Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH2:3][CH2:2]1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>>[CH3:26][N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[N:11][C:10]=23)=[O:18])[CH2:21][CH2:22]1
Reactant: O=C(O)c1cccc2oc(N3CCOCC3)nc12
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)c2cccc3oc(N4CCOCC4)nc23)CC1

Procedure:
Following general procedure GP-C1, a mixture of 2-morpholinobenzoxazole-4-carboxylic acid and 4-amino-1-methylpiperidine were coupled to provide N-(1-methylpiperidin-4-yl)-2-morpholinobenzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=2[CH3:20])[CH2:7][CH2:6]1.C1COCC1>CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[CH3:20])[CH2:7][CH2:6]1
Reactant: COCCN1CCN(c2ccc([N+](=O)[O-])cc2C)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COCCN1CCN(c2ccc(N)cc2C)CC1

Procedure:
A solution of 0.85 g (3.04 mmol) 1-(2-methoxy-ethyl)-4-(2-methyl-4-nitro-phenyl)-piperazine in 20 ml MeOH:THF=1:1 is hydrogenated in the presence of 0.2 g 10% Pd/C (Engelhard 4505). The reaction mixture is filtered (2 glass fiber filters used) and the filtrate is concentrated in vacuo to afford the title compound as an oil.
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+].CC(C)=O.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][C:37](Cl)=[O:38]>O>[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][C:37]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[O:38]
Reactant: Cn1nnnc1C=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(Cl)Cc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1nnnc1C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
In 40 ml of water were dissolved 416 mg of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylic acid and 660 mg of sodium hydrogencarbonate. To the solution was added 10 ml of acetone and further added dropwise with stirring at 0°-5° C., 20 ml of an acetone solution containing 323 mg of 2-thienylacetyl chloride. The mixture was stirred for 30 minutes under ice-cooling and for additional 3 hours at room temperature. The acetone was distilled off at room temperature under reduced pressure. The residual solution was washed with ether, adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The ethyl acetate was removed under reduced pressure, and, upon washing the residue with ether, there was obtained 590 mg of 7-(2-thienylacetamido)-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].IC.[CH3:32]COCC>CN(C=O)C>[CH3:32][N:22]1[C:23]2[C:19](=[CH:18][C:17]([S:14]([N:10]3[CH2:11][CH2:12][CH2:13][C@H:9]3[CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:16])=[O:15])=[CH:25][CH:24]=2)[C:20](=[O:27])[C:21]1=[O:26]
Reactant: CCOCC
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a solution of 10 (193 mg, 0.5 mmol) in DMF (3 mL) was added 60% NaH (30 mg, 0.75 mmol) at room temperature. The mixture was stirred 15 min, then iodomethane (0.5 mL) was added. The mixture was stirred overnight at ambient temperature, then ether (75 mL) was added, washed with water (30 mL) and saturated NaCl (30 mL), and dried over Na2SO4. After evaporation of the solvent, the crude product was purified with ether to afford 85 mg (43%) of 11a as a yellow solid, mp 160.1-160.9° C. 1H NMR (300 MHz, CDCl3) δ 8.07 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 8.01 (s, 11H), 7.25 (t, J=8.4 Hz, 2H), 6.92 (m, 3H), 6.81 (d, J=7.8 Hz, 2H), 4.15 (dd, J=9.0 Hz, J=2.7 Hz, 1H), 4.00 (m, 1H), 3.92 (m, 1H), 3.51 (m, 1H), 3.30 (m, 1H), 3.26 (s, 3H), 2.04 (m, 2H), 1.81 (m, 2H). Anal. Calcd for C20H20N2O5S: C, 59.99, H, 5.03; N, 7.00. Found: C, 59.80, H, 5.03; N, 6.91.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[CH3:11][NH:12][C:13](=[S:16])[NH:14][NH2:15]>N1C=CC=CC=1>[N:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:15][NH:14][C:13]([NH:12][CH3:11])=[S:16])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CNC(=S)NN
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=S)NNC(=O)c1ccncc1
Reaction time: 8 h

Procedure:
4-Pyridoyl chloride hydrochloride (10.0 g, 5.62×10-2 mole) and 4-methylthiosemicarbazide (5.91 g, 5.62×10-1 mole) were stirred at room temperature in pyridine (150 ml). After stirring overnight, the pyridine was evaporated at reduced pressure and the concentrate was washed with H2O. The undissolved product was collected by filtration and dried by suction.
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[NH2:22][CH:23]1[CH2:27][CH2:26][O:25][CH2:24]1>>[CH:13]([NH2:14])([CH3:18])[CH3:12].[O:25]1[CH2:26][CH2:27][CH:23]([NH:22][C:3]([C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])[CH:6]=2)=[O:4])[CH2:24]1
Reactant: NC1CCOC1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)on1
Product: CC(C)N
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC2CCOC2)on1
Yield: 164.6 %

Procedure:
As described for example 28, 3-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (377 mg, 1.28 mmol), was converted using 3-aminotetrahydrofuran (335 mg, 3.84 mmol), instead of isopropyl amine, to the title compound (368 mg, 82%) which was obtained as a colourless gum after purification by chromatography (silica, heptane:ethyl acetate=4:1 to 4:1). MS: m/e=350.4 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4](=O)[NH:3][CH:2]=1.P(Cl)(Cl)([Cl:14])=O.S(Cl)(Cl)=O>>[Cl:14][C:2]1[N:3]=[CH:4][C:5]2[C:10](=[N:9][CH:8]=[CH:7][N:6]=2)[N:1]=1
Reactant: O=c1[nH]cnc2nccnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Clc1ncc2nccnc2n1

Procedure:
Reaction of pteridin-4(3H)-one IV′ with chlorinating agents such as phosphorous oxychloride or thionyl chloride affords chloro-pteridine V′. Suitable solvent for this reaction includes methylene chloride chloroform or toluene.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se-:9][Se-:10].[Mg+2].Cl>O>[CH2:1]([Se:9][Se:10][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: [Se-][Se-]
Agent: Cl
Agent: [Mg+2]
Solvent: O
Product: c1ccc(C[Se][Se]Cc2ccccc2)cc1

Procedure:
About 12.6 grams (0.1 moles) benzylchloride is now added by dropwise addition over a period of 15 minutes to the magnesium diselenide reagent. In about 5 to 10 minutes after the mixture of these materials, the reddish brown color of the solution appears discharged. This solution is diluted further by the addition of 200 milliliters water and the addition of 10 milliliters concentrated hydrochloric acid. Upon cooling of this solution, the solids contained within the flask are collected by filtration and recrystallized from ethanol. Yield: 14 grams of yellow crystals (m.p. 94°C). Infrared spectral analysis of this material confirms that it is dibenzyl diselenide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7]C)=[O:6].C(C1C=C(C=C(OC(C)C)C=1)C(O)=O)#N>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Agent: CC(C)Oc1cc(C#N)cc(C(=O)O)c1
Product: CC(C)Oc1ccc(C(=O)O)cc1Cl

Procedure:
Prepared from methyl 3-chloro-4-isopropoxybenzoate according to the procedure for 3-cyano-5-isopropoxybenzoic acid. LCMS-ESI (m/z) calculated for C10H11CLO3: 214.7. found 215.0 [M+H]+, tR=3.22 min. 1H NMR (400 MHz, CDCl3) δ 12.94 (s, 1H), 7.98-7.74 (m, 2H), 7.26 (d, J=8.9 Hz, 1H), 4.80 (dt, J=12.1, 6.0 Hz, 1H), 1.33 (t, J=5.6 Hz, 6H).
Reaction SMILES: Cl.[CH:2]1([N:8]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:15][N:16]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:39][CH:40]([S:42](Cl)(=[O:44])=[O:43])[CH3:41]>>[CH:24]1([N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([S:42]([CH:40]([CH3:41])[CH3:39])(=[O:44])=[O:43])[CH2:20][CH2:19]3)=[CH:15][N:16]=2)=[O:10])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: O=C(Nc1ncc(CN2CCNCC2)s1)N(C1CCCCC1)C1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 44 %

Procedure:
Prepared as described in general procedure (Q) using 1,1-dicyclohexyl-3-(5-piperazin-1-ylmethyl-thiazol-2-yl)-urea hydrochloride (36 mg, 0.08 mmol), DIEA (42 μL, 0.24 mmol) and propane-2-sulfonyl chloride (18 μL, 0.16 mmol) to afford 18 mg (44%) of the desired product after purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([NH:17][C:18]([O:20][CH2:21][C:22]1C=CC=C[CH:23]=1)=[O:19])[C@H:14]([OH:16])[CH3:15])=[O:10])[C:2]1C=CC=C[CH:3]=1.[H][H].[OH-].[Na+]>CO.[Pd].O.O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[C@H:14]([OH:16])[CH3:15])=[O:10])[CH:2]=[CH2:3]
Reactant: C[C@@H](O)[C@@H](CNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CCOC(=O)NC[C@@H](NC(=O)OCC=C)[C@@H](C)O
Yield: 71 %

Procedure:
A solution of (2R,3R)-1,2-bis(benzyloxycarbonylamino)-3-hydroxybutane (80.5 g) in methanol (800 ml) was hydrogenated under atmospheric pressure of hydrogen over palladium on carbon (10%, 8 g) for 5 hours at ambient temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give a syrup. To a solution of the syrup in a mixture of water (400 ml) and tetrahydrofuran (400 ml) in tetrahydrofuran (90 ml) under ice-cooling with stirring, keeping the pH between 8.5 and 9.5 with 4N aqueous sodium hydroxide. After stirring for one hour, the mixture was extracted with ethyl acetate (800 ml), washed with brine (400 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (600 g) and eluted with a mixture of methanol and chloroform (1:99, V/V) to give (2R,3R)-1,2-bis(allyloxycarbonylamino)-3-hydroxybutane (41.78 g) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:20]O.C[O-].[Na+]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([C:12]([F:15])([F:13])[F:14])[C:3]=1[C:4]([O:6][CH3:20])=[O:5]
Reactant: O=C(O)c1c(C(F)(F)F)ccc(Cl)c1Cl
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(C(F)(F)F)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.04 g of 2,3-dichloro-6-trifluoromethylbenzoic acid in 10 ml of toluene was added 0.71 g of thionyl chloride and 1 drop of pyridine and the mixture was heated at reflux for 3 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and 2,3-dichloro-6-trifluoromethylbenzoyl chloride obtained was added to a solution which is prepared by dissolving 28% methanol solution of 0.77 g of sodium methoxide into 10 ml of methanol at a temperature of from 5 to 10° C., and the solution was stirred for 2 hours at room temperature. After condensing the reaction mixture, it was extracted with ether. The extract was washed with IN-aqueous hydrochloric acid, water and saturated saline solution in series and then dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, and the oily substance obtained was purified by using silica gel column chromatography to obtain 0.89 g of the title compound (nD 23.3-1.4801).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[CH3:28][C@H:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][NH:36][C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:28])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@H](NCC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1)c1ccccc1
Reaction time: 14 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carbaldehyde (35 mg, 0.096 mmol) was dissolved in THF (2 mL) and (S)-α-methylbenzylamine (0.013 mL, 0.115 mmol) was added. The solution was stirred at rt for 10 h, at which time the THF was removed in vacuo and the residue dissolved in EtOH (5 mL), and sodium cyanoborohydride (13 mg, 0.192 mmol) and a catalytic drop of glacial acetic acid were added. Stirring was permitted for 14 h, at which time the solvent was removed in vacuo, the residue was taken up in EtOAc. The organic phase was washed with 10% aq. sodium carbonate, dried over magnesium sulfate, and concentrated. Purification was accomplished via silica gel flash chromatography (30 g silica gel, 5:95 7M methanolic ammonia:ethyl acetate.) The title compound was obtained as a yellow oil. (Yield: 21 mg, 0.045 mmol, 47%) 1H NMR (400 MHz, CDCl3) 7.62, 7.39-7.23, 7.14, 7.09-7.02, 6.86, 6.57, 5.45, 4.59, 4.06, 3.76-3.63, 2.74, 2.39-2.15, 1.76-1.52, 1.33, 0.98, 0.63
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([C:10](=[O:15])N(OC)C)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)=O.CC(C)=O.C[Li].C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:9][C@H:8]([NH:7][C:6](=[O:16])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10](=[O:15])[CH3:17]
Reactant: O=C=O
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
A solution of tert-butyl{(1S)-1-[methoxy(methyl)carbamoyl]ethyl}carbamate (5.26 g) in tetrahydrofuran (300 mL) was cooled with dry ice/acetone under a nitrogen atmosphere, and 1.6 mol/L-methyllithium/diethyl ether solution (38.8 mL) was added. After stirring at the same temperature for 1.5 hr, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentration under reduced pressure to give the title compound as a colorless oil (yield: 4.48 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.Cl[C:12]1[CH:21]=[N:20][C:15]2[N:16]=[CH:17][N:18]=[CH:19][C:14]=2[CH:13]=1>[OH-].[K+]>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][C:19]3[C:14]4[CH:13]=[CH:12][CH:21]=[N:20][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Clc1cnc2ncncc2c1
Reactant: Oc1ccc2c(c1)CCC2
Agent: [K+]
Agent: [OH-]
Product: c1cnc2ncnc(Oc3ccc4c(c3)CCC4)c2c1
Yield: 60 %

Procedure:
To a solution of 5-hydroxyindan (1.342 g, 10 mM) in 80 ml of aqueous potassium hydroxide solution containing 1.683 g (30 mM) of solid potassium hydroxide is added 6-chloro-pyrido[2,3-d] pyrimidine (1.656 g, 10 mM). The reaction mixture is stirred for about 0.5 h at room temperature until most of the 6-chloro-pyrido[2,3-d]pyrimidine dissolves and then heated on the steam bath for further 0.5 h. The mixture is cooled, filtered and the residue recrystallized from hot aqueous ethanol to give pure title compound in 60% yield.
Reaction SMILES: Br.[C:2]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH:7](Br)[CH2:6]1)(=[O:4])[CH3:3].N[N:14]=[CH:15][NH:16][C:17]([NH2:19])=[S:18].[OH-].[Na+].[OH-].[NH4+:23]>C(O)C.CO.C(Cl)(Cl)Cl>[C:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:19]=[C:17]([NH:16][C:15]([NH2:23])=[NH:14])[S:18][C:7]=2[CH2:6]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCC(=O)C(Br)C1
Reactant: [NH4+]
Reactant: NN=CNC(N)=S
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: CC(=O)N1CCc2nc(NC(=N)N)sc2C1
Reaction time: 48 h
Yield: 9 %

Procedure:
N-Acetyl-3-bromo-4-piperidone hydrobromide (12.09 g, 40 mmol) was added to a suspension of aminoiminomethylthiourea (4.735 g, 40 mmol) in ethanol (40 ml) at 70°. After completion of the addition, the reaction mixture was allowed to stir at 40° for 48 hours. Addition of sodium hydroxide (1.6 g, 40 mmol) was followed by stirring at 40° for an additional 72 hours. Removal of solvent gave a crude oil which was subjected to column chromatography (eluant: 89:10:1 of chloroform:methanol:concentrated ammonium hydroxide) to provide the title product (822 mg, 3.4 mmol, 9% yield).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[H-].[Na+].[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(#N)C>[CH3:7][N:8]([Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC#N
Product: CN(C(=O)C(F)(F)F)[Si](C)(C)C(C)(C)C

Procedure:
To 800 ml of dry benzene:acetonitrile (v/v, 1:1) was added 127 g (1.0 mole) of N-methyl-trifluoroacetamide. To this solution, while stirring and maintaining the temperature at 0 degress C., was slowly added 23.5 g (0.98 mole) of sodium hydride. The solution was then stirred for 4 hours at 4 degrees C. At this time, 173.34 g (1.15 mole) of t-butyldimethylsilyl chloride was added in four equal aliquots over a period of 80 minutes. After the last addition the solution was stirred for 2 hours at 4 degrees C. The precipitate of sodium chloride was then removed from the reaction mixture by filtration under dry nitrogen and the resulting filter cake washed twice with 100 ml each of dry benzene. Washings and filtrate were combined and concentrated. The remaining yellow solution was fractionally distilled with the distillate at 158-172 degrees C. being collected. Redistillation of this fraction gave the desired product.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[C:9]([O-])([O-])(OCC)[CH3:10].CC1N2C([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=CC=CC2=NN=1>>[CH3:9][C:10]1[N:4]2[CH2:5][CH:6]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:7][CH2:8][C:3]2=[N:1][N:2]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: Cc1nnc2cccc(-c3ccccc3)n12
Reactant: NNc1ccccn1
Product: Cc1nnc2n1CC(c1ccccc1)CC2

Procedure:
A solution of 0.85 g. of the above hydrazinopyridine in 10 ml. of ethyl orthoacetate is heated at reflux for 5 hours. On cooling pale yellow plates are separated which are washed with hexane to give 0.55 g. of 3-methyl-5-phenyl-1,2,4-triazolo[4,3-a]pyridine, m.p. 182°-184° C.
Reaction SMILES: C(N(CC)CC)C.[O:8]([C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[Cl:34][C:35]12[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([C:38]3=O)[CH2:36]1)[CH2:42]2>C1COCC1.CCCCCC.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[O:8]([C:16]1[CH:17]=[C:18]([C:19](=[C:40]2[CH:41]3[CH2:43][CH:37]4[CH2:36][C:35]([Cl:34])([CH2:44][CH:39]2[CH2:38]4)[CH2:42]3)[O:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][CH:33]=1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCOc2ccccc2)c1
Reactant: O=C1C2CC3CC1CC(Cl)(C3)C2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(OCCOc2ccccc2)=C2C3CC4CC2CC(Cl)(C4)C3)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Into a 500 mL three-neck flask equipped with magnetic stirrer, pressure-equalizing addition funnel and nitrogen line was charged with 150 mL anhydrous THF. Titanium tetrachloride(12 mL) was added dropwise over a period of 30 minutes. After stirring the suspension for 20 minutes, 18 parts of zinc was added in small portions. The reaction mixture was heated under reflux for 2 hours and 29 mL of triethylamine was added dropwise. After refluxing one hour a solution 5.0 parts of ester (54) and 3.0 parts of 5-chloroadamantan-2-one in 35 mL of dry THF was added over a period of 45 minutes. The reaction mixture was heated for one hour. TLC on silica gel plate of the mixture showed the presence of starting ester. One part of 5-chloroadamantan-2-one in 20 mL of dry THF was added dropwise over 30 minutes and refluxed for two hours. The mixture was cooled to room temperature, diluted with 400 mL of hexane and decanated. The residue was washed three times with 150 mL of hexane. The combined hexane layer was filtered and evaporated under reduced pressure to give an oily material which was purified by chromatography on silica gel column using 5% ethyl acetate/hexane as an eluant. The fractions were checked by TLC on silica gel plate and the desired fractions were combined. The solvent was evaporated under reduced pressure to give an oil, yield 4.9 parts. The structure was confirmed by 1H NMR. The reaction proceeded as follows:
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].C([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:18](=[O:25])[N:17]([CH2:26][C:27]([NH:29][C:30]3[C:35]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:33]=[CH:32][C:31]=3[CH:39]([CH3:41])[CH3:40])=[O:28])[C:16]2=[O:42])=[CH:11][CH:10]=1)#N.Cl[CH2:44]Cl>CO.O>[CH:36]([C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:39]([CH3:41])[CH3:40])[C:30]=1[NH:29][C:27](=[O:28])[CH2:26][N:17]1[C:18](=[O:25])[C:19]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:15]([C:12]2[CH:11]=[CH:10][C:9]([S:3]([CH3:44])(=[O:5])=[O:2])=[CH:14][CH:13]=2)[C:16]1=[O:42])([CH3:37])[CH3:38]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CN1C(=O)N(c2ccc(C#N)cc2)C2(CCCCC2)C1=O
Reactant: O=S([O-])OO
Reactant: ClCCl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1C(=O)N(c2ccc(S(C)(=O)=O)cc2)C2(CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.421 g (0.684 mmol; 2.2 eq.) of oxone is added to a solution of 0.158 g (0.311 mmol; 1 eq.) of N-(2,6-diisopropylphenyl)-2-[1-(4-methylsulfanylphenyl)-2,4-dioxo-1,3-diazaspiro[4.5]dec-3-yl]acetamide (prepared according to Example 2) in 5 ml of methanol and 2 ml of demineralized water. The reaction medium is stirred at room temperature for 18 hours. Water and dichloromethane are added, and the organic phase is washed several times with water, dried over sodium sulfate and then concentrated to dryness. The product N-(2,6-diisopropylphenyl)-2-[1-(4-methanesulfonyl-phenyl)-2,4-dioxo-1,3-diazaspiro[4.5]dec-3-yl]acetamide is obtained in the form of a solid.