Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([OH:17])=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:3]=1.[H-].[Na+].Br[CH2:27][CH2:28][O:29][P:30](=[O:47])([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH:5]=[C:6]2[C:15]=1[C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([O:17][CH2:27][CH2:28][O:29][P:30](=[O:47])([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:9][C:8]=1[O:7]2
Reactant: O=P(OCCBr)(OCc1ccccc1)OCc1ccccc1
Reactant: O=c1c2ccc(O)cc2oc2cc(N3CCOCC3)cc(O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c2ccc(OCCOP(=O)(OCc3ccccc3)OCc3ccccc3)cc2oc2cc(N3CCOCC3)cc(O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
A solution of 1,6-dihydroxy-3-morpholin-4-yl-xanthen-9-one in anhydrous DMF (2.0 mL) was treated with sodium hydride (27.7 mg, 0.693 mmol). After 15 minutes, a solution of phosphoric acid dibenzyl ester 2-bromoethyl ester (267.0 mg, 0.693 mmol) in DMF (1.0 mL), was added, and reaction mixture was stirred overnight at room temperature. The reaction mixture then was dissolved in EtOAc (250 mL) and washed with water (6×50 mL) and brine (1×50 mL). The organics were dried. (Na2SO4) and concentrated. The residue then was purified via Biotage chromatography using 80% EtOAc in hexanes as, eluent to yield 132 mg (31%) of phosphoric acid dibenzyl ester 2-(8-hydroxy-6-morpholin-4-yl-9-oxo-9H-xanthen-3-yloxy)-ethyl ester as a white solid. 1H NMR (CDCl3, 400 MHz) δ: 12.82 (s, 1H), 8.12 (d, 1H), 7.34 (m, 10H), 6.82 (d, 1H), 6.73 (s, 1H), 6.24 (s, 1H), 6.22 (s, 1H), 5.04 (m, 4H), 4.38 (m, 2H), 4.18 (m, 2H), 3.83 (m, 4H), 3.38 (m, 4H).
Reaction SMILES: [C:1]1([N:7]2[C:13](=[O:14])[CH2:12][C:11](=[O:15])[NH:10][C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:23][C:24]([N:26]([CH:33]1[CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>CN(C=O)C>[CH:33]1([N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](=[O:25])[CH2:23][N:10]2[C:11](=[O:15])[CH2:12][C:13](=[O:14])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:19]=[CH:18][CH:17]=[CH:16][C:9]2=3)[CH2:35][CH2:34]1
Reactant: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1
Reactant: O=C(CBr)N(c1ccccc1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1CC(=O)N(c1ccccc1)C1CC1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a stirred solution of 500 mg (1.98 mmol) 1-Phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2,4-dione in 15 mL DMF is added 103 mg (2.58 mmol, 1.3 equiv) 60 wt % NaH at ambient temperature and stirred 0.5 h. To this solution is added 504 mg (1.98 mmol, 1.0 equiv) 2-Bromo-N-cyclopropyl-N-phenyl-acetamide, prepared as in Part A, in 1 mL DMF and stirred 18 h at ambient temperature. The solvent is removed in vacuo and the residue taken into 50 mL EtOAc, washed successively with H2O (30 mL), 1N HCl (30 mL), satd. NaHCO3 (30 mL), and brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo to a brown oil. The crude product is purified by flash chromatography on 15 g silica gel eluted with EtOAc/Hexanes (1:1, 450 mL). Appropriate fractions were combined and concentrated in vacuo to give 572 mg (1.34 mmol) of N-Cyclopropyl-2-(2,4-dioxo-5-phenyl-2,3,4,5,tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-phenyl-acetamide as a white foam: 1H NMR (CDCl3, 300 MHz) δ7.50-7.07 (m, 13H), 6.92 (d, 1H, J=7.3), 3.60 (d, 1H, J=11.9), 3.51 (d, 1H, J=12.0), 3.30 (m, 1H), 0.86 (m, 2H), 0.60 (m, 2H); TLC Rf =0.35 (EtOAc/Hexanes, 2:1).
Reaction SMILES: FC(F)(F)C1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2C=1.Br[CH2:15][C:16](=O)[C:17]([CH3:20])([CH3:19])[CH3:18].C(O)C>[Pt](=O)=O.CO>[CH3:18][C:17]([C:16]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:15]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)CBr
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCO
Product: CC(C)(C)c1cn2c(n1)CNCC2

Procedure:
2-(1,1-Dimethylethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine was prepared in an analogous manner to that described above for 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (Intermediate 4) but starting from 1-bromo-3,3-dimethyl-2-butanone instead of 3-bromo-1,1,1-trifluoro-2-propanone and using platinum (IV) oxide and ethanol in the place of 10% palladium on carbon paste and methanol for the hydrogenation step.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[NH2:44][N:45]1[CH2:50][CH2:49][CH2:48][N:47]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)[C:46]1=[O:58]>C(Cl)Cl.O>[F:57][C:54]1[CH:53]=[CH:52][C:51]([N:47]2[CH2:48][CH2:49][CH2:50][N:45]([NH:44][C:26](=[O:28])/[CH:25]=[CH:24]/[C:14]3[CH:15]=[CH:16][C:17]([N:18]4[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]4)=[C:12]([O:11][CH3:10])[CH:13]=3)[C:46]2=[O:58])=[CH:56][CH:55]=1
Reactant: NN1CCCN(c2ccc(F)cc2)C1=O
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C/C(=O)NN2CCCN(c3ccc(F)cc3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 100 %

Procedure:
IPEA (0.51 mL), (E)-3-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]acrylic acid (150 mg) and BOPCl (0.18 g) were added to a solution of 1-amino-3-(4-fluorophenyl)tetrahydropyrimidin-2-one (132 mg) in methylene chloride (5 mL) at room temperature, and the reaction solution was stirred at room temperature for 13 hours. Water was added to the reaction solution, followed by extraction with chloroform. The resulting extract washed with a saturated sodium bicarbonate solution. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 261 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[CH2:4][CH:5]=[CH:6][CH2:7][CH3:8].Cl[C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13](Cl)[N:12]=1.[OH2:19]>O1CCCC1>[CH2:3]([O:9][C:11]1[N:16]=[C:15]([O:19][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH3:8])[N:14]=[C:13]([O:9][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH3:8])[N:12]=1)[CH2:4][CH:5]=[CH:6][CH2:7][CH3:8]
Reactant: CCC=CCCO
Reactant: O
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC=CCCOc1nc(OCCC=CCC)nc(OCCC=CCC)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To 16.6 g of sodium hydride (purity: 60% or more), 600 mL of tetrahydrofuran was added and the resultant reaction mixture was cooled down to 0° C., followed by dropping 40.1 g of 3-hexen-1-ol into the reaction mixture at 4° C. or less to be added. After the completion of the dropping, the resultant reaction mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was cooled down again to 0° C. and into the reaction mixture, 18.4 g of 2,4,6-trichloro-1,3,5-triazine dissolved in 120 mL of tetrahydrofuran was slowly dropped at 15° C. or less to be added. At room temperature, the reaction was effected over one night and to the reaction mixture, water was added, followed by extracting the resultant reaction mixture with ethyl acetate. The extract was washed with water and was dried over anhydrous sodium sulfate and from the extract, the solvent was distilled off to obtain 33.1 g of a crude product. The crude product was purified with a column (ethyl acetate:hexane=1:10) to obtain 23.22 g of 2,4,6-tri(3-hexene-1-oxy)-1,3,5-triazine which is the objective substance as a transparent oil. Yield: 61%, Purity: 98.6% (GC)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O-:24][C:25]#[N:26].[K+].O>C(O)(=O)C>[NH2:26][C:25]([N:6]([CH2:5][C:4]1[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=1[O:2][CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:24]
Reactant: COc1ccccc1CNc1ccccc1Oc1ccccc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1CN(C(N)=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.2 %

Procedure:
In 20 ml of acetic acid was dissolved 1.54 g of N-(2-methoxybenzyl)-2-phenoxyaniline synthesized in the same manner as in Example 1(1), and then an aqueous potassium cyanate solution (1.23 g of potassium cyanate and 10 ml of water) was added dropwise to the solution, followed by stirring at room temperature for 2.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:3) to give 1.69 g of N-aminocarbonyl-N-(2-methoxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6](F)[C:5]([CH2:14][NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][CH:3]=1.[OH-].[K+].C(O)(=O)C[C:26](CC(O)=O)(C(O)=O)[OH:27]>C1COCC1.CO.O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:27][CH3:26])[C:5]([CH2:14][NH:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1c(CNC(=O)C(C)(C)C)ccc(Cl)c1C(=O)O
Temperature: 100 °C

Procedure:
To a solution of ethyl 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate (Intermediate-2; step-2, 1.00 g, 3.31 mmol) in THF:MeOH:H2O (2:2:1; 5 mL) was added KOH (930 mg, 16.57 mmol). The reaction mass was heated in a sealed tube at 100° C. for 3 h. The reaction mass was neutralized with citric acid and concentrated. The residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to afford 700 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 13.65 (br s, 1H), 8.08 (t, 1H), 7.29-7.26 (d, J=8.4 Hz, 1H), 7.22-7.19 (d, J=8.7 Hz, 1H), 4.25 (d, J=5.7 Hz, 2H), 3.79 (s, 3H), 1.13 (s, 9H); MS (m/z): 300.05 (M+H)+.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[NH:6][C:7]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]([C:18]([O:20][CH3:21])=[O:19])=[CH:10][C:8]=2[N:9]=1.IC.[C:24](=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH3:24][N:9]1[C:8]2[CH:10]=[C:11]([C:18]([O:20][CH3:21])=[O:19])[C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:7]=2[N:6]=[C:5]1[CH3:4]
Reactant: COC(=O)c1cc2nc(C)[nH]c2cc1C(=O)OC
Reactant: O=C([O-])O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CI
Solvent: CO
Product: COC(=O)c1cc2nc(C)n(C)c2cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
Sodium methoxide (1.96 g, 36.3 mmol) is added to a solution of dimethyl 2-methyl-5,6-benzimidazoledicarboxylate (8.50 g, 34.2 mmol) in methanol. The reaction mixture is stirred 0.5 hour at room temperature, treated with iodomethane (2.15 mL, 34.5 mmol) stirred overnight, acidified to pH 6 with acetic acid, treated with sodium bicarbonate to pH 8 and extracted with chloroform. The extracts are combined, dried (MgSO4) and concentrated in vacuo to yield the title product as a pink solid (6.25 g, 69.7%). A small portion is recrystallized from ethyl acetate to afford the title product as pink crystals, mp 147°-148° C.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:13]1[C:14]2[S:25][CH:24]=[CH:23][C:15]=2[N:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[C:3]1([CH:9]([C:13]2[C:14]3[S:25][CH:24]=[CH:23][C:15]=3[N:16]=[C:17]([C:19]([F:21])([F:22])[F:20])[N:18]=2)[C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1nc(Cl)c2sccc2n1
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(c1ccccc1)c1nc(C(F)(F)F)nc2ccsc12
Reaction time: 0.17 h
Yield: 22.9 %

Procedure:
A suspension of NaH (60% dispersion in oil, 60 mg, 1.5 mmol) in DMF (5 mL) and toluene (15 mL) at room temperature was treated with phenylacetonitrile (0.16 g, 1.37 mmol), stirred for 10 min, treated with a solution of 4-chloro-2-trifluoromethylthieno[3,2-d]pyrimidine (0.3 g, 126 mmol) in DMF (2 mL), stirred for 15 min, treated with water (5 mL) and the phases separated. The aqueous phase was extracted with EtOAc (2×50 mL), the combined organic phase washed with water (3×10 mL), brine (10 mL), dried (MgSO4), concentrated in vacuo and the resulting orange oily solid crystallised from heptane to give the title compound (0.1 g, 25%) as a gold solid.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])=[O:8].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[O:28]=[C:27]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[CH2:26][NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C[C@H](NC(=O)c1cccn1N)c1ccccc1
Product: C[C@H](NC(=O)c1cccn1NC(=O)CNC(=O)OC(C)(C)C)c1ccccc1
Yield: 97.9 %

Procedure:
The title compound was prepared from (S)-1-amino-N-(1-phenylethyl)-1H-pyrrole-2-carboxamide (3.50 g, 15.3 mmol) and 2-(tert-butoxycarbonylamino)acetic acid (2.67 g, 15.3 mmol) following the experimental procedure described in Preparation 73a. 5.79 g (89% yield) of the desired compound were obtained.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:57]=[CH:56][C:21]([CH2:22][N:23]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:34]([C:36]4[N:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]5=[C:38]([C:45]5[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=5)[C:48]([OH:50])=[O:49])[N:37]=4)=[O:35])[CH:30]=3)[N:25]([CH3:54])[C:24]2=[O:55])=[CH:20][CH:19]=1.O>CN(C=O)C.CCOCC>[ClH:2].[F:17][C:18]1[CH:57]=[CH:56][C:21]([CH2:22][N:23]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:34]([C:36]4[N:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]5=[C:38]([C:45]5[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=5)[C:48]([O:50][CH2:3][CH2:4][N:5]5[CH2:10][CH2:9][O:8][CH2:7][CH2:6]5)=[O:49])[N:37]=4)=[O:35])[CH:30]=3)[N:25]([CH3:54])[C:24]2=[O:55])=[CH:20][CH:19]=1
Reactant: ClCCN1CCOCC1
Reactant: Cn1c(=O)n(Cc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(-c4cccc(C(=O)O)c4)c4ccccn34)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cn1c(=O)n(Cc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(-c4cccc(C(=O)OCCN5CCOCC5)c4)c4ccccn34)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.6 %

Procedure:
0.022 g (0.61 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 0.189 g (1.37 mmol) of potassium carbonate are added, under an inert atmosphere, to 0.3 g (0.55 mmol) of 3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic acid in 8 ml of DMF. After stirring for 18 h at ambient temperature and then for 8 hours at 50° C., the reaction medium is hydrolysed with water, and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The yellow solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 0.61 ml of a 1N aqueous solution of hydrochloric acid is added to 0.334 g of the yellow solid obtained, in 5 ml of methanol. The reaction medium is stirred for 1 hour at ambient temperature. Dyethyl ether is added and then the reaction medium is filtered. The precipitate obtained is rinsed with dyethyl ether and then dried under reduced pressure at 50° C. overnight. 0.298 g of a yellow solid is obtained.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][C:4](=O)[OH:5].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>COCCOC.O>[C:17]([O:16][C:14]([NH:1][C@H:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][CH2:4][OH:5])=[O:15])([CH3:19])([CH3:20])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
To a solution of Boc-L-Asp-OtBu (3.00 g, 10.4 mmol) in 1,2-dimethoxyethane (10 mL) was added at −15° C. 4-methylmorpholine (1.14 mL, 10.4 mmol) and isobutyl chloroformate (1.35 mL, 10.4 mmol). After stirring for 10 min at −15° C. the precipitate was filtered off and washed with cold 1,2-dimethoxyethane (20 mL). To the filtrate was added at −15° C. a solution of sodium borohydride (0.59 g, 15.6 mmol) in water (5 mL). After 5 min water (250 mL) was added. The reaction mixture was extracted with ethyl acetate (3×100 mL), the combined organic layers dried over sodium sulphate, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[Br:11]Br.O>C(O)(=O)C.ClCCl>[Br:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=Cc1cc(F)c(O)c(Br)c1
Temperature: 20 °C
Reaction time: 7 h
Yield: 63.9 %

Procedure:
To a mixture of 3-fluoro-4-hydroxybenzaldehyde (700 mg, 5.0 mmol) in acetic acid (5 mL) and dichloromethane (5 mL) was added bromine (0.5 mL, 9.8 mmol) at 0° C. The resulting mixture was stirred at 20° C. for 7 hours and then it was poured into water (50 mL), filtrated, the filtered cake was dried to give Intermediate 77 (700 mg, yield 64%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15].C([O-])([O-])=[O:26].[K+].[K+].C1(C)C=CC=CC=1>CCO>[CH3:12][O:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH:9]3[CH2:11][CH2:10]3)=[O:26])=[CH:4][CH:3]=2)=[CH:20][CH:21]=1)=[O:15]
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc(CC2CC2)cc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(C(=O)C3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Procedure I′: 1.8 g of (4-bromophenyl)cyclopropylmethane (8.0 mmol), 1.80 g of (4-methoxycarbonylphenyl)boronic acid (10.0 mmol) are put into flask with 8.0 ml of aqueous 2M K2CO3 and 90 ml of toluene:EtOH=20:1. The mixture is deoxygenated and stirred at room temperature under N2 for 30 min. 280 mg of tetrakis(triphenylphosphine)-palladium is added. The reaction mixture is stirred under reflux for overnight. Organic layer is separated from water layer and water layer is extracted with CH2Cl2. All organic layers are combined together and dried over Na2SO4 and evaporated. The crude product is applied to silica-gel column chromatography (Hexane:AcOEt=8:1→3:1). 4′-Cyclopropanecarbonyl-biphenyl-4-carboxylic acid methyl ester is recrystallized from hexane/AcOEt (849 mg, 38%). Mass spectrum (m/e): 214 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH:7]([I:27])[CH:8]1[O:26][C@H:11]2[CH2:12][C@@H:13]([OH:25])[C@H:14](/[CH:15]=[CH:16]/[C:17]([OH:24])([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1.[C:35](=[O:38])(O)[O-].[Na+]>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH:7]([I:27])[CH:8]1[O:26][C@H:11]2[CH2:12][C@@H:13]([O:25][CH:6]3[CH2:5][CH2:4][CH2:3][CH2:35][O:38]3)[C@H:14](/[CH:15]=[CH:16]/[C:17]([O:24][CH:34]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1
Reactant: CCCCCC(C)(O)/C=C/[C@@H]1[C@H]2CC(C(I)CCCC(=O)OC)O[C@H]2C[C@H]1O
Reactant: O=C([O-])O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCC(C)(/C=C/[C@@H]1[C@H]2CC(C(I)CCCC(=O)OC)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Temperature: -4 °C
Reaction time: 4.5 h

Procedure:
To a solution of 1.067 g of (13E)-(5RS,6RS,9α,11α,15RS)-5-iodo-6,9-epoxy-11,15-dihydroxy-15-methylprost-13-enoic acid methyl ester [prepared as described in Reference Example 2(c)] in 20 ml of methylene chloride were added 1.4 mg of p-toluenesulphonic acid and 1.337 g of 2,3-dihydropyran and the mixture was stirred at -4° C. for 4.5 hours. The reaction mixture was then neutralised with an aqueous solution of sodium bicarbonate and extracted with chloroform. The extract was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 1.2 g of the title compound having the following physical characteristics:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[C:5]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)[CH3:2].[C:41]([O-:44])(=[O:43])[CH3:42].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(#N)C>[CH2:1]([O:3][C:4](=[O:40])[C:5]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:43][C:41](=[O:44])[CH3:42])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:40][C:4](=[O:3])[CH3:5])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1cc(OCCCCCCCCCCBr)c(C(=O)OCC)cc1OCCCCCCCCCCBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OCCCCCCCCCCOC(C)=O)c(C(=O)OCC)cc1OCCCCCCCCCCOC(C)=O

Procedure:
46.4 g (67.0 mmol) diethyl-2,5-bis-(10-bromodecoxy)terephthalate, 65.8 g (671 mmol) potassium acetate and 3.4 g (8.5 mmol) Aliquat 336® in 350 ml absolute acetonitrile are heated under N2 under reflux for 48 hours. After distilling off the solvent, the reaction mixture is taken up in 300 ml chloroform, insoluble salts are filtered off and the filtrate is washed twice with 150 ml water. The organic phase is dried over Na2SO4 and the solvent is then distilled off. 300 ml petroleum ether are added to the remaining, oily residue, the product crystallising out after 16 hours at -20° C. It is then recrystallized from ethanol.