Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7](OCC)=[O:8])=[CH:5][CH:4]=1)#[N:2].O.[NH2:15][NH2:16]>C(O)C>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([NH:15][NH2:16])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1ccc(C#N)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a 250 mL round bottom flask charged with ethyl 4-cyanobenzoate (16.85 g, 96.2 mmol) in 95% ethanol (75 mL) was added hydrazine mono-hydrate (18.2 mL, 64% solution, 240 mmol). This mixture was heated to reflux for a period of 4.5 h, then allowed to cool to room temperature over a 16 h period. The solvent was removed under reduced pressure and the yellow residue was taken up in ice-cold water (150 mL). The light yellow solid was filtered off and washed with additional cold water (50 mL). The solid was then dried under high vacuum to yield the title compound as a light yellow solid (13.98 g, 90%). 1H NMR (400 MHz, DMSO-d6, δ in ppm) 10.05 (br s, 1H), 7.95 (AA′XX′, J=8.5 Hz, 4H), 4.61 (br s, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([N:13]1[CH:17]=[C:16]([CH2:18][C@@H:19]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:20]([NH2:22])=[O:21])[N:15]=[N:14]1)[CH2:8][CH2:7][CH2:6]2)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[CH3:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([NH:23][C@H:19]([CH2:18][C:16]2[N:15]=[N:14][N:13]([C@H:9]3[C:10]4[C:5](=[CH:4][C:3]([CH2:1][N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[CH:12][CH:11]=4)[CH2:6][CH2:7][CH2:8]3)[CH:17]=2)[C:20]([NH2:22])=[O:21])(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(C=O)ccc43)nn2)C(N)=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(CN5CCCCC5)ccc43)nn2)C(N)=O)cc1
Temperature: 60 °C

Procedure:
A mixture of (R)-3-(1-((R)-6-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylbenzenesulfonamido)propanamide (0.21 g, 0.45 mmol) and piperidine (0.20 g, 2.2 mmol) in 5 mL 1,2-dichloroethane was heated to 60° C. for 30 min. The reaction mixture was cooled and treated with NaBH(OAc)3 and a drop of HOAc. The resulting mixture was heated to 80° C. for 16 h. The reaction mixture was cooled, quenched with H2O, and extracted with CHCl3 (3×). The combined extracts were dried over MgSO4, concentrated and purified by SiO2 (5% MeOH/CH2Cl2) to give a white solid. MS (m/z): 537.4 (m+H).
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][NH:14][NH:13]1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:25]([O:32][C:33]([N:14]1[CH2:15][CH2:16][CH2:17][C@@H:12]([C:10](=[O:11])[NH:9][CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:13]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(NCCc1ccccc1)[C@@H]1CCCNN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1ccccc1)[C@@H]1CCCN(C(=O)OCc2ccccc2)N1
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
To a solution of (S)-hexahydro pyridazine-3-carboxylic acid phenethyl-amide (376 mg, 1.59 mmol) and Et3N (0.66 mL) in CH2Cl2 (10 mL) at 0° C., is added benzylchloroformate (270 mg, 1.59 mmol) dropwise. After stirring at −5° C. for 1.5 hours, the reaction mixture is diluted with CH2Cl2 (50 mL) and washed with 10 mL of water. The organic layer is dried over Na2SO4 and concentrated to give (S)-3-phenethylcarbamoyl-tetrahydro-pyridazine-1-carboxylic acid benzyl ester (580 mg) as pale gum without further purification for next step reaction. (NMR and MS data confirmed, U-3133-59).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](O)=O)=[CH:14][CH:15]=1.[OH-].[Na+]>O>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1
Reactant: Nc1ccccc1S
Reactant: Cc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 76.3 %

Procedure:
125 g (1 mol) of o-aminothiophenol, 136 g (1 mol) of p-toluic acid and 600 g of polyphosphoric acid were admixed and stirred into nitrogen gas at 170°-200° C. for 4 hours. After the reaction mixture was cooled to 100° C., it was poured in 5 l of water. The mixture was adjusted to pH 5 with NaOH and the resulting crystals were filtered off, whereupon 220 g of 4-(benzothiazol-2-yl) toluene was obtained as crude crystals. Recrystallization from n-hexane gave 172 g of pure product as colorless prisms melting at 84°-85° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].O.N>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:16]2[NH:10][C:11](=[O:12])[NH:13][C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CNC(=O)N1
Agent: N
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccc(O)cc2)N1
Temperature: 90 °C
Yield: 82.9 %

Procedure:
In a 200 mL egg-plant shaped flask, 14.7 g (120 mmol) of 4-hydroxybenzaldehyde was mixed with 15.6 g (156 mmol) of hydantoin, 80 mL of water, and 14.4 g of 28% ammonia water, and the mixture was heated at 90° C. for 12 hours with stirring. After the liquid reaction mixture was cooled to room temperature, the precipitated crystals were collected by filtration. The crystals were then washed twice with water and twice with ethanol. The crystals were dried to give 20.3 g of 5-(4-hydroxybenzylidene)hydantoin. Subsequently, 18.8 g (92.2 mmol) of the product was added to a 500 mL egg-plant shaped flask and then dissolved in 180 mL of N,N-dimethylformamide. To the solution were added to 27.1 g (221 mmol) of ethyl chloroacetate and 30.5 g (221 mmol) of potassium carbonate. The mixture was heated at 120° C. for 2 hours with stirring. After the liquid reaction mixture was cooled to room temperature, the solvent was removed by distillation under reduced pressure. Water was added to the residue, and then the mixture was extracted three times with ethyl acetate. The organic layers were collected, washed twice with water and once with saturated brine, and then dried with sodium sulfate. The sodium sulfate was then removed by filtration. After the solvent was removed by distillation under reduced pressure, the resulting brown crystals were recrystallized with a mixed solvent of ethyl acetate and hexane. The crystals were then dried to give 9.96 g of 5-[4-(2-ethoxy-2-oxoethoxy)benzylidene]-3-(2-ethoxy-2-oxoethyl)hydantoin. In a 50 mL egg-plant shaped flask, 4.50 g (12.0 mmol) of the product was mixed with 7.57 g (72.0 mmol) of diethanolamine, and the mixture was heated at 120° C. for 1 hour with stirring. After the liquid reaction mixture was cooled to room temperature, the precipitated yellow crystals were recrystallized with a mixed solvent of ethanol and water. The crystals were then dried to give 4.46 g of compound 3 (yield: 18%).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](O)=[O:9])([CH3:3])[CH3:2].CN(C)C=O.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[CH:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([Cl:23])=[O:9])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1SC(C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Cl)cc1SC(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of 3-isopropylthio-4-methoxybenzoic acid (2.5 g; that is prepared as described in Reference Example 49) in toluene (25 mL) and dimethylformamide (0.2 mL) is treated with thionyl chloride (2.5 mL) and the solution is stirred at 60° C. for 3 hours. The solution is concentrated, treated with toluene (10 mL) and again evaporated to dryness, to give 3-isopropylthio-4-methoxybenzoyl chloride (2.7 g), in the form of a light brown oil.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15](=[O:22])[CH:16]=[CH:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)[CH3:13].[N+:23]([CH3:26])([O-:25])=[O:24]>CC#N>[CH2:12]([O:14][C:15](=[O:22])[CH2:16][CH:17]([CH2:26][N+:23]([O-:25])=[O:24])[CH2:18][CH:19]1[CH2:20][CH2:21]1)[CH3:13]
Reactant: CCOC(=O)C=CCC1CC1
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)CC(CC1CC1)C[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
DBU (4.1 g, 26.9 mmol) is added to a solution of 4-cyclopropyl-2-butenoic acid ethyl ester (3.4 g, 26.9 mmol) and nitromethane (9.13 g, 135 mmol) in 20 mL of CH3CN. The solution is warmed to 60° C. under Ar for 4 hours, then stirred at room temperature overnight. The CH3CN is evaporated, and the residue is taken up in 50 mL of EtOAc. The solution is washed with saturated KH2PO4 (3×50 mL) followed by 50 mL of brine. The organic layer is dried over Na2SO4 and evaporated to give an oil which is chromatographed (MPLC) over silica gel with 25% EtOAc/hexane to give 2.4 g of 4-cyclopropyl-3-nitromethyl-butanoic acid ethyl ester 3.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[S:15][C:16]([C:21](=[O:23])[CH3:22])=[CH:17][C:18]=1[C:19]#[N:20].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH3:12][S:13]([C:14]1[S:15][C:16]([C:21](=[O:23])[CH3:22])=[CH:17][C:18]=1[C:19]#[N:20])=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1sc(C(C)=O)cc1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc(C#N)c(S(C)=O)s1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
5.0 g of 83% m-chloroperbenzoic acid are gradually added while stirring at a temperature of 0°-5° C. in 45 minutes to a solution of 5.0 g of 2-methylthio-3-cyano-5-acetylthiophene in 500 ml of methylene chloride. After stirring for another 30 minutes at 5° C., a saturated solution of sodium bicarbonate in approximately 50 ml of water is added; the reaction mixture is then stirred for 60 minutes. The organic layer is separated, washed with water and dried. After distilling off the solvent, the desired product is obtained in a yield of 4.6 g; melting-point 150° C.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl>CCOCC>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])=[CH:12][CH:11]=1
Reactant: O=C(Cl)C1CCC1
Reactant: COc1ccc(CCN)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)C2CCC2)cc1
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Cyclobutanecarbonyl chloride (5.5 g) was added to a solution of 2-(4-methoxyphenyl)ethylamine (7 g) and triethylamine (6.5 ml) in ether (300 ml) at ambient temperature. The mixture was stirred overnight, poured onto water and acidified with 2M hydrochloric acid, then the mixture was extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine, dried and the solvents removed in vacuo to give a residue. This was washed with petroleum ether and dried in vacuo to give N-[2-(4-methoxyphenyl)ethyl]cyclobutanecarboxamide as a solid (9.54 g), mp 118°-20° C.
Reaction SMILES: Br[C@H:2]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@H:3]1[O:8][C:6](=[O:7])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4]1.[N-:19]=[N+:20]=[N-:21].[Na+]>>[N:19]([C@@H:2]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@H:3]1[O:8][C:6](=[O:7])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4]1)=[N+:20]=[N-:21]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](Br)CC2CCCCC2)OC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CC(C)[C@@H]1C[C@@H]([C@H](CC2CCCCC2)N=[N+]=[N-])OC1=O
Temperature: 0 °C

Procedure:
42.5 g (0.135 mol) of 5(R)-bromo-6-cyclohexyl-2(S)-isopropyl-4(S)-hexanolide and 35 g (0.54 mol of NaN3 in 480 ml of N,N'-dimethyl-N,N'-propylene urea (DMPU) are stirred at room temperature for 72 hours and then poured onto 1 liter of ice-cold 0.1N HCl. The mixture is then extracted three times with ether, and the combined organic phases are washed twice with 0.1N HCl and three times with brine and dried with MgSO4. After concentrating the solvent by evaporation, the residue is recrystallised from hexane: m.p. 38.5°-39°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]=[CH:21][C:22]4[S:23][C:24]([Cl:27])=[CH:25][CH:26]=4)[C@@H:15]([CH3:28])[C:14]3=[O:29])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.C([O-])(=O)C.[NH4+:41]>>[NH2:41][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]=[CH:21][C:22]4[S:23][C:24]([Cl:27])=[CH:25][CH:26]=4)[C@@H:15]([CH3:28])[C:14]3=[O:29])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: C[C@H]1C(=O)N(Cc2ccc3c(Cl)ccnc3c2)CCN1CC=Cc1ccc(Cl)s1
Agent: CC(=O)[O-]
Solvent: Oc1ccccc1
Product: C[C@H]1C(=O)N(Cc2ccc3c(N)ccnc3c2)CCN1CC=Cc1ccc(Cl)s1
Temperature: 120 °C
Yield: 42.7 %

Procedure:
(S)-1-(4-Chloroquinolin-7-ylmethyl)-4-[3-(5-chlorothiophen-2-yl)-allyl]-3-methylpiperazin-2-one(0.35 g, 0.82 mmol) is treated with phenol (2 g) and ammonium acetate (0.7 g, 9.1 mmol) and heated to 120° C. in a sealed vessel for 1 hour. Upon cooling, the solution is partitioned between 2 N NaOH and ethyl acetate. The organic layer is separated and washed with fresh 2 N NaOH (3×100 mL) and water. The organic layer is concentrated and the residue is purified by reverse phase HPLC to give the title compound as a white solid (0.15 g, 0.35 mmol). MS (ISP) m/z 427, 429, (M+H), Cl pattern.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][O:7][CH2:8][C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][CH2:14][NH:13][C:12](=O)[CH2:11][CH2:10]1.B.C1COCC1.CO.Cl>C1COCC1>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][O:7][CH2:8][C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C1CCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CCCN1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCNCCC2)cc(C(F)(F)F)c1
Temperature: 65 °C

Procedure:
To a solution of 5-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-5-phenylazocan-2-one (16 mg) in THF (0.10 mL) at room temperature was added borane-THF complex (1.50 M solution in THF, 93 μL) and the resulting solution was heated at 65° C. in a sealed vial for 3 h. The solution was cooled to room temperature, and methanol (0.10 mL) was added slowly followed by 1N hydrochloric acid (0.10 mL), and the reaction mixture was heated at 65° C. for 2 h. The solvents were removed in vacuo, dichloromethane and 1N sodium hydroxide were added, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give the title compound as an oil. 1H NMR (400 MHz, CDCl3) δ 1.57 (4H, m), 1.87 (1H, broad, s), 2.09 (4H, m), 2.72 (2H, m), 2.88 (2H, m), 3.43 (2H, s), 4.41 (2H, s), 7.21 (1H, m), 7.39 (4H, m), 7.54 (2H, s), and 7.21 (1H, s). HPLC retention time (1.87 min, column: 4.6×50 mm XTERRA C18 S5, flow rate: 5 mL/min, gradient: 0-100% MeOH/H2O 0.1% TFA over 2 min). MS: 446 (MH+).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C([O:16][C:17]1[CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)=[O:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24])(=O)C.[CH3:37][C:38]1[O:42][C:41]([CH2:43]O)=[CH:40][CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[OH:16][C:17]1[CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:43][C:41]3[O:42][C:38]([CH3:37])=[CH:39][CH:40]=3)[CH:31]=2)=[O:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(/C=C/C(=O)Nc2cccc(O)c2)cc1OC(C)=O
Reactant: Cc1ccc(CO)o1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C(=O)Nc2cccc(OCc3ccc(C)o3)c2)cc1O
Reaction time: 16 h
Yield: 1.7 %

Procedure:
Diethylazodicarboxylate (1.13 mL 5.83 mmol) was added dropwise to a solution of (E)-3-(3-acetoxy-4-methoxy-phenyl)-N-(3-hydroxy-phenyl)-acrylamide (0.763 g, 2.33 mmol), (5-methyl-furan-2-yl)-methanol (0.392 g, 3.5 mmol) and triphenylphosphine (1.53 g, 5.83 mmol) in dry THF (20 mL) at 0° C. The resulting solution was allowed to reach RT and stirred for 16 hrs. The reaction mixture was then diluted with DCM and washed with water, aqueous hydrochloric acid, and brine. The organic layer was then dried over sodium sulphate and evapored. The resulting raw material was taken up, without further purification, with a 3N methanolic solution of hydrochloric acid (5 mL-15 mmols) and stirred at RT for 16 hrs, concentrated under reduced pressure, taken up with solvent an re-evaporated (3 times with MeOH and once with acetone) to give a residue that was purified by silica gel column chromatography (eluant DCM/MeOH 98/2) to obtain 15 mg of the title (E)-3-(3-hydroxy-4-methoxy-phenyl)-N-[3-(5-methyl-furan-2-ylmethoxy)-phenyl]-acrylamide.
Reaction SMILES: [H-].[Na+].[Br-].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH2:9][PH3+].[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:29]=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)/[CH:29]=[CH:9]\[C:8]1[CH:7]=[C:6]([O:5][CH3:4])[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc(C[PH3+])cc(OC)c1OC
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc(/C=C\c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a stirred suspension of sodium hydride (0.75, 31.4 mmol) in N,N-dimethylimidazolidinone (10 ml) was added 3,4,5-trimethoxy-benzyl-phosphonium bromide (8.26 g 15.71 mmol) under argon. The aldehyde (4.0 g, 1258 mmol) from Example 40 was added to the deep red solution followed by 2 ml of N,N-dimethylimidazolidinone. Before adding ice (10 g)-water (75 ml) the mixture was stirred overnight. Upon extraction with ethyl acetate (3×100 ml), the organic phase was washed with water (3×75 ml), dried and evaporated to a dark colored mass (9.0 g). The crude product in hexane-ethyl acetate (9:1) was chromatographed on a column of SILICA GEL (200 g) to afford a mixture of E- and Z-isomers (3.70 g, 61% yield). A 1.1 g sample of the mixture was rechromatographed on a column of SILICA GEL and eluted with hexane-ethyl acetate (19:1) to furnish Z-isomer (0.25 g) and E-isomer (0.32 g). The Z-isomer was further purified by preparative TLC (hexane-ethyl acetate, 7:3) to yield 3', 4'-Dibenzyloxy-3,4,5-trimethoxy-(Z)-stilbene as a chromatographically homogeneous and viscous oil: IR νmax 1581, 1509, 1462, 1454, 1412, 1265, 1237, 1128, 1007 cm-1 ; 1H-NMR (400 MHz) 3.731 (6H, s, 2×OCH3), 3.856 (3H, s, OCH3), 4.856 (2H, s, ArCH2), 5.121 (2H, s, ARCH2), 6.589 (2H, s, ArH), 6.600 (3H, m, ArH), 6.747 (1H, d, J=8.6 Hz, ArH), 6.758 (1H, brs, ArH), 7,273-7,407 (10H, ArH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NCCCN(C)C)C.[NH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: Nc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1ccccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of commercially available (R)-tert-butoxycarbonylamino-phenyl-acetic acid (1.00 g, 3.98 mmol), dimethyl-pyridin-4-yl-amine (0.49 g, 3.98 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (0.84 g, 4.38 mmol) in anhydrous dichloromethane (30 mL), a solution of 2-aminobenzoic acid (0.55 g, 3.98 mmol) and triethylamine (0.56 mL, 4.38 mmol) in anhydrous dichloromethane (6 mL) was added drop wise at 0-5° C. The reaction was stirred at room temperature for 4 h, then the resulting solution was washed with 1N HCl solution, water and brine After drying over Na2SO4, the solvent was removed to give the intermediate 2-((R)-2-tert-butoxycarbonylamino-2-phenyl-acetylamino)-benzoic acid. To a solution of this intermediate in dry dichloromethane (20 mL), dimethyl-pyridin-4-yl-amine (0.19 g, 1.59 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (0.84 g, 4.38 mmol) were added. The mixture was stirred at room temperature for 2 h, then washed with 1N HCl solution, then with water and brine, dried over Na2SO4 and evaporated to dryiness. The intermediate [(R)-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-phenyl-methyl]-carbamic acid tert-butyl ester was dissolved in dry pyridine (5 mL) and aminoguanidine hydrogencarbonate (0.60 g, 4.38 mmol) was added. The mixture was heated under microwave condition at 180° C. for 30 minutes, the solvent was then evaporated and the crude purified by flash column chromatography on silica gel eluting with DCM/CH3OH 96/4, to afford title compound (0.16 g, 10% yield).
Reaction SMILES: [Sn](Cl)Cl.[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:18])=[C:9]([CH:17]=1)[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[N:19]([O-])=O.[Na+]>Cl>[Cl:18][C:8]1[CH:7]=[CH:6][C:5]([NH:4][NH2:19])=[CH:17][C:9]=1[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=N[O-]
Reactant: CCOC(=O)C=Cc1cc(N)ccc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: CCOC(=O)C=Cc1cc(NN)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
First, 60 g of tin (II) chloride was dissolved in 60 ml of concentrated hydrochloric acid, and the mixture was cooled to −30° C., to which a diazonium solution prepared from 19 g of ethyl 5-amino-2-chlorocinnamate and 6.3 g of sodium nitrite was added dropwise at 0° C. or lower. The reaction mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration. These crystals were added to ice-water, neutralized with 2N aqueous sodium hydroxide, and extracted with chloroform. The chloroform layer was dried and concentrated, which afforded 7.0 g of ethyl 2-chloro-5-hydrazinocinnamate.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([NH:5][C:6](=[NH:25])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](C(CCCCCC)C([O-])=O)=[CH:11][CH:10]=1)=[NH:4].CN(C)C(NC(=N)NCC1C=CC(CC[N:43](CC)[C:44](=[O:46])[O-:45])=CC=1)=N>>[C:9]([O:45][C:44](=[O:46])[NH:43][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][NH:7][C:6]([NH:5][C:3](=[NH:4])[N:2]([CH3:1])[CH3:26])=[NH:25])=[CH:14][CH:13]=1)([CH3:14])([CH3:10])[CH3:8]
Reactant: CCCCCCC(C(=O)[O-])c1ccc(CNC(=N)NC(=N)N(C)C)cc1
Reactant: CCN(CCc1ccc(CNC(=N)NC(=N)N(C)C)cc1)C(=O)[O-]
Product: CN(C)C(=N)NC(=N)NCc1ccc(NC(=O)OC(C)(C)C)cc1

Procedure:
In a similar manner 4-{[3-(N,N-Dimethylcarbamimidoyl)guanidino]methyl}phenyl-octanoate (Example 14) and 4-{[3-(N,N Dimethylcarbamimidoyl)guanidino]methyl}phenyl-diethylcarbamate (Example 15) were synthesized.