Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]([C:13]([OH:15])=O)[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]1=2.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1>O1CCCC1>[CH3:27][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:13]([CH:5]2[C:4]3[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=3[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]2=3)=[O:15])[CH2:22][CH2:23]1
Reactant: O=C1Nc2ccccc2C(C(=O)O)c2ccccc21
Reactant: CN1CCC(N)CC1
Solvent: C1CCOC1
Product: CN1CCC(NC(=O)C2c3ccccc3NC(=O)c3ccccc32)CC1
Temperature: 40 °C
Yield: 68.7 %

Procedure:
A quantity of 3.5 gm (0.022 mol) of N,N'-carbonyldiimidazole is added to a suspension of 5 gm (0.02 mol) of 5,11-dihydro-6-oxo-6H-dibenz[b,e]azepin-11-carboxylic acid in 100 ml of tetrahydrofuran, and the mixture is heated to 40° C. for 30 minutes. Then, 2.5 gm (0.022 mol) of 4-amino-1-methylpiperidine are added, and the mixture is heated for a further two hours at 40° C. After cooling, the solvent is removed in vacuo, and the residue is purified by column chromatography on silica gel [ethylene chloride/methanol (9:1)]. Subsequently, 4.8 gm (68%) of the desired compound, M.p.: 230°-231° C., are obtained from the eluate. According to the mixed melting point, thin layer chromatography, and IR spectrum, the substance is identical to the product obtained in Example 3.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([CH3:39])([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:22]2[S:26][C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[N:24][C:23]=2[CH3:37])[CH2:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:38])[CH3:6])C.[OH-].[Na+]>CCO>[CH3:39][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:22]2[S:26][C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=3)=[N:24][C:23]=2[CH3:37])[CH2:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:38])([CH3:6])[C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN(Cc2cccs2)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(CN(Cc2cccs2)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OC(C)(C)C(=O)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
To a solution of example 90 (780 mg, 1.32 mmol) in EtOH (20 mL) was added 1N NaOH (4 mL, 3 eq.) and the reaction was stirred at 80° C. for 2h. When all of the starting material had disappeared, the reaction cooled, evaporated to dryness, taken up with 1N HCl, extracted with CH2Cl2 and the organic phase washed with water. The organic layer was then dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was chromatographed eluting with CH2Cl2 (100%) then CH2Cl2/MeOH (90/10) to afford the title compound as a yellow solid (410 mg, 55.4%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH3:19])[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:13]=2[CH:28]=1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH3:19])[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:13]=2[CH:28]=1
Reactant: CCCc1nc2ccc(NC(=O)OC(C)(C)C)cc2n1Cc1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2ccc(N)cc2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.7 %

Procedure:
6-t-Butoxycarbonylamino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (700 mg) (example 1) is dissolved in a mixture solvent of methylene chloride (10 ml) and trifluoroacetic acid (1 ml), and the solution is stirred for five hours at room temperature. A small amount of methylene chloride is added into the reaction solution, and the solution is washed with sodium carbonate aqueous solution. After it is dried, the solvent is removed through evaporation. The residue is crystallized using a mixture solvent of normal hexane and ether, and 6-amino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (455 mg) is obtained. 1H-NMR (CDCl3, δ): 1.01 (3H, t, J=7.5 Hz), 1.86 (2H, m), 2.73 (2H, t, J=7.5 Hz), 5.30 (2H, s), 6.41 (1H, d, J=1.5 Hz), 6.48 (1H, d, J=7.5 Hz), 6.66 (1H, dd, J=7.5 and 1.5 Hz), 7.10 (1H, t, J=7.5 Hz), 7.25 (1H, t, J=7.5 Hz), 7.46 (1H, d, J=7.5 Hz), 7.57 (1H, d, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17][OH:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1>ClCCl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH:17]=[O:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(CO)nn1-c1ncccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)c1cc(C=O)nn1-c1ncccc1Cl
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A little at a time, 3.90 g (44.9 mmol) of manganese(IV) oxide were added to a solution of 3.00 g (11.2 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-(hydroxymethyl)-1H-pyrazole-5-carboxylate in 162 mg of dichloromethane, and the mixture was stirred at 40° C. for 4 hours. After cooling to 20° C., a further 3.90 g (44.9 mmol) of manganese(IV) oxide were added, and the mixture was heated at 40° C. overnight. After cooling to 20° C., the mixture was filtered through Celite and the filtrate was freed from the solvent under reduced pressure.
Reaction SMILES: [OH:1][CH:2]([NH:7][C:8]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:11]=1)=[O:9])[C:3]([F:6])([F:5])[F:4].[H-].[Na+].[CH3:31]I>ClCCl.CN(C=O)C.CCCCCC>[CH3:31][O:1][CH:2]([NH:7][C:8]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=2)[N:11]=1)=[O:9])[C:3]([F:6])([F:5])[F:4]
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NC(O)C(F)(F)F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NC(OC)C(F)(F)F)c1

Procedure:
0.6 g (0.0015 mol) of N-(1-hydroxy-2,2,2-trifluoroethyl)-4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxamide was dissolved in a mixed solvent of dichloromethane and DMF. The obtained solution was mixed with 0.064 g (ca. 60% in mineral oil; 0.0015×1.1 mol) of NaH and then with 0.42 g (0.0015×2.0 mol) of methyl iodide, followed by treating the solution under reflux for about 8 hours. The reaction solution was distributed in hexane-saturated sodium bicarbonate water and washed with saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: CN(C)CCCN=C=O.[CH2:10]([C:17]1[NH:25][C:24]2[C:23](=[O:26])[N:22]([CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:21](=[O:33])[N:20]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[CH:38][CH:37]=3)[C:19]=2[N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.NN.[H][H]>[Pd]>[NH2:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][CH2:34][N:20]2[C:19]3[N:18]=[C:17]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:25][C:24]=3[C:23](=[O:26])[N:22]([CH2:27][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[C:21]2=[O:33])=[CH:41][CH:40]=1
Reactant: [H][H]
Reactant: CN(C)CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Agent: [Pd]
Agent: CN(C)CCCN=C=O
Agent: NN
Solvent: O
Product: CN(C)CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By methods well known in the art 3-dimethylaminopropyl isocyanate is converted into 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-dimethylaminopropyl)xanthine, which in turn, is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminopropyl) xanthine.
Reaction SMILES: C(O[CH:5]([C:28]1[CH:37]=[C:31]2[C:32](=[O:36])[O:33][CH2:34][CH2:35][N:30]2[N:29]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.P([O-])([O-])([O-])=O>C1COCC1.[Pd]>[O:13]=[C:12]1[N:11]2[C@H:7]([S:8][CH:9]=[C:10]2[C:14]([OH:16])=[O:15])/[C:6]/1=[CH:5]\[C:28]1[CH:37]=[C:31]2[C:32](=[O:36])[O:33][CH2:34][CH2:35][N:30]2[N:29]=1
Reactant: CC(=O)OC(c1cc2n(n1)CCOC2=O)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=C(O)C1=CS[C@@H]2/C(=C\c3cc4n(n3)CCOC4=O)C(=O)N12
Reaction time: 3 h
Yield: 59.3 %

Procedure:
To a solution of 4-nitrobenzyl (5R)-6-[(acetyloxy)(4-oxo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.22 g, 0.37 mmol) in THF (15 ml), under nitrogen, was added 15 ml of a phosphate buffer solution (0.5M, pH 6.5), and 80 mg of 10% Pd/C. The mixture was hydrogenated at 40–50 psi for 3 hr, and then filtered through Celite. The filter pad was washed with THF, and the filtrate was extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate and evaporated. The residue was washed with ether to give 0.07 g of a yellow solid; MS m/e 320 (MH+); 1H NMR (DMSO-d6) δ 4.55–4.57 (m, 2H), 4.76–4.80 (m, 2H), 6.50 (s, 1H), 6.63 (s, 1H), 7.58 (s, 1H), 7.76 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[O:12])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[O:20]1CCOCC1.[OH-].[Na+:27]>O>[NH2:3][C:4]1[C:5]([S:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[O:12])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:20])=[O:1].[Na+:27]
Reactant: O=C1Cc2cccc(S(=O)c3ccccc3Cl)c2N1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)[O-])cccc1S(=O)c1ccccc1Cl

Procedure:
A mixture of 2-oxo-7-(2-chlorophenylsulfinyl)indoline (5.0 g.), dioxane (30 ml.), sodium hydroxide (2.5 g.) and water (30 ml.) was refluxed for 8 hours with stirring. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in water under heating and filtered. The filtrate was adjusted to about pH 4 with 5% sulfuric acid and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in 1N sodium hydroxide (14.2 ml.) under heating and the solution was evaporated to dryness under reduced pressure. The oily residue was dissolved in ethanol (20 ml.) and crystallized with diethyl ether to give crystals of the captioned compound (2.9 g.). mp 248° to 251° C. (dec.).
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(OC2CCCCC2)cc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(OC2CCCCC2)ccc1C(=O)O)c1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
0.077 mL of 2.0 mol/L aqueous sodium hydroxide was added drop-wise to a mixed solution of 1 mL of methanol and 1 mL of tetrahydrofuran containing 35 mg of methyl 2-(benzamido)-4-(cyclohexyloxy)benzoate at room temperature and stirred at the same temperature overnight and at 40° C. for 6 hours and 30 minutes. 0.050 mL of 2.0 mol/L aqueous sodium hydroxide was added at room temperature and stirred at she same temperature for 4 hours and 30 minutes. The solvent was evaporated under reduced pressure and water was added and pH was adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid. A solid substance was separated by filtration to obtain 25 mg of 2-(benzamido)-4-(cyclohexyloxy)benzoic acid as white solid.
Reaction SMILES: [C:1]([N:4]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH:15]2[CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:19]2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)([OH:3])=[O:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)(Cl)Cl>[C:1]([N:4]1[C:16]2[C:15]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:19]3)=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)([OH:3])=[O:2]
Reactant: CCCCN1CCC(CC2CCCC3c4ccccc4N(C(=O)O)C23)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Product: CCCCN1CCC(Cc2cccc3c4ccccc4n(C(=O)O)c23)CC1

Procedure:
N-Carboxy-[1-butylpiperidin-4-ylmethyl]-1,2,3,4,4a,9a-hexahydrocarbazole (0.530 g, 1.32 mmol) was dissolved in chloroform (25 ml) and treated with 2,3-dichloro-5,6-dicyano-1, 4-benzoquinone (0.329 g, 1.58 mmol) with stirring. The mixture was heated to reflux for 12 hours, cooled, and more 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.329 g 1.58 mmol) added with stirring. The mixture was heated to reflux for 12 hours, cooled and evaporated under reduced pressure. The residue was purified by Silica-gel chromatography, eluting with 2%MeOH/CHCl3 to give the title compounds as 3:1 mixture. The mixture was separated by preparative HPLC using a Waters Micro Bondapak C18 (300 mm×7.8 mm) column and eluting with 75:25 MeCN: 0.1M Ammonium Acetate (pH 5.0).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:7].CN(C)CCN(C)C.[C:24](=[O:26])=[O:25].[OH-].[Na+]>C(OCC)C>[CH2:6]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[C:12]([CH:13]=1)[C:24]([OH:26])=[O:25])[CH3:7]
Reactant: O=C=O
Reactant: CCc1ccc(OC)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CCc1ccc(OC)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
n-Butyl lithium (2.5M in hexanes, 38.5 ml, 100.0 mmol) was added dropwise under a nitrogen atomosphere to a stirred solution of 4-ethylanisole (11.7 g, 86.0 mmol) and N,N,N′,N′-tetramethylethylenediamine (10 ml, 88.0 mmol) in anhydrous diethyl ether (100 ml) and the mixture was stirred and held at 30° C. for 16 hours. The mixture was cooled and poured slowly in to a mixture of excess solid carbon dioxide in anhydrous diethyl ether. Upon warming to room temperature the mixture was made basic by the addition of 2M sodium hydroxide, the aqueous layer was separated and acidified to pH 2 or below by the addition of concentrated hydrochloric acid. The mixture was extracted with diethyl ether, the organic layer separated and the solvent removed in vacuo to afford 5-ethyl-2-methoxybenzoic acid (5.7 g, 37%) as a pale yellow oil. 1H NMR (DMSO-d6) 12.50 (1H, br s), 7.48 (1H, d), 7.33 (1H, dd), 7.03 (1H, d), 2.56 (2H, q), 1.17 (3H, q). MS: [M+H]− 181.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[CH:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH2:11].C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:12]1(/[CH:10]=[CH:11]/[C:2]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: OCc1ccc(I)cc1
Reactant: C=CC1CCCCC1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OCc1ccc(/C=C/C2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 23 h
Yield: 31.1 %

Procedure:
4-Iodobenzyl alcohol (2.34 g) was dissolved in DMF (40 mL), added with vinylcyclohexane (1.32 g), triethylamine (1.81 mL), and bis(triphenylphosphine)palladium (II) chloride (700 mg), and stirred for 23 hours at 80° C. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the residues were purified by silica gel column chromatography (8 to 30% ethyl acetate/hexane) to obtain the title compound (672 mg) as a yellow solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[C:9]1([C:15]2[CH2:21][CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16]=2[C:26]2[CH:31]=[CH:30][C:29]([CH:32]=[CH:33][C:34]#[N:35])=[CH:28][CH:27]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1.Cl>[C:9]1([C:15]2[CH2:21][CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16]=2[C:26]2[CH:27]=[CH:28][C:29]([CH:32]=[CH:33][C:34]3[NH:35][N:7]=[N:6][N:5]=3)=[CH:30][CH:31]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#CC=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C(=Cc1nnn[nH]1)c1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Reaction time: 0.17 h

Procedure:
To a solution of aluminum chloride (175 mg, 1.31 mmol) in THF (4 mL) at 0° C. was added sodium azide (170 mg, 2.61 mmol) then nitrile (5c) (133 mg, 0.38 mmol). The mixture was stirred 10 min and was heated to reflux. After refluxing 5 h the mixture was diluted with 1N HCl, and was extracted with EtOAc. The combined organic layers were washed with water and dried (MgSO4). The solvent was removed under reduced pressure and the residue was chromatographed (silica gel, 10-20% methanol/CH2Cl2) to give the tetrazole (5d, compound XIX, R3=H, R6=H as a white solid (84 mg, 56%): 1H NMR (CDCl3) δ 7.49 (d, J=16.8 Hz, 1H),7.34-7.06 (m, 12H), 6.91 (d, J=8.0 Hz, 2H), 6.79 (dd, J=7.3, 1.5 Hz, 1H), 2.84 (t, J=7.0 Hz, 2H), 2.38 (t, J=7.0 Hz, 2H), 2.16 (m, 2H); ESI m/z: 389 (M−H−, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[S:9]([CH3:12])(=[O:10])=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN(c1ccc(Br)cc1)S(C)(=O)=O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)N(CC(=O)O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A suspension of tert-butyl [(4-bromophenyl)(methylsulfonyl) amino]acetate (intermediate 2, 1.00 g, 2.74 mmol) and silica gel (13.7 g) in toluene (88 mL) was heated at reflux for 4 h. The reaction was cooled to room temperature and filtered, the filter cake was washed with methanol/dichloromethane (20/80; 2×100 mL). Evaporation of the combined organic filtrates gave the title compound as a white solid (0.81 g, 95%). LC/MS: 2.81 min; z/e 325 and 327, calcd (M+18) 325 and 327. 1H NMR (400 MHz: MeOD): 7.45 (2H), 7.35 (2H), 4.45 (2H), 3.05 (3H).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[C:10]([CH3:21])=[N:11][O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[OH:8])[CH:2]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:17]3[CH:16]=[CH:15][C:14]([C:13]4[O:12][N:11]=[C:10]([CH3:21])[C:9]=4[CH:7]([C:3]4[CH:2]=[C:1]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:6]=[CH:5][CH:4]=4)[OH:8])=[CH:19][CH:18]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cccc(-c2ccccc2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cccc(-c5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using biphenyl-3-yl-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. Additionally, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0)
Reaction SMILES: CS(O[CH:6]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:7]1)(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O>[N:22]([CH:6]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:7]1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(OS(C)(=O)=O)C2
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(N=[N+]=[N-])C2

Procedure:
A solution of 5.90 g (18.47 mmol) of tert-butyl 2-methanesulfonyloxy-7-azaspiro[3.5]nonane-7-carboxylate (WO 2003/084 948) and 3.60 g (55.41 mmol) of sodium azide in 27 mL of N,N-dimethylformamide is refluxed for 12 hours under an inert atmosphere.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[S:10])[CH:5]=[CH:6][CH:7]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[N:11][C:12](=[O:14])[CH3:13])[S:10][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)NC(=S)Nc1cccc(I)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSC(=NC(C)=O)Nc1cccc(I)c1

Procedure:
19.1 g (0.05 M) of N-(3-iodophenyl)-N'-acetylthiourea, 4.2 g (0.03 M) of potassium carbonate, 3.8 ml (0.06 M) of methyliodide and 100 ml of acetone are boiled during 4 hours. The acetone is distilled off. Water is added to the residue, it is heated up to 50°-60° and is ground. The sediment is filtered. After drying 19.8 g (100% of the theoretical yield) of N-(3-iodophenyl)-N'-acetyl-S-methylisothiourea are obtained with a melting point of 80°-90° C. After being twice recrystallized from ethanol and isopropanol, 9.9 g (50% of the raw product) of N-(3-iodophenyl)-N'-acetyl-S-methylisothiourea are obtained with a melting point of 92°-93°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:26][CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCCCOc1ccc(N)cc1
Product: CCCCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-butoxycarbonyl)-4-piperidone (5.00 g) and 4-butoxyaniline (3.95 g) was treated in the same manner as described in Preparation Example 37 to give brown powder of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:17][CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].Cl>C(#N)C>[CH3:24][C:23]([O:22][C:20](=[O:21])[CH2:19][CH2:18][NH:17][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (1.0 g, 4.4 mmol, 1 equiv.) in acetonitrile (10 mL) at 0° C. was added triethylamine (0.672 mL, 4.8 mmol, 1.1 equiv.) and H-beta-Ala-OtBu HCl (0.8 g, 4.4 mmol, 1 equiv.). After removing the cooling bath the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and to the residue water (20 mL) was added. The precipitate was collected, washed with water and ether to afford N-(5-bromo-2-chloro-4-pyrimidinyl)-β-alanine 1,1-dimethylethyl ester (0.52 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH2:22]C2C=CN=CC=2)[C:9](=[O:21])[NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][N:15]=2)[CH2:4][CH2:3]1.C([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=O>>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]([CH2:22][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[C:9](=[O:21])[NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][N:15]=2)[CH2:6][CH2:7]1
Reactant: O=Cc1cccnc1
Reactant: C[C@H]1CC[C@H](N(Cc2ccncc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Product: C[C@H]1CC[C@H](N(Cc2cccnc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[3-(trans-4-Methyl-cyclohexyl)-3-pyridin-4-ylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-formyl-pyridine.