Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([C:32]3([C:37]#[N:38])[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:31]=2)[C:26](O)=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:39][C:40]1[CH:45]=[CH:44][C:43]([C@H:46]([NH2:48])[CH3:47])=[CH:42][CH:41]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([C:32]3([C:37]#[N:38])[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:31]=2)[C:26]([NH:48][C@@H:46]([C:43]2[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=2)[CH3:47])=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@](C)(Cc1ccccc1)c1nnc(-c2cc(C(=O)O)cc(C3(C#N)CCCC3)c2)o1
Reactant: C[C@@H](N)c1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)cc(C2(C#N)CCCC2)c1)c1ccc(F)cc1

Procedure:
A solution of 3-(5-((2R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-cyanocyclopentyl)benzoic acid (20 mg, 0.039 mmol), (R)-1-(4-fluorophenyl)ethanamine (0.017 mL, 0.13 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (24 mg, 0.05 mmol) and diisopropylethylamine (0.024 mL, 0.14 mmol) in 0.4 mL DMF was stirred at rt overnight. Purification by reverse phase preparative HPLC (5-95% MeCN/H2O containing 0.1% TFA, C18 PRO YMC 20×150 mm) gave 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-cyanocyclopentyl)-N—((R)-1-(4-fluorophenyl)ethyl)benzamide. 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.16 (m, 1H), 8.10 (d, J=1.5 Hz, 1H), 7.39 (m, 2H), 7.28 (m, 3H), 7.06 (m, 4H), 6.56 (d, J=7.5 Hz, 1H), 5.33 (m, 1H), 5.07 (bs, 1H), 3.59 (d, J=13.6 Hz, 1H), 3.40 (d, J=13.6 Hz, 1H), 2.55 (m, 2H), 2.16-1.98 (m, 6H), 1.72 (s, 3H), 1.64 (d, J=7.0 Hz, 3H), 1.41 (s, 9H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:40][C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)[N:23]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:40]([C:41]3[CH:42]=[CH:43][C:44]([CH3:47])=[CH:45][CH:46]=3)=[O:9])[N:23]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3ccc(C)cc3)n(Cc3ccccc3)c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(C)cc3)n(Cc3ccccc3)c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A solution of 1.08 g of 3-chloroperbenzoic acid (80%) in 100 ml of dichloromethane is added dropwise to a solution of 2.46 g of 4,5-bis(4-methoxyphenyl)-1-benzyl-2-(4-methylphenylthio)imidazole in 50 ml of dichloromethane. The mixture is stirred for 3 hours at room temperature, the solution is washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with ethyl acetate/hexane 2:3, thus producing 2.17 g of 4,5-bis-(4-methoxyphenyl)-1-benzyl-2-(4-methylphenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10]CC=C)=[CH:6][CH:5]=1.C(N(CC)[C:18]1[CH:23]=CC=C[CH:19]=1)C>C(OCC)C>[CH2:23]([C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=1[OH:10])[C:3]([O:2][CH3:1])=[O:14])[CH:18]=[CH2:19]
Reactant: C=CCOc1ccc(C(=O)OC)cc1
Reactant: CCN(CC)c1ccccc1
Solvent: CCOCC
Product: C=CCc1cc(C(=O)OC)ccc1O
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of methyl-4-allyloxy-benzoate (4.74 g, 24.7 mmol) in N,N-diethylaniline (10 mL) was heated at reflux for 48 hours and cooled to room temperature. The mixture was diluted with diethyl ether (50 mL), washed with aqueous HCl (10% v/v, 3×20 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (10:1→5:1, hexanes:EtOAc) to afford 5 (3.55 g, 75%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.86-7.84 (m, 2H), 6.85 (dd, J=2.8, 7.7 Hz, 1H), 6.07-5.95 (m, 1H), 5.68 (s, 1H), 5.21-5.15 (m, 2H), 3.88 (s, 3H), 3.45 (d, J=6.3 Hz, 2H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[OH:17])[CH:5]=[N:4][CH:3]=[N:2]1.F[C:19]1[CH:20]=[CH:21][C:22]([N+:27]([O-:29])=[O:28])=[C:23]([CH:26]=1)[NH:24][CH3:25].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:25][NH:24][C:23]1[CH:26]=[C:19]([O:17][C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:20]=[CH:21][C:22]=1[N+:27]([O-:29])=[O:28]
Reactant: Oc1ccc(C(F)(F)F)cc1Cn1cncn1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cc(Oc2ccc(C(F)(F)F)cc2Cn2cncn2)ccc1[N+](=O)[O-]
Yield: 59.4 %

Procedure:
The solution of 2-(1H-1,2,4-triazol-1-ylmethyl)-4-(trifluoromethyl)phenol (1.0 g) from Example 62, 5-fluoro-N-methyl-2-nitroaniline (700 mg) and K2CO3 (0.57 g) in DMF (10 ml) was heated at 100° C. for 90 minutes. After the solution was left to stand at room temperature, water was added to the solution, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by chromatography on a silica gel column (methylene chloride:methanol=99:1), to give the title compound (960 mg; 59%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19](O)[C:14]=3[O:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:19]1[C:14]2[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(-c2noc3c(O)ncnc23)cc1
Product: CS(=O)(=O)c1ccc(-c2noc3c(Cl)ncnc23)cc1
Yield: 80.1 %

Procedure:
3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-ol (0.5 g, 1.7 mmol) was suspended in POCl3 (10 mL) and refluxed for 12 h. The reaction was poured into ice carefully and precipitates filtered. The solid was dissolved in ethyl acetate (15 mL) and purified under SiO2 with 30% ethyl acetate in hexane to afford the desired compound (0.42 g, 80.1%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@H:10]3[CH2:12][C@H:11]3NC)[C:4]=2[CH2:3][CH2:2]1.[CH2:15]([N:17](CC)CC)C.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@H:10]3[CH2:12][C@H:11]3[CH2:15][NH:17][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C:4]=2[CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: CN[C@@H]1C[C@@H]1c1cccc2c1CCO2
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)NC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Yield: 37.1 %

Procedure:
The title compound was prepared by the general procedure described in Example 1 using (cis)-2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1-yl methyl amine (0.79 mmol), triethylamine (2.37 mmol) and isobutyryl chloride (0.95 mmol). Purification by recrystallization from EtOAc/Hexanes provided 76 mg of the desired product (37%) as colorless plates. HPLC purity>98%. m.p. 125-126°;
Reaction SMILES: C([Si](C)(C)[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[CH:14]=[C:9]2[C:8]([Sn](CCCC)(CCCC)CCCC)=[CH:7]1)(C)(C)C.Br[C:40]1[C:44]([CH3:45])=[CH:43][S:42][CH:41]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.CCOC(C)=O.CC#N.CC#N.Cl[Pd]Cl>[CH3:23][N:21]([CH3:22])[C:18]1[CH:17]=[CH:16][C:15]([C:13]2[CH:14]=[C:9]3[C:8]([C:40]4[C:44]([CH3:45])=[CH:43][S:42][CH:41]=4)=[CH:7][NH:6][C:10]3=[N:11][CH:12]=2)=[CH:20][CH:19]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn([Si](C)(C)C(C)(C)C)c2ncc(-c3ccc(N(C)C)cc3)cc12
Reactant: Cc1cscc1Br
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cscc1-c1c[nH]c2ncc(-c3ccc(N(C)C)cc3)cc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
A mixture of 7 (129.7 mg, 0.186 mmol), 3-bromo-4-methylthiophene (30 μL, 0.30 mmol), PdCl2(MeCN)2 (4.8 mg, 18.6 μmol), tri-o-tolylphosphine (11.4 mg, 37.5 μmol) in toluene (1.7 mL) was stirred under N2 at 85° C. overnight. The reaction mixture was cooled to r.t., diluted with AcOEt (3 mL), and extracted with 10% aqueous HCl ((4×0.5 mL). combined aqueous solutions were washed with CH2Cl2 (2 mL), and basified with 10% aqueous NaOH (2.5 mL). The mixture was extracted with CH2Cl2:MeOH=19:1 (4×3 mL). Combined extracts were washed with brine, dried (MgSO4), and concentrated in vacuum. The residue was purified by preparative TLC using CH2Cl2:MeOH=19:1 as eluent to afford 8 (12.9 mg, 21%) as tan solid. 1H NMR (400 MHz, CDCl3) δ 2.34 (d, J=1.0 Hz, 3H), 3.01 (s, 6H), 6.85 (d, J=8.9 Hz, 2H), 7.10 (dq, J=3.3, 1.0 Hz, 1H), 7.36 (d, J=3.3 Hz, 1H), 7.41 (d, J=1.2 Hz, 1H), 7.53 (d, J=8.9 Hz, 2H), 8.14 (d, J=2.1 Hz, 1H), 8.59 (d, J=2.1 Hz, 1H), 10.00 (bs, 1H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[CH3:63][C:64]([O:67][C:68]([NH:70][C@H:71]([C:77](OC1C=CC([N+]([O-])=O)=CC=1)=[O:78])[CH2:72][CH2:73][C:74]([NH2:76])=[O:75])=[O:69])([CH3:66])[CH3:65].C(Cl)(Cl)Cl.CO>O1CCCC1>[NH:70]([C:68]([O:67][C:64]([CH3:66])([CH3:65])[CH3:63])=[O:69])[C@H:71]([C:77]([NH:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12])=[O:78])[CH2:72][CH2:73][C:74](=[O:75])[NH2:76]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 80 %

Procedure:
At 0° C. the solution of 467 mg (0.51 mmol) of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12) in 20 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which he pre-cold solution of 195 mg, (0.53 mmol) of Boc-Gln-Onp in 10 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at room temperature for 96 h and TLC (chloroform/methanol, 9:1) indicated complete disappearance of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12). The reaction mixture was evaporated to dryness and the residue was purified on sinica gel chromatography (CHCl3/CH3OH, 10:1) to provide 450 mg (80%) of the title compound as a glassy mass. Mp 80–82° C., FAB-MS (m/e) 1111.3[M+H]+, 1132.5[M+Na]+,1010.0[M-Boc]+.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].BrC[CH2:7][CH2:8][CH2:9][C:10]1C=[CH:19][CH:18]=[C:12]2[C:13]([NH:15][C:16](=[O:17])[C:11]=12)=O.C([O-])([O-])=O.[K+].[K+].C[C:28]([CH3:30])=[O:29]>>[CH3:2][N:3]([CH3:4])[CH2:19][CH2:18][CH2:12][CH2:13][N:15]1[C:16](=[O:17])[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:30]2[C:28]1=[O:29]
Reactant: O=C1NC(=O)c2c(CCCCBr)cccc21
Reactant: CC(C)=O
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)CCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
Dimethylamine hydrochloride (1.2 g; 12.5 mmol) and, 1 hr later, 4-bromobutylphtalimide (3.5 g; 12.4 mmol) are added to a suspension of K2CO3 (4.3 g; 31 mmol), in acetone (5 mL) at 25° C.; the suspension is then refluxed overnight. After cooling at r.t., the mixture is filtered and evaporated to dryness; silica gel flash chromatography of the residue oil (eluent CHCl3/CH3OH 8:2) yields N-(4-dimethylamino-butyl)-phtalimide as a white solid (2.2 g; 8.94 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C:30](=O)[CH:31]([CH3:33])[CH3:32])[CH:7]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:5])[CH3:2].O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=2)=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:9][C:30]=1[CH:31]([CH3:32])[CH3:33])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C(=O)C(C)C)C(C(=O)c1ccccc1)c1ccc(F)c(Oc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(C(C)C)oc(-c2ccccc2)c1-c1ccc(F)c(Oc2ccccc2)c1

Procedure:
185 g (0.4 mmol) of the compound from Example 22 are boiled in a water separator for 2.5 hours with 15.2 g (0.05 mol) of p-toluenesulphonic acid hydrate in 2 l of toluene. 7 ml of water separates from the mixture. After cooling, the mixture is washed twice with saturated bicarbonate solution and once with sodium chloride solution, dried over sodium sulphate and concentrated to dryness. The residue is recrystallized from ethanol.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH:7]([CH:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]#[N:9].C(N(CC)CC)C.[CH3:25][OH:26].[OH2:27]>>[C:8]([CH:7]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:17][C:25](=[O:26])[NH:6]1)(=[O:27])[NH2:9]
Reactant: O
Reactant: CO
Reactant: N#CC(N)C(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Product: NC(=O)C1NC(=O)OC1c1ccccc1

Procedure:
To a solution of α-amino-β-hydroxy-β-phenylpropane nitrile bisulphate salt (6 g, 23 mmoles) in 50 ml MeOH/H2O (m:m/1:1) triethylamine (TEAM) (9.6 g, 69.2 mmoles) was added. Subsequently, for 6 hours CO2 was bubbled through the solution at 40° C. During the reaction the pH of the solution fell from 9.7 to 7.8. A white solid substance crystallized out of the solution. This substance was filtered off and dried in a vacuum. The yield was 4.7 g (22.8 moles, 99 wt. % ), obtained in the form of white crystals having a melting point: 249-250° C.; 1H NMR (200 MHz, DMSO) d (ppm): 3.30 (0.5H, s, H2O), 4.42 (1H, δ, J=8.37 Hz, NCHCO), 5.79 (1H, d, J=8.37 Hz, OCHPh), 6.85 (1H, s, NH), 7.20 (1H, s, NH), 7.30 (5H, m, Ph), 8.00 (1H, s, NH); 13C NMR (200 MHz, DMSO) δ (ppm): 59.41 (NCHCO), 78.75 (OCHHPh), 126.82 (Ph), 127.94 (Ph), 128.41 (Ph), 135.44 (Ph), 15.02 (NC=OO), 169.77 (C=ONH2); IR (KBr,cm-1): 3396 (NH2), 3273 (NH2), 3200, 1740 (C=O), 1719, 1684 (C=O), 1611 Mass (El): 206 M, 189, 163, 105, 77, 44. The experiment was repeated under different conditions. The results are shown in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][C:10](OCC(C)C)=O)=[CH:4][C:3]=1[NH:17][C:18](=[O:21])[O:19][CH3:20].[C:22]1([CH3:38])[CH:27]=CC(S(OC2CCC(C)C2)(=O)=O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:24][CH2:23][CH:22]([CH3:38])[CH2:27]2)=[CH:4][C:3]=1[NH:17][C:18](=[O:21])[O:19][CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(C)C2)cc1
Reactant: COC(=O)Nc1cc(OC(=O)OCC(C)C)c(Cl)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)Nc1cc(OC2CCC(C)C2)c(Cl)cc1F
Reaction time: 5 h
Yield: 75 %

Procedure:
A solution of methyl N-(2-fluoro-4-chloro-5-isobutyloxycarbonyloxyphenyl)carbamate (5.37 g, 16.8 mmol) prepared by the process as shown in Reference Example 3, 3-methylcyclopentyl p-toluenesulfonate (5.0 g, 20.2 mmol) and potassium carbonate (2.32 g, 16.8 mmol) in methanol (50 ml) was stirred for 5 hours under refluxing. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (100 ml), and the mixture was extracted with ethyl acetate (50 ml×3 times). The organic layer was dried, and the solvent was distilled off under reduced pressure to obtain methyl N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}carbamate as grey white crystals (3.81 g, 12.6 mmol, 75.2% yield).
Reaction SMILES: [B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[CH:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:37][CH:36]=3)[C:31]2=[O:48])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[CH3:58][N:59]([CH3:64])[CH2:60][C:61](O)=[O:62]>CN(C=O)C.O>[CH3:58][N:59]([CH3:64])[CH2:60][C:61]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH:34]=[CH:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:37][CH:36]=3)[C:31]2=[O:48])=[CH:28][CH:29]=1)=[O:62]
Reactant: Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Reactant: CN(C)CC(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Reaction time: 0.17 h

Procedure:
TOTU (327 mg) was added to a solution of 1-(4-aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (343 mg) in DMF (3 ml) at 0° C. After 10 minutes, Hünig base (130 mg) and then a solution of dimethylglycine (103 mg) in DMF (1 ml) was added. After a reaction time of 12 hours at room temperature, the mixture was mixed with water and extracted with ethyl acetate. The organic phase was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 428.50 (C25H24N4O3); MS (ESI): 429 ([M+H]+) was obtained as hydrotrifluoroacetate in this way.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7]I)[N:6]=1.[C-:9]#[N:10].[Na+]>CS(C)=O.C(OCC)C.O>[Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:9]#[N:10])[N:6]=1
Reactant: Brc1nc(CI)cs1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1csc(Br)n1
Reaction time: 0.67 h
Yield: 85.1 %

Procedure:
A solution of 2-bromo-4-(iodomethyl)thiazole (2.11 g, 6.942 mmol) in DMSO (15 mL) under nitrogen was treated with sodium cyanide (345.0 mg, 7.039 mmol) and allowed to stir for 40 minutes. The reaction was diluted with diethyl ether/water and the layers separated, the aqueous was extracted further with ether (2×) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated. The resultant residue was purified by column chromatography (3:1 Petroleum ether/EtOAc) to afford the product as a white solid (1.20 g, 86% Yield). 1H NMR (CDCl3, 400 MHz) δ 3.91 (2H, s), 7.31 (1H, s); MS (ES+) 204.95
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16].C[Sn](C)(C)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(OCC)(=O)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]=O>[CH3:14][O:13][C:12]1[N:8]([CH2:7][C:6]2[CH:17]=[C:2]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:3]=[CH:4][C:5]=2[CH3:18])[C:9](=[O:16])[N:10]([CH3:15])[N:11]=1
Reactant: COc1nn(C)c(=O)n1Cc1cc(Br)ccc1C
Reactant: C[Sn](C)(C)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nn(C)c(=O)n1Cc1cc(-c2ccccn2)ccc1C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
To a solution of 0.44 g (1.4 mmol) of 4-(5-bromo-2-methylbenzyl)-5-methoxy-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 299 of the present invention) in 8 ml of N,N-dimethylformamide were added 30 mg (0.042 mmol) of PdCl2(PPh3)2 and 0.12 g (1.4 mmol) of copper (II) oxide powder and the mixture was stirred at 80° C. under an atmosphere of nitrogen for 30 minutes. To the reaction mixture was added a solution of 0.48 g (2.0 mmol) of trimethyl(2-pyridyl)tin in 4 ml of N,N-dimethylformamide and the mixture was stirred at 80° C. under an atmosphere of nitrogen for 3 hours. After cooling to room temperature, the reaction mixture was poured into ice water, and ethyl acetate was added thereto. The mixture was filtered with cotton and separated, and the organic layer was washed twice with water, dried and concentrated. The residue (0.43 g) was subjected to silica gel preparative thin layer chromatography (developed with ethyl acetate) to obtain 0.18 g of 5-methoxy-2-methyl-4-{2-methyl-5-(2-pyridyl)benzyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 152 of the present invention) as a viscous oil.
Reaction SMILES: [Br-:1].[Mg+2].[Br-].S(O[CH2:9][CH2:10][CH:11]([CH2:13][CH2:14][CH2:15][CH:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:22])[CH3:17])[CH3:12])(=O)(=O)C.O>CCOCC>[CH2:9]([Br:1])[CH2:10][CH:11]([CH2:13][CH2:14][CH2:15][CH:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:22])[CH3:17])[CH3:12]
Reactant: [Br-]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOS(C)(=O)=O
Agent: [Mg+2]
Solvent: O
Solvent: CCOCC
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCBr
Reaction time: 8 h

Procedure:
Magnesium bromide etherate (17 g, 55 mmol) and a stir bar were added to a 500 mL round bottom flask. The flask was sealed and flushed with nitrogen and anhydrous diethyl ether (200 mL) added via cannula. A solution of phytanyl mesylate (10.9 g, 28.9 mmol (FW=377)) in anhydrous ether (50 mL) was also added via canulla, and the suspension stirred overnight. The following morning a precipitate had formed on the side of the flask. Chilled water (200 mL) was added (ppte dissolved) and the mixture transferred to a 1000-mL separating funnel. After shaking, the organic phase was separated. The aqueous phase was then extracted with ether (2×150 mL) and all ether phases combined. The ether phase was washed with water (2×150 mL), brine (150 mL) and dried over anhydrous Mg2SO4. The solution was filtered, concentrated, and purified by flash chromatography. Final yield 9.5 g (26.3 mmol, 91.1%).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](=[O:37])[C:34](O)=[O:35].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:34](=[O:35])[C:33]([C:29]1[S:28][CH:32]=[CH:31][CH:30]=1)=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: O=C(O)C(=O)c1cccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N2CCN(C(=O)C(=O)c3cccs3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (74 mg, 0.20 mmol) in CH2Cl2 (1 mL) at 0-5° C. was treated with a catalytic amount of 4-dimethylaminopyridine (DMAP) and 2-thiophene glyoxylic acid (37 mg, 0.24 mmol) followed by DCC (50 mg, 0.24 mmol). The reaction mixture was allowed to warm to room temperature and stir for 3 h. After this time the reaction mixture was evaporated and the residue purified by silica gel flash chromatography with 25% then 35% EtOAc/hexanes as eluant to afford the title compound as yellow foam (93 mg, 93%). LC/MS (Method B) 4.27 min, [M+1]+ 505.