Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11]3[CH2:12][CH2:13][N:14]4[CH2:19][C@H:18]5[CH2:20][C@@H:21]([O:30]C(C6C=C(OC)C(OC)=C(OC)C=6)=O)[C@H:22]([O:28][CH3:29])[C@@H:23]([C:24]([O:26][CH3:27])=[O:25])[C@H:17]5[CH2:16][C@@H:15]4[C:10]=3[NH:9][C:7]=2[CH:8]=1.C[O-].[Na+]>CO>[CH3:29][O:28][C@@H:22]1[C@@H:23]([C:24]([O:26][CH3:27])=[O:25])[C@@H:17]2[C@@H:18]([CH2:19][N:14]3[C@H:15]([CH2:16]2)[C:10]2[NH:9][C:7]4[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[C:11]=2[CH2:12][CH2:13]3)[CH2:20][C@H:21]1[OH:30]
Reactant: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](O)[C@@H]1OC
Yield: 995.2 %

Procedure:
A suspension of reserpine (1 g, 0.16 mmol) in a solution of sodium methoxide (0.150 g, 4.8 mmol) in methanol (50 ml) was refluxed until disappearance of the starting material (1 h), then cooled and concentrated under vacuum to one third of the volume. The solution was diluted with water (60 ml) and pH was adjusted to 1 with concentrated hydrochloric acid. The aqueous solution was then repeatedly washed with ethyl ether. The aqueous phase was then alkalinized with concentrated ammonia and repeatedly extracted with methylene chloride (4×30 ml). The combined organic phases were dried over sodium sulfate and concentrated under vacuum to give an amorphous residue (0.66 g), used for the following step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:28])[N:4]([CH2:14][C:15]([NH:17][CH:18]([CH:25]([CH3:27])[CH3:26])[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])=[O:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.[C:39](O)(=[O:43])[C:40]([CH3:42])=[O:41].COC1C=CC(CC(O)=O)=CC=1>CN(C)C1C=CN=CC=1.ClCCl.O1CCCC1>[O:28]=[C:3]1[C:2]([NH:1][C:39](=[O:43])[C:40]([CH3:42])=[O:41])=[CH:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]1[CH2:14][C:15]([NH:17][CH:18]([CH:25]([CH3:26])[CH3:27])[C:19](=[O:24])[C:20]([F:22])([F:23])[F:21])=[O:16]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(=O)C(F)(F)F
Reactant: CC(=O)C(=O)O
Agent: CN(C)c1ccncc1
Agent: COc1ccc(CC(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)C(=O)Nc1ccc(-c2ccccc2)n(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c1=O
Reaction time: 72 h

Procedure:
2-(3-Amino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide was subjected to procedure similar to Acylation Method B, but substituting: dichloromethane for tetrahydrofuran, 4-dimethylaminopyridine for 1-hydroxybenzotriazole, and pyruvic acid for 4-methoxyphenyl acetic acid. After 72 h, dichloromethane was added and the mixture was washed (water, brine), dried (magnesium sulfate) and evaporated. Chromatography, eluting with dichloromethane:methanol (gradient, 99.5:0.5, 99:1), gave the title compound as a pale yellow solid; TLC: Rf =0.44, dichloromethane:methanol (98:2); MS: m/z=466(M+1).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=4[O:26][CH3:27])=[N:11][C:10]=3[N:9]([CH3:28])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>ClCCl>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:25]=[CH:24][C:20]([C:21]([N:33]5[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]5)=[O:22])=[CH:19][C:18]=4[O:26][CH3:27])=[N:11][C:10]=3[N:9]([CH3:28])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1CCNCC1
Reactant: COc1cc(C(=O)O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCN(C)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
To a 2 ml dichloromethane suspension of 86 mg (0.23 mmol) of the compound obtained in Example 65, 31 μl (0.28 mmol) of N-methylpiperazine and 53 mg (0.28 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was stirred at room temperature for 18 hours. Then, an aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1˜10/1) to obtain 80 mg (75%) of the captioned compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:12]([O:24][CH2:25][O:26][CH3:27])[C@H:13]([OH:23])[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[CH3:9].[CH3:28][O:29][C:30](=[O:46])[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[O:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:28][O:29][C:30](=[O:46])[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[O:38][C:39]1[CH:40]=[CH:41][C:42]([O:23][C@H:13]([C@@H:12]([C:5]2[CH:6]=[C:7]([O:10][CH3:11])[C:8]([CH3:9])=[C:3]([O:2][CH3:1])[CH:4]=2)[O:24][CH2:25][O:26][CH3:27])[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:43][CH:44]=1
Reactant: COCO[C@H](c1cc(OC)c(C)c(OC)c1)[C@H](O)CCCc1ccccc1
Reactant: COC(=O)c1ccc(C)cc1Oc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCO[C@H](c1cc(OC)c(C)c(OC)c1)[C@H](CCCc1ccccc1)Oc1ccc(Oc2cc(C)ccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To a tetrahydrofuran (4 ml) solution of (±)-(1R*,2R*)-1-(3,5-dimethoxy-4-methylphenyl)-1-(methoxymethoxy)-5-phenylpentan-2-ol (142 mg) and methyl2-(4-hydroxyphenoxy)-4-methylbenzoate (249 mg), triphenylphosphine (262 mg) and diethyl azodicarboxylate (0.47 ml) were added, followed by stirring at room temperature overnight. The reaction mixture was concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the title compound (128 mg) having the following physical properties.
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1)[NH2:15].[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42]>C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42].[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:44]([NH:43][C:41](=[O:42])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[F:34])=[S:45])[CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccccc1F
Agent: O=C(N=C=S)c1ccccc1F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4F)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
2-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (66 mg, yield 86%).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:2]1.C(OC(=O)[NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(C)(C)C>>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:29]3[CH2:30][CH2:31][CH:26]([NH2:25])[CH2:27][CH2:28]3)=[CH:13][CH:12]=2)[CH2:2]1
Reactant: O=Cc1ccc([C@H]2COc3cccnc3O2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
Intermediate M is prepared from Intermediate C and Piperidin-4-yl-carbamic acid tert-butyl ester according to Example 217.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:33]=[CH:32][C:31]([F:34])=[CH:30][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C@@H:24]([C:26](=O)[NH2:27])[CH3:25])=[CH:19][C:18]=3[F:29])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:33]=[CH:32][C:31]([F:34])=[CH:30][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C@@H:24]([C:26](=[S:44])[NH2:27])[CH3:25])=[CH:19][C:18]=3[F:29])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(N)=S
Yield: 163.1 %

Procedure:
A solution of (R)-2-(benzo[1,3]dioxol-5-yloxy)-N-[4-(1-carbamoyl-ethoxy)-2-fluoro-benzyl]-5-fluoro-nicotinamide (1.0 g, 2.12 mmol) and Lawesson's reagent (0.52 g, 1.27 mmol) in dry tetrahydrofuran (10 ml) was stirred at room temperature 2 h. The solvent was removed in vacuo. The residue was adsorbed onto silica gel and purified by column chromatography (20% ethyl acetate/hexane) to afford 1.01 g of a yellow solid (98% yield).
Reaction SMILES: CS[C:3]1[CH2:4][C:5](=[O:21])[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:8]=2[N:9]=1.[C:22]([O:26][C:27](=[O:30])[NH:28][NH2:29])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[C:22]([O:26][C:27]([NH:28][NH:29][C:3]1[CH2:4][C:5](=[O:21])[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:8]=2[N:9]=1)=[O:30])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CSC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1

Procedure:
3.16 g of 2-(methylthio)-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one and 1.41 g of t-butylcarbazate in 60 ml of dimethyl formamide are refluxed for 20 hours while a slow stream of nitrogen is bubbled through the reaction. The reaction is worked up as described in Example 29, Method A, to give the title compound.
Reaction SMILES: C1C(N)=CC=C([As](O)(O)=O)C=1.BrCC(Br)=O.C(=O)=O.[Br:20][CH2:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([As:31](O)(=[O:33])[OH:32])=[CH:27][CH:26]=1)=[O:23]>C([O-])([O-])=O.[Na+].[Na+].O.C(Cl)Cl.Br.CO.[Na+].[I-]>[Br:20][CH2:21][C:22]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([As:31]([OH:33])[OH:32])=[CH:29][CH:30]=1)=[O:23]
Reactant: O=C(CBr)Nc1ccc([As](=O)(O)O)cc1
Agent: Br
Agent: Nc1ccc([As](=O)(O)O)cc1
Agent: O=C(Br)CBr
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=C(CBr)Nc1ccc([As](O)O)cc1
Temperature: 4 °C
Reaction time: 0.17 h
Yield: 42.7 %

Procedure:
p-Arsanilic acid (10 g, 46.07 mmol) was dissolved in a 1.18 M Na2CO3 solution, made from Na2CO3 (15 g, 141.5 mmol) dissolved in H2O (120 mL) in a 500 mL round-bottom flask. The solution was cooled in a 4° C. fridge for 2 hours and then placed in an ice bath upon a magnetic stirrer. A solution of bromoacetyl bromide (9 mL, 101.4 mmol) in CH2Cl2 (14 mL) was added in 4 aliquots to the flask while the mixture was vigorously stirred. Addition took about 1 min with CO2 evolution. The mixture was allowed to stir in the ice-bath for 5 min, and then at room temperature for 30 min till CO2 evolution ceased. The mixture was decanted into a 250 mL separatory funnel. Additional CH2Cl2 (10 mL) was added and the layers were allowed to separate for about 10 min. The CH2Cl2 layer was separated and the aqueous layer was placed in a 400 mL beaker. The solution was stirred and acidified with 98% H2SO4 (2.8 mL) to pH 4. A white precipitate resulted which was collected by filtration (14.83 g, 95% yield). The resulting 4-(2-bromoacetylamino)benzenearsonic acid (“BRAO”) (14.83 g, 43.88 mmol) was dissolved in 1:1 HBr/MeOH (210 mL) in a 500 mL 3-neck round bottom flask. NaI (5 mg) was added and the mixture was stirred. SO2 was bubbled through at ca. 2 bubbles/second and after 10 min a white precipitate started to form. SO2 was bubbled through for a further 20 h and the mixture was stirred at a medium speed. The solid was collected by filtration, washed with the filtrate then water (30 mL×3), and placed on the rotary evaporator at 50° C. for 5 h to give 4-(2-bromoacetylamino)benzenearsonous acid (6.04 g, 38.8% yield). A portion of the 4-(2-bromoacetylamino)benzenearsonous acid (500 mg, 1.553 mmol) was dissolved in nitrogen-flushed DMSO (10 mL) and added drop-wise over about 1 min to an solution of S-penicillamine (265 mg, 1.77 mmol) in an aqueous NaHCO3 solution (840 mg, 10 mmol) which used nitrogen-saturated H2O (20 mL). The addition took place in a 100 mL round-bottom flask and the clear solution was stirred on a low speed under argon for 4 h. The solution was acidified with 98% H2SO4 (about 0.2 mL) to pH 5. Acetone (500 mL) was stirred vigorously, and the acidified solution was added drop-wise over about 5 min to yield a white precipitate. The supernatant was centrifuged, decanted, and the resulting white solid was further washed and re-centrifuged with acetone (20 mL×2), transferred with acetone (40 mL) into a 100 mL pear-shaped flask and dried on the rotary evaporator at 25° C. for 2 h. Crude Penicillamine-arsenoxide was found to be about 30% pure by internal standard 1H-NMR.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][N:6]=[CH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[O:4]>[Pd].C(O)C>[CH3:1][O:2][C:3]([NH:5][NH:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[O:4]
Reactant: COC(=O)NN=Cc1ccc2[nH]cc(CCN(C)C)c2c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)NNCc1ccc2[nH]cc(CCN(C)C)c2c1
Temperature: 50 °C
Yield: 88.9 %

Procedure:
A 50 ml pressure vessel is charged with N′-[3-(2-dimethylamino-ethyl)-1H-indol-5-ylmethylene]hydrazine-carboxylic acid methyl ester (Example 9; 793 mg, 2.74 mmol), ethanol (10.8 ml), and the catalyst (5% Pd/C type E-4522, 158.6 mg). The vessel is sealed and purged with argon (three times), heated in an oil bath to 50° C., and then pressurized with hydrogen (75.4 bar). The stirrer is started (800 rpm), and the hydrogenation allowed to proceed over night. After cooling to ambient temperature the pressure vessel is vented, and the reaction mixture filtered over a pad of Hyflo to remove the catalyst. Removal of the solvent gives the product as a pale yellow residue (707 mg, 88.9%), which is pure by NMR.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[O:40]1[C:45]2[CH:46]=[CH:47][C:48](B(O)O)=[CH:49][C:44]=2[O:43][CH2:42][CH2:41]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([C:48]3[CH:47]=[CH:46][C:45]4[O:40][CH2:41][CH2:42][O:43][C:44]=4[CH:49]=3)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccc2c(c1)OCCO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC
Yield: 22.9 %

Procedure:
A similar procedure as described in Example 44, step 3 was used, starting from 4-[3-[6-(3-bromo-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (305 mg, 0.5 mmol), 1,4-benzodioxane-6-boronic acid (184 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55 mg, 0.075 mmol), and cesium carbonate (331 mg, 1.0 mmol) to obtain 4-[3-{6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-ethoxy-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (76 mg, 23%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C39H50O9 (M+Na)+ 685.3347. found 685.3353.
Reaction SMILES: B(O)O.Br[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1.[O:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1>>[O:13]1[CH:17]=[CH:16][C:15]([C:5]2[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=2)=[CH:14]1
Reactant: O=Cc1cccc(Br)n1
Reactant: OB(O)c1ccoc1
Agent: OBO
Product: O=Cc1cccc(-c2ccoc2)n1

Procedure:
6-(furan-3-yl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and furan-3-ylboronic acid (65 mg, 93.2 mg theoretical, 69.8%). LC-MS m/z 174.2 (M+1).
Reaction SMILES: [C:1]([NH:4][N:5]1[CH2:9][C:8]([CH3:12])(NC)[N:7]([CH3:13])[C:6]1=[O:14])(=[O:3])[CH3:2].CN>CO>[C:1]([NH:4][N:5]1[CH:9]=[C:8]([CH3:12])[N:7]([CH3:13])[C:6]1=[O:14])(=[O:3])[CH3:2]
Reactant: CNC1(C)CN(NC(C)=O)C(=O)N1C
Agent: CN
Solvent: CO
Product: CC(=O)Nn1cc(C)n(C)c1=O

Procedure:
68.5 ml of aqueous methylamine solution (40%) are added dropwise to a solution of 78 g of 3-acetylmethyl-2,3-dihydro-5-methyl-2-oxo-1,3,4-oxadiazole in 500 ml of acetonitrile. After the slightly endothermal reaction has subsided, the orange mixture is stirred-for 30 minutes at 48° and then evaporated. The residue is treated with 100 ml of tetrahydrofuran and 200 ml of ethyl acetate, during which process crystals precipitate. The crystals are filtered off, washed with ethyl acetate and dried under reduced pressure at 60°. This gives a mixture of 1-acetylamino-2,3-dihydro-3,4-dimethyl-2-oxo-1H-imidazole and 1-acetylamino-3,4-dimethyl-4-methylamino-2-oxo-imidazolidine. A sample of this mixture is separated on silica gel using ethyl acetate/methanol (2:1) as eluent, yielding the pure 1-acetylamino-2,3-dihydro-3,4-dimethyl-2-oxo-1H-imidazole which melts at 199°-201° and the pure 1-acetylamino-3,4-dimethyl-4-methylamino-2-oxo-imidazolidine which melts with decomposition at 150°-152°. Another sample of the above-mentioned mixture is heated to 175° and held at this temperature until the evolution of methylamine gas has ceased. The residue is cooled and stirred with a small amount of methanol. Filtration of the suspension gives the pure title compound melting after drying at 199°-201°.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:5](OCC)=[O:6].[NH:17]([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([CH3:26])=[CH:21][N:20]=1)[NH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:25][C:23]1[C:22]([CH3:26])=[CH:21][N:20]=[C:19]([N:17]2[C:5](=[O:6])[C:4]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:3][NH:18]2)[CH:24]=1
Reactant: CCOC(=O)C(=CN(C)C)c1cccnc1
Reactant: Cc1cnc(NN)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1cnc(-n2[nH]cc(-c3cccnc3)c2=O)cc1C
Temperature: 25 °C

Procedure:
220 mg (1.0 mmol) of the compound from Example 2A are initially charged in 5 ml of ethanol. 137 mg (1.0 mmol) of the compound from Example 21A and 38 mg (0.2 mmol) of p-toluenesulfonic acid are added, and the mixture is stirred under reflux for 16 h. The mixture is then allowed to cool to RT, and the solid formed is filtered off, washed with tert-butyl methyl ether and dried under high vacuum. This gives 28 mg of the title compound. The mother liquor is put aside and used for preparing the hydrochloride (see Example 87).
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:27]=1[O: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][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:23]Cl)[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][CH3:18].[N-:66]=[N+:67]=[N-:68].[Na+]>C(Cl)(Cl)Cl.CN(C)C=O>[CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:27]=1[O: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][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:23][N:66]=[N+:67]=[N-:68])[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][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1cc(CN=[N+]=[N-])cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
3,4,5-Tris(octadecyloxy)benzyl chloride (4.02 g, 4.31 mmol) was dissolved in a mixed solvent of chloroform (40 mL) and N,N-dimethylformamide (120 mL), sodium azide (418 mg, 6.42 mmol) was added, and the mixture was stirred at 80° C. for 3 hr. After completion of the reaction, the reaction mixture was cooled to room temperature and washed with purified water (150 mL). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, methanol was added thereto, and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (3.92 g, 97.4%) as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[N:11][C:10]2[O:13][CH2:14][CH2:15][C:9]=2[CH:8]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].B1(C=C)OB([CH:30]=[CH2:31])OB(C=C)O1.C1C=CN=CC=1.O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:30]([C:7]1[N:12]=[N:11][C:10]2[O:13][CH2:14][CH2:15][C:9]=2[CH:8]=1)=[CH2:31]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: O=S(=O)(Oc1cc2c(nn1)OCC2)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: COCCOC
Product: C=Cc1cc2c(nn1)OCC2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 5,6-dihydrofuro[2,3-c]pyridazin-3-yl trifluoromethanesulfonate (500 mg, 1.85 mmol) in dimethoxyethane (20 ml) was degassed then treated with tetrakis(triphenylphosphine)palladium (0) (116 mg), potassium carbonate (257 mg), 2,4,6-trivinylcyclotriboroxane pyridine complex (for a preparation of this reagent see F. Kerins and D. F. O'Shea, J. Org. Chem. 2002, 67, 4968-4971) (416 mg) and water (3.6 ml). The mixture was stirred at 80° C. for 2 hours then partitioned between DCM and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with 10% methanol in DCM then the combined organic extracts dried and evaporated. The residue was chromatographed eluting with ethyl acetate affording a white solid (111 mg, 36%).