Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:30][O:31][CH2:32][CH2:33][O:34]C=O)[C:10]([NH:12][CH:13]2[C:28](=[O:29])[N:15]3[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:37].O1CCCC1>CO>[ClH:37].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:30][O:31][CH2:32][CH2:33][OH:34])[C:10]([NH:12][CH:13]2[C:28](=[O:29])[N:15]3[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCOC=O)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCO)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.1 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), conc. hydrochloric acid (0.6 g.), tetrahydrofuran (7.5 ml.) and methanol (15.0 ml.) was stirred at room temperature for 6 hours. After concentrating the resultant solution in vacuo, the residue was pulverized with a mixture of methanol and diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-(2-aminothiazol-4-yl)-2-(2-hydroxyethoxyimino)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 1.36 g.).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([CH:24]=[O:25])=[C:7]([CH:21]=[CH:22][CH:23]=1)[O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[C:1]([NH:4][C:5]1[C:6]([CH:24]=[O:25])=[C:7]([CH:21]=[CH:22][CH:23]=1)[O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(COc2cccc(NC(C)=O)c2C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1cccc(OCc2ccc(C(=O)O)cc2)c1C=O

Procedure:
Ethyl 4-(3-acetylamino-2-formylphenoxymethyl)benzoate (0.45 g, 0.00132 N) was suspended in 95% ethanol (10 ml) with stirring and treated with 1N sodium hydroxide solution (1.32 ml) over 1 hour. The mixture was then diluted with water (3 ml) and stirred at room temperature overnight. A further 15 ml of water was added and the mixture stirred at room temperature (4 hr). The mixture was then extracted with ethyl acetate and the aqueous phase acidified with concentrated hydrochloric acid with cooling. The precipitated solid was filtered off, washed well with water, and recrystallised from ethanol to give 4-(3-acetylamino-2-formylphenoxymethyl)benzoic acid, m.p. 242°-244° C. (dec.) (Found: C, 65.27; H, 4.93; M, 4.23%. C17H15NO5 requires C, 65.17; H, 4.83; N, 4.47%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[N+:14]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:14][C:17]3[CH:23]=[CH:22][CH:21]=[C:19]([NH2:20])[CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(Nc2ncnc3cc(N)ncc23)c1
Temperature: 200 °C
Reaction time: 1.5 h
Yield: 16.4 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (307 mg, 1.60 mmol) (described in a previous experimental) and 3-nitroaniline (2.00 g, 14.5 mmol) is stirred at 200° C. for 1.5 h, and the crude product is suspended in MeOH/THF (4:1, 250 mL) and hydrogenated over 5% Pd/C (2 g) at 60 psi and 20° C. for 24 h. The solution is filtered over celite, washing thoroughly (hot MeOH), and is then absorbed onto alumina and chromatographed on alumina (4-8% EtOH/CHCl3) to give 7-amino-4-(3-aminoanilino)pyrido[4,3-d]pyrimidine (66 mg, 16%) as a green solid,. 1H NMR (DMSO) δ 9.57 (1H, brs), 9.30 (1H, s), 8.33 (1H, s), 7.04 (1H, t, J=2.0 Hz), 6.99 (1H, t, J=8.0 Hz), 6.88 (1H, brd, J=8.0 Hz), 6.55 (2H, brs), 6.40 (1H, s), 6.34 (1H, dd, J=7.9, 1.3 Hz), 5.10 (2H, brs).
Reaction SMILES: [C:1]([C:4]([C@@:6]([C:21](=[O:23])[CH3:22])([C@:8]([C:18](=[O:20])[CH3:19])([C@:10]([C:15](=[O:17])[CH3:16])([C@@H:12]([CH3:14])[OH:13])[OH:11])[OH:9])[OH:7])=[O:5])(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.B(F)(F)F.CCOCC>ClCCl>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C@:15]2([CH3:16])[O:17][C@:4]([C:1](=[O:3])[CH3:2])([OH:5])[C@:6]([C:21](=[O:23])[CH3:22])([OH:7])[C@@:8]([C:18](=[O:20])[CH3:19])([OH:9])[C@@:10]2([C:12](=[O:13])[CH3:14])[OH:11])=[CH:28][CH:27]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(=O)C(=O)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@](O)(C(C)=O)[C@@H](C)O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc([C@]2(C)O[C@@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@]2(O)C(C)=O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
D-Fucose (3) (4.95 g, 30.14 mmol) was dissolved in 30 mL of acetic anhydride and 30 mL of pyridine and stirred for 12 h. The solvent was removed in vacuo. Column chromatography (2:1 hexane/EtOAc) yielded 10.15 g (quant.) of 1,2,3,4-tetraacetyl-D-fucose (as a mixture of α-and β-anomer). 1,2,3,4-tetraacetyl-D-fucose (20.0 g, 60.2 mmol) and p-methoxyphenol (MPOH) (10.46 g, 84.3 mmol) were dissolved in 220 mL of dichloromethane and cooled to 0° C. BF3.OEt2 (21.4 g, 19.0 mL, 150.5 mmol) was added and the mixture stirred overnight. The reaction mixture was quenched by addition of saturated NaHCO3 solution, washed 2 times with water, dried over Na2SO4, concentrated and the residue was purified by column chromatography (3:1 hexane/EtOAc) yielding 16.8 g (71%) of 4-methoxyphenyl 1,2,3,4tetraacetyl-α-D-fucose (Only the β-anomer reacts, α-anomer could be recovered). 4-methoxyphenyl 1,2,3,4-tetraacetyl-α-D-fucose (3.90 g, 9.85 mmol) was dissolved in 150 mL of methanol and 6 mL of 0.5 M NaOMe solution were added. The mixture was stirred for 6 h. The solvent was removed in vacuo. Column chromatography (3:1 dichloromethane/methanol) afforded 2.63 g (99%) as a colorless solid: [α]D: +201.6 (c=0.32, CH3OH). 1H NMR (CD3OD, 300 MHz) δ 1.18 (d, J=6.6 Hz, 3H), 3.74 (s, 3H), 3.89 (m, 2H), 4.09 (quart., J=6.0 Hz, 1H), 5.31 (d, J=3.6 Hz, 1H), 6.82 (d, J=9.3 Hz, 2H), 7.04 (d, J=9.3 Hz, 2H). 13C NMR (CD3OD, 75 MHz) 16.3, 55.7, 67.9, 69.5, 71.2, 73.2, 100.0, 115.1, 119.0, 152.2, 156.0. MALDI-HRMS: m/z [M+Na]+ calcd 293.0996, obsd 293.0994.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:20][CH:21]=O)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:15]([O:14][C:13]([N:12]([CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH2:20][CH2:21][NH:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:19])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOC(=O)CN
Reactant: CC(C)(C)OC(=O)N(CC=O)CCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CNCCN(CCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-Butyl [2-(4-nitrophenyl)ethyl](2-oxoethyl)carbamate (0.52 g, 1.7 mmol) in MeOH (10 mL) was added ethyl aminoacetate hydrochloride (0.31 g, 2.2 mmol), sodium cyanoborohydride (1.1 g, 5.1 mmol), and a few drops of acetic acid. The mixture was allowed to stir at 25° C. for 16 hours. LC showed clean reaction. The product was purified by silica gel chromatography (Hexane:EtOAc) to deliver Ethyl [(2-{(tert-butoxycarbonyl) [2-(4-nitrophenyl)ethyl]amino}ethyl)amino]acetate. LC-MS (IE, m/z): 396 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:16]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:30]=[N+:31]([O-:54])[CH:32]=[C:33]([Cl:53])[C:34]=1[CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH:45]([F:47])[F:46])=[C:40]([O:48][CH2:49][CH:50]2[CH2:52][CH2:51]2)[CH:39]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:16]([O:18][CH2:19][C:20]([O:22][C@H:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH:45]([F:46])[F:47])=[C:40]([O:48][CH2:49][CH:50]2[CH2:51][CH2:52]2)[CH:39]=1)[CH2:35][C:34]1[C:33]([Cl:53])=[CH:32][N+:31]([O-:54])=[CH:30][C:29]=1[Cl:28])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc(C(=O)OCC(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
A mixture of 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoyloxy)acetic acid (0.192 g, 0.476 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.200 g, 0.476 mmol), EDC (0.274 g, 1.428 mmol), and DMAP (0.058 g, 0.476 mmol) in DCM (20 ml) was stirred at RT for 2 hours. The mixture was washed with HCl 1N and with NaHCO3 5%; the organic layer was dried over Na2SO4, and the solvent was removed. The crude was purified by flash chromatography on silica gel cartridge (DCM:MeOH=99:1) to afford (S)-4-(2-(2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.296 g, 0.367 mmol, 77% yield, MS/ESI+ 805.0 [MH]+).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[S:10]([C:14]1[CH:15]=[C:16]([NH:20][C:21]2[N:30]=[CH:29][C:28]3[CH:27]=[CH:26][C:25]4[N:31]=[C:32]([C:34]([OH:36])=O)[S:33][C:24]=4[C:23]=3[N:22]=2)[CH:17]=[CH:18][CH:19]=1)(=[O:13])(=[O:12])[NH2:11].[C:37]([O:41][C:42]([NH:44][CH:45]1[CH2:49][CH2:48][NH:47][CH2:46]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:37]([O:41][C:42](=[O:43])[NH:44][CH:45]1[CH2:49][CH2:48][N:47]([C:34]([C:32]2[S:33][C:24]3[C:23]4[N:22]=[C:21]([NH:20][C:16]5[CH:17]=[CH:18][CH:19]=[C:14]([S:10](=[O:12])(=[O:13])[NH2:11])[CH:15]=5)[N:30]=[CH:29][C:28]=4[CH:27]=[CH:26][C:25]=3[N:31]=2)=[O:36])[CH2:46]1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: NS(=O)(=O)c1cccc(Nc2ncc3ccc4nc(C(=O)O)sc4c3n2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2nc3ccc4cnc(Nc5cccc(S(N)(=O)=O)c5)nc4c3s2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
Diisopropylethylamine (68 μl, 0.39 mmol) was added to a mixture of 8-(3-Sulfamoyl-phenylamino)-thiazolo[4,5-h]quinazoline-2-carboxylic acid (78 mg, 0.19 mmol), 3-(tert-butoxycarbonylamino)pyrrolidine (36.2 mg, 0.19 mmol) and PyBrop (91 mg, 0.19 mmol) in dimethylformamide (1 ml). The reaction mixture was stirred at room temperature for 12 h. The reaction was concentrated under reduced pressure, redissolved in isopropanol (˜10 mL) and water was added (˜5 mL). The precipitate formed was isolated by filtration and washed with water (1×5 mL), dilute NaHSO4 (1×5 mL), water (1×5 mL), saturated Na2CO3 (1×5 mL), water (1×5 mL), isopropanol (1×5 mL), diethyl ether (4×5 mL) giving a yellow powder (87 mg, 80% yield). MS (ES+) 570, (ES−) 568.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[Br:22][C:23]1[CH:24]=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:27][C:28]=1F.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:28]3[CH:27]=[CH:26][C:25]([C:30]([F:33])([F:32])[F:31])=[CH:24][C:23]=3[Br:22])[CH:14]=2)=[CH:8][C:7]=1[CH3:20]
Reactant: COC(=O)CCc1ccc(Oc2cccc(O)c2)cc1C
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Temperature: 100 °C
Reaction time: 6 h
Yield: 82.3 %

Procedure:
A mixture of 3-[4-(3-hydroxy-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (8.18 g, 28.6 mmol), 3-bromo-4-fluorobenzotrifluoride (6.80 g, 28.0 mmol) and 325 mesh potassium carbonate (4.64 g, 33.68 mmol) in dry DMSO (80 mL) is heated to 100° C. and stirred for about 6 hours under N2. The reaction is cooled and acidified with 1 N HCl. The mixture is then diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 15/1 hexanes/ethyl acetate to afford about 11.74 g (81%) of the titled compound. Rf=0.76 (9/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C24H20O4F3Br 509, found 526 and 528 (M+NH4, 100%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([O:11][CH3:12])=[N:5][C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46](O)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]>C(Cl)Cl>[CH3:12][O:11][C:4]1[C:3]([NH:2][C:46](=[O:47])[C:45]2[CH:49]=[C:41]([CH2:40][C:34]3[C:35](=[O:39])[C:36]([O:37][CH3:38])=[C:31]([O:30][CH3:29])[C:32](=[O:55])[C:33]=3[CH3:54])[CH:42]=[CH:43][C:44]=2[O:50][C:51](=[O:53])[CH3:52])=[CH:8][CH:7]=[C:6]([O:9][CH3:10])[N:5]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ccc(N)c(OC)n1
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(OC)nc3OC)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 58.5 %

Procedure:
3-Amino-2,6-dimethoxypyridine hydrochloride (0.306 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.160 g, 0.313 mmol, 59%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8].[NH2:33][C@H:34]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:35][OH:36]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:33][C@@H:34]([CH2:35][OH:36])[CH2:37][CH:38]([CH3:40])[CH3:39])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Reactant: CC(C)C[C@@H](N)CO
Product: CC(C)C[C@H](CO)Nc1ccc(C(=O)c2sc(Nc3ccc(N4CCN(C)CC4)cc3)nc2N)cc1[N+](=O)[O-]

Procedure:
This compound was prepared from the compound of Example 15 and (R)-2-amino-4-methyl-1-pentanol (Aldrich) by the procedure used in Example 57. Mass spectrum (ES) MH+=554.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2].[CH:10](=O)[CH3:11].C(O)(=O)C.C([O-])(=O)C.[NH4+]>CN(C)C=O.[C].[Pd]>[C:1]([CH:3]([CH2:10][CH3:11])[C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2]
Reactant: N#CCC(=O)NC(N)=O
Reactant: CC=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCC(C#N)C(=O)NC(N)=O

Procedure:
Cyanoacetylurea (38.7 g) was suspended in N,N-dimethylformamide (77.4 ml), and acetaldehyde (18.8 ml), acetic acid (3.43 ml) and ammonium acetate (2.31 g) were added. This suspension was subjected to catalytic hydrogenation in the presence of 10% palladium carbon (0.78 g, 50% wet product) under normal pressure at 30° C. for 5 hours. The catalyst was filtered off. Water (350 ml) was added to the filtrate to allow precipitation of crystals. The crystals were collected by filtration to give crystals of N-(2-cyanobutanoyl)urea (yield 24.2 g). 1H-NMR(270 MHz, DMSO-d6)δ 0.99(3H,t), 1.75-1.95(2H,m), 3.86(1H,t), 7.42(2H,br), 10.50(1H,br)
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]2[CH2:11][CH2:10][N:9]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: CCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.5 %

Procedure:
A solution of 3-phenylpyrrolidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and hexanoyl chloride (336.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 1-(3-phenylpyrrolidin-1-yl)hexan-1-one are collected and the solvent is removed in vacuo to give 405 mg of colorless oil.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30](O)=[O:31])=[CH:25][CH:24]=4)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH:36]1([CH2:39][NH2:40])[CH2:38][CH2:37]1>>[CH:36]1([CH2:39][NH:40][C:30](=[O:31])[CH:29]([C:26]2[CH:25]=[CH:24][C:23]([C:21]3[CH:20]=[CH:19][C:18]4[N:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:35])([F:34])[F:1])=[O:6])[CH:9]=5)[CH:15]=[N:16][C:17]=4[CH:22]=3)=[CH:28][CH:27]=2)[CH3:33])[CH2:38][CH2:37]1
Reactant: CC(C(=O)O)c1ccc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cc1
Reactant: NCC1CC1
Product: CC(C(=O)NCC1CC1)c1ccc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cc1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 14 starting from 2-(4-{1-[3-({[(2,2,2-trifluoro ethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}phenyl)propanoic acid (prepared by the procedure for Example 14, step 3) and cyclopropylmethylamine (Aldrich, Cat. No. 359521), LCMS (M+H)+: m/z=536.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:30]=1.C(N(CC)CC)C>ClCCl>[C:33]([C:32]1[CH:35]=[CH:36][C:29]([NH:28][C:6](=[O:7])[C:5]2[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][CH2:1][CH3:2])=[CH:30][C:31]=1[C:37]([F:38])([F:39])[F:40])#[N:34]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Cl
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-ethoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluoromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[OH:31])[C:5]2=[CH:4][CH:3]=1.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35].CCN(CC)CC>CN(C=O)C.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]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[CH:27]=[CH:26][C:25]=3[OH:31])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2O)N1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(O)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 83 °C

Procedure:
To a stirred solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-hydroxy-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione (100 mg) in DMF (2 mL) were added PdCl2(PPh3)2 (18 mg), CuI (4 mg), trimethylsilyl acetylene (Aldrich, 0.40 mL) and Et3N (Aldrich, 0.62 mL) and the mixture was purged with nitrogen and then heated at 83° C. for 3 hrs. The solvent was removed and the crude was directly used for next step. MS (H+), 549.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=[O:31])[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:32][C:33]1[CH:34]=[C:35]([OH:41])[CH:36]=[CH:37][C:38]=1[C:39]#[N:40].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[O:31])[CH:8]=[CH:7][C:3]=1[C:4]([O:41][C:35]1[CH:36]=[CH:37][C:38]([C:39]#[N:40])=[C:33]([Cl:32])[CH:34]=1)=[O:5]
Reactant: CCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)Cl)c(Cl)c3)cc2)cc1
Reactant: N#Cc1ccc(O)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)Oc4ccc(C#N)c(Cl)c4)c(Cl)c3)cc2)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
The crude 2-chloro-4-{[p-(p-hexylphenyl)benzoyl]oxy}benzoyl chloride obtained was dissolved in 125 ml of benzene and then added dropwise to a solution of 4.0 g of 3-chloro-4-cyanophenol in 100 ml of pyridine. The mixture was stirred at a bath temperature of 65° C. overnight, then poured into ice-cold, dilute hydrochloric acid and extracted with diethyl ether. The extract was washed several times with 3N hydrochloric acid, then washed neutral with water, dried and evaporated. The crude 4'-hexyl-4-biphenylcarboxylic acid 3-chloro-4-[(3-chloro-4-cyanophenoxy)carbonyl]phenyl ester obtained was chromatographed on silica gel with toluene/dichloromethane (1:1). The fractions (8.2 g) which were practically pure according to thin-layer chromatography were recrystallized once from ethyl acetate and once from ethyl acetate and a small amount of hexane; m.p. (C-N) 95° C., cl.p. (N-I) 235° C.