Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:20][CH:21]([OH:30])[CH2:22][S:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O.O>[CH2:1]([O:8][C:9]1[C:14]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:20][CH:21]([OH:30])[CH2:22][S:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCSCC(O)Cc1cccc(C2CCCC2)c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCSCC(O)Cc1cccc(C2CCCC2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
0.675 g (1.63 mmol) of methyl 7-(2-benzyloxy-3-cyclopentylphenyl)-6-hydroxy-4-thiaheptanoate (Example 1) is dissolved in 10 ml of methanol/water 9:1, and 0.7 g (17.5 mmol) of NaOH dissolved in a little water is added. The mixture is left to stir at room temperature overnight, then the solvent is removed by distillation in vacuo, and the residue is acidified with cold 1N hydrochloric acid. Three extractions with diethyl ether are carried out, and the organic phases are washed twice with saturated brine and dried over sodium sulfate, and the solvent is removed by distillation in vacuo. 444 mg (66% of theory) of 7-(2-benzyloxy-3-cyclopentylphenyl)-6-hydroxy-4-thiaheptanoic acid are obtained.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1>C1COCC1.O>[F:30][C:31]1[CH:38]=[CH:37][C:34](/[CH:35]=[CH:10]/[CH2:9][CH2:8][OH:7])=[CH:33][CH:32]=1
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OCC/C=C/c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 47.6 %

Procedure:
n-Butyllithium (1.6M in H, 100 ml) was added dropwise to a stirred suspension of (3-hydroxypropyl)triphenylphosphonium bromide (32.1 g) in dry THF (200 ml) cooled to 0° under nitrogen. A solution of 4-fluorobenzaldehyde (9.93 g) in dry THF (100 ml) was added dropwise and the mixture stirred under nitrogen at 0° C. for 30 min and at room temperature for a further 1.5 h. The mixture was carefully diluted with water (25 ml), the solvent evaporated in vacuo at 40° and the residue partitioned between EA (200 ml) and water (200 ml). The aqueous phase was re-extracted with EA (200 ml), the organic phase combined, dried and evaporated in vacuo to give a brown oil. Purification by FCC eluting with CX-ER (1:1) gave the title compound as a colourless oil (6.33 g). T.l.c. (CX-ER 1:1) Rf 0.13
Reaction SMILES: [N:1]([CH:4]([CH2:12][F:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-]>CO.[Pd]>[F:13][CH2:12][CH:4]([NH2:1])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=NC(CF)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(CF)Cc1ccccc1
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of (2-azido-3-fluoro-propyl)benzene (0.6 g) in MeOH (50 mL) was added 10% Pd/C catalyst and the suspension was hydrogenated for 2 hr. at 3 atmospheres pressure. The filtered reaction mixture and MeOH washings were concentrated to an oil which was chromatographed over silica gel with an ammoniated mixture of MeOH/ether (1:9) to give 0.38 g of the title compound. MS ES (M++H)=154.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[C:10]([C:16]#[CH:17])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:21]=1>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[C:10]([C:16]#[C:17][C:24]2[CH:25]=[CH:20][CH:21]=[C:22]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[CH:23]=2)=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1nc(C)ccc1OCC(=O)OC(C)(C)C
Product: CCCS(=O)(=O)c1cccc(C#Cc2nc(C)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (2-ethynyl-6-methyl-pyridin-3-yloxy)-acetic acid tert-butyl ester (Intermediate 86) and 1-bromo-3-(propane-1-sulfonyl)-benzene (Intermediate 5), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:26]1([CH2:32][CH2:33][NH2:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][NH:34][CH2:33][CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: NCCc1ccccc1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 2-phenylethylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=NO.Cl.C=[O:16].O>O1CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=[O:16]
Reactant: C=O
Reactant: Cc1cccc([N+](=O)[O-])c1C=NO
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc([N+](=O)[O-])c1C=O

Procedure:
At 65° C., 14 g of 2-methyl-6-nitrobenzaldoxime (80 mmol) are stirred in a mixture of 55 ml of 5% strength hydrochloric acid, 37 g of a 37% strength solution of formaldehyde, 50 ml of water and 100 ml of tetrahydrofuran for 24 hours. The phases are subsequently separated, and the dark phase is extracted with methylene chloride/water. The organic phase is dried with sodium sulfate and concentrated. This gives 10.1 g of crude product which is purified by filtration over silica gel using toluene as mobile phase.
Reaction SMILES: [CH:1](=[C:8]1[C:12](=[O:13])[O:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCC(Cl)(Cl)Cl>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:1]=[C:8]([C:12]([OH:11])=[O:13])[N:9]=1
Reactant: O=C1OC(c2ccccc2Cl)=NC1=Cc1ccccc1
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Temperature: 60 °C
Yield: 35 %

Procedure:
A solution of 22 (12 mmol) in tetrachloroethane was added to the suspension of AlCl3 (36 mmol) in tetrachloroethane (50 ml). The resulting mixture was heated to 60° C. for 1.5 hrs. The reaction mixture was quenched by addition of 1 M HCl (50 ml). Then, the mixture was basified by addition of NaOH (1M aqueous solution), the resulted layers were separated, and the aqueous layer was acidified by HCl (aqueous solution). This aqueous phase was extracted with CH2Cl2, dried over MgSO4 and finally the solvents were removed under reduced pressure, to give 35% yield of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:8][CH2:7]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[F:46][C:47]1[CH:48]=[CH:49][C:50]2[N:51]([CH:53]=[C:54]([C:56](O)=[O:57])[N:55]=2)[CH:52]=1.C([O-])(O)=O.[Na+]>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH:12]2[CH2:13][CH2:14][N:15]([C:56]([C:54]3[N:55]=[C:50]4[CH:49]=[CH:48][C:47]([F:46])=[CH:52][N:51]4[CH:53]=3)=[O:57])[CH2:16][CH2:17]2)[CH2:10][CH2:11]1
Reactant: Clc1ccc(OC2CCN(C3CCNCC3)CC2)cc1Cl
Reactant: O=C(O)c1cn2cc(F)ccc2n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cn2cc(F)ccc2n1)N1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Yield: 34.8 %

Procedure:
4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see step b of Example 2) was dissolved in dichloromethane (5 ml), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.425 g), 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (0.126 g) and triethylamine (0.254 ml) were added. After 16 hours at room temperature dichloromethane and aqueous NaHCO3 solution were added. The product was extracted with dichloromethane, the combined organic extracts were washed with water, dried with MgSO4 and concentrated. Purification by reverse phase HPLC (with a gradient eluent system (45% MeCN/NH4OAc aq (0.1%) to 95% MeCN//NH4OAc aq (0.1%)) (any excess NH4OAc was removed by dissolving the compound in ethyl acetate and washing with aqueous saturated NaHCO3 followed by drying of the organics with magnesium sulfate and evaporation of solvent) gave the title compound (0.104 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6]2[C:7]([O:9][C:10](=[O:11])[CH:3]1[CH2:4][CH2:5]2)=O.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[N:28][CH:27]=[C:26]([Cl:30])[N:25]=2)[CH2:20][CH2:19]1.C1(C)C(C)=CC=CC=1>O>[Cl:30][C:26]1[N:25]=[C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:7](=[O:9])[CH:6]4[C:2]([CH3:1])([CH3:12])[CH:3]([CH2:4][CH2:5]4)[C:10]3=[O:11])[CH2:23][CH2:22]2)[CH:29]=[N:28][CH:27]=1
Reactant: CC1(C)C2CCC1C(=O)OC2=O
Reactant: NCCCCN1CCN(c2cncc(Cl)n2)CC1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1(C)C2CCC1C(=O)N(CCCCN1CCN(c3cncc(Cl)n3)CC1)C2=O

Procedure:
2,2-Dimethylcyclopentane-1,3-dicarboxylic anhydride (1.68 g., 10 mmole) and 1-(4-aminobutyl)-4-(6-chloro-2-pyrazinyl)piperazine (2.97 g., 11 mmole) were combined in 500 ml. of xylene and refluxed for 48 hours with Dean-Stark water removal. Concentration in vacuum, column chromatography on 100 g. of silica gel with chloroform, and recrystallization from 50 ml. of isopropanol with addition of 4N isopropanolic HCl gave 0.55 g. of the title compound as the monohydrochloride; m.p. 210° C. (d).
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][CH:8]([C:16]([NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])=[O:17])[C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].[C:34]([C:36]1[CH:37]=[CH:38][C:39]([N:42]2CCNCC2)=[N:40][CH:41]=1)#[N:35]>>[C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][CH:8]([C:9]([N:11]2[CH2:12][CH2:13][N:42]([C:39]3[CH:38]=[CH:37][C:36]([C:34]#[N:35])=[CH:41][N:40]=3)[CH2:15][CH2:14]2)=[O:10])[C:16]([NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:20])=[O:21])=[O:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCN(CC)C(=O)C(Cc1ccc(C#N)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Product: N#Cc1ccc(CC(C(=O)NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCN(c3ccc(C#N)cn3)CC2)cc1
Yield: 75.8 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (300 mg) obtained in Example 111 (4) and N-(5-cyano-2-pyridyl)piperazine (166 mg). This was purified by silica gel column chromatography to give the title compound (284 mg) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>CCO.O>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH:8]=[N:12][OH:13])=[N:6][CH:7]=1
Reactant: Cc1cc(C=O)ncc1Br
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C=NO)ncc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a solution of the compound obtained in Step B (3.1 g) in EtOH (47.5 ml) and water (23 ml) were added hydroxylamine hydrochloride (1.4 g) and sodium acetate (1.9 g). The reaction was stirred for 15 min at room temperature. The white solid was filtered off and the solution concentrated in vacuo to afford the crude title product (2.2 g, white solid), which was used directly for the next step. LCMS (Method F) 2.09 min, M+H 564/566.
Reaction SMILES: [H-].[Na+].N1([C:12]([C:14]2[C:15]([NH:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=2)=[O:13])C2C=CC=CC=2N=N1.C(OC(C)(C)C)(=O)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].OS([O-])(=O)=O.[Na+].FC(F)(F)C(O)=O>CN(C=O)C.C(Cl)Cl>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:12]([C:14]1[C:15]([NH:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=1)=[O:13])[CH3:35]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: CSc1ncc(C(=O)n2nnc3ccccc32)c(NC2CCCCC2)n1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)c1cnc(SC)nc1NC1CCCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 6.07 g, 151.60 mmol) was added portionwise, under nitrogen atmosphere, at 0° C., to a mixture of benzotriazol-1-yl-(4-cyclohexylamino-2-methylsulfanyl-pyrimidin-5-yl)-methanone (25.4 g, 68.95 mmol) and tert-butyl ethyl malonate (14.36 mL, 75.83 mmol) in anhydrous DMF (400 mL) and the resulting mixture was stirred at RT for 15 h. The reaction mixture was poured into a mixture of NaHSO4 (aq 10%, 1 L) and ice (200 mL) and then was carefully extracted with EtOAc (2×200 mL). The combined organic extracts were washed with water (2×100 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The yellow oil obtained was dissolved in DCM (30 mL) and trifluoroacteic acid (60 mL) was added. The reaction mixture was heated at reflux for 1 h. The resulting mixture was cooled and the solvent was evaporated under reduced pressure. NaHCO3 (sat'd aq) was added until pH 7 was reached and the resulting mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane 10/90 to 15/85) to afford 20.9 g (90% yield) of 3-(4-cyclohexylamino-2-methylsulfanyl-pyrimidin-5-yl)-3-oxo-propionic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([S:26](=[O:33])(=[O:32])[N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:36])=O>>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([S:26](=[O:33])(=[O:32])[N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:14][C:10]=1[C:11]([Cl:36])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(C)S(=O)(=O)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Product: CCCN(C)S(=O)(=O)c1cc(C(=O)Cl)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
2.9 Reaction of 2,4-dibenzyloxy-5-(N-methyl-N-propylsulfamoyl)benzoic acid with thionyl chloride gives the compound 2,4-dibenzyloxy-5-(N-methyl-N-propylsulfamoyl)benzoyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.CO.O1CCCC1>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1nc(C=Cc2cccc([N+](=O)[O-])c2)cs1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1nc(CCc2cccc(N)c2)cs1

Procedure:
N-{4-[2-(3-Nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (E,Z mixture) (315 mg) in a mixed solvent of methyl alcohol (3 ml), tetrahydrofuran (6 ml), and acetic acid (1 ml) was hydrogenated over 10% Palladium on carbon (50% wet, 200 mg) under 4.3 atmospheric pressure at room temperature for 3 hours. The catalyst was removed off by filtration, and the filtrate was evaporated in vacuo. The residue was poured into water, the pH of the aqueous layer was adjusted to 9 with aqueous sodium hydrogen carbonate. The resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (9 g) using a mixed solvent of n-hexane and ethyl acetate (2:1 to 1:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give syrup. The syrup of the objective compound was changed to solid in freezer (275 mg, 96.6%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(NCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([OH:53])(=[O:52])[CH2:46][CH2:47][CH2:48][CH2:49][C:50]#[CH:51]>CN(C=O)C.[Cu]I>[C:18]([C:14]1[C:13](=[O:20])[NH:12][C:11]2[S:10][CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:51]#[C:50][CH2:49][CH2:48][CH2:47][CH2:46][C:45]([OH:53])=[O:52])[CH:7]=[CH:6][CH:5]=3)[C:16]=2[C:15]=1[OH:17])#[N:19]
Reactant: N#Cc1c(O)c2c(-c3cccc(Br)c3)csc2[nH]c1=O
Reactant: C#CCCCCC(=O)O
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: N#Cc1c(O)c2c(-c3cccc(C#CCCCCC(=O)O)c3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(3-bromo-phenyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (50 mg, 0.15 mmol) in 1.5 mL DMF was added diethylamine (0.16 mL, 1.5 mmol), followed by copper(I) iodide (trace), Pd(PPh3)Cl2 (3.5 mg, 0.005 mmol), and triphenylphosphine (12 mg, 0.04 mmol). The resulting mixture was stirred at rt for 5 min, after which hept-6-ynoic acid (63 μL, 0.5 mmol) was added. The reaction was then heated to 120° C. using microwave reactor for 25 min, filtered, concentrated and purified by reverse phase HPLC to give the titled compound. MS (ESI) m/e 391 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.54 (m, 4H), 2.22 (m, 4H), 6.68 (s, 1H), 7.21–7.26 (m, 2H), 7.37–7.44 (m, 2H).
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:36]([O:38][C:39](=[O:52])[CH:40]([O:49][CH2:50][CH3:51])[CH2:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)[CH3:37].N(C(OCC)=O)=NC(OCC)=O>>[CH2:36]([O:38][C:39](=[O:52])[CH:40]([O:49][CH2:50][CH3:51])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:10][CH2:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:44][CH:43]=1)[CH3:37]
Reactant: OCC=C(c1ccccc1)c1ccncc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCC=C(c2ccccc2)c2ccncc2)cc1)OCC
Yield: 42.5 %

Procedure:
Reaction of 3-phenyl-3-pyridin-4-yl-prop-2-en-1-ol (0.50 g, 2.37 mmol), triphenylphosphine (0.68 g, 2.61 mmol), 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (0.68 g, 2.84 mmol) and diethyl azodicarboxylate (0.46 g, 2.63 mmol) in an identical manner to example 1 gave the title compound (435 mg, 43%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O.CCCCCCC>C1COCC1.C(OCC)(=O)C>[CH3:22][O:12][C:11](=[O:13])[C@H:9]([CH3:10])[N:8]([C:14]1[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=1)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)c1cc(F)cc(F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COC(=O)[C@H](C)N(C(=O)OC(C)(C)C)c1cc(F)cc(F)c1
Yield: 86 %

Procedure:
N-t-butoxycarbonyl(3,5-difluorophenyl)alanine (2.6 g, 8.6 mmol) in 35 mL of dry THF under nitrogen is stirred with 2.0 g (14.5 mmol) of pulverized K2CO3 and 1.0 mL (10.5 mmol) of dimethylsulfate at 40° C. for 17 h. The mixture is diluted with ethyl acetate, washed twice with 1 N KH2PO4, once with 1 N NaHCO3, twice with water, and finally with brine. The organic phase is dried with Na2SO4 and concentrated to a sticky solid. Trituration with heptane affords 2.32 g (7.4 mmol, 85%) of N-t-butoxycarbonyl(3,5-difluorophenyl)alanine methyl ester as a white solid. 1H NMR (CDCl3) δ 6.72-6.56 (m, 3H), 5.04 (d, J=8 Hz, 1H), 4.57 (q, J=6 Hz, 1H), 3.75 (s, 3H), 3.14 (dd, J=6, 14 Hz, 1H), 3.01 (dd, J=6, 14 Hz, 1H), 1.43 (s, 9H).
Reaction SMILES: [Na][Na].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.I[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([O-:18])=[O:17].[Na+].COCCOCCN(CCOCCOC)CCOCCOC>CN1CCCC1=O.[Cu]Cl>[C:8]([C:7]1[CH:11]=[CH:12][C:4]([O:3][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[CH:5][CH:6]=1)([OH:10])=[O:9]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C([O-])c1ccccc1I
Agent: Cl[Cu]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(Oc2ccccc2C(=O)O)cc1
Reaction time: 4 h
Yield: 58 %

Procedure:
A mixture of 40 g (0.22 mol) of the disodium salt of 4-hydroxybenzoic acid, 54 g (0.2 mol) of sodium 2-iodobenzoate, 1.98 g (0.02 mol) of copper(I) chloride and 6.47 g (0.02 mol) of tris-[2-(2-methoxyethoxy)-ethyl]amine (TDA) in 500 ml of N-methylpyrrolidone is kept at 180° C. for 4 hour,. The solvent is then removed by distillation, the residue is diluted with about 1 litre of water and the mixture is acidified with concentrated hydrochloric acid. The product which has precipitated is filtered off and dried under a high vacuum. 29.7 g (58%) of 2-(4-carboxyphenoxy)benzoic acid, melting point 220°-223° C., result as a brown powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C@H:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)[NH2:12])=[CH:2]1.[CH3:24][CH2:25][CH2:26][CH2:27][C:28](=O)[CH2:29][CH2:30][CH2:31][CH3:32]>C(O)CCC>[CH2:27]([C:28]1([CH2:29][CH2:30][CH2:31][CH3:32])[C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]=2[CH2:10][C@H:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)[NH:12]1)[CH2:26][CH2:25][CH3:24]
Reactant: CCCCC(=O)CCCC
Reactant: N[C@H](Cc1csc2ccccc12)c1nc(-c2ccccc2)c[nH]1
Solvent: CCCCO
Product: CCCCC1(CCCC)N[C@@H](c2nc(-c3ccccc3)c[nH]2)Cc2c1sc1ccccc21
Yield: 9 %

Procedure:
To a solution of (1R)-2-(1-benzothiophen-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)-1-ethanamine (1 g, 2.5 mmol) in n-butanol (20 ml) was added 5-nonanone (2.2 ml, 13 mmol) and the mixture refluxed overnight. The solvent was removed under reduced pressure. To the residue was added water (15 ml) followed by a 10% NaHCO3 solution until neutral pH and extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with water (2×10 ml), dried over MgSO4, filtered. The solvent was evaporated under reduced pressure to afford an oil which was purified by column chromatography on silica gel using ethyl acetate/heptane 1:1 as eluent. After removing the solvent, diisopropyl ether was added to the residue. The resulting white precipitate was filtered off and washed with diisopropyl ether to afford 0.1 g of the title product. Melting point: 198-200° C.