Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:11][N:10]=1)[CH3:8].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N:1]1([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:11][N:10]=2)[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(-c2ccc(C(C)Br)nc2)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(C(C)n3ccnc3)nc2)cc1
Temperature: 50 °C
Yield: 71.6 %

Procedure:
To a stirred solution of 1H-imidazole (0.069 g, 1.0 mmol) in DMF (7 mL) was added 2-(1-bromoethyl)-5-(4-methoxyphenyl)pyridine (0.150 g, 0.50 mmol) and K2CO3 (354 mg, 2.5 mmol). The reaction was heated at 50° C. for about 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), the organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 100-200μ) using 2% methanol in DCM eluent to afford 2-(1-(1H-imidazol-1-yl)ethyl)-5-(4-methoxyphenyl)pyridine as an off-white solid (0.1 g, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.80 (d, 1H), 7.99 (dd, 1H), 7.80 (s, 1H), 7.63 (d, 2H), 7.26 (s, 1H), 7.03 (d, 1H), 7.21 (d, 2H), 6.89 (s, 1H), 5.64-5.59 (m, 1H), 3.78 (s, 3H), 1.81 (d, 3H), LC-MS m/z calcd for [M+H]+ 280.14. found 280.2.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[O:10]=O.CC1C=C(C)C=C(C)C=1CC1C=C(C)C=C(C)C=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(=O)C>[CH3:9][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[OH:10]
Reactant: O=O
Reactant: Cc1cc(C)cc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1cc(C)cc(Cc2c(C)cc(C)cc2C)c1
Solvent: CC(=O)O
Product: Cc1cc(C)c(O)c(C)c1

Procedure:
In a flask, 30 mmol of mesitylene, 4.5 mg (0.02 mmol) of palladium(II) acetate, 323 mg (about 0.14 mmol) of H4PMo11V1O40-nH2O, and 10 ml of acetic acid were placed and were stirred at a constant temperature of 90° C. in an atmosphere of oxygen gas at 1 atm (0.1 MPa) for 15 hours. The resulting reaction mixture was analyzed by gas chromatography to find that 8.5 mmol of 1,3,5-trimethyl-2-(3′, 5′-dimethylbenzyl)benzene, and 1 mmol of 2,4,6-trimethylphenol were produced.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][OH:13].CCN(CC)CC.[Cl:21][C:22](OC(Cl)(Cl)Cl)=[O:23]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][O:13][C:22]([Cl:21])=[O:23]
Reactant: O=[N+]([O-])c1cccc(F)c1CCO
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cl)OCCc1c(F)cccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of 2-(2-fluoro-6-nitrophenyl)ethanol (500 mg, 2.7 mmol) and Et3N (273 mg, 2.7 mmol, dist. over KOH) in THF (6.75 ml, dist. over CaH2) was dropped into a solution, cooled to 0° C., of trichloromethyl chloroformate (641 mg, 3.24 mmol) in THF (6.75 ml, see above) for 5 min. It was stirred for 1 h while cooling in an ice bath and then stirred for 1 h at room temperature. The mixture was filtered over Celite. Rewashing the filter cake with THF and removing the solvent and excess reagent from the pooled filtrates by distillation at 30° C. in a high vacuum yielded 2-(2-fluoro-6-nitrophenyl)ethoxycarbonyl chloride (620 mg, 93%) as a light-brown oil.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11](=[O:14])[C:12]=1I)=[CH:9][C:8]([F:15])=[CH:7][CH:6]=2)[CH3:2].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([F:23])[CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O.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>[F:16][C:17]1[CH:18]=[C:19]([C:12]2[C:11](=[O:14])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([F:15])[CH:9]=3)[NH:4][C:3]=2[CH2:1][CH3:2])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CCc1[nH]c2ccc(F)cc2c(=O)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCc1[nH]c2ccc(F)cc2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 2-ethyl-6-fluoroquinolin-4(1H)-one (4.00 g, 21 mmol), I2 (10.62 g, 2.0 eq) and Na2CO3 (3.33 g, 1.5 eq) in THF (100 mL) was stirred at rt overnight. To the reaction mixture was added Na2S2O3 solution, after 2 min the resulted mixture was filtered, washed with water and dried in the air to give a white solid as 2-ethyl-6-fluoro-3-iodoquinolin-4(1H)-one. Mass Spectrum (ESI) m/e=318 (M+1). A mixture of 2-ethyl-6-fluoro-3-iodoquinolin-4(1H)-one (400 mg, 1.3 mmol), 3,5-difluorophenylboronic acid (398 mg, 2.0 eq), Na2CO3 (401 mg, 3.0 eq) and tetrakis(triphenylphosphine)palladium(0) (73 mg, 0.05 eq) in acetonitrile/water (15 mL/5 mL) was purged with N2 and heated to reflux. After overnight, the reaction mixture was cooled at rt, partitioned between water and EtOAc. The layers were separated and the aq layer was extracted with EtOAc (10 mL×2). The combined organic layers were washed with water (10 mL×2), brine (10 mL), dried over Na2SO4, filtered, and concd under reduced pressure. The residue was purified by combiflash on silica gel (EtOAc/DCM, 1:2) to give 3-(3,5-difluorophenyl)-2-ethyl-6-fluoroquinolin-4(1H)-one as a white solid. Mass Spectrum (ESI) m/e=304 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([C:12](=[CH2:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[OH-:20].[Na+].OO.Cl>C1COCC1.O>[CH3:19][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][OH:20])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: C=C(CCCCC)c1ccc2c(c1)SCCC2(C)C
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(CO)c1ccc2c(c1)SCCC2(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4,4-dimethyl-7-(1-methylene-hexyl)-thiochroman (0.939 g, 3.42 mmole) in 15 mL of THF at 0° C., was treated with 3.42 mL of 1M BH3.THF complex. The reaction mixture was stirred at room temperature for three hours and then cooled to 0° C. The mixture was treated successively with 0.59 mL of water, 0.67 mL of 3M sodium hydroxide and 0.67 mL of 30% hydrogen peroxide. The reaction mixture was stirred at room temperature for two hours and then diluted with 20 mL of water. The pH was adjusted to 4.0 with 10% HCl and then extracted with three 25 mL portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow oil. The product was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to yield 0.532 g of 2-(4,4-dimethyl-thiochroman-7-yl)-heptan-1-ol as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)=[CH:10][CH:9]=1.[CH3:22][C:23]1([CH3:32])[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25](=O)[CH2:24]1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[C:16]1([C:14](=[C:25]2[CH2:26][C:27]([CH3:30])([CH3:29])[CH2:28][C:23]([CH3:32])([CH3:22])[CH2:24]2)[C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][OH:1])=[CH:9][CH:10]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: O=C(c1ccccc1)c1ccc(OCCOCCO)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccccc2)c2ccc(OCCOCCO)cc2)CC(C)(C)C1
Temperature: 25 °C

Procedure:
To a stirred suspension of Zn (0.59 g, 8.94 mmol) in THF (10 mL) was added TiCl4 (0.50 mL, 4.47 mmol) dropwise. The mixture was refluxed under nitrogen for 2.5 h. Cooled to room temperature, a solution of 7 (0.32 g, 1.12 mmol) and 3,3,5,5-tetramethylcyclohexanone (0.53 g, 3.35 mmol) in THF (15 mL) was added and the reaction mixture was refluxed for another 2.5 h. Cooled to room temperature, the reaction was quenched with 10% K2CO3 (40 mL). The quenched reaction mixture was filtered through a pad of celite and the pad was washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel, the layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to a pale yellow oil. The residue was further purified by chromatography on a silica gel column eluted with a gradient from hexanes to 45% EtOAc:hexanes to give 8 as a white solid. Crystallization from 10:1 hexanes:EtOAc yielded colorless needles (0.27 g, 59%). mp 116-117° C. 1H NMR (400 MHz, CD3OD): δ0.91 (s, 6H), 0.93 (s, 6H), 1.29 (s, 2H), 1.95 (s, 2H), 1.99 (s, 2H), 3.60-3.65 (m, 2H), 3.65-3.70 (m, 2H), 3.80-3.85 (m, 2H), 4.05-4.15 (m, 2H), 6.85 (d, J=8.6 Hz, 2H), 7.06 (d, J=8.6 Hz, 2H), 7.10-7.20 (m, 3H), 7.20-7.30 (m, 2H). LRMS (ESI): m/z 409 (M+H)+. Anal. Calcd for C27H36O3: C, 79.37; H, 8.88. Found: C, 79.23; H, 8.95.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[N:9]([CH2:11][CH2:12][CH3:13])[CH:10]=1)=[O:5])C.C1COCC1.O.[OH-].[Li+].O>>[CH2:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[C:8]1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:31]([C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:30]=[N:29][N:28]=2)=[CH:19][CH:20]=1)[CH2:12][CH3:13]
Reactant: CCCn1cc(C(=O)OCC)nc1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCn1cc(C(=O)O)nc1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 40 h
Yield: 99.3 %

Procedure:
1-Propyl-2-[2′-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-1H-imidazole-4-carboxylic acid ethyl ester (400 mg, 607 μmol) was dissolved in THF (12.0 mL, 148 mmol). A solution of lithium hydroxide monohydrate (127 mg, 3.0 mmol) in water (4.0 mL, 222 mmol) was then added and the mixture was stirred at 40° C. for 40 hours to yield the title compound (380 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C@@:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)[C@@]1(C)CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@]1(C)CCCN(Cc2ccccc2)C1
Yield: 92.3 %

Procedure:
(S)-3-Methylpiperidine-3-carboxylic acid ethyl ester (1.16 g, 6.8 mmol), benzyl chloride (0.82 ml, 7.1 mmol), K2CO3 (1.22 g, 8.8 mmol) and KI (0.056 g) were stirred and heated in DMF (50 ml) for 2.5 h. The cooled solution was poured into water and extracted with EtOAc (3×50 ml). The combined extracts were washed several times with water and finally with brine. Drying, filtering and evaporation of the solvent gave 1.64 g of the target compound as a yellowish oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:20]([O:22][C:23](=[O:27])[CH2:24][CH2:25]Cl)[CH3:21].O>CN(C)C=O>[CH2:20]([O:22][C:23]([CH:24]([C:15]1[NH:16][C:17]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[CH:19][CH:18]=2)[CH3:25])=[O:27])[CH3:21]
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CCOC(=O)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 60% sodium hydride (15 g) in dimethylformamide (30 ml) was added a N,N-dimethylformamide solution of 5-benzyloxyindole (5.0 g) at 0° C. After 15 minutes a solution of ethyl-3-chloropropionate (3.1 ml) in N,N-dimethylformamide was added dropwise and the reaction mixture stirred for a further 5 hours at ambient temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 15%-ethyl acetate in n-hexanes to yield the title product (6.81 g).
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[CH:5]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:30])[C:14]2[O:20][C:19]3[C:21]([Cl:26])=[CH:22][C:23]([NH2:25])=[CH:24][C:18]=3[CH2:17][S:16](=[O:28])(=[O:27])[C:15]=2[CH:29]=1)=[O:10])([CH3:7])[CH3:6].COC(C1C=C(C)C2OC3C(Cl)=CC(N)=CC=3CS(=O)(=O)C=2C=1)=O>C(O)=O>[CH:5]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:30])[C:14]2[O:20][C:19]3[C:21]([Cl:26])=[CH:22][C:23]([NH:25][CH:1]=[O:2])=[CH:24][C:18]=3[CH2:17][S:16](=[O:28])(=[O:27])[C:15]=2[CH:29]=1)=[O:10])([CH3:7])[CH3:6]
Reactant: O=C[O-]
Reactant: Cc1cc(C(=O)OC(C)C)cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Agent: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1O2
Agent: [Na+]
Solvent: O=CO
Product: Cc1cc(C(=O)OC(C)C)cc2c1Oc1c(Cl)cc(NC=O)cc1CS2(=O)=O
Temperature: 0 °C

Procedure:
Sodium formate (0.040 g, 0.581 mmol) was added to a suspension of 2-amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid isopropyl ester (0.23 g, 0.581 mmol) [prepared by hydrolysis of compound of Example 1 and followed by esterification using isopropanol/H2SO4] in formic acid (20 mL) and refluxed for 1.5 h. The reaction mixture was cooled and poured into ice water (100 mL). The solid precipitated was filtered, washed with water and dried. The crude product was crystallised with ethylacetate/pet. ether 60-80° C. to obtain the title compound. Yield: 0.12 g (48%); mp: 212-215° C.; 1H NMR (DMSO-d6, 300 MHz): δ 1.30 (d, 6H, OCH(CH3)2), 2.64 (s, 3H, CH3), 5.12 (m, 1H, OCH(CH3)2), 5.25 (s, 2H, CH2, trans minor isomer), 5.32 (s, 2H, CH2, cis major isomer), 7.33 (d, 1H, Ar, trans minor isomer), 7.50 (d, 1H, Ar, trans minor isomer), 7.69 (d, 1H, Ar, cis major isomer), 7.86 (d, 1H, Ar, cis major isomer), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar), 8.30 (s, 1H, CHO, cis major isomer), 8.80 (d, 1H, CHO, trans minor isomer), 10.40 (d, 1H, NH, trans minor isomer), 10.57 (s, 1H, NH, cis major isomer); MS: m/e (ES−) 422 (M−1); analysis: C19H18ClNO6S requires C, 53.84,H, 4.28, N, 3.30, Cl, 8.36, S, 7.56; found: C, 54.27,H, 4.45, N, 2.94, Cl, 8.76, S, 7.77%.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23](I)([CH3:25])[CH3:24]>>[C:1]1([S:7]([C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([O:20][CH:23]([CH3:25])[CH3:24])[CH2:15]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)I
Reactant: CC(C)(CCCN1CCCC(O)C1)S(=O)(=O)c1ccccc1
Product: CC(C)OC1CCCN(CCCC(C)(C)S(=O)(=O)c2ccccc2)C1

Procedure:
The title compound was prepared from 1-(4-benzenesulfonyl-4-methylpentyl)-3-hydroxypiperidine and i-propyl iodide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:22][C:21]([CH3:23])=[C:20]([C:24]([O:26]C)=[O:25])[CH:19]=3)[CH2:14][C@H:13]2[O:28][CH3:29])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:22][C:21]([CH3:23])=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=3)[CH2:14][C@H:13]2[O:28][CH3:29])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C(=O)OC)c(C)s3)C[C@H]2OC)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C(=O)O)c(C)s3)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl cis(±)-5-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-2-methylthiophene-3-carboxylate obtained in Example (188e) (16 mg) was dissolved in methanol (1 ml) and THF (1 ml). A 2 N aqueous lithium hydroxide solution (1 ml) was added, and the mixture was stirred at room temperature overnight. The organic solvent was evaporated under reduced pressure. Then, the residue was neutralized with 1 N hydrochloric acid, diluted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was recrystallized from an ethyl acetate/hexane solvent to obtain the title compound as crystals.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:17][C@@H:6]1[S:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[C:1]([O:4][C@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:17][C@@H:6]1[S:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](SCC=Cc2ccccc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@H](SCCCc2ccccc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A solution of 2 (800 mg) in ethyl acetate (10 ml) and acetic acid (10 μl) containing 10% palladium-on-charcoal (400 mg) is hydrogenated overnight at room temperature. The catalyst is filtered off and washed with ethyl acetate. The combined filtrates are evaporated in vacuo to give 6 (780 mg, 97%); m.p. 73°-74° C. (ethyl ether-petroleum ether); [α]D27 +86.0±0.9° (C 1.08, chloroform).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH:5]=[CH:6][C:7]([NH:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=[O:8].B([O-])([O-])O[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.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>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:2]2[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]([NH:9][C:10]2[CH:22]=[CH:21][C:13]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=2)=[O:8])=[CH:29][CH:30]=1
Reactant: COc1ccc(OB([O-])[O-])cc1
Reactant: O=C(C=Cc1cccc(Br)c1)Nc1ccc(CN2CCCCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cccc(C=CC(=O)Nc3ccc(CN4CCCCC4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.6 %

Procedure:
A suspension of 1-(4-(3-bromocinnamoyl amino)benzyl)piperidine (0.4 g), 4-methoxyphenyl borate (0.14 g), 1M potassium carbonate (2 ml) and ethanol (1 ml) in toluene (5 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the suspension was added tetrakistriphenylphosphinepalladium (0.05 g), and the mixture was refluxed over night. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (methanol/triethylamine/ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 1-(4-(3-(4-methoxyphenyl)-cinnamoylamino)benzyl)piperidine (Compound 84) (0.38 g) as colorless crystals.
Reaction SMILES: CC(N)(C)C[C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[O:20]1[CH2:22][C@H:21]1[CH2:23][O:24][C:25]1[C:37]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1>CCO>[OH:20][C@@H:21]([CH2:22][N:30]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[CH:16][CH:17]=1)[CH2:29][CH:37]([CH3:25])[CH3:36])[CH2:23][O:24][C:25]1[C:37]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: CC(C)(N)Cc1ccc(Oc2ccc(O)cc2)cc1
Solvent: CCO
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(Oc2ccc(O)cc2)cc1
Temperature: 60 °C

Procedure:
4-(4-(2-Methyl-2-aminopropyl)phenoxy)phenol (0.40 g, 1.55 mmol) was combined with (S)-4-(oxiranylmethoxy)-9H-carbazole (0.250 g, 1.0 mmol) in EtOH (50 mL) and the mixture heated at 60° C. for 20 hours. The mixture was then concentrated in vacuo and the resulting residue chromatographed over silica (1-10% MeOH/CHCl3) which allowed for isolation of the product as the free base. The free base was then dissolved in minimal EtOAc and treated with diethyl ether (25 mL) saturated with HCl. Filtration and drying netted 0.410 g (76%) of product as the HCl salt. MS (FD+):497. m.p. 80-85° C. (dec). Anal. Calcd for C31H32N2O4.1.3HCl: C, 68.31; H, 6.16; N, 5.14. Found: C, 68.30; H, 6.75; N, 4.62.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])[CH:5]=[CH:6][CH:7]=1.Br[C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Br:30])[CH:29]=1.C([Mg]Br)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([Br:30])[CH:29]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: CON(C)C(=O)CC(c1cccc(Br)c1)c1ccccc1C
Agent: CC(C)[Mg]Br
Product: Cc1ccccc1C(CC(=O)c1cncc(Br)c1)c1cccc(Br)c1

Procedure:
In analogy to example 74, step 5, from 3-(3-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 98, step 4) and 3,5-dibromopyridine (CAS RN: [625-92-3]) using i-propylmagnesium bromide instead of n-butyllithium was prepared the title compound as a white solid, MS (ESI+): m/z=457.9738 ([M+H]+, 1Br).