g, 53%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2Br)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:37]2[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=2)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N1CCn2c(Cc3ccc(Cl)cc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)N1CCn2c(Cc3ccc(Cl)cc3-c3ccc(Cl)cc3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 80 °C
Yield: 49.4 %

Procedure:
In a sealed tube was placed a stirred solution of 9-benzyloxy-6-(2-bromo-4-chlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (380) (80 mg, 0.155 mmol) in dioxane (3 mL). 4-Chlorophenyl boronic acid (24.248 mg, 0.155 mmol) and a 1N solution of K2CO3 [(64.279 mg, 0.465 mmol) dissolved in 0.7 mL water] were added at room temperature and the reaction was degassed for 30 min under argon. To the reaction mixture, Pd(triphenyl phosphine)4 (17.916 mg, 0.016 mmol) was added, followed by 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (12.729 mg, 0.031 mmol) and the reaction was further degassed for another 10 min. The reaction mixture was heated at 80° C. for 20 min (reaction was monitored by LC-MS). After completion of the reaction, the mixture was filtered and the filtrate was diluted with water (5 mL). After extraction with ethyl acetate (2×20 mL), the organic part was dried over sodium sulphate and concentrated. The resulting crude product was purified by column chromatography (using amine bound silica gel as stationary phase) to get 9-benzyloxy-6-(5,4′-dichloro-biphenyl-2-ylmethyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (381) (42 mg, 49.39%) as a white solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH3:14])[CH:4]1O)#[N:2].Cl.C(OCC)(=O)C.C(OC(C)C)(C)C>N1C=CC=CC=1>[C:1]([C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH3:14])[CH:4]=1)#[N:2]
Reactant: COc1cccc2c1CCC(C#N)C2O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC(C)OC(C)C
Product: COc1cccc2c1CCC(C#N)=C2

Procedure:
A mixture of the compound obtained in step (iv) above (16.2 g, 0.079 mol) and POCl (30 ml, 0.32 mol) in pyridine (200 ml) is heated for 3 hours to 120° C. ext.. The reaction mixture is then cooled and made acidic by the dropwise addition of 2N HCl. The solution is treated with ethyl acetate, the organic phase is recovered, washed with a saturated sodium bicarbonate solution and then with water. The organic phase is dried over sodium sulfate, filtered and concentrated to dryness yielding the compound indicated in the title [9.8 g); m.p. 47°-49° C. (isopropyl ether).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=CC3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=3.[OH2:17].[C:18]([OH:21])(=O)[CH3:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:18](=[O:21])[C:19]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=3
Reactant: O
Reactant: Clc1ccc2ccc3ccc(Br)cc3c2c1
Reactant: CC(=O)O
Product: O=C1C(=O)c2ccc(Br)cc2-c2cc(Cl)ccc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-6-chlorophenanthrene from Step 2 (1.71 g; 5.86 mmol) in 35 mL of acetic acid was added 2.3 g (23.5 mmol) of CrO3. The mixture was stirred 2 hrs at 100° C., cooled down to room temperature, poured into 300 mL of water and stirred for 1 hr. The suspension was filtered, washed with water and Et2O and pumped under reduced pressure to afford 1.67 g of 3-bromo-6-chlorophenanthrene-9,10-dione as a solid.
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1.[Cl-].[NH4+]>O1CCCC1>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3([CH2:14][CH2:15][C:16]([OH:19])([CH3:1])[CH2:17][CH2:18]3)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1
Reactant: [Li]C
Reactant: O=C1CCC2(CC1)C(=O)Nc1cc(Br)ccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCC2(CC1)C(=O)Nc1cc(Br)ccc12
Temperature: 0 °C
Reaction time: 4.5 h

Procedure:
Methyllithium (1.6 M in diethyl ether, 4.89 mL, 7.82 mmol) was added dropwise to a stirred solution of 6′-bromospiro[cyclohexane-1,3′-indoline]-2′,4-dione (preparation 10a, 1.00 g, 3.40 mmol) in tetrahydrofuran (30 mL) at −78° C. The mixture was warmed to 0° C. over 3 hours and stirred at room temperature for additional 4.5 hours. Saturated aqueous ammonium chloride (20 mL) was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (97:3 dichloromethane/methanol) gave the two pure isomers of the title compound.
Reaction SMILES: [SH:1][C:2]([CH3:12])([CH3:11])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:10])[CH2:7][CH:8]=O.[CH2:13]([O:15][C:16]([CH:18]=[C:19]([CH3:31])[CH2:20]P(=O)(OC(C)C)OC(C)C)=[O:17])[CH3:14].CN(C)C=O.[OH-].[Na+]>CCCCCC.O>[SH:1][C:2]([CH3:11])([CH3:12])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:10])[CH2:7][CH:8]=[CH:20][C:19]([CH3:31])=[CH:18][C:16]([O:15][CH2:13][CH3:14])=[O:17]
Reactant: CCOC(=O)C=C(C)CP(=O)(OC(C)C)OC(C)C
Reactant: CC(CC=O)CCCC(C)(C)S
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=C(C)C=CCC(C)CCCC(C)(C)S
Reaction time: 0.5 h

Procedure:
A mixture of 5 g. of 7-mercapto-3,7-dimethyloctan-1-al 8.5 g. of di-isopropyl 3-ethoxycarbonyl-2-methylprop-2-enyl-phosphonate, and 40 ml. of dimethylformamide, under nitrogen and cooled in an ice-bath, is stirred for 0.5 hours and then ground NaOH (1.165g.) is added. The reaction mixture is stirred at room temperature for 3 hours and then hexane-water (1/1) added. The organic layer is washed with water and brine, dried over calcium sulfate and concentrated. The concentrate is filitered through Florisil using hexane and hexane/ether. The filtrate is concentrated and then distilled to yield ethyl 11-mercapto-3,7,11-trimethyldodeca-2,4 -dienoate (mostly trans-2, trans-4).
Reaction SMILES: Cl.Cl.[CH2:3]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH:14]([NH2:16])[CH3:15])[CH3:4].Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][NH:22]2.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:3]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH:14]([NH:16][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][NH:22]2)[CH3:15])[CH3:4]
Reactant: Clc1ncnc2[nH]cnc12
Reactant: CCn1c(C(C)N)nc2ccccc21
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(C(C)Nc2ncnc3[nH]cnc23)nc2ccccc21
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(1-ethyl-1H-1,3-benzodiazol-2-yl)ethan-1-amine dihydrochloride (346 mg, 1.32 mmol), 6-chloro-9H-purine (204 mg, 1.32 mmol) and DIPEA (904 μL, 5.28 mmol) in n-butanol (2.5 mL) was stirred in a sealed tube for 3 h at 120° C. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and triturated with a mixture EtOAc/diethyl ether, filtered and further washed with additional diethyl ether affording racemic 107 as a pale pink solid (182 mg, 45%). LCMS: RT 2.18 min [M+H]+ 308.1. 1H NMR (CDCl3, 400 MHz): δ 8.51 (1H, s), 7.95 (1H, s), 7.76 (1H, d, J=7.17 Hz), 7.39-7.34 (1H, m), 7.31-7.15 (3H, m), 6.03 (1H, br), 4.51-4.39 (1H, m), 4.37-4.26 (1H, m), 1.97-1.80 (4H, m), 1.43 (3H, t, J=7.21 Hz)
Reaction SMILES: C=C(O[C:5](=[O:27])[NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:14]([CH3:24])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][N:19]=[C:18]([Cl:23])[CH:17]=3)[C:10]([CH3:25])=[CH:9][C:8]=1[F:26])C.Cl.[F:29][C:30]([F:35])([F:34])[CH2:31][CH2:32][NH2:33].CN1CCCC1.O>C1COCC1>[Cl:23][C:18]1[CH:17]=[C:16]2[C:21]([CH:22]=[C:13]([C:11]3[C:10]([CH3:25])=[CH:9][C:8]([F:26])=[C:7]([NH:6][C:5]([NH:33][CH2:32][CH2:31][C:30]([F:35])([F:34])[F:29])=[O:27])[CH:12]=3)[C:14]([CH3:24])=[N:15]2)=[CH:20][N:19]=1
Reactant: NCCC(F)(F)F
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(Cl)cc3nc2C)c(C)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(F)c(NC(=O)NCCC(F)(F)F)cc1-c1cc2cnc(Cl)cc2nc1C
Temperature: 25 °C
Yield: 96.3 %

Procedure:
Heat a mixture of prop-1-en-2-yl(5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)carbamate (0.20 g, 0.518 mmol), 3,3,3-trifluoropropylamine hydrochloride (0.093 g, 0.622 mmol) and 1-methylpyrrolidine (0.068 mL, 0.648 mmol) in THF (5 mL) at 55° C. overnight. Cool to RT, add H2O, extract with EtOAc (2×), wash the combined organics with brine (2×), dry over MgSO4 and concentrate to dryness to afford the title compound (220 mg, 96%). 1H NMR (400 MHz, DMSO-d6): δ 9.23 (s, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.23 (d, J=12.3 Hz, 1H), 6.75 (t, J=5.9 Hz, 1H), 3.58-3.02 (m, 2H), 2.42 (m, 2H), 2.41 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([CH2:8][C:9]([CH3:17])([CH3:16])[CH:10](C(O)=O)[C:11]#[N:12])=[O:7])[CH3:4].C([O-])(=O)C.[Na+].Cl>O>[CH2:3]([O:5][C:6]([CH2:8][C:9]([CH3:17])([CH3:16])[CH:10]([Br:1])[C:11]#[N:12])=[O:7])[CH3:4]
Reactant: CCOC(=O)CC(C)(C)C(C#N)C(=O)O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(C)(C)C(Br)C#N
Temperature: 20 °C
Reaction time: 5 h
Yield: 76.6 %

Procedure:
40 g (0.25 mol) of bromine were added dropwise to a solution of 42.6 g (0.2 mol) of 3-carboxy-3-cyano-2,2-dimethyl-propane-1-carboxylic acid ethyl ester and 41 g of sodium acetate in 400 ml of water at 20° C. The mixture was subsequently stirred at 20° C. for 5 hours. It was then acidified with dilute HCl and extracted twice with 100 ml of methylene chloride each time. The organic solutions were dried over sodium sulphate and then concentrated. The residue was first introduced dropwise into a flask, which was heated to 200° C., whereupon continuous evolution of CO2 started, and was then twice subjected to fractional distillation. 38 g (76.5% of theory) of 3-bromo-3-cyano-2,2-dimethyl-propane-1-carboxylic acid ethyl ester were obtained in the form of a colorless oil of boiling point 92°-95° C./2.5 mm Hg.
Reaction SMILES: B(Br)(Br)Br.[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[C:13]=1[O:20]C>C(Cl)Cl>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:13]=1[OH:20]
Reactant: COc1cccc(CCCCCCBr)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(CCCCCCBr)c1O
Yield: 95.5 %

Procedure:
Boron tribromide (266 mL, 0.266 mol, 1M in methylene chloride) was added dropwise over 1 hour to a cooled (-65°) solution of 40.0 g (0.133 mol) of 1-(6-bromohexyl)-2,3-dimethoxybenzene in 800 mL of anhydrous methylene chloride which was stirred in an argon atmosphere. The cooling bath was then removed and the reaction mixture was stirred for 1.5 hours. After cooling in an ice bath, 100 mL of water and 50 mL of 3N HCl were added and the mixture was stirred for 2 hours. The organic layer was separated, dried and concentrated under reduced pressure to an oil which was purified by HPLC using 5% methanol-chloroform to yield 34.7 g of 1-(6-bromohexyl)-2,3-dihydroxybenzene as an oil. To this was added 32 mL (0.28 mol) of benzyl chloride, 46 g (0.28 mol) of potassium iodide, 122 g (0.88 mol) of potassium carbonate and 700 mL of anhydrous acetone and the reaction mixture was stirred at reflux for 72 hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to an oil which was purified by HPLC using 1% ethyl acetate-hexane to give 47 g (74% yield) of 1-(6-Iodohexyl)-2,3-bis-(phenylmethoxy) benzene as an oil. The nmr spectrum was consistent with the structure (CH2I at δ3.14) and the mass spectrum showed the molecular ion at m/e 500 (C26H29IO2).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:7]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])[CH2:6][CH2:5][O:4]1.CN1CCOCC1.[O:21]=[C:22]1[CH:26]([NH:27][C@H:28]([C:30](O)=O)C)[CH2:25][CH:24]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]CC)[O:23]1>>[CH2:24]([O:23][C:22](=[O:21])[C@@H:26]1[CH2:25][CH2:30][CH2:28][N:27]1[C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][CH:7]1[CH2:6][CH2:5][O:4][C:3]1=[O:2])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCCCCCCCC1CC(N[C@@H](C)C(=O)O)C(=O)O1
Reactant: C[C@H](NC1CCOC1=O)C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Product: C[C@H](NC1CCOC1=O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1

Procedure:
Conducting a reaction and treatments in the same manner as in Step (3) of Example 1 except that N-(2-oxo-3-tetrahydrofuranyl)-L-alanine hydrochloride was used in a form neutralized with N-methylmorpholine in place of Isomer BCD of N-(2-oxo-5-octyl-3-tetrahydrofuranyl)-L-alanine, was obtained as a colorless syrupy substance N-(2-oxo-3-tetrahydrofuranyl)-L-alanyl-L-proline benzyl ester [in the formula (I), R1 =R2 =H, R3 =CH3, R4 and R5 =--(CH2)3 --, R6 =-CH2Ph (Compound 13)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][C@@H:30](O)[CH2:31][C@H:32]([OH:34])[CH3:33].COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C@@H:30]([CH3:29])[CH2:31][C@H:32]([OH:34])[CH3:33])=[CH:5][CH:4]=1.[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: COc1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(O[C@@H](C)C[C@@H](C)O)cc1
Reaction time: 14 h

Procedure:
After 4-methoxyphenol (300 mg, 2.41 mmol), triphenylphosphine (761 mg, 2.89 mmol), (2R,4R)-2,4-pentanediol (302 mg, 2.89 mmol), and THF (12 mL) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (680 mg, 2.89 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 14 hours. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 mL,×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 30% ethyl acetate-hexane solution) to give (4S,2R)-4-(4-methoxyphenoxy)pentane-2-ol as a colorless oily substance (418 mg, yield: 82%/4-methoxyphenol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6]1[CH:7]=[N:8][C:9]([OH:12])=[N:10][CH:11]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].N12CCN(CC1)CC2.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6]1[CH:11]=[N:10][C:9]([O:12][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:8][CH:7]=1
Reactant: Oc1ncc(Oc2ccc(Cl)c(Cl)c2)cn1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ncc(Oc2ccc(Cl)c(Cl)c2)cn1)c1ccccc1
Yield: 65.3 %

Procedure:
A solution of 5-(3,4-dichloro-phenoxy)-pyrimidin-2-ol (0.51 g, 2.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.34 g, 2.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.22 g, 2.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.51 g, 65% yield) as an off-white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])(=O)CC.[OH-:18].[Na+].[N+]([C:23]1[CH:28]=CC=C[CH:24]=1)([O-])=O>>[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:24](=[O:18])[CH2:23][CH3:28])=[CH:12][C:11]=1[O:16][CH3:17]
Reactant: CCC(=O)Oc1ccccc1OC
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: CCC(=O)c1ccc(O)c(OC)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
Powdered anhydrous aluminum chloride (3.0 g, 22.5 mmol) was dissolved in anhydrous nitrobenzene (10 mL) at 100° C. The solution was cooled and 2-methoxyphenyl propionate (2.0 g, 11.1 mmol) was added rapidly. The reaction mixture was heated at 60° C. for 1.5 h and cooled, 3 N NaOH was added, and the mixture was stirred for 15 min. The suspension was filtered off, washed with water. The filtrate was then washed with CH2Cl2 twice, acidified with 3 N HCl, extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography (petroleum ether/EtOAc=10/1 to 5/1) to give the desired product (874 mg, 44% yield) as a yellow oil.