Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]([C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:12][CH:11]=2)=[CH:6][N:5]=1.[CH3:27][Si:28]([CH2:31][CH2:32][O:33][CH2:34]Cl)([CH3:30])[CH3:29]>CN(C=O)C>[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:34][O:33][CH2:32][CH2:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[C:13]([C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:12][CH:11]=2)=[CH:6][N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cnc(Cl)nc2)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cnc(Cl)nc2)n1COCC[Si](C)(C)C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.23 g, 5.72 mmol) was added in one portion to a stirred solution of (S)-tert-butyl 2-(5-(2-chloropyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (152d-1, 2.0 g, 5.72 mmol) in dry DMF (45 mL) at ambient temperature under N2. The mixture was stirred for 5 min. before SEM chloride (1.01 mL, 5.72 mmol) was added in approx. 0.1 mL increments. The mixture was stirred for 3 h before being quenched with sat'd NH4Cl soln and diluted with ethyl acetate. The organic phase was washed with sat'd NaHCO3 soln and brine, dried over (Na2SO4), filtered, and concentrated. The original aqueous phase was extracted twice more and the combined residue was purified by Biotage™ flash chromatography (40M column, 50 mL/min, preequilibration with 5% B for 750 mL, followed by step gradient elution with 5% B to 5% B for 150 mL, 5% B to 75% B for 1500 mL, then 75% B to 100% B for 750 mL where solvent B is ethyl acetate and solvent A is hexanes). Concentration of the eluant furnished the title compound as a pale yellow foam (2.35 g, 85%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[O:22]1[CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCCOC1CCCCO1
Solvent: ClCCl
Product: C(CCC1CO1)COC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 11.57 g of 6-(2-tetrahydropyranyloxy)-hex-1-ene in 200 mL of methylene chloride is added 10.8 g m-chloroperbenzoic acid and the mixture is stirred at room temperature for 18 hours. The reaction is quenched by the addition of saturated aqueous sodium bicarbonate solution followed by saturated sodium sulfite solution. The organic phase is dried, filtered and evaporated to give a clear oil which is purified by chromatography over silica gel using hexane/ether (4:1) as eluent to obtain 1,2-epoxy-6-(2-tetrahydropyranyloxy)-hexane; IR (CH2CH2): 1450, 1135, 1033 cm-1.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].[CH3:18][C:19]1([CH3:30])[CH2:23][C:22](=O)[CH:21]([C:25](OCC)=[O:26])[CH2:20]1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[OH:10][C:9]1[C:8]2[C:22]3[CH2:23][C:19]([CH3:30])([CH3:18])[CH2:20][C:21]=3[C:25](=[O:26])[O:12][C:7]=2[CH:6]=[C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])[CH:11]=1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: CCOC(=O)C1CC(C)(C)CC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)CC(C)(C)C3
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 13.5 g. of 5-(3-methyl-2-octyl)-resorcinol and 10.5 g. of 4,4-dimethyl-2-carboethoxycyclopentanone [Canadian J. of Chem. 47, 1982-1988 (1969)] in 59 ml. of benzene was added 4.3 ml. of phosphorous oxychloride with stirring and refluxing for 6 hours. After the red solution was allowed to stand at room temperature for 8 hours, it was added to an ice and sodium carbonate solution. The colorless mixture was extracted with ether, dried over magnesium sulfate and concentrated. The mixture was extracted with cold pentane and the pentane was discarded. The residue [9-hydroxy-7-(3-methyl-2-octyl)-2,2,-dimethyl-4-oxo-1,2,3,4-tetrahydrocyclopenta[c] [l]benzopyran] was obtained as a gummy solid.
Reaction SMILES: [I:1]Cl.[CH3:3][O:4][C:5]([C:7]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[C:8]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([Si](C)(C)C)=[CH:28][C:27]=1[F:36])=[O:6]>C(Cl)Cl>[CH3:3][O:4][C:5]([C:7]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[C:8]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([I:1])=[CH:28][C:27]=1[F:36])=[O:6]
Reactant: COC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2cnccc2n1Cc1ccc(OC)cc1
Reactant: ClI
Solvent: ClCCl
Product: COC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
Iodine monochloride (1M in DCM, 1.13 mL) was added dropwise over 10 minutes to a cooled (−10° C.) solution of 3-(2-fluoro-4-trimethylsilanyl-phenylamino)-1-(4-methoxy-benzyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (269 mg, 0.56 mmol) in DCM (5 mL). The mixture was allowed to warm to ambient temperature and stirred for 20 minutes then quenched by the addition of saturated sodium thiosulphate solution (1 mL). The solution was partitioned between DCM (30 mL) and water (20 mL), the organic layer was separated, dried (Na2SO4), filtered and evaporated to give an orange oil. The oil was purified by flash column chromatography on silica (Si-PPC, cyclohexane:EtOAc, gradient 90:10 to 40:60) to provide the title compound as a yellow solid (240 mg, 80%). LCMS (method B): RT=2.59 min, M+H+=532.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10](=[O:19])[NH:9][N:8]=1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[C:30]([O:29][C:27]([CH2:26][N:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:2]([Cl:1])[CH:3]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]1=[O:19])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: COc1ccc(CNc2n[nH]c(=O)c3ccc(C#N)cc23)cc1Cl
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CNc2nn(CC(=O)OC(C)(C)C)c(=O)c3ccc(C#N)cc23)cc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 153.6 %

Procedure:
4-(3-Chloro-4-methoxybenzyl)amino-6-cyanol-1(2H)-phthalazinone (0.20 g) prepared in Example 21 was dissolved in 5 ml of N-methyl-2-pyrrolidinone, followed by the addition of 0.14 g of t-butyl bromoacetate and 0.24 g of potassium carbonate. The obtained mixture was stirred at 80° C. for 4 hours and poured into water, followed by extraction with ethyl acetate. The organic phase was washed with water twice and with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and freed from the solvent by vacuum distillation. The title compound (0.41 g) was obtained as a yellow crystal.
Reaction SMILES: C(O[C@@H:8]1[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C@@H:25]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C@H:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:9]1[O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])(=O)C(C)(C)C.[C:43]1([SH:49])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl>[C:43]1([S:49][C@@H:8]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C@@H:25]([O:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:30])[CH3:31])[C@H:17]([O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[C@H:9]2[O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:13])[CH3:14])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
To a solution of 43 (1.49 g, 2.49 mmol) in 50 mL CH2Cl2 is added thiophenol (0.64 mL, 686 mg, 6.22 mmol) followed by boron trifluoride diethyl ether complex (1.53 mL, 1.76 g, 12.45 mmol). The reaction mixture is stirred at room temperature for 4 h and quenched by the slow addition of 10 mL saturated NaHCO3 solution. The reaction mixture is diluted with 100 mL of CH2Cl2, washed with H2O (100 mL), saturated NaCl (100 mL), dried over Na2SO4, filtered, concentrated and purified by flash chromatography (5% EtOAc/hexane) to afford 1.24 g (82%) of 1-deoxy-1-(phenylthio)-2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranose 44: Rf 0.25 (5% EtOAc/hexane); 1H NMR (CDCl3, 270 MHz) δ 7.47-7.50 (m, 2H), 7.22-7.30 (m, 3H), 5.34 (app t, J=9.4 Hz, 1H, H-3), 5.08 (app t, J=9.7 Hz, 1H, H-4), 5.03 (app t, J=9.7 Hz, 1H, H-2), 4.73 (d, J=9.8 Hz, 1H, H-1), 4.25 (dd, J=12.2, 1.6 Hz, 1H, H-6), 4.04 (dd, J=12.2, 5.9 Hz, 1H, H-6), 3.76 (ddd, J=10.2, 5.9, 1.6 Hz, 1H, H-5), 1.21 (s, 9H), 1.20 (s, 9H), 1.14 (s, 9H), 1.10 (s, 9H); 13C NMR (CDCl3, 68 MHz) δ 177.8, 176.9, 176.2, 176.1, 132.5, 132.2, 129.2, 129.1, 128.1. 128.8, 86.4, 76.3, 73.1, 69.3, 67.5, 62.1, 38.7, 38.6, 27.4, 27.0, 29.9; FABMS C32H48O9S (MNa+) calcd 631.2917, found 631.2943.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([CH2:8][CH2:9][O:10][CH3:11])[C:4](=[O:12])[CH:3]=1.[I:13][C:14]1[N:15]=[C:16]([CH3:20])[NH:17][C:18]=1[CH3:19]>>[I:13][C:14]1[N:15]=[C:16]([CH3:20])[N:17]([C:2]2[CH:7]=[N:6][N:5]([CH2:8][CH2:9][O:10][CH3:11])[C:4](=[O:12])[CH:3]=2)[C:18]=1[CH3:19]
Reactant: Cc1nc(I)c(C)[nH]1
Reactant: COCCn1ncc(Cl)cc1=O
Product: COCCn1ncc(-n2c(C)nc(I)c2C)cc1=O

Procedure:
The title compound, light yellow waxy solid, MS: m/e=375.2 (M+H+), was prepared in accordance with the general method of example 23b from 5-Chloro-2-(2-methoxy-ethyl)-2H-pyridazin-3-one and 4-iodo-2,5-dimethyl-1H-imidazole.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:19](=[O:20])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C)C=O>[CH3:21][C:22]1[N:23]([CH2:2][CH2:3][CH2:4][CH:5]2[C:19](=[O:20])[C:9]3[C:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:11][O:12][C:8]=3[CH2:7][CH2:6]2)[CH:24]=[CH:25][N:26]=1
Reactant: O=C1c2c(-c3ccccc3)noc2CCC1CCCCl
Reactant: Cc1ncc[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nccn1CCCC1CCc2onc(-c3ccccc3)c2C1=O
Temperature: 76 °C
Yield: 40.2 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (5.80 g) and dimethylformamide (57.0 ml) was added 2-methylimidazole (3.30 g), diisopropylethyl amine (10.5 ml) and sodium iodide (9.04 g) at room temperature with stirring. The reaction was flushed with nitrogen and warmed at 76° C. for 1 hour. Upon cooling to room temperature, dilute aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous layer extracted twice with ethyl acetate and once with ether. The combined organic layers were washed with brine and concentrated to give the crude product. Drying was accomplished by azeotroping with benzene. Purification via flash column chromatography (silica gel, 2% triethylamine/0-20% methanol/ether) afforded 2.70 g (40%) of 6,7-dihydro-5-[3-(2-methyl-1H-imidazol-1-yl)-propyl]-3-phenyl -1,2-benzisoxazol-4(5H)-one. Recrystallization from dichloromethane/ether/pentane gave the product, m.p. 97°-99° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=1)[CH:5]=[O:6]
Reactant: Oc1cccc(F)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2cccc(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 3-fluorophenol.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O)([CH3:17])([CH3:16])[CH3:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCl.C(O)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:21][C:20]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:19]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(C=O)cc1C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1C(C)(C)C
Temperature: 20 °C
Reaction time: 12 h

Procedure:
The synthesis is carried out in argon condition. 2 g (10.7 mmol) of N-Boc-piperazine and 2.06 g (10.7 mmol) of 3-tert-butyl-4-methoxybenzaldehyde are mixed in 30 ml of dry dichloromethane. After dissolution 2 drops of acetic acid is added, then 4.24 g (20 mmol) of NaBH(OAc)3 is added and the mixture is stirred for 12 h at 20° C. Then 20 ml of 5% NaHCO3 aqueous solution is added dropwise with care to the reaction mixture. The organic layer is separated, washed with 5% Na2CO3 solution, dried over sodium sulfate, filtered off and concentrated in vacuum at 50÷80° C. The residue (3.5 g of yellow oil) is used on the next step.
Reaction SMILES: [OH:1][C@H:2]1[CH2:15][C@@H:14]([OH:16])[C@H:13]([CH2:17][CH2:18]/[CH:19]=[CH:20]/[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:25]1[CH2:35]CN2C(=NCCC2)C[CH2:26]1.C(I)(C)C>C(#N)C>[CH:25]([O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7]/[CH:6]=[CH:5]\[CH2:4][C@@H:3]1[C@@H:13]([CH2:17][CH2:18]/[CH:19]=[CH:20]/[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:14]([OH:16])[CH2:15][C@@H:2]1[OH:1])([CH3:35])[CH3:26]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCC/C=C/CC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Solvent: CC(C)I
Solvent: CC#N
Product: CCCC/C=C/CC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC(C)C)[C@@H](O)C[C@H]1O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The compound 28 obtained obove (237 mg, 0.70 mmole) was dissolved in acetonitrile (3 ml), and 1,8-diazabicyclo[5.4.0]-7-undecene (0.178 ml, 1.2 mmole) and isopropyl iodide (0.12 ml, 1.2 mmole) were added thereto and the mixture was stirred at room temperature for 15 hours. Then, the reaction mixture was treated following the procedure similar to that of Example 5, to yield 266 mg of the title compound 29 as a colorless oil (quantitative).
Reaction SMILES: [CH:1]([C:13]1[CH:14]=[N:15][N:16]([CH:18]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:19]([NH:21][C:22]2[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:23]=2[O:32][CH3:33])=[O:20])[CH:17]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>C1COCC1.[Pd]>[CH2:1]([C:13]1[CH:14]=[N:15][N:16]([CH:18]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:19]([NH:21][C:22]2[C:23]([O:32][CH3:33])=[CH:24][C:25]([O:30][CH3:31])=[CH:26][C:27]=2[O:28][CH3:29])=[O:20])[CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [H][H]
Reactant: CCCCCCCCCCC=Cc1cnn(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1cnn(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
In addition to the procedures followed in Example 122, (±)-4-(1-dodecenyl)-α-phenyl-N-(2,4,6-trimethoxyphenyl)-1H-pyrazole-1-acetamide (0.46 g, 0.9 mmol) was dissolved in 75 mL THF and 5% Pd/C (0.1 g) was added. Hydrogen gas (50 psi) was added and the reaction mixture was stirred at room temperature for 2 hours. Filtered to remove the catalyst and concentrated the filtrate to give an oil. Triturated with hexanes to give the title compound as a cream-colored solid (0.45 g, 97%); mp 77°-79° C.
Reaction SMILES: [C:1]([N:9]1[CH2:17][C@@H:16]([OH:18])[CH2:15][C@H:10]1[C:11]([O:13]C)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[C:1]([N:9]1[CH2:17][C@@H:16]([O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:15][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1C[C@@H](C(=O)O)N(C(=O)c2ccccc2)C1
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
A solution of (cis)-1-benzoyl-4-hydroxy-L-proline, methyl ester (169.2 g, 0.679 mole) and triethylamine (104.2 ml, 0.747 mole) in dichloromethane (3.3 liters) was cooled to -10° C. under nitrogen and treated dropwise with methanesulfonyl chloride (59.85 ml, 0.74 mole). The reaction was stirred an additional 30 minutes at -5° C. to -10° C. and the volatiles were removed in vacuo. The residue was treated with ethyl acetate and washed with water, 1N HCl, saturated sodium bicarbonate solution, and brine. The organic solution was dried, filtered, and concentrated in vacuo. The residue was dissolved in THF (2.1 liters) and treated with 3.36 N LiOH solution (423 ml) and stirred at room temperature for 1 hour. The THF was removed in vacuo and the aqueous solution was acidified to pH 4. The resulting solid was filtered, washed with ice water, and recrystallized from 95% ethanol-ethyl acetate to afford 130 g of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=1.[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH2:27]>>[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH:27][C:11]1[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:13][N:12]=1
Reactant: CSc1ncc(Cc2ccccn2)c(=O)[nH]1
Reactant: Cc1[nH]cnc1CSCCN
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccccn2)c(=O)[nH]1

Procedure:
An intimate mixture of 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone (4.7 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (3.4 g) was heated at 130°-135° for 7 hours. The cooled residue was triturated with hot water to give 2-[2-(5-methyl-4-imidazolylmethythio)ethylamino]-5-(2-pyridylmethyl)-4-pyrimidone and this product was treated with dilue ethanolic HCl to give the title compound m.p. 207°-210° (aqueous ethanol)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:30][CH:31]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:30][CH:31]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:29][CH2:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][N:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)=[CH:27][CH:26]=2)=[CH:40][CH:39]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)C(F)Cc1ccc(O)cc1
Reactant: OCc1ccc(CN(CCc2ccccc2)c2nc(-c3ccccc3)cs2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)C(F)Cc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
To a solution of [4-[[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl]phenyl]methanol (725 mg, 1.81 mmol), ethyl 2-fluoro-3-(4-hydroxyphenyl)propanoate (300 mg, 1.81 mmol) and tributylphosphine (550 mg, 2.72 mmol) in tetrahydrofuran (30 mL) was added 1,1′-(azodicarbonyl)-dipiperidine (685 mg, 2.72 mmol), and the mixture was stirred at room temperature for 16 hr. The insoluble materials were filtered off and the filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:97-40:60) to give the title compound (798 mg, yield 78%, 2 steps) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[N+:12]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[C:20]2Cl)([O-:14])=[O:13].Cl.C(=O)([O-])O.[Na+]>CN1C(=O)CCC1.O1CCOCC1>[N+:12]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([C:10]1[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=3)[NH:3][C:2]=1[CH3:1])[CH:21]=[CH:20]2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Reactant: Cc1ccc2[nH]c(C)cc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c(C)c(-c3ccc4cccc([N+](=O)[O-])c4n3)c2c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
2,5-Dimethylindole (300 mg) and 8-nitro-4-chloroquinoline (430 mg) were suspended in NMP (10 ml) containing 4M HCl in dioxane (2 drops) and maintained under a nitrogen atmosphere. The reaction was heated to 120° C. with stirring for 8 hours. When cooled, the mixture was basified with saturated sodium hydrogen carbonate solution and extracted into ethyl acetate, dried (MgSO4) and evaporated under reduced pressure to give an oil. The oil was purified by flash column chromatography using 2:1 isohexane/ethyl acetate as eluent to give the sub-title compound (560 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH2:9][CH2:10][CH3:11].[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][C:26](=[O:28])[CH:25]=[C:24]([OH:29])[CH2:23]2)=[CH:18][CH:17]=1)[CH3:15]>O1CCCC1>[C:8]([C:25]1[C:26](=[O:28])[CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([CH2:14][CH3:15])=[CH:21][CH:20]=2)[CH2:23][C:24]=1[OH:29])(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCc1ccc(C2CC(=O)C=C(O)C2)cc1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)C1=C(O)CC(c2ccc(CC)cc2)CC1=O
Reaction time: 8 h

Procedure:
51 g (0.51 mol) of triethylamine and--with ice cooling--54 g (0.51 mol) of butyryl chloride are dripped into a solution of 110 g 0.51mol) of the 5-(4-ethylphenyl)-3-hydroxy-2-cyclohexen-1-one, obtained in accordance with the foregoing instructions, in 500 ml of tetrahydrofuran. After 8 hours at room temperature, the mixture is filtered and the precipitate is washed with tetrahydrofuran. The filtrate is concentrated, the residue is taken up in 500 ml of ethyl acetate and 6.2 g of 4-N,N-dimethylaminopyridine is added. The homogeneous solution is kept for 40 hours at room temperature, is then concentrated and the residue is taken up in 10% strength potassium hydroxide solution. The undissolved constituents are separated off, and the filtrate is acidified to pH 1. The product which precipitates out is filtered off and dried under reduced pressure.
Reaction SMILES: O[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:20])=O>CCOCC>[Cl:20][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Oc1noc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Clc1noc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Hydroxy benzisoxazole 11 (1.03 gr, 6.25 mmol), triethylarnine (632 mg, 6.25 mmol) and phosphorousoxychloride (1.92 gr, 12.5 mmol) were heated in a sealed tube at 150° C. for 18 h. After this time the reaction was cooled to room temperature and diluted with ether and carefully quenched with excess ice/water. The resulting mixture was stirred for 15 min then the organic layer was washed with water (2×), brine (1×), dried with magnesium sulfate, filtered and evaporated to afford 12 as a white solid after column chromatography (hexanes/ethyl acetate, 97:3); 1H-NMR (CDCl3, 500 MHz) δ 7.65-7.63 9 m, 2H), 7.42 (dd, 1H).