Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([Br:14])[C:3]=1[O:4][CH2:5][C:6](=O)[CH3:7].C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[CH3:7][CH:6]([NH2:21])[CH2:5][O:4][C:3]1[C:2]([Br:1])=[CH:12][C:11]([Br:13])=[CH:10][C:9]=1[Br:14]
Reactant: CC(=O)COc1c(Br)cc(Br)cc1Br
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)COc1c(Br)cc(Br)cc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of 1 g 1-(2,4,6-tribromo-phenoxy)-propan-2-one (2.6 mmol) in 20 ml methanol is added 2.9 g ammonium acetate (39 mmol). The mixture is cooled to 0° C. and 0.81 g sodiumcyanoborohydride (13 mmol) is added. The reaction mixture is stirred overnight at ambient temperature. The completion of the reaction is confirmed by TLC. The reaction mixture is concentrated and the remaining residue is dissolved with 1.5 N HCl and washed with diethylether. The aqueous layer is neutralised and extracted with ethylacetate. The ethylacetate layer is dried over anhydrous sodium sulphate and the solvent removed. 0.32 g 1-methyl-2-(2,4,6-tribromo-phenoxy)-ethylamine (32%) is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[C:6](/[CH:10]=[CH:11]/[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[C:5]([CH3:25])[CH:4]=1)#[N:2].C(=O)([O-])[O-:27].[K+].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.O>[NH2:2][C:1]([C:3]1[CH:4]=[C:5]([CH3:25])[C:6](/[CH:10]=[CH:11]/[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]2)=[C:7]([CH3:9])[CH:8]=1)=[O:27]
Reactant: Cc1cc(C#N)cc(C)c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C(N)=O)cc(C)c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 738 %

Procedure:
To a suspension of 133 mg of tert-butyl 4-[(E)-2-(4-cyano-2,6-dimethylphenyl)vinyl]piperidine-1-carboxylate in 5 ml of acetone and 2 ml of water, 146 mg of hydrogen peroxide-urea complex and 7 mg of potassium carbonate were added, followed by stirring overnight. Then, 221 mg of hydrogen peroxide-urea complex was added and the mixture was stirred overnight, and 293 mg of hydrogen peroxide-urea complex was further added, followed by stirring for 4 days. An aqueous solution of sodium sulfate was added to the reaction mixture and extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform-methanol) to give 134 mg of tert-butyl 4-{(E)-2-[4-(aminocarbonyl)-2,6-dimethylphenyl]vinyl}piperidine-1-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])=[CH:4][CH:3]=1.O[C@H:20]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N(C(OCC)=O)=NC(OCC)=O>[CH2:31]([C@H:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])=[CH:17][CH:18]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(OCc1ccccc1)[C@H](O)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(O[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
Into a solution of tert-butyl 2(4-hydroxybenzoyl)hydrazinecarboxylate (200 mg, 0.79 mmol) and benzyl (R)-(+)-2-hydroxy-3-phenylpropionate (Aldrich) (270 μL, 1.19 mmol) were added triphenylphosphine polymer bound (Fluka, 3 mmol/g, 400 mg) and diethyl azodicarboxylate (190 μL) at 0° C. The resulting mixture was allowed to stir for 2 hr at 0° C. After filtration and rinsing the resin with DCM, the filtrate was evaporated off under vacuo to give a brown residue. Purification by flash chromatography (SiO2, AcOEt/chexanes (2/3)) gave the title compound as a white powder (216 mg, 56%) in 99.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:9][C:10]1[N:17]=[C:16]([NH:18][CH2:19][CH2:20][CH2:21][OH:22])[C:15]([F:23])=[CH:14][C:11]=1[C:12]#[N:13].ClC1N=C(Cl)C(F)=CC=1C#N.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:1]([O:22][CH2:21][CH2:20][CH2:19][NH:18][C:16]1[C:15]([F:23])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:9])[N:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N#Cc1cc(F)c(NCCCO)nc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCNc1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
To a solution of t-butyldimethylsilyl chloride (0.73 g, 4.79 mmol) in CH2Cl2 (21 mL) was added 2-chloro-5-fluoro-6-[(3-hydroxypropyl)amino]nicotinonitrile [prepared as in Example 302] and starting from 2,6-dichloro-5-fluoronicotinonitrile] (1.0 g, 4.35 mmol), followed by Et3N (0.48 g, 4.79 mmol) and DMAP (0.01 g, 0.09 mmol). The resulting cloudy mixture was stirred at rt for 18 h, and then diluted with CH2Cl2. The organic layer was washed with water, dried (MgSO4), filtered, and then concentrated under reduced pressure. The product (1.47 g, 98%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.46 (d, 1H), 3.67 (t, 2H), 3.49 (t, 2H), 1.77 (qt, 2H), 0.84 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)(C)(C)C.Cl.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([NH:25]N)=[CH:21][CH:20]=1)#[N:18]>Cl.O>[NH2:7][CH:8]1[CH2:13][CH2:12][C:11]2[NH:25][C:22]3[CH:23]=[CH:24][C:19]([C:17]#[N:18])=[CH:20][C:21]=3[C:10]=2[CH2:9]1
Reactant: N#Cc1ccc(NN)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: Cl
Solvent: O
Product: N#Cc1ccc2[nH]c3c(c2c1)CC(N)CC3
Yield: 82.1 %

Procedure:
Combine (4-oxocyclohexyl)carbamic acid tert-butyl ester (40.9 g, 192 mmol) and 4-cyanophenylhydrazine hydrochloride (25.0 g, 147 mmol) in concentrated hydrochloric acid (100 mL) and water (200 mL) and heat at reflux for 18 h. Allow to cool and collect the precipitate. Wash with Na2CO3 solution and azetrope with CHCl3, absolute EtOH, and CHCl3 again to obtain 25.5 g of a white solid (82%). MS (ES): m/z 212 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=O.[CH2:11](Br)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].O>C(O)C>[C:12]([C:11]1[O:1][C:2]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=2[CH:4]=1)(=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(O)c(C=O)c1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc2oc(C(=O)c3ccccc3)cc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a solution of 2-hydroxy-5-methylbenzaldehyde (1 g) and phenacyl bromide (1.06 g) in ethanol (10 ml) potassium carbonate (2.03 g) was added. The mixture was stirred at 80° C. for 1 h. Then the reaction mixture was poured into water (50 ml) and extracted with dichloromethane (3×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4), and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel (hexane/ethyl acetate 12:1) to give 2-benzoyl-5-methylbenzofuran (1.1 g) as yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[C:47]3([CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[C:46](=[O:53])[N:45]=[CH:44]2)=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:50]3[CH2:49][CH2:48][C:47]4([N:43]([C:40]5[CH:39]=[CH:38][C:37]([F:36])=[CH:42][CH:41]=5)[CH:44]=[N:45][C:46]4=[O:53])[CH2:52][CH2:51]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C1N=CN(c2ccc(F)cc2)C12CCNCC2
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC4(CC3)C(=O)N=CN4c3ccc(F)cc3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]dec-2-en-4-one hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:48]=[CH:47][CH:46]=[CH:45][C:7]=1[C:8]([NH:10][C:11]1[CH:42]=[CH:41][C:14]([C:15]([N:17]([CH3:40])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[O:32])=[O:16])=[CH:13][C:12]=1[O:43][CH3:44])=[O:9].[C:49]([OH:58])(=[O:57])[C@@H:50]([C@H:52]([C:54]([OH:56])=[O:55])[OH:53])[OH:51]>C(O)C.O>[C:54]([CH:52]([CH:50]([C:49]([OH:58])=[O:57])[OH:51])[OH:53])([OH:56])=[O:55].[NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:48]=[CH:47][CH:46]=[CH:45][C:7]=1[C:8]([NH:10][C:11]1[CH:42]=[CH:41][C:14]([C:15]([N:17]([CH3:40])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[O:32])=[O:16])=[CH:13][C:12]=1[O:43][CH3:44])=[O:9]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1ccccc1OCCCN
Solvent: CCO
Solvent: O
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-[(3-aminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (10.7 g) in ethanol (155 ml) was added a solution of L-(+) tartaric acid (2.43 g) in ethanol (60 ml) at 80° C. The solution was stirred at ambient temperature for 1 hour. The solvent was removed at reduced pressure and resulting solid was dissolved in distilled water (1 l) and the solution was filtered through micro filter and the filtrate was lyophilized to give 4-[2-[(3-aminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide tartrate (5.2 g).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: FC(F)(F)c1c[nH]c(-c2ccc(OCC3CO3)cc2)n1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCC(O)COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1

Procedure:
A solution of 2-[4-(2,3-epoxypropoxy)phenyl]trifluoromethylimidazole (2.5 g.) in tert. butylamine (20 ml.) is heated 6 hours at reflux. The excess tert.butylamine is removed by distillation at atmospheric pressure over steam. The residue is triturated with nitromethane (5 ml.) and the resulting solid removed by filtration. After recrystallization from acetonitrile, (1.2 g.) of 2-[4-(3-tert. butylamino-2-hydroxypropoxy)-phenyl]-4-trifluoromethylimidazole is obtained, m.p. 185.5°-186.5° C.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:12][O:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:12][O:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1ccc(C=O)cc1OC
Yield: 62.3 %

Procedure:
A solution of vanillin (47)(40.00 g, 262.89 mmol) and methyl-4-bromobutyrate (50.00 g, 276.18 mmol) in DMF (200 mL) was allowed to stir over potassium carbonate (51.53 g, 372.40 mmol) for 16 hours. Water was added to the reaction mixture at which time the product crystallised. The resulting mixture was filtered and dried in vacuo for 16 hours to afford the keto-ester (48) as a white solid (41.3 g, 66%). MP=57-59° C. 1H NMR (250 MHz, CDCl3) δ 9.80 (s, 1H), 7.46-7.40 (m, 2H), 6.97 (d, J=8.1 Hz, 1H), 4.16 (t, J=6.3 Hz, 2H), 3.92 (s, 3H), 3.70 (s, 3H), 2.57 (t, J=7.2 Hz, 2H), 2.20 (pent, J=6.7 Hz, 2H). 13C NMR (67.8 MHz, CDCl3) 188.2 (Cl), 173.7 (C12), 153.8 (Cquat.), 152.0 (Cquat.), 144.1 (Cquat.), 125.8 (Cmethine), 110.3 (C3), 108.5 (C6), 69.0 (C9), 57.0 (C8), 52.2 (C13), 30.6 (C11), 24.5 (C10). It was decided to adopt the numbering system shown in the figure below for the molecule for ease of peak assignment in 13C NMR.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10](=O)[CH2:11][C:12]([O:14]CC)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]([C:21]1[CH:31]=[CH:30][C:24]([C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1)=[N+:19]=[N-:20].[O-]CC.[Na+].O>C(O)C>[CH2:28]([NH:27][C:25]([C:24]1[CH:30]=[CH:31][C:21]([N:18]2[C:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:11]([C:12]([OH:14])=[O:13])[N:20]=[N:19]2)=[CH:22][CH:23]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)CC(=O)CCCc1ccccc1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 10.5 h
Yield: 92.6 %

Procedure:
Ethyl 6-phenyl-3-oxohexanoate (1.11 g, 4.73 mmol, 1.25 eq.) obtained in Example 100a) and 4-azido-N-ethylbenzamide (0.719 g, 3.78 mmol) were dissolved in ethanol (20 ml), sodium ethoxide (357 mg, 4.73 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 10.5 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (1.32 g, 3.50 mmol, 92.6%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C@@H:13]([OH:18])[C:14]([O:16][CH3:17])=[O:15].N1C=CN=C1>CN(C)C=O>[Si:1]([O:18][C@H:13]([C:12]1[CH:19]=[CH:20][CH:21]=[C:10]([Cl:9])[CH:11]=1)[C:14]([O:16][CH3:17])=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H](O)c1cccc(Cl)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
A solution of 31.6 g of t-butyldimethylsilyl chloride in 200 ml of dimethylformamide was added dropwise, whilst ice-cooling, to a solution of 28 g of methyl (R)-3-chloromandelate (prepared as described in Preparation 47) and 28.5 g of imidazole in 300 ml of dimethylformamide, and the resulting mixture was stirred at the same temperature for 30 minutes, after which it was allowed to stand overnight at 40° C. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was mixed with water and ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:15 by volume mixture of ethyl acetate and hexane as the eluent, to give the title compound as crystals, melting at 36°-38° C. [α]D23 -39.1° (c=1.014, chloroform)
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:14](#[N:17])[CH:15]=[CH2:16]>CCO>[OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][N:5]([CH2:16][CH2:15][C:14]#[N:17])[CH2:4][CH2:3]1
Reactant: C=CC#N
Reactant: OC1(c2ccccc2)CCNCC1
Solvent: CCO
Product: N#CCCN1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.1 %

Procedure:
To a solution of 4-hydroxy-4-phenylpiperidine (3.11 g, 17.5 mmol, 1.00 equiv) in EtOH (30 mL) was added acrylonitrile (2.89 mL, 43.8 mmol, 2.50 equiv) dropwise at 0° C. The mixture was stirred at room temperature for 1.5 hours and then concentrated to afford 3.71 g (92%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(OC(N1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])=O)C>C(#N)C.O>[CH:16]1([O:15][C:9]2[CH:8]=[C:7]([CH:2]([N:1]3[C:36](=[O:37])[C:35]4=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]4[C:33]3=[O:42])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.8 %

Procedure:
A mixture of 3-amino-3-(3-cyclopentyloxy-4-methoxyphenyl)propanoic acid (3.00 g, 10.8 mmol) and sodium carbonate (1.20 g, 11.3 mmol) in acetonitrile (30 mL) and water (30 mL) under nitrogen was stirred at room temperature for 15 minutes. To the resulting solution was added N-ethoxycarbonyl phthalimide (2.36 g, 10.8 mmol). The resulting mixture was stirred at room temperature for 18 hours. Most of solvent was removed in vacuo. To the solution was added hydrochloric acid (6N) until the pH of solution <1 to give a suspension and stirring was continued for 1 hour. The suspension was filtered, the solid was washed with water (2×10 mL), and then was dried in a vacuum oven overnight (60° C., <1 torr) to afford 3-(3-cyclopentyloxy-4-methoxy-phenyl)-3-phthalimidopropanoic acid as a white solid (3.0 g, 68% yield): mp, 168.0–169.0° C.; 1H NMR (DMSO-d6) δ 1.55–1.88 (m, 8H, C5H8), 3.27 (dd, J=6.9, 16.5 Hz, 1H, CHH), 3.51 (dd, J=8.9, 16.5 Hz, 1H, CHH), 3.71 (s, 3H, CH3), 4.71–4.75 (m, 1H, CH), 5.61 (dd, J=6.9, 8.8 Hz, 1H, NCH), 6.87–6.95 (m, 2H, Ar), 7.03 (br s, 1H, Ar), 7.81–7.91 (m, 4H, Ar), 12.4 (br s, 1H, OH); 13C NMR (DMSO-d6) δ 23.51, 32.14, 32.17, 36.07, 50.08, 55.52, 79.57, 112.15, 113.97, 119.39, 123.17, 131.09, 131.19, 134.66, 146.77, 149.16, 167.67, 171.72; Anal Calcd for C23H23NO6: C, 67.47; H, 5.66; N, 3.42. Found: C, 67.21; H, 5.46; N, 3.45.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[CH2:6][C:5]2=[O:13].[N+:14]([O-])([OH:16])=[O:15]>CCOCC>[CH3:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:5](=[O:13])[CH:6]([N+:14]([O-:16])=[O:15])[C:7]2=[O:12]
Reactant: Cc1cc2c(cc1C)C(=O)CC2=O
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Product: Cc1cc2c(cc1C)C(=O)C([N+](=O)[O-])C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5,6-dimethyl indane-1,3-dione (0.52 g; 0.003 mole) suspended in anhydrous ether (5 ml.) was stirred at 10°C during the dropwise addition of fuming nitric acid (1.0 ml.). After the addition was complete the mixture was stirred at ambient temperature for 1 hr. and the precipitated yellow solid filtered. m.p. (water, hydrochloric acid) 111°-113°C. (Found: C, 60.11; H, 4.10; N, 6.14; C11H9NO4 requires: C, 60.28; H, 4.14; N, 6.39%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22](I)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:31]5[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(I)cc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3ccc(-c4ccc(C#N)cc4)cc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 416, starting from 2-[(S)-1-Phenylethylamino]-4-[6-iodobenzimidazol-1-yl]pyrimidine and 4-cyanophenylboronic acid. Mass spectrum (ESI) 417.3 (M+1).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1>>[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CC1CCCCN1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: CC1CCCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1

Procedure:
The product from Example 1C and 2-methylpiperidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.88 (m, 1H), 7.80 (m, 4H), 7.60 (m, 2H), 6.82 (s, 1H), 3.1-3.8 (m, 7H), 1.6-2.1 (m, 6H), 1.45 (d, 3H, J=6 Hz); MS (DCI) m/z 345 (M+H)+;
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[C:25]1([S:31]([O-:34])(=[O:33])=[S:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Na+].C(OCC)(=O)C>C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:25]1([S:31]([O:34][C@@H:6]2[O:7][C@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]2[O:4][C:1](=[O:3])[CH3:2])(=[O:33])=[S:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=S([O-])(=S)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](OS(=O)(=S)c2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 70 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
2,3,4,6-Tetra-O-acetyl-α-galactopyranosyl bromide (2.0 g, 5 mmol) was dissolved in anhydrous acetonitrile (80 mL). To this sodium phenylthiosulfonate (2.02 g, 10.3 mmol) and tetrabutylammonium bromide (160 mg, 0.5 mmol) were added. The resulting mixture was stirred under argon at 70° C. After a 5 h period, t.l.c. (petrol:ethyl acetate, 1:1) indicated the formation of a product (Rf 0.4) with complete consumption of the starting material (Rf 0.6). The solution was concentrated in vacuo. The crude oil was partitioned between DCM (50 mL) and water (50 mL), and the aqueous layer re-extracted with DCM (2×50 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (petrol:ethyl acetate, 2:1) to afford the title product (1.7 g, 65%, 2 steps) as a white crystalline solid; mp 53-54° C.; [α]D27+24.2 (c, 1.0 in CHCl3); δH (400 MHz, CDCl3) 1.98, 2.03, 2.06, 2.11 (4×3H, 4×s, 4×OAc), 3.85 (1H, dd, J5,6 8.8 Hz, J6,6′ 14.0 Hz, H-6), 3.95-4.00 (2H, m, H-5, H-6), 5.11 (1H, dd, J2,3 9.7 Hz, J3,4 3.3 Hz, H-3), 5.23 (1H, at, J10.3 Hz, H-2), 5.25 (1H, d, J1,2 10.2 Hz, H-1), 5.43 (1H, dd, J3,4 3.6 Hz, J4,5 1.0 Hz, H-4), 7.54-7.68 (3H, m, Ar—H), 7.93-7.97 (2H, m, Ar—H).