Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]([CH2:16][C:15]3[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=3)[C:2]2=[NH:1])=[CH:14][CH:13]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Nc1nc2ccccc2[nH]1
Product: N=c1n(Cc2ccc(F)cc2)c2ccccc2n1Cc1ccc(F)cc1

Procedure:
The title compound was prepared from 2-aminobenzimidazole and 4-fluorobenzyl bromide by Procedure A. The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 148-150° C.). MS(ES+) m/z 351 ([M+1]+, 100). 1NMR (DMSO-d6) δ 5.07 (s, 4H), 5.75 (br s, 1H), 6.78-6.91 (m, 4H), 7.12-7.18 (m, 4H), 7.30-7.42 (m, 4H).
Reaction SMILES: [CH:1](=[C:8]([CH2:12][C:13]([N:15]1[CH2:23][C@H:22]2[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:16]1)=[O:14])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Rh]>[CH:5]1[CH:4]=[CH:3][C:2]([CH2:1][C@H:8]([C:9]([OH:11])=[O:10])[CH2:12][C:13]([N:15]2[CH2:16][C@H:17]3[C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:23]2)=[O:14])=[CH:7][CH:6]=1
Reactant: O=C(O)C(=Cc1ccccc1)CC(=O)N1C[C@H]2CCCC[C@H]2C1
Agent: [Rh]
Product: O=C(O)[C@H](CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1

Procedure:
The preparation was carried out in the same manner as in Example 1, except that 10.04 mg of PCPPM was used instead of 3.02 mg of PCPPM of Example 1, and 328 mg of CATAXA/rhodium-1,5-cyclooctadiene complex (S/C=3,000), which is an immobilized rhodium, was used instead of 1.18 mg of rhodium-1,5-cyclooctadiene-chloride complex of Example 1. After the reaction, 2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid was not detected, and the optical purity of mitiglinide thus obtained was 95.5% e.e.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH:5]=[CH:6]1)[C:3](=O)[NH:2]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:15]([N:2]1[CH2:3][C@@H:4]2[CH2:7][C@H:1]1[CH:6]=[CH:5]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C1N[C@@H]2C=C[C@H]1C2
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C1=C[C@@H]2C[C@H]1CN2Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a round bottom flask containing commercially available, (1S,4R)-2-azabicyclo[2.2.1]hept-5-en-3-one (2.0 g, 18.3 mmol), in THF (100 mL) at 0° C. was added a solution of LiAlH4 (1 M in THF, 40.3 mL, 40.3 mmol), and the reaction mixture was refluxed overnight. The reaction mixture was then cooled to 0° C. and carefully quenched by the dropwise addition of H2O (15 mL). Celite and solid Na2CO3 were added to the slurry and the reaction mixture was vigorously stirred at room temperature for 3 h. The slurry was then filtered and the solids washed with THF. Benzyl bromide (2.4 mL, 20.2 mmol) and an aqueous solution of Na2CO3 (3.2 g in 30 mL H2O) were added to the filtrate and the reaction mixture stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was extracted with EtOAc (3×). The combined organics were washed with H2O, brine, dried with MgSO4, filtered, and concentrated to provide crude (1S,4R)-2-benzyl-2-azabicyclo[2.2.1]hept-5-ene as a yellow oil, which was directly hydroborated according to the procedure of F. Carroll et al. [J. Med. Chem. 1992, 35, 2184-2191]. The crude alcohol was purified by silica gel chromatography (0-15% MeOH (with 5% NH4OH) in DCM) to give intermediate B-6 as a clear oil (2.66 g, 13.1 mmol, 71% over 3 steps). MS (ESI) mass calcd for C13H17NO, 203.1. m/z found 204.1 [M+H]+. 1H NMR (500 MHz, Chloroform-d) δ 7.39-7.28 (m, 4H), 7.26-7.21 (m, 1H), 4.18-4.09 (m, 1H), 3.76-3.66 (m, 2H), 3.06 (br. s, 1H), 2.51 (dt, J=9.0, 3.0 Hz, 1H), 2.44-2.35 (m, 2H), 1.90-1.81 (m, 1H), 1.68-1.53 (m, 2H), 1.38-1.30 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:21](O)=[O:22])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CN(C)C=O>[C:58]1([NH:57][C:21]([C:15]2[C:14]3[C:18](=[CH:19][CH:20]=[C:12]([NH:11][S:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)(=[O:9])=[O:10])[CH:13]=3)[NH:17][N:16]=2)=[O:22])[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: O=C(O)c1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Yield: 12.7 %

Procedure:
N-Phenyl-5-(3-fluorobenzenesulfonylamino)-1H-indazole-3-carboxamide can be obtained as described in Example 18 from 0.45 g of 5-(3-fluorobenzenesulfonylamino)-1H-indazole-3-carboxylic acid, 11 ml of dimethylformamide, 0.56 g of 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 0.38 g of diisopropylethylamine and 0.14 g of aniline. 70 mg of N-phenyl-5-(3-fluorobenzenesulfonylamino)-1H-indazole-3-carboxamide are thus obtained in the form of a brown solid melting above 260° C. (Analysis: C20H15FN4O3S.0.73H2O % calculated C, 58.54; H, 3.68; F, 4.63; N, 13.65; O, 11.69; S, 7.81. % found C, 58.09; H, 3.18; N, 13.58; S, 7.43).
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1.Cl>O1CCCC1.O>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH2:20][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[O:21])=[CH:15][CH:14]=1
Reactant: CCOC(=O)OCC
Reactant: COc1ccc(C(C)=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(OC)cc1

Procedure:
In 60 ml of tetrahydrofuran was suspended 18.7 g of 60% sodium hydride followed by addition of 39.4 of diethyl carbonate. Then, a solution of 25 g of p-methoxyacetophenone in 70 ml of THF was added dropwise with refluxing and the mixture was further refluxed for 5 hours. After cooling, the reaction mixture was poured slowly into iced water, neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The resulting oil was distilled under reduced pressure to provide 30.1 g of the desired compound as a pale yellow oil. b.p. 161°-164° C. (3 mmHg).
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=4[F:32])=[C:20]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:19]=3)[N:13]=[CH:12][N:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=4[F:32])=[C:20]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:19]=3)[N:13]=[CH:12][N:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(c1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cc(C(CC(=O)O)C4CC4)ncn3)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(6-((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methoxy)pyrimidin-4-yl)propanoate (112 mg) in THF (2.0 mL) and methanol (1.0 ml) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at 50° C. for 30 min. 1N Hydrochloric acid (2.0 mL) was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (96 mg) as a white amorphous solid.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[F:16])[S:4][N:3]=1.[Al](CC)(CC)[CH2:18][CH3:19]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:18]([C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[F:16])[S:4][N:3]=1)[CH3:19]
Reactant: Cc1ccc(-c2snc(Cl)c2C#N)c(F)c1
Reactant: CC[Al](CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCc1nsc(-c2ccc(C)cc2F)c1C#N
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-chloro-5-(2-fluoro-4-methylphenyl)-1,2-thiazole-4-carbonitrile (500 mg, 1.98 mmol, 1.00 equiv), 1,4-dioxane (20 mL), Pd(PPh3)4 (343 mg, 0.30 mmol, 0.15 equiv), Al(Et)3 (6.0 mL). The resulting solution was stirred for 3 h at 110° C. The reaction was then quenched by the addition of 3 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 150 mg (31%) of 3-ethyl-5-(2-fluoro-4-methylphenyl)-1,2-thiazole-4-carbonitrile as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([Se:16][C:17]#[C:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.O[N:29]1[C:33]2C=C[CH:36]=[CH:37][C:32]=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.C(N)CCC>C1COCC1>[CH2:33]([NH:29][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([C:18]#[C:17][Se:16][C:3]2[C:2]([CH3:1])=[CH:11][C:10]3[C:9]([CH3:12])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:14])([CH3:15])[C:5]=3[CH:4]=2)=[N:20][CH:21]=1)[CH2:32][CH2:37][CH3:36]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc2c(cc1[Se]C#Cc1ccc(C(=O)O)cn1)C(C)(C)CCC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCCCN
Solvent: C1CCOC1
Product: CCCCNC(=O)c1ccc(C#C[Se]c2cc3c(cc2C)C(C)(C)CCC3(C)C)nc1

Procedure:
In a manner similar to that of Example 10, 300 mg (0.72 mmol) of 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinic acid are reacted with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300 mg (1.45 mmol) of 1,3-dicyclohexylcarbodiimide and 63.5 mg (0.87 mmol) of butylamine in 20 ml of THF. After purification on a column of silica (ethyl acetate 20/heptane 80), 60 mg (17%) of a yellow solid are obtained. m.p.=172° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].B(O)(O)[C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1.Cl[C:20]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:37]=[CH:36][C:35]([C@@H:38]([NH:40][C:41](=[O:43])[CH3:42])[CH3:39])=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH:23]=[CH:22][N:21]=1>O1CCOCC1.CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:20]3[N:25]=[C:24]([N:26]4[CH2:31][CH2:30][CH:29]([C:32]5[CH:37]=[CH:36][C:35]([C@@H:38]([NH:40][C:41](=[O:43])[CH3:42])[CH3:39])=[CH:34][CH:33]=5)[CH2:28][CH2:27]4)[CH:23]=[CH:22][N:21]=3)=[CH:9][C:10]=2[O:16][CH2:15]1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccnc(Cl)n3)CC2)cc1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccnc(-c4ccc5c(c4)OCO5)n3)CC2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Under argon atmosphere 0.2 mL Na2CO3-solution (2 mol/L) and 3 mg (0.004 mmol) bis(triphenylphosphine)-palladium(II) chloride are added to a mixture of 50 mg (0.30 mmol) 3,4-(methylenedioxy)phenylboronic acid and 36 mg (0.10 mmol) (S)—N-(1-{4-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (compound XIV.3) in 2 mL dioxane/1 mL MeOH. The mixture is stirred at 90° C. for 3 h. After that time, the mixture is diluted with DMF/water and is filtered. The filtrate is purified using reversed phase HPLC (water (+0.1% TFA)/MeOH) to yield the desired product.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:41][CH2:42][CH2:43][C:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:45]>CC(=O)CC>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:41][CH2:42][CH2:43][C:44](=[O:45])[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:8][CH2:7]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: O=C(CCCCl)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)c1
Temperature: 78 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
To a solution of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2 g, 0.47 mmol), potassium carbonate (0.097 g, 0.7 mmol) and sodium iodide (0.021 g, 0.14 mmol) in 2-butanone (5 mL), was added 4-chlorobutyrophenone (0.076 mL, 0.47 mmol, d=1.138). After stirring at 78° C. for 18 hours, the reaction mixture was filtered, concentrated and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.11 g, 41%); MS for C35H41N3O4 m/z 568.16 (M+H)+.
Reaction SMILES: [C:1]([O:12][CH:13]1[CH:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][CH:15]([CH3:22])[CH2:14]1)(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([O-])=[O:5].C(Cl)(=O)C(Cl)=O>>[OH:5][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([O:12][C@H:13]1[C@H:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][C@@H:15]([CH3:22])[CH2:14]1)=[O:11]
Reactant: CC1CCC(C(C)C)C(OC(=O)c2ccccc2C(=O)[O-])C1
Agent: O=C(Cl)C(=O)Cl
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)c1ccccc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
3.78 g (12.4 mmol) monomenthyl (−)-phthalate (Fluka) was heated at reflux in 19 ml oxalyl chloride (18 eq.) for 1.5 h. The excess oxalyl chloride was distilled under vacuum. 2.75 g crude acid chloride was then diluted in 5 ml THF cooled to −80 under argon, and 0.97 g (3 eq.) NABH4 was added. The reaction mixture was maintained under stirring at 0° for 10 min and at ambient temperature for 30 min. The mixture was then poured over cold 5% KHSO4 then extracted using diethyl ether. Chromatography of the crude product over silica gel (93:7 toluene/ether) yielded 1.85 g (55%) pure (1R,3R,4S)-3-p-menthanyl 2-hydroxymethylbenzoate in the form of a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:39]=[CH:38][S:37][CH:36]=3)=[CH:29][C:12]=2[O:13][CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:7]=1)=[O:5])[CH3:2].O>[OH-].[K+].CO>[OH2:3].[CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:39]=[CH:38][S:37][CH:36]=3)=[CH:29][C:12]=2[O:13][CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1-c1cc(C(=O)OCC)[nH]n1)c1ccccc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccsc3)cc2OC(CCC(=O)O)c2ccccc2C)n[nH]1
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
To a stirred suspension of ethyl (RS)-4-[2-(5-ethoxycarbonylpyrazol-3-yl)-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate (4 g) in 15% potassium hydroxide in methanol (100 mL, w/v) at room temperature is added water (10 mL). The solid slowly dissolves and after stirring for 15 minutes the reaction mixture is partitioned between ethyl acetate (200 mL) and 2 N hydrochloric acid (200 mL). The organic phase is washed with water (200 mL), dried over magnesium sulphate and evaporated. The residue is recrystallised from a mixture of ethyl acetate and cyclohexane to give (RS)-4-[2-(5-ethoxycarbonylpyrazol-3-yl)-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid hydrate (1.9 g), m.p.167-168° C. [Elemental analysis:- C,63.9; H,5.39; N,5.22%. Calculated for C28H28N2O6S.0.5H2O:- C,63.5; H,5.48; N,5.29%].
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([Cl:21])=[C:19]([CH2:22][N:23]3[C:27](=[O:28])[CH2:26][CH2:25][C:24]3=[O:29])[N:18]=[C:17]3[S:30][C:31]4[CH2:32][NH:33][CH2:34][CH2:35][C:36]=4[C:16]=23)=[CH:11][CH:10]=1)C1C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:21][C:20]1[C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[C:16]2[C:36]3[CH2:35][CH2:34][NH:33][CH2:32][C:31]=3[S:30][C:17]2=[N:18][C:19]=1[CH2:22][N:23]1[C:24](=[O:29])[CH2:25][CH2:26][C:27]1=[O:28]
Reactant: O=C1CCC(=O)N1Cc1nc2sc3c(c2c(-c2ccc(OCc4ccccc4)cc2)c1Cl)CCNC3
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C1CCC(=O)N1Cc1nc2sc3c(c2c(-c2ccc(O)cc2)c1Cl)CCNC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a solution of the compound obtained in Example 14 (600 mg) in methylene chloride (20 ml) was added titanium tetrachloride (1.1 g) while cooling with ice. After stirring for 2 hours at room temperature followed by addition of water (10 ml), the stirring was continued for further 15 minutes. After discontinuing the stirring, the aqueous layer was isolated, and neutralized with saturated aqueous sodium bicarbonate, and then extracted with ethyl acetate-tetrahydrofurane (3:1, v/v). The extracted organic layer was washed with water, dried (MgSO4) and then the solvent was distilled off to obtain the title compound (305 mg, 62%). The product was recrystallized from dimethylformamide-water. A colorless prism crystal. M.p. 286 to 287° C.
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([O:16][CH3:17])[C:10]=1[CH:18]=[CH:19][N+:20]([O-])=O>O1CCCC1>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([O:16][CH3:17])[C:10]=1[CH2:18][CH2:19][NH2:20]
Reactant: COc1cc(Cl)cc(Cl)c1C=C[N+](=O)[O-]
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Cl)cc(Cl)c1CCN
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 96.8 %

Procedure:
To a stirred suspension of lithium borohydride (0.20 g; 9.0 mmol) in 15 mL tetrahydrofuran at ambient temperature was added chlorotrimethylsilane, dropwise over 2 minutes. Gas was evolved and the mixture warmed slightly. After stirring for 20 minutes, gas evolution had ceased, and argon gas was bubbled through the mixture for 2 minutes to remove the remaining trimethylsilane that had formed. A solution of 1,5-dichloro-3-methoxy-2-(2-nitrovinyl)benzene (0.56 g; 2.3 mmol) in 10 mL THF was then added dropwise with stirring at ambient temperature over 4 minutes. The resulting mixture was then stirred and heated to reflux. After 90 minutes, the heat was removed, and after cooling to ambient temperature, the mixture was cooled in an ice bath and carefully quenched with 15 mL of methanol. The solvent was evaporated, and the residue was partitioned between 30 mL of 20% KOH and 15 mL of dichloromethane. The organic layer was dried over sodium sulfate and evaporated to give 0.49 g of 2-(2,4-dichloro-6-methoxyphenyl)ethanamine as a cloudy yellow oil. MS (apci, pos) m/z=220.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH2:10][O:11][CH2:12][CH2:13]O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:33]1[CH2:38][CH2:37][CH2:36][C@@H:35]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH2:42]([O:41][C:39]([C@@H:35]1[CH2:36][CH2:37][CH2:38][N:33]([CH2:13][CH2:12][O:11][CH2:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:34]1)=[O:40])[CH3:43]
Reactant: Cc1cccc(C(=CCOCCO)c2ccccc2)c1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccccc2)c2cccc(C)c2)C1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 38.4 %

Procedure:
A mixture of 2-(3-(3-methylphenyl)-3-phenyl-2-propen-1-yl-oxy)ethanol (16 g, 60 mmol) and triethylamine (15.1 g, 149 mmol) in dry toluene (75 ml) kept under a nitrogen atmosphere was cooled to 5° C. and a solution of methanesulphonyl chloride (13.7 g, 119 mmol) in dry toluene (75 ml) was added dropwise keeping the temperature below 10° C. When addition was complete the reaction mixture was stirred for 1.5 h at 5° C. Water was added (100 ml) and the mixture was stirred at room temperature for 0.5 h. The phases were separated and the aqueous phase was extracted with a small portion of toluene. The combined organic extracts was washed with brine, dried (Na2SO4) and filtered. To the filtrate was added ethyl (R)-3-piperidinecarboxylate (10.3 g, 66 mmol) and potassium carbonate (9.9 g, 72 mmol) and the mixture was heated at reflux temperature for 6 days. Another portion of ethyl (R)-3-piperidinecarboxylate (5.3 g) was added and the mixture was heated at reflux temperature for another 24 h. The reaction mixture was poured into ice water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined organic extracts was washed with a sodium citrate buffer solution (2×100 ml, pH 5) and then extracted with a 5% aqueous citric acid solution (4×30 100 ml). Toluene (120 ml) was added to the combined acidic extracts and sodium hydroxide pellets was added to the mixture until the pH was measured at 8.5. The phases were separated and the organic phase was dried (Na2SO4). The solvent was evaporated in vacuo to give 9.4 g (39 %) of (R)-N-(2-(3-(3-methylphenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [Na].[Br:2][C:3]1[S:7][C:6]([CH:8]=O)=[CH:5][CH:4]=1.[N:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N+:11]=[N-:12]>CCO>[N:10]([C:13](=[CH:8][C:6]1[S:7][C:3]([Br:2])=[CH:4][CH:5]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N+:11]=[N-:12]
Reactant: O=Cc1ccc(Br)s1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccc(Br)s1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A solution of sodium (2.76 g, 120 mmol) in absolute EtOH (120 mL) was cooled in an ice-bath and a mixture of 5-bromo-2-formylthiophene (5.73 g, 30 mmol) and ethyl azidoacetate (15.49 g, 120 mmol) was added dropwise during 30 min period. The bath was removed and the reaction mixture was stirred at room temperature for another 30 min. A cold solution of saturated aqueous NH4Cl solution (100 mL) was added and the resulting solution was extracted with diethyl ether (3×100 mL) and the combined organic layers were washed with brine (200 mL), dried over Na2SO4. After removing diethyl ether under reduced pressure, the crude product was purified by column chromatography (EtOAc/Hexane: 1/50) to give acrylate 60 (3.81 g, 42%) as a light yellow solid.