Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[CH3:18][NH2:19].[BH4-].[Na+].CO>C1COCC1>[CH3:18][NH:19][C@H:4]1[CH2:5][CH2:6][C@H:1]([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:2][CH2:3]1
Reactant: CN
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reaction time: 1.5 h

Procedure:
To a suspension of ketone 5 (10.4 g, 0.045 mol) in 2-PrOH (520 mL) was added methylamine (33.7 mL of a 2.0 M solution in THF, 0.067 mol). A clear, amber solution formed after ca 15 minutes, and a precipitate gradually formed a few minutes later. After 1.5 hours, the reaction mixture was cooled in an ice/water bath, NaBH4 (2.6 g, 0.067 mol) was added, and stirring was continued at 0° C. for 35 minutes. The reaction mixture was stirred at room temperature for 15 hours. MeOH (ca 2 mL) was added to quench any excess NaBH4 (no gas evolution was observed), and the solvents were removed under reduced pressure. The residue was partitioned between 1N HCl (500 mL) and EtOAc (250 mL). The aqueous layer was separated, adjusted to pH 7-8 with solid NaHCO3, and washed with EtOAc (200 mL). A precipitate formed during the wash, which was collected by vacuum filtration and dried to give 6-[trans-4-(methylamino)cyclohexyl]-3H-benzoxazol-2-one 15 (5.0 g, 46%). The organic layer was separated, and TLC analysis (89:10:1 CH2Cl2:MeOH:NH4OH) showed it contained compound 15. Compound 15 was also shown by TLC analysis to be present in the initial EtOAc extraction. The organic extracts were combined, concentrated under reduced pressure, dissolved in a minimal amount of MeOH, and a solid was precipitated out with diethyl ether. The solid was collected by vacuum filtration and dried to give 15 (1.6 g, 13%) as the HCl salt. To the aqueous layer (ca 1L), which also showed the presence of additional 15 by TLC, was added solid NaCl (ca 80 g), and the solution was concentrated under reduced pressure to approximately half its original volume. A solid formed and was collected by vacuum filtration and dried to give 15 (1.3 g, 12%). The solids were combined to give 6-[trans-4-(methylamino)cyclohexyl]-3H-benzoxazol-2-one 15 (7.9 g, 73%): 1H NMR (500 MHz, CD3OD): δ 7.10 (d, J=1.5 Hz, 1H), 7.03 (dd, J=8, 1.5 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 2.67-2.52 (m, 2H), 2.49 (s, 3H), 2.15-2.12 (m, 2H), 1.97-1.94 (m, 2H), 1.61-1.52 (mi, 2H), 1.38-1.30 (m, 2H).
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:18]1[C:19]2[N:20]([CH:25]=[CH:26][N:27]=2)[N:21]=[C:22]([Cl:24])[CH:23]=1.O1CCOCC1>ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Cl:24][C:22]1[CH:23]=[C:18]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:19]2[N:20]([CH:25]=[CH:26][N:27]=2)[N:21]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(Cl)nn2ccnc12)c1ccccc1
Temperature: 100 °C
Yield: 87.5 %

Procedure:
To a 16×100 mm tube was added benzenesulfonamide (58 mg, 0.37 mmol), tris(dibenzylideneacetone)dipalladium (0) (2 mg, 0.0022 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4 mg 0.0077 mmol) and cesium carbonate (240 mg, 1.25 mmol). The tube was evacuated and back filled with nitrogen. 8-Bromo-6-chloroimidazo[1,2-b]pyridazine (120 mg, 0.447 mmol) from Example I(1), step 1b and 1,4-dioxane (1.0 ml) was then added. The mixture was allowed to heat at 100° C. for 16 hours. The solution was then diluted with dichloromethane, filtered and concentrated in vacuo to afford crude N-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzenesulfonamide 100 mg (73%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[C:49]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:48]=1)[C:38]([O:40][C@H:41]([CH3:45])[C@H:42](O)[CH3:43])=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30]>ClCCl.CN(C)C1C=CN=CC=1.CCCCCC.C(OCC)(=O)C>[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[C:49]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:48]=1)[C:38]([O:40][C@H:41]([CH3:45])[C@H:42]([O:8][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])[CH3:43])=[O:39])=[O:35])([CH3:31])([CH3:32])[CH3:30]
Reactant: O=C(O)c1ccccc1
Reactant: C[C@@H](O)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H](OC(=O)c1ccccc1)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of benzoic acid (0.57 g, 4.8 mmol) in anhydrous dichloromethane was added triethylamine (1.7 mL, 12 mmol) and 2,4,6-trichlorobenzoyl chloride (0.9 mL, 5.76 mmol). The mixture was stirred for 30 min and a solution of (1R,2R)-2-hydroxy-1-methylpropyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (2.4 g, 4.4 mmol) in dichloromethane was slowly added to the reaction mixture, followed by the addition of a catalytic amount of 4-(dimethylamino)pyridine. The mixture was stirred at room temperature for 16 h, washed with 10% citric acid, dried over Na2SO4, and concentrated. Chromatography (silica gel, 20% ethyl acetate in hexane) of the residue afforded 2.6 g (90% yield) of (1R,2R)-1-methyl-2-phenylcarbonyloxypropyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate. 1H NMR (400 MHz, CDCl3): δ 1.26 (d, J=6.4 Hz, 6H), 1.39 (s, 9H), 2.78 (m, 1H), 2.96 (m, 1H), 4.51 (m, 1H), 4.89 (d, 1H), 5.10 (s, 4H), 5.15 (m, 1H), 6.57 (d, J=8 Hz, 1H), 6.71 (s, 1H), 6.77 (d, J=8 Hz, 1H), 7.25-7.43 (m, 12H), 7.52 (t, J=7.6 Hz, 1H), 7.99 (d, J=7.6 Hz, 2H).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Na+].Cl[C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[NH:17][CH:18]=[N:19]2>O1CCCC1>[CH2:1]([O:11][C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[NH:17][CH:18]=[N:19]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ncnc2nc[nH]c12
Reaction time: 1 h
Yield: 61.3 %

Procedure:
1-Decanol (13ml, 68.2mmol) was added in one portion to a stirred suspension of a 60% dispersion of sodium hydride in oil (2.70 g, 67.5mmol) in dry tetrahydrofuran (70 ml) under an atmosphere of nitrogen. Gas was evolved. After 0.5 h 6-chloropurine (3.00 g, 19.4 mmol) was added and the suspension heated at reflux for 3.5 h. The tetrahydrofuran was removed in vacuo and the residue suspended in dilute hydrochloric acid (200 ml). The acidic suspension was stirred for 1 h then neutralised with saturated sodium hydrogen carbonate solution. The suspension was stirred vigorously with 60-80 petroleum ether (500 ml) and the solid removed by filtration. The solid was recrystallised from methanol to give a white solid (3.29 g, 11.9 mmol, 61%).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[Br:18][C:19]1[CH:20]=[C:21]2[C:31](=[C:32]([F:34])[CH:33]=1)[O:30][C:24]1[CH:25]=[N:26][C:27]([Cl:29])=[CH:28][C:23]=1[C:22]2([CH3:36])O.CCOC(C)=O.C(=O)(O)[O-].[Na+]>ClCCCl>[Br:18][C:19]1[CH:20]=[C:21]2[C:31](=[C:32]([F:34])[CH:33]=1)[O:30][C:24]1[CH:25]=[N:26][C:27]([Cl:29])=[CH:28][C:23]=1[C:22]2=[CH2:36]
Reactant: CC1(O)c2cc(Cl)ncc2Oc2c(F)cc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: C=C1c2cc(Cl)ncc2Oc2c(F)cc(Br)cc21

Procedure:
Pyridinium p-toluene-sulfonate (2.53 g, 10.06 mmol) was added to a solution of 7-bromo-3-chloro-9-fluoro-5-methyl-5H-chromeno[2,3-c]pyridin-5-ol (3.15 g, 9.14 mmol) in DCE (91 mL) at 55° C. The reaction was stirred 2.5 hours at which time TLC analysis (10:1 Hex/EtOAc) showed the reaction to be complete. The reaction was poured into saturated aqueous sodium bicarbonate (150 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (4×150 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude product 7-bromo-3-chloro-9-fluoro-5-methylene-5H-chromeno[2,3-c]pyridine which was concentrated and used without further purification. MS m/z=327.9 [M+H].
Reaction SMILES: C([N:8]1[CH2:19][CH2:18][N:17](CC2C=CC=CC=2)[CH2:16][CH2:15][N:14](CC2C=CC=CC=2)[CH2:13][CH2:12][N:11]([CH2:34][C:35](=[O:82])[NH:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][NH:45][C:46](=[O:81])[CH2:47][N:48]2[CH2:59][CH2:58][N:57](CC3C=CC=CC=3)[CH2:56][CH2:55][N:54](CC3C=CC=CC=3)[CH2:53][CH2:52][N:51](CC3C=CC=CC=3)[CH2:50][CH2:49]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[N:11]1([CH2:34][C:35](=[O:82])[NH:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][NH:45][C:46](=[O:81])[CH2:47][N:48]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][NH:8][CH2:9][CH2:10]1
Reactant: O=C(CN1CCN(Cc2ccccc2)CCN(Cc2ccccc2)CCN(Cc2ccccc2)CC1)NCCOCCOCCNC(=O)CN1CCN(Cc2ccccc2)CCN(Cc2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(CN1CCNCCNCCNCC1)NCCOCCOCCNC(=O)CN1CCNCCNCCNCC1

Procedure:
A 100 mL Autoclave pressure reactor was charged with 9.2 g (8.3 mmol) of 8, 50 mL of ethanol and 3 g of 10% Pd/C. The reactor was pressurized to 220 psig with hydrogen for 3 hours at 80° C. The mixture was filtered and the filtrate was concentrated to a slightly yellow oil. 1H NMR, 13C NMR, and mass spectroscopy data were consistent with 9. The yield of 9 was essentially quantitative.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][C:4]12[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH:9]1[CH2:8][CH:7]=[CH:6][CH2:5]2.[H][H]>CO.[Pd]>[ClH:1].[CH3:2][NH:3][C:4]12[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: CNC12CC=CCC1Cc1ccccc12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC12CCCCC1Cc1ccccc12

Procedure:
General procedure: A solution of 5 g of N-methyl- 1,4,9,9a-tetrahydro-4aH-fluoren-4a-amine hydrochloride in 100 ml of methanol is hydrogenated by shaking it with 0.5 g of 20% palladium on charcoal catalyst in contact with a hydrogen atmosphere. When the theoretical amount of hydrogen corresponding to hydrogenation of one double bond has been absorbed, the catalyst is removed by filtration and the solvent distilled under reduced pressure to yield N-methyl1,2,3,4,9,9a-hexahydro-4aH-fluoren-4a-amine hydrochloride; mp 202° to 203° C. following recrystallization from methanol-ether. The free base is obtained by treating an aqueous solution of the hydrochloride with sodium hydroxide and extracting with ether. The hydrobromide is obtained by adding a slight excess of hydrogen bromide to a solution of the free base in ether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])/[CH:4]=[CH:5]/[C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1
Reactant: COC(=O)/C=C/c1nccn1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1nccn1C

Procedure:
(E)-3-(1-Methyl-1H-imidazol-2-yl)-acrylic acid methyl ester (0.86 g) is dissolved in MeOH (10 ml) and hydrogenated at 3 bar at RT for 2 h using Pd/C (10%, 0.1 g) as catalyst. After filtration and evaporation of the solvent the compound (0.87 g) is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[Si:22]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: COC(=O)c1ccc(O)c(C2CCCC2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)c(C2CCCC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.4 %

Procedure:
A 100 mL 3-necked flask equipped with a magnetic stirrer and a nitrogen inlet was charged with 1.79 g of methyl 4-hydroxy-3-cyclopentylbenzoate, 1.22 g of imidazole (Aldrich), 30 mL of anhydrous DMF, and 1.47 g of tert-butyldimethylsilyl chloride (Aldrich). The solution was stirred at RT under nitrogen for 24 h and then concentrated in vacuo to give a thick oil. This material was subjected to flash chromatography on silica gel (95:5 hexane-EtOAc) to afford 2.43 g (89%) of methyl 4-((tert-butyldimethylsilyl)oxy)-3-cyclopentylbenzoate as a clear liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:29][CH2:30][N:26]([CH3:25])[C:27]4=[O:31])=[CH:3][C:4]=3[CH3:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3C)CC2)c(C)c1
Yield: 83 %

Procedure:
Using (4-bromo-2-methylphenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (233 mg) described in Preparation Example 118 and 1-methylimidazolidin-2-one (90 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (203 mg) was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:36][CH:35]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc(C(=O)c2ccccc2)cc1
Yield: 16.2 %

Procedure:
Using the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.51 g, 2.0 mmol) was reacted with 4-benzoylbenzoyl chloride (2.0 mmol) to provide 0.15 g of N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin1-yl)butyl]-4-benzoylbenzamide as a white solid, m.p. 159-161° C. 1H NMR (500 MHz, CDCl3) δ8.06 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 2H), 7.81 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.0 Hz, 2H), 7.60 (m, 2H), 7.49 (t, J=8.0 Hz, 2H), 7.48 (t, J=8.0 Hz, 1H), 7.24 (broad s, 1H), 6.86 (broad s, 1H), 6.60 (t, J=6 Hz, 1H), 4.69 (t, J=7.0 Hz, 2H), 3.62 (q, J=6.0 Hz, 2H), 2.14 (quintet, J=7.0 Hz, 2H), 1.82 (quintet, J=7.0 Hz, 2H); MS (EI) m/e 463.2002 (463.2008 calcd for C28H25N5O2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.F[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+]>CN(C)C(=O)C>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)=[CH:14][CH:15]=1)#[N:18]
Reactant: N#Cc1ccc(F)cc1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(CC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 15.2 g of p-hydroxyphenylacetic acid and 12.1 g of p-fluorobenzonitrile in 125 ml of N,N-dimethylacetamide is added, with vigorous stirring, 27.6 g of anhydrous potassium carbonate. The mixture is heated at 155°-160° C. under an Argon atmosphere with rapid stirring for 4 hours. After cooling to room temperature the mixture is poured into 300 ml of saturated NaHCO3. The mixture is extracted with two 100 ml portions of ether. The aqueous layer is acidified with 50 ml of concentrated HCl. The product is filtered washed with water (ca 500 ml) and dried to give a white solid mp 125.5°-127.5° C. A portion is recrystallized from 7:3 methanol-water (10 ml) to give white needles, mp 126.5°-128.5° C.
Reaction SMILES: O([Si](C)(C)C)[K].[CH2:7]([O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH3:8]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:7]([O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:13][CH:12]=1)[CH3:8]
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Pd]
Agent: C[Si](C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCCCC/C=C\c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Following General Procedure II, a mixture of KOSiMe3 (570 mg, 4.0 mmol, 2.0 equiv), (Z)-21 (379 mg, 2.2 mmol, 1.1 equiv), ethyl-4-iodobenzoate (2.0 mmol) and Pd(dba)2 (58 mg, 0.1 mmol, 0.05 equiv) was stirred at room temperature for 15 min, and then was filtered through SiO2. Purification by column chromatography (RP C18, MeOH/H2O, 9/1) and Kugelrohr distillation afforded 411 mg (83%) of (Z)-154f as colorless oil.
Reaction SMILES: [N:1]12[CH2:8][C:5]([C:9]([NH:11][C:12]3[C:13](O)=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])=[O:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2>C(O)(=O)CC>[N:1]12[CH2:8][C:5]([C:9]3[O:10][C:13]4[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=[CH:21][C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: COC(=O)c1cccc(NC(=O)C23CCCN(CC2)C3)c1O
Solvent: CCC(=O)O
Product: COC(=O)c1cccc2nc(C34CCCN(CC3)C4)oc12
Yield: 21.3 %

Procedure:
A solution of methyl 3-(1-azabicyclo[3.2.1]octane-5-carboxamido)-2-hydroxybenzoate (500 mg, 1.64 mmol) in proponic acid 10 ml) was heated to reflux for 2 days. The resulting solution was concentrated under vacuum, the crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 20:1 to 2:1), 100 mg methyl 2-(1-azabicyclo[3.2.1]octan-5-yl)benzo[d]oxazole-7-carboxylate was obtained. Yield: 21%. LC-MS (ESI) (m/z): 287 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][N:14]([CH:18]([CH2:20][CH3:21])[CH3:19])[C:15](Cl)=[S:16])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH:18]([CH2:20][CH3:21])[CH3:19])[C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:16])=[CH:22][CH:23]=1
Reactant: Nc1ccccc1
Reactant: CCC(C)N(Cc1ccc(Cl)cc1)C(=S)Cl
Solvent: Cc1ccccc1
Product: CCC(C)N(Cc1ccc(Cl)cc1)C(=S)Nc1ccccc1
Yield: 68.2 %

Procedure:
19 g of aniline were dissolved in 300 ml of toluene. To the resulting solution, a solution of 28 g of N-(4-chlorobenzyl)-N-sec.-butyl-thiocarbamoyl chloride in 70 ml of toluene was added dropwise, under cooling and stirring. After the dropwise addition, the temperature of the solution was gradually raised, and then the solution was stirred at a temperature of 70°-80° C. for about 5 hours. The solution was cooled to precipitate aniline hydrochloride, which was then separated by filtration. The toluene layer was washed with 100 ml of cold water and dried with anhydrous sodium sulfate. Then, the toluene was distilled off. The residue was subjected to recrystallization from a mixture of hexane and ethyl alcohol, whereby 23 g of N-(4-chlorobenzyl)-N-sec.-butyl-N'-phenylthiourea were obtained. Yield: 70%. Melting point: 134°-134.5° C.
Reaction SMILES: [CH2:1]([OH:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1>CO.[Pd]>[CH2:1]([OH:13])/[CH:2]=[CH:3]/[CH:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH2:5]1
Reactant: COc1cc(/C=C/CO)ccc1O
Agent: [Pd]
Solvent: CO
Product: COC1=C(O)C=CC(/C=C/CO)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
Dihydroconiferyl aldehyde (DCAL) was synthesized as follows: To a solution of coniferyl alcohol (720 mg, 4 mmol) in methanol (10 ml) was added palladium-charcoal (10%, 100 mg), with the resulting solution stirred under an H2 atmosphere for 4 hours (h) at ambient temperature. After the catalyst was removed by filtration, the resulting solution was evaporated to dryness in vacuo. The resulting residue was dissolved in acetone, subjected to preparative TLC and extracted with acetone; evaporation of the solvent afforded dihydroconiferyl alcohol (DCA, 650 mg, 90%). To the purified DCA (600 mg, 3.3 mmol) in CH2Cl2 (5 ml) was added DMSO (3.4 ml, 36.6 mmol), triethylamine (1 ml, 13.2 mmol), and pyridine sulfur trioxide (1.58 mg, 9.9 mmol), with the resulting mixture stirred for 30 min at ambient temperature. After reaction, the solution was poured into H2O in a separatory funnel, extracted with ether, washed successively with saturated (NH4)Cl, saturated NaHCO3, H2O and saturated NaCl, and finally with NaSO4. The solvent was evaporated and the resulting extract subjected to preparative TLC, with dihydroconiferyl aldehyde extracted with acetone. Evaporation of the solvent afforded dihydroconiferyl aldehyde (202 mg, 1.1 mmol, 33%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(O[C@H]([C@H](C(O)=O)OC(=O)C1C=CC=CC=1)C(O)=O)(=O)C1C=CC=CC=1.[CH2:38]([C:40]1[CH:41]=[CH:42][C:43]([CH2:46][CH2:47][O:48][C:49]2[CH:62]=[CH:61][C:52]([CH2:53][CH:54]3[S:58][C:57](=[O:59])[NH:56][C:55]3=[O:60])=[CH:51][CH:50]=2)=[N:44][CH:45]=1)[CH3:39]>CC(O)C>[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)([OH:10])(=[O:9])=[O:8].[CH2:38]([C:40]1[CH:41]=[CH:42][C:43]([CH2:46][CH2:47][O:48][C:49]2[CH:62]=[CH:61][C:52]([CH2:53][C@H:54]3[S:58][C:57](=[O:59])[NH:56][C:55]3=[O:60])=[CH:51][CH:50]=2)=[N:44][CH:45]=1)[CH3:39]
Reactant: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O[C@@H](C(=O)O)[C@@H](OC(=O)c1ccccc1)C(=O)O)c1ccccc1
Solvent: CC(C)O
Product: CCc1ccc(CCOc2ccc(C[C@H]3SC(=O)NC3=O)cc2)nc1

Procedure:
To a solution of p-toluenesulphonic acid (0.8 g) in IPA (12 mL) at 40° C. was added R)-5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione (−)-O,O′-dibenzoyl-L-tartrate
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.P(Br)(Br)[Br:14].[OH-].[Na+]>CCOCC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:14])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(Cl)ccc1CBr
Reaction time: 1 h

Procedure:
To a stirred solution of 10 g of 4-chloro-2-nitrobenzyl alcohol in 200 mL of ether is added dropwise a solution of 17.7 g phosphorus tribromide in 100 mL of ether. The temperature of the reaction mixture is maintained at 15° or lower by means of cooling with an ice-water bath. On completion of the addition the reaction mixture is allowed to stir for an additional 1 hour at 15° and then at room temperature overnight. The reaction mixture is neutralized with 100 mL of 3N sodium hydroxide, and the layers are separated. The ethereal extracts are washed with 2×250 mL of brine, dried over anydrous sodium sulfate; the solvent is evaporated to dryness under reduced pressure to yield 4-chloro-2-nitrobenzyl bromide melting at 50°.