Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:12]#[N:13])[NH:6][C:7](=O)[CH:8]([CH3:10])[CH3:9])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1.CCCCCCC.C1COCC1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:6]=[C:7]([CH:8]([CH3:10])[CH3:9])[S:24][C:12]=1[NH2:13])=[O:14])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C#N)NC(=O)C(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CCOC(=O)c1nc(C(C)C)sc1N
Yield: 392.2 %

Procedure:
Stir cyano-isobutyrylamino-acetic acid ethyl ester (139 g, 701 mmol) mechanically stir as a slurry in toluene (1.4 L) at rt under N2. Add lawesson's reagent (170 g, 420 mmol, 0.6 eq.) in portions and heat the thick slurry to 70° C. and stir for 12 hours until complete by TLC (2:1/heptane:THF). Cool the mixture and concentrate to dryness in vacuo on a rotovapor to obtain 353 g of thick yellow oil that was partially purified by silica gel plug (1 Kg silica gel 60, 1.5 vol. warm 2:1/THF:heptane as diluent, 2:1/heptane:THF as eluent). Combine the product containing filtrates and concentrate to dryness in vacuo on a rotovapor to obtain 194 g of crude solid. Dissolve the solid in EtOAc (400 mL) at 50-60° C. with stirring, then allow to cool gradually to rt. Precipitate the product and was cool to 0-5° C. with stirring for 30 minutes, isolate by suction filtration, rinse with cold EtOAc (2×50 mL), then dry in a vacuum oven at 50° C. to afford a first crop of 76.3 g (51%) of the title compound. Obtain a second crop of 17.6 g (12%)=from the filtrate after concentration in vacuo and silica gel chromatography (1 Kg silica gel 60, 2:1/heptane:THF). 1H NMR (300 MHz, DMSO-d6) δ 7.23 (bs, 2H), 4.21 (q, 2H, J=6.95 Hz), 3.02 (dq, 1H, J=6.95 Hz), 1.27 (t, 3H, J=6.95 Hz), 1.22 (d, 6H, J=6.95 Hz). 3C NMR (75 MHz, DMSO-d6) δ 163.72, 160.08, 156.20, 118.08, 58.99, 32.27, 22.35 (2); 14.46. IR (CHCl3) 3483, 3347, 2975, 2933, 2868, 1668, 1582, 1530, 1494, 1464, 1409, 1382 cm−1. HRMS (ES) M/z calculated for C9H14N2O2S 215.0854, found 215.0842.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5]/[C:6](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([O:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[C:14]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:13]=1)/[C:7]([O:9]C)=[O:8].Cl>O1CCCC1.O>[CH2:27]([O:26][C:14]1[CH:13]=[C:12](/[CH:11]=[C:6](\[O:5][CH3:4])/[C:7]([OH:9])=[O:8])[CH:17]=[CH:16][C:15]=1[O:18][S:19]([C:22]([F:25])([F:23])[F:24])(=[O:21])=[O:20])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCOc1cc(/C=C(\OC)C(=O)OC)ccc1OS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1cc(/C=C(\OC)C(=O)O)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 68 °C
Reaction time: 5 h
Yield: 64.8 %

Procedure:
1.53 g (36.3 mmol) of lithium hydroxide monohydrate are added to a solution of 7.5 g (18.2 mmol) of methyl (Z)-2-methoxy-3-(3-butoxy-4-(trifluoromethanesulphonyloxy)phenyl)acrylate in 50 ml of a tetrahydrofuran/water 10/1 mixture. The reaction mixture is stirred at 68° C. for 5 hours. The reaction mixture is acidified with a 2N hydrochloric acid solution down to pH=1. The reaction mixture is extracted with two times 100 ml of a heptane/ethyl acetate 1/2 mixture. The organic phases are combined and then dried over sodium sulphate. The solvents are evaporated and then the residue is taken up in 30 ml of pentane. 4.7 g of (Z)-3-(3-Butoxy-4-(trifluoromethane-sulphonyloxy)phenyl)-2-methoxyacrylic acid are obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])=[CH:4][CH:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2C[C@H]2CN2CCC[C@H]2C)=[CH:21][CH:20]=1.[NH3:35]>>[CH3:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:35])=[CH:23][CH:24]=2)=[CH:3][CH:4]=1
Reactant: C[C@@H]1CCCN1C[C@@H]1C[C@H]1c1ccc(Br)cc1
Reactant: N
Reactant: C[C@H]1CCCN1C[C@@H]1C[C@H]1c1ccc(Br)cc1
Product: C[C@H]1CCCN1C[C@@H]1C[C@H]1c1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
The title compound was prepared using the procedure described in Example 3D substituting 1-[2-(4-bromo-phenyl)-(1R,2R)-cyclopropylmethyl]-(2S)-2-methyl-pyrrolidine (the product from Example 4A) for 1-[2-(4-bromo-phenyl)-(1R,2R)-cyclopropylmethyl]-(2R)-2-methyl-pyrrolidine (the product from Example 3C). 1H NMR (300 MHz, CD3OD) 1.22 (m, 2H), 1.42 (d, J=6 Hz, 3H), 1.53 (m, 1H), 1.76 (m, 1H), 2.08 (m, 3H), 2.31 (m, 1H), 3.09 (dd, J=12 Hz, J=6 Hz, 1H), 3.23 (m, 1H), 3.39 (dd, J=12 Hz, J=6 Hz, 1H), 3.50 (m, 1H), 3.67 (m, 1H), 7.27 (d, J=9 Hz, 2H), 7.61 (d, J=6 Hz, 2H), 7.78 (s, 4H). MS (DCl—NH3) m/z 317 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:23][CH3:24])[C@@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(Cl)C(Cl)=CC=1O.C1(N=C=NC2CCCCC2)CCCCC1.[NH:50]1[CH2:57][CH2:56][CH2:55][C@H:51]1[C:52]([OH:54])=[O:53].C(N(CC)CC)C>O1CCCC1.C1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]([CH2:23][CH3:24])[C@@H:12]([C:20]([N:50]1[CH2:57][CH2:56][CH2:55][C@H:51]1[C:52]([OH:54])=[O:53])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(=O)OCc1ccccc1)[C@H](Cc1ccccc1)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cc(Cl)c(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCN(C(=O)OCc1ccccc1)[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 4 h

Procedure:
2.6 g (0.008 mole) of N-benzyloxycarbonyl-N-ethyl-D-phenylalanine (Example 3, Step 2) are dissolved in 10 ml of tetrahydrofuran and at 0° C. 1.6 g (0.008 mole) of 2,4,5-trichlorophenol and 1.65 g (0.008 mole) of dicyclohexylcarbodiimide are added, then the mixture is left to stand at room temperature for 4 hours. The residue is dissolved in 40 ml of benzene, washed twice with 20 ml of a 5 percent solution of sodium hydrogen carbonate, twice with 20 ml of water, then it is dried over anhydrous sodium sulfate and evaporated on a water bath having a temperature of about 40° C. at 15 to 20 millibars. The residual oil is dissolved in 10 ml of pyridine, 0.92 g (0.008 mole) of L-proline and 1.12 ml (0.008 mole) of triethylamine are added and the mixture is stirred till the dissolution of proline at room temperature. Then the solution is left to stand for 4 to 5 hours, subsequently it is evaporated on a water bath having a temperature of about 40° C. at 15 to 20 millibars. The residue is dissolved in a mixture of 25 ml of water and 10 ml of diethyl ether. The aqueous layer is washed twice with 10 ml of diethyl ether and the combined ether extracts are washed with 10 ml of a 5 percent solution of sodium hydrogen carbonate. The aqueous layers are combined and acidified to pH 2 with 3N hydrochloric acid. The separated product is extracted three times with 15 ml of benzene, the benzene layers are combined, washed three times with 5 ml of water, dried over anhydrous sodium sulfate and evaporated on a water bath having a temperature of about 40° C. at 15 to 20 millibars. Yield 2.2 g (64%) of an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][NH2:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:8][CH2:9][CH2:10][NH2:11]
Reactant: Brc1ccccn1
Reactant: NCCN
Product: NCCNc1ccccn1
Yield: 14.2 %

Procedure:
2-Bromopyridine (10.00 g, 63.3 mmol) was added dropwise to 1,2-diaminoethane (76.00 g, 126.6 mmol) under nitrogen at 20° C. with stirring. The reaction mixture was stirred at 20° C. for 4 h. and then under reflux for 24 h. The reaction mixture was concentrated in vacuo and purified by column chromatography on flash silica eluting with dichloromethane, ethanol and ammonia (30:8:1) to afford the title compound as a red oil (1.23 g). TLC SiO2, (Dichloromethane, ethanol, ammonia; 30:8:1) Rf=0.14 Mass Spectrum m/z 138 (MH+ for C7H11N3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21]CC(O)=O.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.F[C:74](F)(F)[C:75]([OH:77])=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:28]=[CH:41][C:40]([Cl:42])=[CH:39][C:38]=2[N:27]=1)[CH2:21][CH2:74][C:75]([NH:50][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:77]
Reactant: O=C(O)C(F)(F)F
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)NCc1ccccc1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and benzylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].C(NC(C)C)(C)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:23])[CH2:21]Br)=[CH:16][CH:15]=1>O1CCCC1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH2:21][CH:2]([CH3:3])[CH:1]=[O:4])=[O:23])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCC=O
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(C)C=O)cc1
Reaction time: 3 h
Yield: 54.7 %

Procedure:
4.36 g (75 mmol) of propionaldehyde were added dropwise under a stream of nitrogen to a solution of 6.46 g (50 mmol) of diisopropylamine, 39 g of molecular sieves 4 Å and 10 mg of 2,6-di-t-butyl-4-methylphenol in 50 ml of tetrahydrofuran, and the mixture was left to stand for 3 hours. At the end of this time, 5.73 g (25 mmol) of 4'-methoxy-2-bromoacetophenone were added to the mixture, and the mixture was left to stand at room temperature overnight. The reaction mixture was then filtered, and 55 ml of 1N aqueous hydrochloric acid were added to the filtrate to separate it into liquid phases. The aqueous layer was separated and extracted twice with ethyl acetate. The organic extracts were combined and washed with water and with a saturated aqueous solution of sodium chloride, in that order. The resulting solution was then dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 2:1 by volume mixture of hexane and ethyl acetate, to give 2.82 g (yield 26%) of the title compound as a pale yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:16])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][Br:16])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Br)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(Br)n1
Temperature: 50 °C

Procedure:
To a mixture of 6-bromo-2-methylpyridine (46.5 g, 0.27 mol) in CCl4 (800 mL) was added NBS (53 g, 0.297 mol) and benzoylperoxide (4.7 g) and refluxed for 2 h in presence of light. The reaction mixture was cooled to 50° C. and filtered off the solid succinimide. The filtrate was concentrated and the crude 6-bromo-2-bromomethylpyridine (71 g) was used for next reaction.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)=[N:10][N:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:35][CH2:36][CH:37]([CH2:42][Br:43])[CH2:38][C:39](Cl)=[O:40]>C1COCC1>[Br:35][CH2:36][CH:37]([CH2:42][Br:43])[CH2:38][C:39]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]3[N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[N:8]=[N:9][N:10]=3)=[CH:26][CH:25]=2)[CH2:20][CH2:21][C:22]1=[O:27])=[O:40]
Reactant: O=C(Cl)CC(CBr)CBr
Reactant: O=C1CCc2cc(OCCCCc3nnnn3C3CCCCC3)ccc2N1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(OCCCCc3nnnn3C3CCCCC3)ccc2N1C(=O)CC(CBr)CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydroquinolin-2(1H)-one (cilostazol, 1, A=H, 2.0 g, 3.50 mmol), N,N-dimethylaminopyridine (0.043 g, 0.35 mmol) and triethylamine (0.5 ml, 0.35 mmol) in THF (100 mL) at 0° C. and under nitrogen, a solution of 4-bromo-3-(bromomethyl)butanoyl chloride (0.97 g, 3.50 mmol) in THF (5 mL) is slowly added and the reaction mixture stirred at room temperature for 2 hours. Then it is partitioned between ethyl acetate and phosphate buffer (pH=3) and extracted with ethyl acetate (3×25 mL). The organic phase is dried over Na2SO4 and concentrated. The crude material is purified by flash chromatography (CH2Cl2/acetone 7:3).
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].Br[CH2:23][CH2:24][C:25]1[CH:33]=[CH:32][C:28]2[O:29][CH:30]=[CH:31][C:27]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2[CH:33]=[CH:32][C:28]3[O:29][CH:30]=[CH:31][C:27]=3[CH:26]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Reactant: BrCCc1ccc2occc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCc2ccc3occc3c2)C1

Procedure:
A mixture containing 3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (1.79 g-see Preparation 10(B)), 5-(2-bromoethyl)benzo[2,3-b]furan (1.2 g-see Preparation 17), anhydrous potassium carbonate (3 g) and acetonitrile (30 ml) was heated under reflux for 30 minutes. The mixture was partitioned between ethyl acetate (30 ml) and 10% aqueous potassium carbonate (30 ml), the layers were separated, and the aqueous layer extracted with ethyl acetate (3×50 ml). The combined ethyl acetate extracts were dried (MgSO4) and concentrated in vacuo to give a brown gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (2%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 1.4 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][NH:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.C(N(CC)CC)C.[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][N:11]([C:36](=[O:37])[CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(C23CCCC2CNCC3)c1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N1CCC2(c3cccc(O)c3)CCCC2C1
Temperature: 70 °C

Procedure:
A solution of 2.17 g. of 4a-(3-hydroxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine prepared as described in Example 23 in 50 ml. of N,N-dimethylformamide containing 3.95 g. of triethylamine was stirred at room temperature while 3.87 g. of phenylacetyl chloride was added dropwise over 15 minutes. Following complete addition, the reaction mixture was heated at 70° C. for two hours, and then poured into 200 ml. of water. The aqueous reaction mixture was extracted several times with diethyl ether, and the ethereal extracts were combined, washed with saturated aqueous sodium chloride solution and with water, and dried. Removal of the solvent by evaporation under reduced pressure afforded 4a-(3-hydroxyphenyl)-2-(2-phenylacetyl)-2,3,4,4a,-5,6,7,7a-octahydro-1H-2-pyrindine. Such product was dissolved in 50 ml. of tetrahydrofuran and stirred while a solution of 4.0 g. of lithium aluminum hydride in 150 ml. of tetrahydrofuran was added dropwise over thirty minutes. The reaction mixture was then heated at reflux for four hours, and then cooled to about 25° C. While the reaction mixture was stirred, 25 ml. of ethyl acetate was added, followed by the addition of a saturated aqueous solution of ammonium tartrate. The reaction mixture was then filtered and the filtrate was concentrated by evaporation of the solvent under reduced pressure. The product thus formed was dissolved in diethyl ether and washed with water and dried. Removal of the solvent then provided 4a-(3-hydroxyphenyl)-2-(2-phenylethyl)- 2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine as an oil. The oil was dissolved in 150 ml. of diethyl ether and stirred while a fifty percent solution of 48% hydrobromic acid in ethanol was added. The hydrobromide salt of the above-named product crystallized and was collected by filtration, affording, after recrystallization from ethyl acetate, 1.3 g. of 4-a-(3-hydroxyphenyl)-2-(2-phenylethyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindinium bromide. M. P. 135-137° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.Cl>O.CN(C=O)C>[CH2:7]([S:14][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: SCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(SCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a stirred mixture of cesium carbonate (12.81 g, 39.33 mmol), benzyl mercaptan (4.7 mL, 39 mmol), and N,N,-dimethylformamide (80 mL) was added 4-fluorobenzaldehyde, slowly over several minutes. The reaction mixture was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature, then diluted with water (500 mL). The resulting mixture was acidified to pH 4 using 1 N aqueous HCl, then extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated. A solution of the crude product and dichloromethane was concentrated over silica gel, and the resulting silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (100% hexanes -15% ethyl acetate in hexanes) afforded 7.70 g (90%) of 4-(benzylsulfanyl)-benzaldehyde as a slightly pink solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:53])[CH2:11][CH:10]([O:12][Si](C(C)C)(C(C)C)C(C)C)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:47][C:46](=[O:48])[O:45][N:44]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:49][CH2:50][CH3:51])[N:25]=[C:24]3[CH3:52])[CH:8]=2)[O:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:12][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:47][C:46](=[O:48])[O:45][N:44]=5)=[CH:35][CH:36]=4)=[C:26]([CH2:49][CH2:50][CH3:51])[N:25]=[C:24]3[CH3:52])[CH:8]=2)[O:3][C:2]([CH3:1])([CH3:53])[CH2:11]1
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)C(O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of 3-{2,2-dimethyl-4-[(triisopropylsilyl)oxy]-3,4-dihydro-2H-chromen-6-yl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (4.0 g) in tetrahydrofuran (20 mL) was added tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 8.2 mL), and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (3.0 g, 95%) as a solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:10][CH:11]1[CH2:20][CH:19]([N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](=[O:24])[CH3:23])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12]1.C(N(C(C)C)C(C)C)C.ClCCl>O1CCOCC1>[CH3:10][C@H:11]1[CH2:20][C@@H:19]([N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](=[O:24])[CH3:23])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:8]
Reactant: CC(=O)N(c1ccccc1)C1CC(C)Nc2ccccc21
Reactant: O=C(Cl)c1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2cccnc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Nicotinoyl chloride (1.1 eq) was added to a solution of N-(2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenylacetamide (100 mg) and N-ethyl-N,N-diisopropylamine (2.2 eq) in dioxane (1 ml). The mixture was stirred overnight at room temperature. Dichloromethane was added and the organic layer was washed by water and sodium carbonate solution and dried over sodium sulfate. The solvent was removed and the mixture was purified by chromatography on silica gel (dichloromethane and ethanol (99:1)) to afford the title compound (30 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1.CCN(CC)CC.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])=[O:21].ClC1C=CC=CC=1CO.Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])=[O:21])=[O:11]
Reactant: COC(=O)[C@@H]1CCCCN1
Reactant: O=C(Cl)OCc1ccccc1Cl
Agent: Cl
Agent: OCc1ccccc1Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
To a vigorously stirred solution of (S)-pipecolic acid methyl ester hydrochloride (500 mg, 2.79 mmol) in dry DCM (10 mL) cooled in an ice-bath, was added dropwise Et3N (705 mg, 6.96 mmol) followed by 2-chlorobenzyl chloroformate (made from 2-chlorobenzyl alcohol using the method described in J. Med. Chem., 1998, 41, 1315–1343) (857 mg, 4.18 mmol). The resulting suspension was stirred at 0° C. for a further 0.75 h, diluted with ethyl acetate (30 mL) and poured into 1.0-M HCl (30 mL). The organic layer was separated and washed sequentially with 1.0-M HCl (20 mL), aq.NaHCO3 (20 mL) and brine (20 mL). The organic layer was then dried (NaSO4), filtered and concentrated under reduced pressure to give a colorless oil. The oil was purified by column chromatography (15% ethyl acetate in hexane) to give the title compound as a colorless viscous oil (824 mg, 95%): 1H NMR (400 MHz, CDCl3) 1.2–1.4 (1H, m), 1.4–1.6 (1H, m), 1.6–1.8 (3H, m), 2.2–2.3 (1H, m), 2.9–3.2 (1H, m), 3.7–3.8 (3H, m), 4.0–4.2 (1H, m), 4.8–5.0 (1H, m), 5.2–5.4 (2H, m), 7.2–7.3 (2H, m), 7.3–7.5 (2H, m)