Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:12]([CH2:13][C:14](=[O:18])[NH:15][N:16]=3)[CH2:11][CH2:10][C:9]=2[CH:19]=1)(=O)C.C(O)C>O.NN>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:12]([CH2:13][C:14](=[O:18])[NH:15][N:16]=3)[CH2:11][CH2:10][C:9]=2[CH:19]=1
Reactant: CC(=O)Nc1ccc2c(c1)CCC1CC(=O)NN=C21
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CCC1CC(=O)NN=C21
Yield: 42.7 %

Procedure:
8-Acetamido-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3[2H]-one (0.7 g) was suspended in hydrazine hydrate (13 ml) and ethanol (2 ml) and heated under reflux for 2 hours. The hot solution was filtered through diatomaceous earth and the filtrate extracted with chloroform. Evaporation of the dried (MgSO4) extract gave a gum which was crystallised by trituration with 1-propanol. The crude solid was fractionated by flash chromatography (CHCl3 eluant) and from the appropriate fraction was obtained 8-amino-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3[2H]-one (0.25 g; m.p. 290-1° from n-propanol/water)ν(Nujol mull) 3465, 3350, 3230, 1658, 1617, 1585 cm-1 ; δ(DMSO-d6) 1.2-1.7 (1H,m,5-H), 1.8-2.9 (6H,m,4,4a,5,6-H) 5.35 (2H,s,NH2), 6.34 (1H,m,7-H), 6.46 (1H,m,9-H), 7.66 (1H,d,10-H), 10.5 (1H,s,NHCO) M+ 215.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:15][O:16][CH2:17][CH3:18])[C:12]([OH:14])=O)[N:10]=1)=[O:4].[NH2:19][CH:20]1[C:46](=[O:47])[N:22]2[C:23]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:24]([CH2:27][O:28][CH3:29])[CH2:25][S:26][C@H:21]12>>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:15][O:16][CH2:17][CH3:18])[C:12]([NH:19][CH:20]2[C:46](=[O:47])[N:22]3[C:23]([C:30]([O:32][CH:33]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])=[C:24]([CH2:27][O:28][CH3:29])[CH2:25][S:26][C@H:21]23)=[O:14])[N:10]=1)=[O:4]
Reactant: COCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: CCON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC)CS[C@H]12)c1csc(NC(=O)CCl)n1
Yield: 84 %

Procedure:
Following the method of Preparation 3, 225 mg of 2-(2-chloroacetamidothiazol-4-yl)-2-ethoxyiminoacetic acid and 200 mg of benzhydryl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate were reacted to give 280 mg of benzhydryl 7-[2-(2-chloroacetamidothiazol-4-yl)-2-ethoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate, in the form of a yellow powder.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:15]=[C:14]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:18])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(=O)([O-])[O-].[Na+].[Na+]>O>[F:5][C:6]1[CH:15]=[C:14]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:18])[C:13]([N+:1]([O-:4])=[O:2])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
With cooling with ice, 110 ml of fuming nitric acid was gradually added to 27.7 g of methyl 2-fluoro-4-[(2-pyridinylcarbonyl)amino]benzoate, and stirred at room temperature for 1.5 hours. With cooling with ice, the reaction liquid was gradually added to a solution of sodium carbonate (138 g) in water (2000 ml), and the formed solid was taken out through filtration. This was dried under reduced pressure to obtain 27.5 g of the entitled compound as a yellow solid.
Reaction SMILES: [O-:1]Cl.[Na+].[Cl:4][C:5]1[N:6]=[C:7]2[N:11]([C:12]=1[CH:13]=[O:14])[CH:10]=[CH:9][S:8]2>O.C(O)(C)(C)C>[Cl:4][C:5]1[N:6]=[C:7]2[N:11]([C:12]=1[C:13]([OH:1])=[O:14])[CH:10]=[CH:9][S:8]2
Reactant: [O-]Cl
Reactant: O=Cc1c(Cl)nc2sccn12
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1c(Cl)nc2sccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of NaOCl (230 mmol) and NaH2PO4 (176 mmol) in water (195 mL) is added dropwise to a solution of 6-chloro-imidazo[2,1-b]thiazole-5-carbaldehyde (26.8 mmol) in tert.-butanol (195 mL) and the mixture is stirred for 8 h at RT. The solvents are partially removed in vacuo and the obtained precipitate is filtered off. The filtrate is made acidic and the obtained precipitate is filtered off to give the desired product as a white solid. LC-MS: tR=0.67 min; [M+H]+=202.9.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[CH2:25](Br)[CH:26]=[CH2:27].O>CN(C)C=O>[CH2:27]([O:19][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:26]=[CH2:25]
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 7-chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (5.00 g) in dimethyl formamide (150 ml) under nitrogen at room temperature, was added sodium hydrogen carbonate (15.47 g). The reaction mixture was stirred at room temperature for 30 mins then allyl bromide (2.39 ml) was added, and stirring continued for a further 36 h at room temperature. The mixture was poured into water (200 ml) and the emerging precipitate was filtered and triturated with boiling methanol to give the desired compound as a beige solid in 50% yield. 1H NMR (360 MHz, DMSO-d6) 5 4.04 (2H, dd, J=6.45 Hz, J=1.84 Hz, OCH2CHCH2), 5.08 (2H, m, OCH2CHCH2), 5.88 (1H, m, OCH2CHCH2), 7.23 (1H, dd, J=12.45 Hz, J=3.00 Hz, 6-H), 7.36 (6H, m, Ph+8-H), 7.81 (1H, d, J=12.45 Hz, 5-H), 11.94 (1H, bs, NH).
Reaction SMILES: Br.Br[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[C:12]([CH3:15])=[CH:13][S:14][C:8]2=[N:7][C:6]=1[CH3:16].Br.Br.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=[C:28]2[NH:36][CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=[C:28]2[NH:36][CH:37]2[CH2:38][CH2:39][N:40]([CH2:3][CH2:4][C:5]3[C:10](=[O:11])[N:9]4[C:12]([CH3:15])=[CH:13][S:14][C:8]4=[N:7][C:6]=3[CH3:16])[CH2:41][CH2:42]2)=[CH:22][CH:21]=1
Reactant: Cc1nc2scc(C)n2c(=O)c1CCBr
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2scc(C)n2c(=O)c1CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 70 °C
Yield: 62.8 %

Procedure:
A mixture of 5.52 parts of 6-(2-bromoethyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one monohydrobromide, 7.3 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 6.4 parts of sodium carbonate and 135 parts of N,N-dimethylformamide was stirred and heated overnight at 70° C. The reaction mixture was poured onto water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (94:6 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 5 parts (62.8%) of 6-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 141.0° C. (compound 1).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:38]#[N:39])[C:19]([C:22]2[CH:27]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=[CH:24][C:23]=2[F:37])=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:38]#[N:39])[C:19]([C:22]2[CH:27]=[C:26]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]4=[N:4][CH:3]=3)[CH:25]=[CH:24][C:23]=2[F:37])=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccc(Cl)cc3C#N)c2)OC1(C)C
Product: N#Cc1cc(Cl)ccc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 4-chloro-2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile by the method of Example 65 to give 4-chloro-2′-fluoro-5′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white solid: δH (360 MHz, CDCl3) 7.29 (1H, d, J 7), 7.43-7.48 (1H, t, J 9), 7.54-7.71 (4H, m), 7.83 (1H, d, J 2), 8.10 (1H, s), 9.02 (1H, d, J 7).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][C:7]([CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[OH:18])=[CH:8][C:4]=2[CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc2sccc2c1
Product: Cc1ccc2sc(C(O)c3ccccc3)cc2c1

Procedure:
Using general procedure B, 5-methyl-benzo[b]thiophene was reacted with benzaldehyde to give (5-methyl-benzo[b]thiophen-2-yl)-phenyl-methanol as a colorless solid. MS: 237.1 ([M+H—H2O]+).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][O:57][P:58]([C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([NH2:67])[CH:62]=1)(=[O:60])[O-:59]>CN(C=O)C.C(N(CC)CC)C>[OH:60][P:58]([C:61]1[CH:62]=[C:63]([NH:67][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])[CH:64]=[CH:65][CH:66]=1)([O:57][CH3:56])=[O:59]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: COP(=O)([O-])c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COP(=O)(O)c1cccc(NC(=O)CC[C@H](N)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boc-Glu-OtBu (303 mg, HOAt (136 mg, 1 mmol) and HATU (380 mg, 1 mmol) were dissolved in 1 mL of DMF, and triethylamine (0.278 ml) was added thereto. 10 minutes later, the mixture of monomethyl(3-aminophenyl)phosphonate and dimethyl ester was added thereto and stirred at room temperature overnight. After removing a solvent, purification was conducted in accordance with the purification process A to obtain a title compound.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:18][CH2:19]O)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1)(=[O:7])=[O:6].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:19][CH2:18][N:4]([CH2:3][CH2:2][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1)(=[O:6])=[O:7]
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)N(CCO)CCO)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)N(CCC2CCCCO2)CCC2CCCCO2)ccc1Cl
Yield: 89.2 %

Procedure:
A solution of N,N-di(2-hydroxyethyl)-4-chloro-3-nitrobenzenesulfonamide (7.1 g, 21.9 mmol), 3,4-dihydro-2H-pyran (4.4 mL, 48 mmol) and p-toluenesulfonic acid hydrate (0.10 g) in methylene chloride (200 mL) was stirred at 20°-25° for 3 days. After washing with a saturated solution of sodium bicarbonate the organic layer was dried (Na2SO4), filtered and concentrated. Flash chromatography of the residue over silica gel with chloroform gave 9.0 g of product.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.P(Cl)(Cl)Cl>O>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][CH:4]=2)=[O:14])=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: Nc1ccc(Cl)cc1
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)c1ccc2cccnc2c1O
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (3.78 g) of Preparation 1 and 4-chloroaniline (2.55 g) in 250 mL xylenes is heated to reflux. To this is added dropwise PCl3 (1.37 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl. The resulting solid is collected, washed with water and dried. The crude product is recrystallized from EtOAc/hexanes to yield 1.96 g of the title product as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][CH:10]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[CH2:11][CH2:12][CH2:13][C:14](OCC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.C(OCC)(=O)C>CO>[O:15]=[C:14]1[CH2:13][CH2:12][CH2:11][CH:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCC(NNC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NN1C(=O)CCCC1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
Ethyl 5-(N′-tert-butoxycarbonylhydrazino)-5-(3-trifluoromethylphenyl)pentanoate (323 mg) was dissolved in methanol (7 mL). A 1 N sodium hydroxide solution (5 mL) was added and the mixture was stirred at room temperature for two hours and 30 minutes. 1 N hydrochloric acid (5 mL) and ethyl acetate were added to the reaction solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the organic layer was concentrated under reduced pressure. The residue was dissolved in dimethylformamide (8 mL). 1-Ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (317 mg) and 1-hydroxybenzotriazole (223 mg) were added and the mixture was stirred at room temperature for 13 hours. 1-Ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (317 mg) was added to the reaction solution, and the mixture was further stirred for one hour. Diethyl ether and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (214 mg). The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][OH:4].[H-].[Na+].[F:12][C:13]([F:28])([S:24](F)(=[O:26])=[O:25])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17]>CCOCC>[F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][O:4][S:24]([C:13]([F:12])([F:28])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])(=[O:26])=[O:25]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2,2,3,3,3-pentafluoropropanol (3.0 g) was added to a suspension of sodium hydride (1.08 g) in dry ether (50 ml) at 0° C. under an argon atmosphere. Stirred at 0° C. for 15 minutes. Perfluoro-1-butanesulphonyl fluoride (12.08 g) was slowly added. Stirred at reflux for 3 hours, cooled and carefully quenched with H2O. Extracted with ether, twice. The combined extracts were washed with saturated brine dried over MgSO4, filtered and evaporated to give 2,2,3,3,3-pentafluoropropyl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulphonate as an oil. Yield 7.9 g. NMR: (CDCl3) δ 4.9 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][O:29][CH3:30])[CH:25]=[C:24]([Br:31])[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])C.[OH-].[Na+]>C(O)C.CCOC(C)=O>[Br:31][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([CH2:28][O:29][CH3:30])[CH:25]=1)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]1[C:10]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:39])=[O:3]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(COC)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCc1cc(Br)cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
To a solution of 4-[3-[6-(3-Bromo-5-methoxymethyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (500 mg, 0.82 mmol) in hot ethanol (20 mL) was added aqueous 2.0 N sodium hydroxide (5 mL). The resulting solution was heated to 60° C. and stirred for 4 h. Then, the reaction mixture was cooled down and diluted with EtOAc, washed with 10% aq. HCl and brine. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford 400 mg (89%) of title compound as a light yellow oil. HR-ES(+) calcd for C27H35O7Br [M+Na]+ 573.1458, observed 573.1459.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].[CH3:14][C:15](C)([O-:17])C.[K+].C(OC(=O)C)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][C:15](=[O:17])[CH3:14])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccc(O)c(OC(C)=O)c1
Reaction time: 0.17 h

Procedure:
3,4-Dihydroxy-benzoic acid ethyl ester (550 mg, 3.02 mmol) was dissolved in DMF (5 ml), potassium tert-butoxide (210 mg, 2.87 mmol) was added and the mixture stirred for 10 min. Acetic anhydride (339 mg, 3.32 mmol) was added and stirring continued for 10 min. The mixture was partitioned between EA and 2 N hydrochloric acid, and the aqueous phase extracted with EA. The combined organic phases were dried over sodium chloride, decanted and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient).
Reaction SMILES: C([BH3-])#N.[Na+].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[CH3:18][C:19]([CH3:21])=O.Cl>CO.O>[CH:19]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[CH:8]=[CH:7][C:6]([OH:5])=[CH:11][CH:10]=2)[CH2:13][CH2:14]1)([CH3:21])[CH3:18]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N1CCN(c2ccc(O)cc2)CC1

Procedure:
Sodium cyanoborohydride (3.78 g.) was added to a stirred solution of N-(4-hydroxyphenyl)piperazine (5.35 g.) and acetone (8.7 g.) in a mixture of methanol (100 ml) and water (20 ml.). The pH of the resulting solution was adjusted to pH 7.5 by the addition of a few drops of N hydrochloric acid and stirring was continued at room temperature (~20° C.) for a period of 19 hours. Upon completion of this step, further acetone (8.7 g.) and sodium cyanoborohydride (1.89 g.) were added to the mixture and the pH was again adjusted to a value of 7.5. After a further period of stirring at room temperature for eight hours, water (100 ml.) was added to the reaction mixture and the precipitated solid product was subsequently collected by means of suction filtration and thereafter vacuum dried over phosphorous pentoxide to constant weight. Recrystallization of the crude material so obtained from a mixture of ethanol and methanol then gave pure 1-isopropyl-4-(4-hydroxyphenyl)piperazine in the form of a crystalline solid (yield, 4.78 g.), m.p. 244°-246° C. The yield of pure product amounted to 72% of the theoretical value.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[N:15]=2)=[O:13])[CH:9]=[CH:8][C:7]=1[OH:24].Br[CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[N:15]=2)=[O:13])[CH:9]=[CH:8][C:7]=1[O:24][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1
Reactant: COC(=O)CCc1cc(C(=O)c2cccc(C(=O)OC)n2)ccc1O
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Product: COC(=O)CCc1cc(C(=O)c2cccc(C(=O)OC)n2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 73.9 %

Procedure:
Under the conditions of example 1A, 640 mg of 3-[5-(6-methoxycarbonyl-2-pyridylcarbonyl)-2-hydroxyphenyl]-propionic acid methyl ester is reacted with 505 mg of (1E)-6-bromo-l-(4-methoxyphenyl)- 1-hexene, worked up and the crude product chromatographed on silica gel with hexane/ethyl acetate (0-15%). 732 mg of 3-{5-[6-methoxycarbonyl-2-pyridylcarbonyl]-2-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-phenyl}-propionic acid methyl ester of melting point 80°-82° C. is obtained.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25](I)=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl-].[Li+].C([Mg]Cl)(C)C.[O:35]1[CH2:38][C:37](=[O:39])[CH2:36]1>O1CCCC1>[C:1]12([CH2:11][O:12][C:13]3[C:25]([C:37]4([OH:39])[CH2:38][O:35][CH2:36]4)=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: O=C1COC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(C2(O)COC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: -40 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a solution of tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoate (0.973 g, 2.00 mmol) in anhydrous tetrahydrofuran (10 mL) was added isopropylmagnesium chloride lithium chloride complex (1.30 M solution in tetrahydrofuran, 1.76 mL, 2.20 mmol) at −40° C. The reaction mixture was stirred for 1 hour at −40° C., after which oxetan-3-one (0.432 g, 6.00 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 hour. After quenched with saturated ammonium chloride solution (10 mL), the mixture was extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with brine (5 mL); dried over sodium sulfate, and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by silica gel column chromatography using 0-50% ethyl acetate in hexanes as eluent to afford the title compound as an amorphous solid (0.336 g, 39%): 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=8.2 Hz, 1H), 6.60 (d, J=12.3 Hz, 1H), 5.01 (d, J=6.9 Hz, 2H), 4.84 (d, J=7.0 Hz, 2H), 3.86 (s, 1H), 3.52 (s, 2H), 2.05-1.94 (m, 3H), 1.78-1.55 (m, 12H), 1.54 (s, 9H).