Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:20]([C:21](=O)[C:22]=2[CH:23]=1)=[CH:19][C:18]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH3:25])=[CH:14][CH:15]=2)[C:10](=O)[C:9]=1[CH:8]=3.CO.C(O)(=O)C.Cl>COCCOCCOC.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:22](=[CH:21][C:20]3[C:7]([CH:6]=2)=[CH:8][C:9]2[C:18](=[CH:17][C:16]4[C:11]([CH:10]=2)=[CH:12][C:13]([CH3:25])=[CH:14][CH:15]=4)[CH:19]=3)[CH:23]=1
Reactant: Cc1ccc2c(c1)C(=O)c1cc3c(cc1C2)C(=O)c1cc(C)ccc1C3
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc2cc3cc4cc5cc(C)ccc5cc4cc3cc2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 24.6 grams of 7,14-dihydro-3,10-dimethylpentacene-5,12-dione in 250 mL of 2-methoxyethyl ether was stirred and flushed with nitrogen for 10 minutes. To this was added in small portions 16.5 grams of sodium borohydride and stirring was continued at room temperature overnight. To the resulting reaction mixture was added slowly over 30 minutes 155 mL of methanol with the temperature maintained below 0° C. The mixture was stirred for 1.5 hours at room temperature. To the mixture was added slowly 360 mL of glacial acetic acid over 10 minutes. The resulting mixture was heated to 60° C. for 1.5 hours. To the mixture was added 100 mL of concentrated hydrochloric acid. The resulting mixture was heated for one hour and cooled to room temperature. To the mixture was added 250 mL of water and stirring was continued for five minutes. The resulting solid was collected by filtration and washed sequentially with 3 L of water, and 1 L of acetone, 1 L of tetrahydrofuran, and 1 L of acetone and dried to give 2,9-dimethylpentacene.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([NH2:33])[CH2:29][CH2:28]1)[CH3:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:33][N:30]3[CH2:31][CH2:32][N:27]([CH2:25][CH3:26])[CH2:28][CH2:29]3)=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CCN1CCN(N)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCN1CCN(NC(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)CC1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
A cold (−40° C.) solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g) in EtOAc (20 mL) was treated with 4-ethylpiperazin-1-amine (0.12 g). T3P (50% in EtOAc, 0.84 mL) and DIPEA (0.24 mL) were added simultaneously and the reaction mixture was stirred for 30 min at −40° C. before being quenched with ice-cold water and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure (35° C., 20 mmHg) to afford 0.280 g of crude compound. Purification by combi-flash chromatography (eluting with 2% MeOH in CH2Cl2) followed by purification on a preparative TLC plate (eluting with 10% MeOH in CH2Cl2) afforded 60 mg (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(4-ethylpiperazin-1-yl)acrylamide. 1H NMR (400 MHz, CF3COOD) δ: 10.75 (s, 1H), 8.31-8.29 (d, J=10.2H), 7.98 (s, 1H), 7.21-7.23 (d, 1H), 6.08-6.10 (d, 1H), 3.52-3.54 (m, 3H), 3.36 (s, 1H), 3.11 (m, 8H), 1.19-1.22 (m, 3H); LCMS for C19H21F6N6O [M+H]+ 463.40; found 463.23 (RT 2.43 min, purity: 98.63%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]O.CS(Cl)(=O)=O.C(N(CC)CC)C.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].C(=O)([O-])O.[Na+]>ClCCl.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][NH:31][CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:32]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1ccc(F)cc1CO
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.8 g (10.7 mmol) of 5-fluoro-2-nitrobenzyl alcohol was dissolved in 20 ml of dichloromethane. 0.9 ml (12.8 mmol) of methanesulfonyl chloride and 2.2 ml (16.1 mmol) of triethylamine were added to the obtained solution, and they were stirred at room temperature for 2 hours. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 20 ml of ethanol. 1.79 g (12.8 mmol) of glycine ethyl ester hydrochloride and 1.35 g (16.1 mmol) of sodium hydrogencarbonate were added to the obtained solution, and they were stirred at 70° C. for 6 hours. The solvent was evaporated. After the extraction with ethyl acetate, the extract was washed with 1 N hydrochloric acid. The obtained aqueous layer was made basic with 1 N sodium hydroxide. After the extraction with ethyl acetate, the obtained organic layer was washed with saturated aqueous sodium chloride solution and then dried. The solvent was evaporated to obtain the title compound.
Reaction SMILES: CO.[I:3][C:4]1[C:5](=[O:35])[C@@H:6]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]2[C:13]=1[CH2:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>[Cl-].[Na+].O>[I:3][C:4]1[C@H:5]([OH:35])[C@@H:6]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]2[C:13]=1[CH2:14][O:15][C:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC1(C)O[C@@H]2C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)=C(I)C(=O)[C@@H]2O1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(I)[C@@H]2O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Into a 500 L reactor was charged 100 L of methanol, followed by addition of 6 (9.7 kg) and CeCl3-7H2O (7.2 kg) in 1 kg portions over 0.5 hour. Temperature of the reaction mixture rose ˜5° C. during the addition. The reaction mixture was cooled down to −10° C., and NaBH4 (0.77 kg) was added in portions (˜150 g) over 1 hour resulting in strong H2 evolution with elevation of the reaction temperature. The transparent reaction mixture was then stirred for 2 hours at 0° C. until HPLC indicated complete conversion. Then 150 L of brine were added to result in white precipitates. The suspension was concentrated under vacuum to remove most of methanol and ethyl acetate (100 L) was added to the resulting residue and the mixture was stirred for 30 minutes. Then the organic layer was separated washed with brine (20 L) and dried over sodium sulfate, filtered and concentrated to dryness, and the residue was used directly in the next step. Sample from the reaction mixture and standard samples for compounds 6 and 7 were applied to a commercial silica gel TLC plate, with petroleum ether/ethyl acetate=4:1 as the mobile phase. 6 and 7 can be detected under UV254 or visualized using iodine treatment. The Rf for 6 was ˜0.55 while the Rf for compound 7 was ˜0.57; 1H-NMR (300 MHz, CDCl3) δ 7.21-7.48 (m, 15H), 5.20 (d, J=5.7 Hz, 1H), 4.77 (t, J=5.7 Hz, 1H), 4.39 (dd, J=5.4, 11.2 Hz, 1H), 3.90 (d, J=12.0 Hz, 1H), 3.79 (d, J=12.0 Hz, 1H), 2.81 (d, J=11.2 Hz, 1H), 1.43 (s, 3H), 1.32 (s, 3H); 13C-NMR DEPT-135 (75 MHz, CDCl3) δ 128.79, 127.89, 127.11, 82.91, 78.14, 76.48, 62.58 (OCH2—), 27.54, 27.11.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][CH:11]([C:13](OC)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[Cl-].[Li+].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH2:10][CH:11]([CH2:13][OH:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1COC(c2ccc(F)cc2)=N1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Product: OCC1COC(c2ccc(F)cc2)=N1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
Methyl 2-(4-fluorophenyl)-1,3-oxazoline-4-carboxylate (1.0 g, 4.5 mmol) was dissolved in 30 ml of absolute ethanol. To this solution was added lithium chloride (0.380 g, 9.0 mmol) and sodium borohydride (0.342 g, 9.0 mmol). The reaction was stirred at room temperature until starting material was consumed (TLC, 15:1 dichloromethane:methanol). Ethanol was removed under reduced pressure and replaced with 35 ml of water. The aqueous solution was acidified to about pH 2 with concentrated HCl, and the acidic solution extracted with ethyl acetate (3×50 ml). The resulting organic layer was washed with water (3×50 ml) and dried with sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue purified using column chromatography (3% MeOH in DCM) to yield [2-(4-fluorophenyl)-1,3-oxazolin-4-yl]methan-1-ol (600 mg, M+1=196.1).
Reaction SMILES: CS[C:3]([S:15][CH3:16])=[C:4]1[CH2:13][CH2:12][CH:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH2:10]2)[C:5]1=[O:14].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].O>C(#N)C>[CH3:16][S:15][C:3]([N:27]1[CH2:26][CH2:25][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:29][CH2:28]1)=[C:4]1[CH2:13][CH2:12][CH:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH2:10]2)[C:5]1=[O:14]
Reactant: CSC(SC)=C1CCC2CC=CC=C2C1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CC#N
Product: CSC(=C1CCC2CC=CC=C2C1=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 48.7 %

Procedure:
2-(Bis-methylthiomethylene)-4,5-dihydro-2H-naphthalen 1-one (11.56 g, 46 mmol) and 1-tert-butyloxycarbonylpiperazine (10.3 g, 55 mmol) were refluxed in acetonitrile (300 ml) for 24 h. The mixture was cooled, water (500 ml) added, and extracted with ethyl acetate (3×200 ml). The combined organics were washed with water and brine, dried (MgSO4), evaporated in vacuo, and the resulting oil purified by flash chromatography, eluting with dichloromethane then dichloromethane:methanol (97:3 v/v) to give 2-(methylthio[4-(tert-butyloxycarbonyl)-1-piperazinyl]methylene)-4,5-dihydro-2H-naphthalen-1-one (8.75 g, 49%) as a foam; δ (360 MHz, CDCl3) 1.49 (9H, s, tBu), 3.31 (3H, s, MeS), 2.86-2.94 (4H, m, CCH2CH2C), 3.3-3.5 (8H, m, NCH2CH2N), 7.18 (1H, d, J=7.5 Hz, H-5), 7.30 (1H, t, J=7.5 Hz, H-7), 7.37 (1H, dt, J=1.4 and 7.5 Hz, H-6), 8.10 (1H, dd, J=1.4 and 7.5 Hz, H-8).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH:12]([NH:15][C:16](=[O:21])[CH2:17][C:18]([CH3:20])=[O:19])([CH3:14])[CH3:13].N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[CH:12]([NH:15][C:16](=[O:21])[CH2:17][C:18]([CH:20]=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])=[O:19])([CH3:14])[CH3:13]
Reactant: CC(=O)CC(=O)NC(C)C
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(C)NC(=O)CC(=O)C=Cc1ccccc1[N+](=O)[O-]
Yield: 78.3 %

Procedure:
o-Nitrobenzaldehyde (43.4 g, 0.29 mole) and acetoacetic isopropylamide (40.0 g, 0.29 mole) are dissolved in benzene (150 ml) and thereto are added piperidine (1.15 ml) and acetic acid (3.45 ml), and the mixture is refluxed and the produced water is removed. After the stoichiometic amount of water is distilled off, the reaction is stopped. After the reaction, the solvent is distilled off under reduced pressure, and the residue is recrystallized from ethanol to give the title compound (62.7 g, yield 78.4%) as colorless prisms, m.p. 132°-135° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17]I)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[OH:25][C:26]1[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[O:28][N:27]=1.CN(C=O)C>CCOCC>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][O:25][C:26]2[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[O:28][N:27]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1cc(O)no1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCI)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCCCC2CCN(C(=O)OC(C)(C)C)CC2)no1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.2 %

Procedure:
A mixture of 4-3 (3.0 g, 8.1 mmol), Cs2CO3 (2.6 g, 8.1 mmol), methyl 3-hydroxy-5-isoxazolecarboxylate (Aldrich) (1.2 g, 8.1 mmol), and DMF (20 mL) was stirred at ambient temperature for 20 h. The reaction mixture was diluted with ether and then washed with H2O and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 3% acetone/CH2Cl2) gave 4-4 (2.7 g) as a colorless solid. Rf 0.17 (silica, 3% acetone/CH2Cl2).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33](=[O:42])[NH:34][CH2:35][CH2:36][CH2:37][NH:38][CH:39]1[CH2:41][CH2:40]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:42])[NH:34][CH2:35][CH2:36][CH2:37][N:38]([C:11](=[O:12])[C:10]1[CH:9]=[C:8]([O:7][C:6]2[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:14]=1)[CH:39]1[CH2:41][CH2:40]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)NCCCNC1CC1
Product: CC(C)(C)OC(=O)NCCCN(C(=O)c1cc(Oc2ccc(C#N)cc2)cc(Oc2ccc(C#N)cc2)c1)C1CC1
Yield: 80.8 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.2 g (3.36 mmol) and (3-cyclopropylamino-propyl)-carbamic acid tert-butyl ester (0.72 g, 3.36 mmol) were used to afford 1.5 g of the required product. 1H NMR (DMSO-d6): δ 0.48 (1H, m), 0.65 (2H, m), 1.38 (9H, s), 1.42 (2H, m), 1.68 (2H, m), 2.95 (2H, m), 3.22 (2H, m), 6.80 (1H, brs), 6.95 (1H, s), 7.08 (2H, m), 7.25 (4H, m), 7.88 (4H, m).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14]N(CCN(C)C)C.[Li]C(CC)C.S(OC)(OC)(=O)=O>CCOCC.O>[C:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Reactant: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CC1CCCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
A solution of N-Boc-Piperidine (15.0 g, 80.95 mmol) in ether (160 mL) was cooled to −78° C. and treated with TMEDA (15.9 mL, 105.2 mmol) followed by sec-BuLi (85 mL, 105.2 mmol) dropwise. The mixture was stirred for 3 h at −78° C. and then treated with a solution of dimethyl sulfate (15.3 mL, 161.9 mmol) in 65 mL of ether. The mixture was warmed to room temperature and then was diluted with water and extracted with ether. The combined extracts were dried over K2CO3 and then concentrated to give a crude product as a colorless oil. The product was purified by column chromatography on silca gel with 5% EtOAc/hexane to afford 16.0 g (81%) of product as a clear oil which was homogeneous by TLC analysis. 1H NMR (300 MHz) 67 4.33 (m, 1 H), 3.92-3.81 (pair of br. d, 1 H), 2.81-2.72 (dt, 1H), 1.60-1.36 (m, 15 H), 1.09-1.07 (d, 3 H); 13C NMR (75 MHz) 154.9 (s), 78.6 (s), 45.9 (s), 38.6 (s), 29.9 (s), 28.4 (s), 25.6 (s), 18.6 (s), 15.6 (s), ppm.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:12][N:11]=1)#[N:2].[CH3:21][NH2:22]>C(O)C>[C:1]([N:3]=[C:4]([NH:22][CH3:21])[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:12][N:11]=1)#[N:2]
Reactant: CN
Reactant: CSC(=NC#N)NCCSCc1nsc(NC(=N)N)n1
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1nsc(NC(=N)N)n1

Procedure:
A suspension of 3-[2-(3-cyano-2-methylisothioureido)ethylthiomethyl]-5-guanidino-1,2,4-thiadiazole (10 g.) in ethanol (200 ml.) was stirred and cooled to 10° with external ice cooling. Methylamine (166 g.) was passed into the suspension over 2 hours at such a rate that the temperature did not rise above 17° with external ice cooling. After 80 g. had been added, all was in solution. After 4 hours the ice bath was removed and excess methylamine was allowed to evaporate overnight. The final volume was about 120 ml. The product was filtered off, washed with a little ethanol, sucked dry and dried at 60°/0.3 m.m. Recrystallisation from aqueous ethanol (1:3 v/v) gave 3-[2-(2-cyano-3-methylguanidino)-ethylthiomethyl]-5-guanidino-1,2,4-thiadiazole, m.p. 198°-199°.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2].Cl[CH2:27][C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:27][C:28]5[N:33]=[CH:32][CH:31]=[CH:30][N:29]=5)=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2]
Reactant: ClCc1ncccn1
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(O)cc3)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCc4ncccn4)cc3)oc2c1

Procedure:
40 mg (119 μmol) 5-ethyl-6-[2-(4-hydroxy-phenyl)-benzoxazol-6-yl]-4,5-dihydro-2H-pyridazin-3-one, 23.5 mg (142 μmol) 2-(chloromethyl)-pyrimidine, 50 mg (362 μmol) potassium carbonate and 2 ml DMF are together heated to 80° C. for 2.5 h. Then the mixture is extracted with 10% sodium carbonate solution and EA. The org. phase is washed with sat. saline solution, dried on sodium sulphate and then the solv. is totally eliminated i.V. The residue is recrystallised from cyclohexane/EA.
Reaction SMILES: [C:1]([C:6]1[CH:41]=[C:40]([C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])[CH:39]=[CH:38][C:7]=1[O:8][CH:9]([CH2:34][CH2:35][CH2:36][CH3:37])[C:10]([NH:12][C:13]1[C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)=[CH:21][C:16]2[NH:17]C(=O)[O:19][C:15]=2[CH:14]=1)=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].C1(C)C(C)=CC=CC=1.[OH-].[Ca+2].[OH-]>C(O)CO>[NH2:17][C:16]1[CH:21]=[C:22]([O:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:28][CH:29]=2)[C:13]([NH:12][C:10](=[O:11])[CH:9]([O:8][C:7]2[CH:38]=[CH:39][C:40]([C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])=[CH:41][C:6]=2[C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:14][C:15]=1[OH:19]
Reactant: CCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc2oc(=O)[nH]c2cc1Oc1ccc(C(C)(C)C)cc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: OCCO
Product: CCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(O)c(N)cc1Oc1ccc(C(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
In a 250-ml flask inert with nitrogen, place 11.3 g (0.018 m) of 6-{2-(2,4-di-t-pentylphenoxy)hexanoyl}amino-5-(4-t-butylphenoxy)-benzoxazol-2-one (Formula I), 120 ml of xylene, 12 ml of ethylene glycol, and 8.0 g of calcium hydroxide. Heat under reflux collecting approximately 7 ml of water-ethylene glycol and 20 ml of xylene in a Dean-Stark trap. Detach the trap and heat under reflux for 5 hrs. Cool to 80° C. and add 100 ml of toluene, 100 ml of hot water, 25 ml of acetic acid, and 2 g sodium hydrosulfite. Stir the mixture at 60°-65° C. for 15 min and filter through a Celite pad to remove interlayer insolubles. Separate toluene-xylene solution, wash with 100 ml of hot water+12 ml of acetic acid+2 g sodium hydrosulfite and 100 ml of hot water twice, and concentrate under a reduced pressure to a thick oil. Dissolve the oil in 200 ml of heptane, add seed crystals, and stand at room temperature over night. Cool in an ice-water bath for 1 hr, collect solid, wash with heptane, and dry in a vacuum oven to give 9.2 g (85%) of 2-amino-5-{2-(2,4-di-t-pentylphenoxy)hexanoyl}amino-4-(4-t-butylphenoxy)-phenol (7b; Y=4-t-butylphenoxy and R′=1-(2,4-di-t-pentylphenoxy)pentyl).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:20]1[CH2:34][CH2:33][CH2:32][C@H:21]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([N:20]1[CH2:34][CH2:33][CH2:32][C@H:21]1[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 83 %

Procedure:
Boc-D-Phe-OH (2.66 g, 10 mole) and L-Pro-OBzl (2.42 g) were coupled using DCC, and Boc-D-Phe-Pro-OBzl was obtained in 83% yield; 1H NMR (CDCl3) δ7.34 (s, 5H), 7.23 (m, 5H), 5.4 (d, 1H), 5.15 (q, 2H), 4.65 (m, 1H), 4.35 (m, 1H), 3.5 (m, 1H), 3.1-2.9 (m, 2H), 2.6 (m, 1H), 2.-1.7 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:6])[CH:4]=[CH2:5].C(N(CC)CC)C.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:31][CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[CH2:25]2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].[OH-].[Li+:33]>O.C(#N)C.O1CCCC1>[Li+:33].[C:14]([C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:31][CH:30]3[CH2:29][N:28]([CH2:5][CH2:4][C:3]([O-:2])=[O:6])[CH2:27][CH:26]3[CH2:25]2)=[CH:22][CH:23]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)c1ccc(N2CC3CNCC3C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(N2CC3CN(CCC(=O)[O-])CC3C2)cc1
Yield: 72.8 %

Procedure:
Acrylic acid methyl ester (189 mg; 2.20 mmol) and triethylamin (0.2 mL) are added to 2-(4-tert-butyl-phenyl)-octahydro-pyrrolo[3,4-c]pyrrole (450 mg; 1.84 mmol) in a 1 to 1 mixture of water and tetrahydrofuran (1.6 mL) and the resulting mixture is irradiated in a mono-mode microwave oven for 30 minutes at 120° C. Lithium hydroxide (92 mg; 3.84 mmol) in water (5 mL) is then added and the reaction mixture is again irradiated in a mono-mode microwave oven for 30 minutes at 100° C. The mixture is then diluted with acetonitrile and the precipitate formed is filtered, collected and dried under high vacuum to afford the desired product (425 mg; 1.34 mmol).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[S:4].[OH:7][CH2:8][C:9](O)=O>O>[NH2:6][N:5]1[C:3]([SH:4])=[N:2][N:1]=[C:9]1[CH2:8][OH:7]
Reactant: O=C(O)CO
Reactant: NNC(=S)NN
Solvent: O
Product: Nn1c(S)nnc1CO
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
A mixture of 10.6 g (0.1 mole) of thiocarbohydrazide and 25.0 g (0.33 mole) of hydroxyacetic acid are heated and stirred at 130° C. for 20 minutes. The mixture is cooled to room temperature and diluted with 25 ml of water. It is then cooled for 24 hours at 11° C., yielding 7.0 g of crystals. The latter are recrystallized from chloroform/methanol, affording 4.5 g of solvated product. The product is dried in vacuo, affording 2.0 g of pale yellow crystals of 4-amino-5-mercapto-4H-1,2,4-triazole-3-methanol. m.p. 150.5°-151.5° C. When the reaction is repeated, using a longer heating time, (1 hour at 125° C.), and is followed by recrystallization from methanol/water, a higher yield of the same product is obtained (80%).