Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH:13]=O)=[C:8]([Cl:15])[CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:32]=[CH:33][C:34]=1[NH2:35])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=1)=[O:22].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[NH:17][C:18]3[CH:19]=[C:20]([C:21](=[O:22])[NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=4)[CH:32]=[CH:33][C:34]=3[N:35]=2)=[C:8]([Cl:15])[CH:7]=1
Reactant: COC(=O)COc1cc(Cl)c(C=O)c(Cl)c1
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)COc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc(C)c(C)c4)cc3[nH]2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3,5-dichloro-4-formylphenoxy)-acetic acid methyl ester (524 mg, 2.0 mmol) and 3,4-diamino-N-(3,4-dimethyl-phenyl)-benzamide (510 mg, 2.0 mmol) (Example 5-1, step 6) in DMSO (15 mL) was added Yb(OTf)3 (248 mg, 0.4 mmol) and the solution was stirred at ambient temperature overnight. The mixture was partioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried with MgSO4, filtered and concentrated. Purification by HPLC (0-80% MeCN/water) gave {3,5-dichloro-4-[6-(3,4-dimethylphenylcarbamoyl)-1H-benzoimidazol-2-yl]-phenoxy}-acetic acid methyl ester as a white solid. MS (m/z) 498.1 (M+1); 1H-NMR (Methanol-d4, 400 MHz): δ 8.36 (d, 1H), 8.09 (dd, 1H), 7.87 (dd, 1H), 7.49 (d, 1H), 7.46 (dd, 1H), 7.31 (s, 2H), 7.16 (d, 1H), 4.93 (s, 2H), 3.83 (s, 3H), 2.31 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:46])[C@@H:13]([CH3:45])[NH:14][C:15](=[O:44])[C@@H:16]([CH2:25][CH2:26][CH2:27][CH:28]([C:40]([O:42][CH3:43])=[O:41])[NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:6][CH:5]=1)([O-])=O.C(O)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C1COCC1>[C:7]1([CH2:10][O:11][C:12](=[O:46])[C@@H:13]([CH3:45])[NH:14][C:15](=[O:44])[C@@H:16]([CH2:25][CH2:26][CH2:27][CH:28]([C:40]([O:42][CH2:43][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:41])[NH:29][C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:9][CH:8]=1
Reactant: COC(=O)C(CCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccccc1
Reactant: OCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)[C@@H](CCCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
A mixture of N-[N2 -[(1,1-dimethylethoxy)carbonyl]-N6 -[(phenylmethoxy)-carbonyl]-(R)-6-[(methoxy)carbonyl]-L-lysyl]-D-alanine 4-nitrophenylmethyl ester (40a, Kolodziejczyk, et. al., Int. J. Pept. Prot. Res., 1992, 39, 382; 683 mg, 1.06 mmol), 4-- molecular sieves (2.15 g, crushed), THF (10.5 mL), and benzyl alcohol (11.0 mL, 105.6 mmol) is stirred for 30 min and then treated with titanium(IV) isopropoxide (82 μl, 0.27 meq). The resulting mixture is heated for 24 h at 85°-90° C. The solids are filtered through diatomaceous earth and the solvent removed. The excess benzyl alcohol is removed by distillation on a Kugelrohr apparatus (approx. 1000μ pressure, 50°-75° C.). The crude orange oil is chromatographed (2.5×31 cm column), gradient of 4:1-2:1 hexane/EtOAc) to provide 40b (633 mg, 88% yield): NMR δ1.39 (d, J=7.2, 3H), 1.43 (s, 9H), 1.40-1.67 (m, 4H), 1.84 (br s, 2H), 4.07 (br s, 1H), 4.40 (m, 1H), 4.58 (apparent quintet, 1H), 5.0 (br d, 1H), 5.07-5.25 (m, 6H), 5.43 (br d, J=7.9, 1H), 6.68 (br d, 1H), 7.33 (m); MS (HR-FAB) m/z 676.3232 (M+H, calcd. for C37H46N3O9, 676.3234).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[C:13]1([CH2:19]CCN)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[C:13]1([CH2:19][CH2:11][CH2:12][NH:8][C:1]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[O:2])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCCCc1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1,1′-carbonyldiimidazole (33.00 g, 0.203 mol) in THF (100 mL) at room temperature under N2, was added 3-phenylpropylamine (25.00 g, 0.185 mol) in THF (50 mL), dropwise. The reaction mixture became clear during the addition of the 3-phenylpropylamine. After completion of the addition, the clear solution was stirred for 30 min at room temperature and then quenched with water (150 mL) and ethyl acetate (200 mL). The layers were separated and the organic layer washed with water (150 mL), brine (150 mL), and dried with Na2SO4. The solvents were removed in vacuo to yield a white wax-like solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]=[C:4]([S:15][CH3:16])[N:3]=1.O.[NH2:18][NH2:19]>CO>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([NH:18][NH2:19])[N:5]=[C:4]([S:15][CH3:16])[N:3]=1
Reactant: CSc1nc(Cl)c(-c2ccccc2)c(Cl)n1
Reactant: NN
Solvent: O
Solvent: CO
Product: CSc1nc(Cl)c(-c2ccccc2)c(NN)n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a cold (ice bath) stirred solution of 25 g (0.09 mole) of 4,6-dichloro-2-methylthio-5-phenylpyrimidine in 250 ml of methanol was added slowly 10 g (0.2 mole) of hydrazine hydrate. After one hour the mixture was allowed to warm to about 20° C., and was then stirred at 20° C. for about 16 hours. The precipitate was separated by filtration to provide 4-chloro-6-hydrazino-2-methylthio-5-phenylpyrimidine. Recrystallization twice from hexanes/cyclohexane provided white crystals, m.p. 134°-135° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7]([Li])(C)([CH3:9])[CH3:8].[CH:12]([C:14]1[CH:26]=[CH:25][C:24]2[C:16](=[CH:17][C:18]3[CH2:22][CH2:21][O:20][C:19]=3[CH:23]=2)[CH:15]=1)=[O:13].[Cl-].[NH4+]>C1COCC1.CCCCC>[CH2:22]1[CH2:21][O:20][C:19]2[CH:23]=[CH:24][C:25]3[C:17]([C:18]1=2)=[CH:16][CH:15]=[C:14]([C:12]([C:2]1[N:3]=[CH:4][NH:5][CH:6]=1)([OH:13])[CH:7]([CH3:9])[CH3:8])[CH:26]=3
Reactant: O=Cc1ccc2cc3c(cc2c1)CCO3
Reactant: [Li]C(C)(C)C
Reactant: Brc1c[nH]cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccc2c3c(ccc2c1)OCC3)c1c[nH]cn1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromo-1H-imidazole (2.11 g) in THF (40 ml) was cooled to −78° C. A solution of tert-butyllithium in pentane (1.7 M; 13 ml) was added to the solution. The mixture was stirred at 5° C. for 2 h and then cooled to −78° C. 6-formyl-2,3-dihydronaphtho[2,3-b]furane (1.46 g) in THF (30 ml) was added to the mixture. The mixture was allowed to room temperature and was stirred for 20 h. Ammonium chloride solution was added to the mixture and extracted with mixed solution of THF and ethyl acetate. The organic layer was dried and concentrated. The residue was purified by silica gel chromatography to give the titled compound (1.01 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH:21][C:22]([NH:24][C:25]3[N:29]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[N:28]=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=3)=[O:23])=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1.ClC(Cl)(Cl)[C:43]([N:45]=C=O)=[O:44]>N1C=CC=CC=1>[C:37]([C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[NH:21][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([O:10][CH2:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:43](=[O:44])[NH2:45])[CH:7]=3)=[CH:12][CH:13]=2)[N:29]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)[N:28]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCc3ccnc(N)c3)c3ccccc23)cc1
Solvent: c1ccncc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCc3ccnc(NC(N)=O)c3)c3ccccc23)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-(2-(2-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (7) (Intermediate D) (50 mg, 0.094 mmol) in pyridine (1.0 mL) was added trichloroacetylisocyanate (12 μl, 0.103 mmol). The mixture was stirred at RT until judged to be complete by LC-MS and solvent was evaporated under reduced pressure. The resulting residue was subjected to SCX capture and release and triturated from DCM (10 mL) to give 4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)-3-(pyridin-2-yl)urea (Example 21) as an off white solid (25 mg, 44%): m/z 578 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (9 H, s), 2.38 (3 H, s), 3.12 (2 H, t), 4.35 (2 H, t), 6.34 (1 H, s), 6.94-6.99 (2 H, m), 7.19 (1 H, dd), 7.33-7.35 (2 H, m), 7.41-7.50 (5 H, m), 7.52-7.56 (1 H, m), 7.60 (1 H, d), 7.87 (1 H, d), 8.09-8.13 (2 H, m), 8.54 (1 H, s), 8.75 (1 H, s), 9.08 (1 H, s).
Reaction SMILES: [F:1][C:2]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[Mg]Br>>[F:1][C:2]1[C:13]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([C:20]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=1[CH3:18])=[O:5]
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Reactant: COc1ccc([Mg]Br)c(C)c1
Product: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)c(C)c1

Procedure:
Prepared according to Method A step B from 2- fluoro-3-trifluoromethyl-N-methoxy-N-methylbenzamide (4.05 g, 16.1 mmol) and 2-methyl-4-methoxyphenylmagnesium bromide (42 mL, 0.5 M in THF) to give 1.76 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].C[Si](Cl)(C)C.O>ClCCl>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Reactant: CCNCC
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)N(CC)CC)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
6.5 g of 4-(3-dibutylaminopropoxyl)benzoyl chloride (V) (0.02 mol) is dissolved in 60 mL of dichloromethane. 1.46 g of diethylamine (0.02 mol, 1 eq) is added and the reaction mixture is cooled to 0° C. 0.43 g TMSCl (0.004 mol, 0.2 eq) is added in 5 min. The reaction mixture is heated to room temperature and stirred for 5 hours. 50 mL of water is added to the mixture, it is stirred for 15 min and the phases are separated. The organic phase is washed with 30 mL of water then it is concentrated. The residue is purified by column chromatography (spheric silica; eluent: toluene:MTBE:methanol=5:4:1) to give 5.58 g of the title compound (VId) (77%) as a yellowish solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46](O)[CH2:45]2>C1COCC1>[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46]([O:10][C:9](=[O:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)([NH2:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:45]2
Reactant: Cc1ccc(C(N)(C(=O)O)c2ccccc2)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1ccc(C(N)(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-methyl-phenyl-amino-phenyl-acetic acid (I244) (870 mg, 3.60 mmol) in dry THF (35 mL), are added DCC (891 mg, 4.32 mmol), HOBt (583 mg, 4.32 mmol) and 3(R)-quinuclidinol (915 mg, 7.20 mmol). The resulting mixture is stirred at RT for 48 hours (UPLC-MS monitoring: complete conversion). The solvent is evaporated and the residue is portioned between EtOAc and 1M K2CO3. The organic phase is dried over Na2SO4, filtered and evaporated to dryness. The resulting crude is dissolved in little DCM and filtered to remove the insoluble. The solution is concentrated under vacuum to obtain the title compound as a yellow solid, which is used in the next step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][NH:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5].[C:16]([NH:20]N)([CH3:19])(C)C.[C:22]12[C:28](=CC=CC=1)[NH:27]C(=O)OC2=O>>[C:8]([NH:7][NH:6][C:4](=[O:5])[C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[NH:1][CH2:19][C:16]1[NH:20][CH2:22][CH2:28][N:27]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(C)(C)NNC(=O)c1ccccc1N
Reactant: CC(C)(C)NN
Product: CC(C)(C)NNC(=O)c1ccccc1NCC1=NCCN1

Procedure:
2-Amino-N′-(tert-butyl)benzohydrazide (prepared from tert-butylhydrazine and isatoic anhydride using the method described in Example 44) and CMI were reacted using conditions described in the general procedure for CMI coupling to give N′-(tert-butyl)-2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]benzohydrazide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C(Cl)(Cl)Cl>[C:17]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])(=[O:20])[CH:18]=[CH2:19]
Reactant: C=CC(=O)Cl
Reactant: O=C1CCCN1CCO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCN1CCCC1=O
Reaction time: 2 h
Yield: 70 %

Procedure:
Into a solution of 50 mL of 1-(2-hydroxyethyl)-2-pyrrolidone and 85 mL of triethylamine in 150 mL of chloroform, a solution of 50 mL of acryloyl chloride in 100 mL of chloroform was dropped over 2 hours with stirring. The reaction mixture was stirred at 4° C. for 20 hours, then at 50° C. for 2 hours. After being cooled, the solution was filtered and the filtrate was washed with a 15% aqueous sodium carbonate solution and then concentrated under vacuum. The obtained oily material was distilled under vacuum to give the title compound in a yield of 70%.
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13](=[O:24])[CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH:27]=[CH:26]1>C1(C)C=CC=CC=1>[CH3:1][CH:2]([NH:12][C:13](=[O:24])[CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:25](=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29])[CH:18]=1)[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc(N)c1
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc(NC(=O)/C=C\C(=O)O)c1
Reaction time: 0.05 h

Procedure:
A stirred solution of 1.0 g. of the N-(1-methyldecyl)-3-(3-aminophenyl)-2-butenamide from Preparation 28 in 25 ml. of toluene was heated on a steam bath, and then 0.32 g. of maleic anhydride was added in one portion. After 3 minutes, the reaction mixture was cooled and the solvent was removed by evaporation in vacuo. The residue was triturated under a mixture of petroleum ether and acetonitrile, and the resulting solid was recrystallized from acetonitrile. This afforded 0.68 g. of the title compound as a light yellow solid, m.p. 126°-128° C. The IR spectrum (KBr disc) showed absorptions at 3333, 2941, 1724, 1639, 1587 and 1563 cm-1. The NMR spectrum (DMSO-d6) showed absorptions at 0.81 (s, 3H), 0.91 (s, 3H), 1.17 (s, 16H), 2.02 (m, 3H), 3.58 (m, 1H), 5.90 (d, 1H), 6.38 (m, 2H), 7.26 (m, 6H) and 10.40 (s, 1H) ppm.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[C:2]1([C:1]2[S:32][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)NNC(=O)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nnc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of ethyl 2-(2-benzoylhydrazinyl)-2-oxoacetate (1 g, 4.23 mmol) in dry THF (5 ml, 61.0 mmol) was added the Lawesson's Reagent (1.079 g, 2.67 mmol). The reaction was stirred at r.t. for 2 h without any reaction. The mixture was then heated to 50° C. and then heated to reflux. Additional Lawesson's Reagent (1.079 g, 2.67 mmol) was added and after 16 h at reflux, the reaction was halfway completed. The mixture was evaporated to dryness and the residue was purified by silica gel column chromatography (50% CH2Cl2/hexanes up to 100% CH2Cl2) to provide the title material (0.35 g, 35%). LC (Method B): 2.063 min, LCMS (APCI) calcd for C11H11N2O2S [M+H]+ m/z 235.05. found 235.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 1.49 (t, J=1.00 Hz, 3H), 4.55 (q, J=1.00 Hz, 2H), 7.45-7.65 (m, 3H), 8.02-8.07 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:5](F)=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[OH:21][CH:22]([CH2:32][OH:33])[CH2:23][NH:24][C:25]([CH3:31])=[CH:26][C:27]([O:29][CH3:30])=[O:28]>C(O)(C)C>[OH:21][CH:22]([CH2:32][OH:33])[CH2:23][NH:24][C:25]([CH3:31])=[C:26]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][N:6]=1)[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)C=C(C)NCC(O)CO
Reactant: O=[N+]([O-])c1cnc(F)c([N+](=O)[O-])c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COC(=O)C(=C(C)NCC(O)CO)c1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.5 g (0.0026 m) 3,5-dinitro-2-fluoropyridine (1) and 0.3 g (0.0026 m) triethylamine in 10 ml isopropanol is added 0.48 g (0.0025 m) methyl 3-(2,3-dihydroxypropyl)amino-2-butenoate (2). This solution is stirred at room temperature for two days, concentrated to an oil in vacuo and the residue is chromatographed on silica gel with 8% methanol/chloroform. The material with Rf =0.5 is collected. This reddish brown material is recrystallized from acetonitrile/n-butylchloride, m.p. 128°-9°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:45]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH2:44].[C:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][CH:56]([CH2:59][C:60](O)=[O:61])[CH2:55][CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:45]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:60](=[O:61])[CH2:59][CH:56]1[CH2:57][CH2:58][N:53]([C:51]([O:50][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:52])[CH2:54][CH2:55]1
Reactant: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 59 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate) and [1-(tert-butoxycarbonyl)piperidin-4-yl]acetic acid as the starting materials in 59% yield. LCMS for C29H35ClN7O3 (M+H)+: m/z=564.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:30]2[NH:34][C:33](=[O:35])[O:32][N:31]=2)[CH:5]=[CH:6][C:7]=1[S:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[F:36][C:37]([F:48])([F:47])[C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>>[F:36][C:37]([F:48])([F:47])[C:38]1[CH:43]=[CH:42][C:41]([C:2]2[C:7]([S:8]([N:11]3[C:19]4[C:14](=[CH:15][C:16]([C:20]5[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=5)=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4]([C:30]3[NH:34][C:33](=[O:35])[O:32][N:31]=3)[CH:3]=2)=[CH:40][CH:39]=1
Reactant: O=c1[nH]c(-c2ccc(S(=O)(=O)N3CCc4cc(-c5ccc(C(F)(F)F)cc5)ccc43)c(Cl)c2)no1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=c1[nH]c(-c2ccc(S(=O)(=O)N3CCc4cc(-c5ccc(C(F)(F)F)cc5)ccc43)c(-c3ccc(C(F)(F)F)cc3)c2)no1

Procedure:
3-{4′-Trifluoromethyl-6-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-biphenyl-3-yl}-4H-[1,2,4]oxadiazol-5-one was synthesized from 3-{3-Chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one (Example 6) by Suzuki-type reaction with 4-trifluoromethyl-phenyl boronic acid under conditions described in Example 11.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1Cl)=[CH:11][CH:10]=[CH:9][C:8]=2[O:15][CH3:16])(=[O:3])[CH3:2].[NH2:17][C:18]1[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>O1CCOCC1>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[CH:11][CH:10]=[CH:9][C:8]=2[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: COc1cccc2c(Cl)c(C(C)=O)cnc12
Reactant: Cc1ccccc1N
Solvent: C1COCCO1
Product: COc1cccc2c(Nc3ccccc3C)c(C(C)=O)cnc12
Reaction time: 2 h
Yield: 45.5 %

Procedure:
A mixture of crude 3-acetyl-4-chloro-8-methoxyquinoline (7.9 g) and o-toluidine (2 ml, 19 mmol) in dioxan (150 ml) was heated under reflux with stirring for 2 hours, then cooled and evaporated. Aqueous sodium bicarbonate was added, the mixture extracted with chloroform, and the organic extract dried and evaporated. Recrystallisation from ethyl acetate and then from ethanol gave 3-acetyl-4-(2-methylphenylamino)-8-methoxyquinoline (2.65 g, 44% from 3-acetyl-8-methoxy-4(1H)-quinolone), m.p. 171°-173°.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[C:19]([Cl:26])[CH:18]=1>ClCCl.CCCCCC>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:15][NH:14][C:12](=[O:13])[CH2:11][C@@H:8]2[CH2:9][CH2:10][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:7]2)=[O:25])=[C:19]([Cl:26])[CH:18]=1
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Reactant: O=C=Nc1ccc(Br)cc1Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1Cl
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (700 mg, 3.31 mmol) in dry dichloromethane (15 mL) was added 4-bromo-2-chloro-1-isocyanatobenzene (770 mg, 3.31 mmol). The reaction was stirred overnight, diluted with hexane (15 mL), and the precipitate collected and washed with hexane to provide the title compound (1.3 g, 2.93 mmol, 88% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.85 (br. s, 1H), 8.82 (br. s, 1H), 8.50-8.23 (m, 1H), 8.05 (dd, J=5.3, 8.8 Hz, 1H), 7.72 (d, J=1.8 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 3.81 (dd, J=7.6, 9.9 Hz, 0.5H), 3.77-3.39 (m, 2H), 3.31-3.13 (m, 1H), 2.94 (d, J=19.5 Hz, 0.5H), 2.64-2.54 (m, 0.5H), 2.47-2.39 (m, 0.5H), 2.28 (dd, J=7.3, 16.7 Hz, 2H), 2.17-1.88 (m, 1H), 1.80-1.47 (m, 2H), 0.81-0.61 (m, 4H).