Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)O)[O:5][CH2:6][CH3:7])[CH3:2].C(Cl)Cl.C(N(S(F)(F)[F:26])CC)C>O>[CH2:1]([O:3][P:4]([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)[F:26])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(OCC)C(O)c1cccc(Br)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOP(OCC)C(F)c1cccc(Br)c1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
Into cold mixture of diethyl[(3-bromophenyl)(hydroxy)methyl]phosphonite (30 g) and CH2Cl2 (120 mL) was added diethylaminosulfur trifluoride (16.44 g, 101.53 mmol) and the mixture was stirred for 2 hours. The mixture was then poured into water and washed with NaHCO3 and brine. Purification by ISCO (hexane/EtOAc 1/1) gave diethyl[(3-bromophenyl)(fluoro)methyl]phosphonite (22.6 g); MS m/e (M+H)+ 325.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[C:12]1(/[C:18](/[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[I-:32].[Na+].O>CC(C)=O>[I:32][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]/[CH:19]=[C:18](\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)/[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: [I-]
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: ICCCCC/C=C(\c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
p-Toluenesulfonate of (E)-7-phenyl-7-(3-pyridyl)-6-hepten-1-ol (15 g, 36 mmoles) and sodium iodide (18 g, 120 mmoles) were dissolved in acetone (100 ml) and the solution was stirred at room temperature for 3 hours. Water (200 ml) was added to the mixture and the product was extracted twice with ethyl ether. The organic layer was washed with water, dried (magnesium sulfate) and concentrated under reduced pressure to give (E)-1-iodo-7-phenyl-7-(3-pyridyl)-6-heptene (13 g, 96%) as an oil.
Reaction SMILES: [NH3:1].C[O:3][C:4]([P:6](=[O:15])([O:11][CH2:12][CH:13]=[CH2:14])[O:7][CH2:8][CH:9]=[CH2:10])=O>O1CCCC1>[C:4]([P:6](=[O:15])([O:11][CH2:12][CH:13]=[CH2:14])[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[NH2:1]
Reactant: C=CCOP(=O)(OCC=C)C(=O)OC
Reactant: N
Solvent: C1CCOC1
Product: C=CCOP(=O)(OCC=C)C(N)=O
Temperature: 35 °C

Procedure:
A slight excess (5-10%) of gaseous ammonia is introduced into a stirring mixture of 11 parts of diallyl methoxycarbonylphosphonate (from triallyl phosphite and methyl chloroformate) and 200 parts of tetrahydrofuran. The temperature increases from 25° to 28° C. spontaneously. The mixture is then heated to 35° C. and maintained at this temperature for 2 hours. The slightly hazy solution is filtered, and solvent is removed from the filtrate at 50° C. under reduced pressure (15 mm.). The residual solid is recrystallized from benzene, giving 6 parts of white crystalline diallyl carbamoylphosphonate, m.p. 91°-94° C.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=O)[CH3:2].[OH:8][C:9]1[CH:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:12]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])=[CH:11][C:10]=1C(C)=O.C([O-])(=O)C.[Na+].C(OCC)(=O)C>O>[CH3:19][S:16]([NH:15][C:13]1[C:12]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])=[CH:11][C:10]2[C:9](=[O:8])[CH:14]=[C:5]([CH3:6])[O:4][C:1]=2[CH:2]=1)(=[O:17])=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1cc(Oc2ccc(F)cc2F)c(NS(C)(=O)=O)cc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(=O)c2cc(Oc3ccc(F)cc3F)c(NS(C)(=O)=O)cc2o1
Yield: 14.4 %

Procedure:
1.06 ml of acetic anhydride was added to 2.0 g of methyl 2-hydroxy-4-methylsulfonylamino-5-(2,4-difluorophenoxy)phenyl ketone and 550 mg of sodium acetate. The mixture was refluxed for 1 hour. The reaction mixture was introduced into a mixture of 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated and washed with water. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 20 ml of ethanol. 12 ml of a 1N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed for 10 minutes. The reaction mixture was introduced into a mixture of 50 ml of ethyl acetate and 50 ml of water. The resulting mixture was adjusted to pH 2.0 with 4N hydrochloric acid. The organic layer was separated, washed with water, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 10 : 1 mixture of toluene and ethyl acetate) to obtain 300 mg (yield: 14.4%) of 7-methylsulfonylamino-2-methyl-6-(2,4-difluorophenoxy)-4H-1-benzopyran-4-one.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[CH2:8][C:6]=2[N:7]=1.[CH:22]([NH:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)=[O:27])([CH3:24])[CH3:23]>>[CH:12]1([CH2:11][N:9]2[CH2:10][C:5]3[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]4[CH3:21])=[N:3][C:2]([C:32]4[CH:31]=[CH:30][C:29]([NH:28][C:26]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:27])=[CH:34][CH:33]=4)=[N:7][C:6]=3[CH2:8]2)[CH2:14][CH2:13]1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(CC1CC1)C2
Reactant: CC(C)NC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC(C)NC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(CC2CC2)C3)cc1

Procedure:
Method as described for example 47 using intermediate 8 and 1-isopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as starting materials. Purified by prep. LCMS (low pH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[OH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][OH:13])=[CH:20][CH:19]=2)(=[O:23])=[O:22])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(CO)cc1
Reactant: Fc1ccc(C2CCCN2)cc1
Product: O=S(=O)(c1ccc(CO)cc1)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, white solid, m.p. 107° C., and MS: m/e=336.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-hydroxymethyl-benzenesulfonyl chloride.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[OH-].[K+].[CH3:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[C:20]([CH3:24])[NH:21]2)=[CH:17][CH:16]=1>CS(C)=O>[CH3:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[C:20]([CH3:24])[N:21]2[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[CH:17][CH:16]=1
Reactant: ClCCN1CCOCC1
Reactant: COc1ccc2cc(C)[nH]c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc2cc(C)n(CCN3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloroethylmorpholine HCl (138 mg, 0.74 mmol) in 0.3 mL DMSO was added pulverized KOH (104 mg, 1.86 mmol), then after 10 min, a solution of 6-methoxy-2-methylindole (138 mg, 0.74 mmol) in 0.2 mL DMSO was added and the reaction stirred at room temperature overnight. The reaction mixture was partitioned between H2O and toluene, and the organic extract washed two times with H2O, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 10% MeOH in CH2Cl2 to give a final yield of 17 mg (0.062 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.45 (s, 3H), 2.50-2.63 (m, 4H), 2.67 (t, J=7.4 Hz, 2H), 3.71-3.83 (m, 4H), 3.90 (s, 3H), 4.18 (t, J=7.4 Hz, 2H), 6.19 (s, 1H), 6.78 (dd, J=8.5 Hz, 2.2 Hz, 1H), 6.81 (s, 1H), 7.42 (d, J=8.5 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.77, 40.98, 54.13, 55.92, 57.74, 66.94, 93.50, 99.82, 108.35, 120.26, 122.51, 135.31, 137.25, 155.53. MS m/z 275.3 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH2:29][N:30]3[CH2:35][CH2:34][NH:33][C@@H:32]([CH2:36][OH:37])[CH2:31]3)[CH:7]=2)[CH2:3][CH2:2]1.C=O.[C:41](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH2:29][N:30]3[CH2:35][CH2:34][N:33]([CH3:41])[C@@H:32]([CH2:36][OH:37])[CH2:31]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN[C@@H](CO)C3)c2c1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN(C)[C@@H](CO)C3)c2c1
Reaction time: 4 h
Yield: 85.2 %

Procedure:
The product of Example 85 (80 mg) was dissolved in dichloromethane (10 mL). Formaldehyde (0.057 mL) and sodium triacetoxyborohydride (98 mg) were then added and the mixture stirred for 4 hours. Water (10 mL) was then added and the mixture extracted with dichloromethane (30 mL). The organics were combined and evaporated under reduced pressure. The residue was purified by HPLC to give the title compound as a solid (70 mg).
Reaction SMILES: C([Li])CCC.[C:6]1([S:12][CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:14][S:15]SC.Cl>CCCCCC.O1CCCC1>[C:6]1([S:12][CH2:13][S:15][CH3:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CSSC
Reactant: CSc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSCSc1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
120 ml. of a 1.3M n-butyllithium solution in n-hexane were added dropwise to a solution of 18.8 ml. of thioanisole in 240 ml. of tetrahydrofuran at -20° C. and the reaction mixture was stirred at that temperature for 2 hours. After cooling to -70° C., 16.4 g. of dimethyldisulphide were added to the reaction mixture, which was then stirred at -70° C. for 15 minutes and at room temperature for 1 hour. The reaction mixture was poured into dilute aqueous hydrochloric acid and extracted with ethyl acetate. The extracts were washed with water and an aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by distillation in vacuo to give 18.0 g. of the title compound having the following physical characteristics:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:31]O)[C:27]([O:29][CH3:30])=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:31][N:11]1[C:10](=[O:15])/[C:9](=[CH:8]/[C:7]2[CH:16]=[CH:17][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)/[S:13][C:12]1=[O:14])[C:27]([O:29][CH3:30])=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(/C=C2\SC(=O)N(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
Compound 2 (285 mg, 1.15 mmol), (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate (251 mg, 1.15 mmol) and triphenylphosphine (452 mg, 1.72 mmol) were dissolved in 11 mL of anhydrous THF, and stirred at room temperature for 5 min. DIAD (338 μL, 1.72 mmol) was added to the reaction mixture and then stirred overnight at 45° C. The reaction mixture was diluted with ethyl acetate and washed with sat'd NH4Cl aqueous solution. The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (30% ethyl acetate in hexanes) to afford compound 21d (99.5%, 517 mg) as a white solid.
Reaction SMILES: [CH:1](=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Br[CH:23]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:24]([O:26][CH3:27])=[O:25].C[Si](C)(C)Cl>[Zn].S(=O)(=O)(O)O>[OH:21][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:23]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:24]([O:26][CH3:27])=[O:25]
Reactant: CCCCCCCCCCCCCCCCCCCC=O
Reactant: CCCCCCCCCCCCCCC(Br)C(=O)OC
Agent: C[Si](C)(C)Cl
Agent: O=S(=O)(O)O
Agent: [Zn]
Product: CCCCCCCCCCCCCCCCCCCC(O)C(CCCCCCCCCCCCCC)C(=O)OC
Temperature: 85 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
Icosanal (1 g, 3.37 millimole) and methyl 2-bromohexadecanoate (977.8 mg, 2.80 millimole) were dissolved in the same mixed solvent (30 ml). The obtained solution (4 ml) was added dropwise to the reaction vessel containing zinc activated by trimethylchlorosilane as described above, and the mixture was stirred at 85° C. for 1 hour. The progress of reaction was confirmed through thin layer chromatography, and the rest of the solution (26 ml) was gradually added under the same conditions and the mixture was stirred for 8 hours. After cooling the reaction mixture with ice, 20% sulfuric acid (50 ml) was added thereto, and the, mixture,, was stirred for 15 minutes. Then the mixture was extracted twice with benzene, and the organic phase was washed twice with 10% sulfuric acid, and successively washed once with saturated aqueous sodium bicarbonate solution, once with 10% sulfuric acid, then twice with water, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic phase, and the obtained residue was dissolved in a developing solvent (n-hexane:ether=8:2) and fractionated through silicagel column chromatography (n-hexane:ether=8:2). The fourth and fifth fractions were pooled and the solvent was distilled off to give methyl 3-hydroxy-2-n-tetradecyl-docosanoate (III) (812.8 mg, yield 51%) in the form of white crystals.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:5]=1[N+:11]([O-:13])=[O:12]>CO>[F:3][C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH:2][CH3:1]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: CN
Solvent: CO
Product: CNc1cccc(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A methanol solution of 40% methyl amine (12.2 mL, 119 mmol) was added dropwise to a methanol solution (39.5 mL) of 2,6-difluoronitrobenzene (7.90 g, 49.7 mmol) under ice cooling, and the mixture was stirred at the same temperature for 0.5 hours, and then stirred at room temperature for 3 hours. The reaction solution was poured into ice water, and precipitated crystals were collected by filtration and washed with water. The resulting crystals were dried at 50° C., thereby obtaining 7.84 g of a red, powdery target compound (yield: 93%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:29])=[N:23][C:24]=2Cl)(=[O:3])[CH3:2].[CH2:30]([C:34]1[NH:35][CH:36]=[CH:37][N:38]=1)[CH2:31][CH2:32][CH3:33]>CC#N>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:29])=[N:23][C:24]=2[N:35]1[CH:36]=[CH:37][N:38]=[C:34]1[CH2:30][CH2:31][CH2:32][CH3:33])(=[O:3])[CH3:2]
Reactant: CCCCc1ncc[nH]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC#N
Product: CCCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 115.3 %

Procedure:
A solution of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloropurine (2.41 g, 5.4 mmol) and 2-butylimidazole (6.68 g, 54 mmol) in CH3CN (60 mL) was stirred at 65° C. under N2 for 32 h (reaction complete, TLC). Volatiles were evaporated in vacuo, and the residue was chromatographed (MeOH/CH2Cl2, 1:90) to give crude 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-(2-butylimidazol-1-yl)-2-chloropurine (3.33 g, contaminated with 2-butylimidazole): 1H NMR (500 MHz, CDCl3) δ 8.56 (s, 1H), 8.24 (s, 1H), 7.10 (s, 1H), 6.26 (d, J=5.8 Hz, 1H), 5.83 (t, J=5.6 Hz, 1H), 5.61 (t, J=5.6 Hz, 1H), 4.43-4.51 (m, 3H), 3.31 (t, J=7.9 Hz, 2H), 2.18 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H), 1.81 (quint, J=7.7 Hz, 2H), 1.50 (sext, J=7.7 Hz, 2H), 0.98 (t, J=7.3 Hz, 3H); HRMS m/z 535.1702 (MH+[C23H28ClN6O7]=535.1708).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:21]OS(C)(=O)=O)[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:21][N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1Cl
Reactant: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC(C)C)n2)cc1Cl
Yield: 76.1 %

Procedure:
Following the procedure of Example 1(10), 6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 76.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:27]([N:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:36][CH:35]1[CH2:47]Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:47][CH:35]2[CH2:36][N:37]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:38][CH2:39][N:34]2[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Product: O=C(c1cn(CC2CN(Cc3ccccc3)CCN2Cc2ccccc2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69 above) with 1,4-dibenzyl-2-chloromethyl-piperazine (described in Journal of Medicinal Chemistry (1999), 42(9), 1587-1603) gave the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[O:21][N:20]=[C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[O:21][N:20]=[C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cc(OCc3ccc4ccccc4n3)no2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2cc(OCc3ccc4ccccc4n3)no2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[3-(2-quinolylmethoxy)-5-isoxazolylmethyl]-1H-pyrazol-4-yl]propionate (721 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[3-(2-quinolylmethoxy)-5-isoxazolylmethyl]-1H-pyrazol-4-yl]propionic acid (608 mg, yield: 90%). This was recrystallized from ethanol-hexane. Melting point: 123–124° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[SH:10].CI.[C:13]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:13][S:10][C:2]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[N:1]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1nc2ncccc2[nH]1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nc2cccnc2[nH]1
Reaction time: 24 h
Yield: 22 %

Procedure:
To a solution of 1H-imidazo[4,5-b]pyridine-2-thiol (5.0 g) in acetone (75 mL) were added MeI (2.3 mL) and K2CO3 (18 g) at room temperature. After stirring for 1 day, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (1.2 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:22][C:23]([C:25]1([CH3:28])[CH2:27][O:26]1)=[O:24]>>[OH:26][C:25]([CH3:28])([CH2:27][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=1)[C:23]([NH:22][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([N+:19]([O-:21])=[O:20])[C:13]=1[CH3:12])=[O:24]
Reactant: Cc1c(NC(=O)C2(C)CO2)cccc1[N+](=O)[O-]
Reactant: COCCc1ccc(O)cc1
Product: COCCc1ccc(OCC(C)(O)C(=O)Nc2cccc([N+](=O)[O-])c2C)cc1

Procedure:
2-Hydroxy-3-[4-(2-methoxyethyl)phenoxy]-2-methyl-N-(2-methyl-3-nitrophenyl)propionamide was prepared as described in Example 1 starting from 4-methoxyethylphenol and 2-methyloxirane-2-carboxylic acid (2-methyl-3-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-2% methanol). 1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.28 (3H, s), 2.72 (2H, t, J=6.8 Hz), 3.22 (3H, s), 3.47 (2H, t, J=6.8 Hz), 3.94 (1H, d, J=9.4 Hz), 4.15 (1H, d, J=9.4 Hz), 6.11 (1H, s), 6.84 (2H, d, J=7.9 Hz), 7.12 (2H, d, J=7.9 Hz), 7.41-7.45 (1H, m), 7.65-7.68 (1H, m), 7.72-7.75 (1H, m), 9.71 (1H, s).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[Cl:12].CCN(CC)CC.CS(C)=[O:22]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[Ag+]>[Cl:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:3]=1[CH:2]=[O:22]
Reactant: CS(C)=O
Reactant: O=[N+]([O-])c1cccc(CBr)c1Cl
Agent: [Ag+]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Product: O=Cc1cccc([N+](=O)[O-])c1Cl
Yield: 20 %

Procedure:
2-Chloro-3-nitrobenzaldehyde (150 mg, 20%) was prepared by reaction of 1-bromomethyl-2-chloro-3-nitrobenzene (1.0 g, 3.9 mmol) with silver p-toluenesulfonate (1.94 g, 1.75 equiv.) in DMSO in the presence of Et3N (4 mL, 7 equiv.) at rt for 1 hour.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:21]CC3C=CC=CC=3)[C:9]=2[O:13]CC2C=CC=CC=2)[C:4]1=[O:29].C(O[C:38]1[C:47](OCC2C=CC=CC=2)=[CH:46][CH:45]=[C:44]2[C:39]=1[CH2:40][CH2:41][CH:42](NC(=O)C(F)(F)F)C2=O)C1C=CC=CC=1.[BrH:64]>>[BrH:64].[OH:13][C:9]1[C:8]([OH:21])=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH2:12][CH:3]([NH:2][CH2:42][CH2:41][CH2:40][C:39]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:38]=1)[C:4]2=[O:29]
Reactant: NC1CCc2c(ccc(OCc3ccccc3)c2OCc2ccccc2)C1=O
Reactant: O=C1c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2CCC1NC(=O)C(F)(F)F
Agent: Br
Agent: Cl
Product: O=C1c2ccc(O)c(O)c2CCC1NCCCc1ccccc1

Procedure:
20 Parts of 2-amino-5,6-dibenzyloxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride is subjected to a procedure similar to that described in Reference Example 11 and the resultant 5,6-dibenzyloxy-2-trifluoroacetamido-3,4-dihydro-1(2H)-naphthalenone is reacted with 60 parts of 3-phenylpropanol p-toluenesulfonic acid ester under the same conditions as set forth in Reference Example 11. The reaction product is then hydrolyzed in a 47% aqueous solution of hydrogen bromide to obtain 3 parts of 5,6-dihydroxy-2-(3-phenylpropylamino)-3,4-dihydro-1(2H)-naphthalenone hydrobromide melting at 215°-217° C (decomposition).