Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]([CH2:8][CH2:9][C:10]([CH3:12])=[O:11])[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=1.C(OCC)(OCC)O[CH2:17][CH3:18].B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)C>[CH2:17]([O:11][C:10]1([CH3:12])[CH2:9][CH2:8][CH:7]2[C:2](=[CH2:1])[CH:3]1[CH2:4][CH2:5][C:6]2([CH3:14])[CH3:13])[CH3:18]
Reactant: CC(=O)CCC1C(C)=CCCC1(C)C
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: C=C1C2CCC(C)(OCC)C1CCC2(C)C
Temperature: 25 °C
Yield: 97.8 %

Procedure:
480 g (2.21 mol) of dihydro-α-ionone, 368 g (2.48 mol) of triethyl orthoformate and 480 ml of abs. ethanol are treated dropwise while stirring during 15 minutes with a solution of 34.5 g (0.31 mol) of boron trifluoride etherate in 500 ml of ethanol and the mixture is subsequently heated to an internal temperature of 46°-48° for 60 minutes. After cooling the reaction mixture to room temperature it is stirred with 600 ml of a 10% aqueous sodium hydroxide solution. After extraction with ether and evaporation of the organic phase there are obtained 668.7 g of a slightly yellow liquid which, after flash distillation in a vacuum, gives 480.5 g of crude product (b.p. 45°-73°, 0.07 mbar). After fractionation in a vacuum over a 20 cm Widmer column there are obtained 406.2 g (82.7% of theory) of a slightly yellowish colored liquid (b.p. 48°-67°, 0.06 mbar) which contains the desired bicyclo-nonane in an isomer ratio of exo:endo=2:1.
Reaction SMILES: C(OC([O:7][CH2:8][C:9]1[CH:54]=[CH:53][CH:52]=[CH:51][C:10]=1[C:11]([O:13][C@:14]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[F:50])([CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1)[C@H:15]([S:17][C@@H:18]1[CH2:23][O:22][C@@H:21](/[CH:24]=[CH:25]/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][C:29]=2[F:36])[O:20][CH2:19]1)[CH3:16])=[O:12])=O)C=C.C([SnH](CCCC)CCCC)CCC.C(OCC)(=O)C>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.CCCCCC>[OH:7][CH2:8][C:9]1[CH:54]=[CH:53][CH:52]=[CH:51][C:10]=1[C:11]([O:13][C@:14]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[F:50])([CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1)[C@H:15]([S:17][C@@H:18]1[CH2:23][O:22][C@@H:21](/[CH:24]=[CH:25]/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][C:29]=2[F:36])[O:20][CH2:19]1)[CH3:16])=[O:12]
Reactant: C=CCOC(=O)OCc1ccccc1C(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)c1ccccc1CO)c1ccc(F)cc1F
Yield: 81 %

Procedure:
A chemical reaction was carried out according to a similar procedure to that described in Example 11-(4) using (1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-cyano-2-fluorophenyl)-1,3-butadienyl]-1,3-dioxan-5-yl]thio]1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propyl 2-[(allyloxycarbonyl)oxymethyl]benzoate (1.52 g, 2.00 mmol), bis(triphenylphosphine)dichloropalladium (5 mg), and tributyltin hydride (620 mg, 2.13 mmol). The obtained crude product was subjected to chromatography on a silica gel (50 g) column (eluent; ethyl acetate:hexane=1:1˜1:0) to afford the title compound (1.096 g, 81% yield) as a colorless amorphous solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:27]I>>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:12]=1[O:25][CH3:26])([CH3:27])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CI
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2F)c1OC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C#N)c1cccc(Oc2ccccc2F)c1OC
Yield: 85 %

Procedure:
Sodium hydride (50%, 1 g), ethyl 2-cyano-2-[2-methoxy-3-(2-fluorophenoxy)phenyl]acetate (7 g) and methyl iodide (4.14 g) were treated in a similar manner to that of Example 10-(5) to give oily ethyl 2-cyano-2-[2-methoxy-3-(2-fluorophenoxy)phenyl]propionate (6.2 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][CH3:6].C(=O)=O.[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>CN(C=O)C.C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[C:18]([O:7][CH2:3][CH2:4][CH2:5][CH3:6])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CCCCO
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1ccc([N+](=O)[O-])c(C(=O)OC)c1

Procedure:
Sodium hydride (302.4 mg) was added to a solution of 1-butanol (0.634 mL) in DMF (15 mL). The reaction mixture was stirred until there was no further evolution of CO2 and then 5-fluoro-2-nitrobenzoic acid methyl ester (1.15 g) was added and the mixture was stirred at room temperature overnight. The reaction was then mixed with ethyl acetate, washed with 10% sodium bicarbonate and 10% citric acid solution, dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC. The product with the molecular weight of 253.26 (C12H15NO5) was obtained in this way; MS (ESI): 254 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:39]=[CH:40][CH:41]=1)[CH2:14][N:15]1[C:19](=[O:20])[C:18]2([CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[N:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl.O1CCOCC1>[O:20]=[C:19]1[C:18]2([CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)[N:17]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:16][N:15]1[CH2:14][C:13]1[CH:12]=[C:11]([CH:41]=[CH:40][CH:39]=1)[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)OCc3ccccc3)c1)CN2c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Yield: 99.6 %

Procedure:
A solution of tert-butyl 3-(3-(benzyloxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (913 mg, 1.646 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 4-5 h. The mixture was concentrated in vacuo and the residue was lyophilized to afford the hydrogen chloride salt of the title compound as a cream solid (747 mg, quant); MS for C28H29N3O3 m/z 456.04 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH-].[Na+].Br[CH2:13][N+:14]([O-:16])=[O:15]>CN(C=O)C.O>[N+:14]([C:13]1[S:1][C:2]2=[N:9][CH:8]=[CH:7][CH:6]=[C:3]2[C:4]=1[NH2:5])([O-:16])=[O:15]
Reactant: N#Cc1cccnc1S
Reactant: O=[N+]([O-])CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])sc2ncccc12
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
To a solution of 2-mercaptonicotinonitrile (1 g, 7.4 mmol) in DMF (20 mL) was added a solution of NaOH (0.88 g, 22 mmol) in water (5 mL) at 0° C. The mixture was stirred for 20 min, then bromonitromethane (2 g, 14.7 mmol) was added dropwise. The resulting mixture was stirred for 1 h at 0° C., diluted with water (100 mL), and filtered. The filter cake was washed with water (20 mL×3) to give a yellow solid (1.1 g, yield 78%), which was used in the next step without further purification. ESI MS: m/z 196 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:41](Cl)([C:44]1[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=1)(=[O:43])=[O:42]>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[N:11]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc3c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1c(C(=O)OC(C)C)ncc2c1c1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1n2S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g of 4-methoxymethyl-6-(triisopropylsilyloxy)-beta-carboline-3-carboxylic acid isopropyl ester, 132 mg of 4-dimethylaminopyridine and 0.45 ml of triethylamine were mixed in 10 ml of dichloromethane at about 4° C. with 615 m of tosyl chloride and then stirred at room temperature for 1 hour. After 16 hours of standing at room temperature, it was diluted with dichloromethane and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. After chromatography on silica gel in the system of cyclohexane/ethyl acetate 1:1, 1.32 g of the title compound was obtained from the isolated organic phase.
Reaction SMILES: C(OC(=O)[NH:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:45])[C:21]([O:37]CC3C=CC=CC=3)=[C:22]([C:24]3[O:25][C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[N:27][N:28]=3)[N:23]=[C:12]21)C1C=CC=CC=1.Br.C(O)(=O)C>C(Cl)Cl>[NH2:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:45])[C:21]([OH:37])=[C:22]([C:24]3[O:25][C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[N:27][N:28]=3)[N:23]=[C:12]21
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(-c2nnc(Cc3ccc(F)cc3)o2)c(OCc2ccccc2)c1=O)OCc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC12CCC(CC1)Cn1c2nc(-c2nnc(Cc3ccc(F)cc3)o2)c(O)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a mixture of benzyl(3-(benzyloxy)-2-(5-(4-fluorobenzyl)-1,3,4-oxadiazol-2-yl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamate, Intermediate 11 (30 mg, 0.048 mmol) in CH2Cl2 (2 mL) was added HBr in acetic acid (0.218 mL, 1.206 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated and dried under high vacuum to afford the title compound (18 mg, 0.038 mmol, 78% yield) as a brown solid. 1H NMR (500 MHz, MeOD) δ ppm 7.39-7.46 (2H, m), 7.08-7.14 (2H, m), 4.38 (2H, s), 4.20 (2H, d, J=3.66 Hz), 2.60 (1H, br. s.), 2.22-2.31 (2H, m), 2.05-2.18 (4H, m), 1.85-1.94 (2H, m). LCMS (M+H)=398.18.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8]2)=[CH:4][C:3]=1[F:17].[C:18]1([CH:24]([C:26]2[CH:27]=[CH:28][C:29]3[O:33][C:32](B(O)O)=[CH:31][C:30]=3[CH:37]=2)[CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:17][C:3]1[CH:4]=[C:5]([CH2:6][N:7]2[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8]2)[CH:15]=[CH:16][C:2]=1[C:32]1[O:33][C:29]2[CH:28]=[CH:27][C:26]([CH:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:25])=[CH:37][C:30]=2[CH:31]=1
Reactant: CC(c1ccccc1)c1ccc2oc(B(O)O)cc2c1
Reactant: COC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(C(C)c5ccccc5)ccc4o3)c(F)c2)C1

Procedure:
According to Scheme B2 and general procedure F, methyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate (0.241 g, 0.797 mmol) and 5-(1-phenylethyl)benzofuran-2-ylboronic acid (0.212 g, 0.797 mmol) were employed to give methyl 1-((3-fluoro-4-(5-(1-phenylethyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylate. According to Scheme B2 and general procedure H, methyl 1-((3-fluoro-4-(5-(1-phenylethyl)benzofuran-2-yl)phenyl)-methyl)azetidine-3-carboxylate (0.275 g, 0.620 mmol) provided 1-((3-fluoro-4-(5-(1-phenylethyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid as a white solid [hS1P1 EC50=99 nM]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (t, J=8.0 Hz, 1H), 7.59 (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.20-7.35 (m, 8H), 7.12-7.20 (m, 1H), 4.28 (q, J=7.0 Hz, 1H), 3.60 (s, 2H), 3.18-3.46 (m, 5H), 1.64 (d, J=7.5 Hz, 3H). MS (ESI) m/z: Calculated: 429.2; Observed: 430.2 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:5]2=O.O.[NH2:23][NH2:24]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])=[CH:7][NH:24][N:23]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: COc1ccccc1-c1coc2cc(O)c(Cl)cc2c1=O
Solvent: O
Solvent: CCO
Product: COc1ccccc1-c1c[nH]nc1-c1cc(Cl)c(O)cc1O

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-7-hydroxy-3-(2-methoxy-phenyl)-chromen-4-one (2.0 g, 6.6 mmol), hydrazine hydrate (5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give 4-chloro-6-[4-(2-methoxy-phenyl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a white solid. Rf 0.8 ethyl acetate/hexane (70/30).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)(=[O:29])=[O:28])([CH3:26])[CH3:25])[N:21]=[C:20]([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[N:19]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)(=[O:28])=[O:29])([CH3:26])[CH3:25])[N:21]=[C:20]([C:36]2[CH:37]=[CH:38][C:39]([NH:40][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:41][CH:42]=2)[N:19]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccccn2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccccn2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenyl chloroformate (0.432 mL, 3.44 mmol) was added to 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-pyridin-2-ylsulfonylpropan-2-yl)pyrimidin-2-yl]aniline (1.3 g, 2.87 mmol) and sodium hydrogen carbonate (0.482 g, 5.73 mmol) in dioxane (20 mL) at RT. The resulting slurry was stirred at RT for 1 hour and then the reaction mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 0%-20% ethyl acetate in DCM, to give the desired material as a yellow dry film (1.62 g).
Reaction SMILES: [CH3:1][O:2][C@:3]12[CH2:17][C@@H:16]([CH2:18][OH:19])[CH2:15][N:14]([CH3:20])[C@@H:13]1[CH2:12][C:11]1[C:21]3[C:8]([N:9]([CH3:22])[CH:10]=1)=[CH:7][CH:6]=[CH:5][C:4]2=3.C(N(CC)CC)C.[S:30](Cl)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>C(Cl)Cl>[S:30]([O:19][CH2:18][C@@H:16]1[CH2:17][C@@:3]2([O:2][CH3:1])[C@@H:13]([CH2:12][C:11]3[C:21]4[C:8](=[CH:7][CH:6]=[CH:5][C:4]2=4)[N:9]([CH3:22])[CH:10]=3)[N:14]([CH3:20])[CH2:15]1)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]
Reactant: CO[C@]12C[C@@H](CO)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@]12C[C@@H](COS(=O)(=O)c3ccc(C)cc3)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Yield: 72.7 %

Procedure:
A mixture of 10 g of 10-methoxy-1,6-dimethylergoline-8β-methanol, 12.4 ml of triethylamine, and 12.6 g of tosyl chloride in 200 ml of methylene chloride is refluxed 5 hr. The solution is washed first with 10% Na2CO3 and then with water, the solvent is evaporated in vacuo, and the residue is crystallized from methanol to give 11 g of 10-methoxy-1,6-dimethylergoline-8β-methanol tosylate; m.p. 169° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Cl>CS(C)=O.O>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: Fc1cccc(CCl)c1
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NCCN1Cc1cccc(F)c1
Reaction time: 0.3 h
Yield: 94 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 150 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of potassium carbonate, 20 g (0.12 mole) of potassium iodide and 36.3 g (0.25 mole) of 3-fluorobenzyl chloride. The reaction mixture was heated with rapid stirring to 100° over 0.3 hours, held at 100° for 1.8 hours and poured with rapid stirring into 1.5 l of cold water. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 500 ml of water, dried over magnesium sulfate overnight and filtered. The filtrate was concentrated to dryness to give 46 g (94%) of a light green semi-solid. The crude product was washed with 125 ml of ether, filtered and air dried to give 13.5 g (28%) of a white solid, m.p. 103°-105°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:16]([F:19])([F:18])[F:17])=[O:13])[CH:6]=[CH:5]2.[CH2:28]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>O1CCCC1>[CH2:28]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C:12]([O:14][CH:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:16]([F:17])([F:18])[F:19])=[O:13])[CH:6]=[CH:5]3)=[O:42])=[CH:39][CH:38]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCC(OC(=O)c1ccc2cc(O)ccc2c1)C(F)(F)F
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc3cc(C(=O)OC(CCCCCCCC)C(F)(F)F)ccc3c2)cc1

Procedure:
To a solution of the 1,1,1-trifluoro-2-decyl-6-hydroxynaphthalene-2-carboxylate (0.5 g) obtained in (1) above, the 4-n-octyloxybenzoic acid (0.4 g) obtained in (2) above in tetrahydrofuran (40 ml) were added dicyclohexylcarbodiimide (0.45 g) and dimethylaminopyridine (0.05 g). The solution was stirred at room temperature overnight. The solution was distilled to remove the solvent. The residue was dissolved in dichloromethane (50 ml) and the solution was washed with dilute aqueous hydrochloric acid solution and water in this order. The organic layer collected was dried over anhydrous magnesium sulfate, and distilled to remove the solvent. The residue was purified by silica-gel column chromatography (developer : hexane/ethyl acetate =20/1) to obtain the titled compound (0.39 g) having specific rotation, [α]D20 =+45.79°.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:24]1([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[N:40]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[N:39]=[C:38]([CH:47]=O)[CH:37]=3)=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][NH:21][CH2:47][C:38]3[CH:37]=[C:36]([C:33]4[CH:34]=[CH:35][C:30]([CH:24]5[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]5)=[CH:31][CH:32]=4)[N:40]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:39]=3)[CH2:17][CH2:18]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:22][CH:23]=1
Reactant: O=Cc1cc(-c2ccc(C3CCCCC3)cc2)n(-c2ccccc2)n1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Product: Clc1ccc(C(c2ccccc2)N2CCN(CCNCc3cc(-c4ccc(C5CCCCC5)cc4)n(-c4ccccc4)n3)CC2)cc1
Yield: 31 %

Procedure:
Compound 101 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 5-(4-cyclohexyl phenyl)-1-phenyl pyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20][C:21](O)=[O:22])=[O:17])([CH3:14])([CH3:13])[CH3:12].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[C:11]([O:15][C:16](=[O:17])[NH:18][CH2:19][CH2:20][C:21](=[C:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])[OH:22])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(O)=C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.9 %

Procedure:
A stirred solution of 2,2-dimethyl-[1,3]dioxane-4,6-dione (7.5 g, 52 mmol), 3-tert-butoxycarbonylamino-propionic acid (9.45 g, 50 mmol), 4-dimethylamino pyridin (9.6 g) in dichloromethane (525 ml) was added dropwise slowly with the solution of N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (11.0 g, 57.5 mmol) in dichloromethane (325 ml). Upon completion of the addition, the mixture was stirred at room temperature overnight, washed with 5% aqueous potassium bisulfate solution (300 ml×4), dried, filtered and concentrated to give [3-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidene)-3-hydroxy-propyl]-carbamic acid tert-butyl ester (18.75 g, 97%) as a light yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13](O)[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:65]=[N+:66]=[N-:67])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CCOC(C)=O>[N:65]([CH:13]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=[CH:11][N:10]=1)[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[N+:66]=[N-:67]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCC(CC)C(O)c1nccn1Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)C(N=[N+]=[N-])c1nccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To 1-(1-benzyl-1H-imidazol-2-yl)-2-ethylbutan-1-ol (1.78 g, 6.88 mmol) in THF (50 mL) at 0° C. was added triphenylphosphine (2.71 g, 10.3 mmol), diethyl azodicarboxylate (1.62 mL, 10.3 mmol) and diphenylphosphorylazide (2.22 mL, 10.3 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with EtOAc and extracted 2 times with 1N HCl. The aqueous layer was washed EtOAc, then basicified with saturated aqueous NaHCO3 and extracted twice with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting oil was purified by column chromatography (SiO2, 100% CHCl3, then MeOH/CHCl3/Et3N, 1:98.5:0.5) to yield a pure oil in 30% yield.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Zn])#[N:2].[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15](Cl)=[O:16]>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([F:9])[C:3]=1[C:1]#[N:2])=[O:16]
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Reactant: N#Cc1c(F)cccc1[Zn]
Solvent: C1CCOC1
Product: N#Cc1c(F)cccc1C(=O)c1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of 2-cyano-3-fluorophenylzinc (80.0 mL, 40.0 mmol, 0.5 M in THF), tetrakistriphenylphosphine palladium(0) (2.3 g, 2.0 mmol) was added in small portions at 0° C. A solution of 3-bromo-4-fluorobenzoyl chloride (10.0 g, 42.1 mmol) in anhydrous THF (20 mL) was then added dropwise and the reaction mixture was stirred at 0° C. for 1 hour. The reaction was quenched by addition of water (150 mL) and the resulting mixture was extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography using 30% ethyl acetate in hexanes to afford the title compound (7.90 g, 61% yield).