Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=[O:12])[CH:4]=[CH:3]1.S(Cl)(Cl)=O.[CH3:18]O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([O:13][CH3:18])=[O:12])[CH:4]=[CH:3]1
Reactant: CO
Reactant: Cn1ccc2cccc(C(=O)O)c21
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2ccn(C)c12
Yield: 59 %

Procedure:
To 70 ml of a methanol solution of 1.82 g (10.4 mmol) of 1-methyl-7-indolecarboxylic acid was added dropwise 3.09 g (26.0 mmol) of thionyl chloride at 0° C. The reaction mixture was refluxed for 2 hours and the solvent was then distilled off under reduced pressure. Ice water was poured onto the resulting residue and ammonium hydroxide was added to render the mixture alkaline. The mixture was extracted three times with ethyl acetate. The combined extracts were washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was isolated and purified by silica gel column chromatography to give 1.16 g (59.0%) of methyl 1-methyl-7-indolecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.[C:41]12([NH2:51])[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2>>[C:41]12([NH:51][C:30]([CH:29]3[CH2:28][CH2:27][S:26](=[O:33])(=[O:34])[N:25]3[CH2:24][C:23]3[CH:35]=[CH:36][CH:37]=[C:21]([CH2:20][N:9]([CH2:8][C:7]4[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([O:39][CH3:40])[C:6]=4[F:38])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:14])([CH3:15])[CH3:13])[CH:22]=3)=[O:31])[CH2:48][CH:47]3[CH2:46][CH:45]([CH2:44][CH:43]([CH2:49]3)[CH2:42]1)[CH2:50]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)NC45CC6CC(CC(C6)C4)C5)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 67.3 %

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7, 0.080 g, 0.134 mmol) was reacted with 1-adamantanamine (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 0.025 g, 0.179 mmol) to form 2-(3-{[(6-chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid adamantan-1-ylamide (0.066 g, 68%). m/z=731 (M+1); HRMS: calcd for C39H57ClFN4O4S. Calc [M+H+] 731.3768. found 731.3766.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[CH2:10]([S:17](Cl)(=[O:19])=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([S:17]([NH:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)(=[O:19])=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cn1cccc1CCN
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: Cn1cccc1CCNS(=O)(=O)Cc1ccccc1

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrol and benzylsulphonyl chloride analogously to Example A.
Reaction SMILES: O=[C:2]1NCN[C@@H](C([O-])=O)C1.[CH2:11]([O:18][C:19](=[O:44])[C@H:20]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:21][C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O1COCOC1>ClCCl.S(=O)(=O)(O)O>[CH2:25]([N:24]1[C:22](=[O:23])[CH2:21][C@H:20]([C:19]([O:18][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:44])[N:32]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:2]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)N[C@H](CC(=O)NCc2ccccc2)C(=O)OCc2ccccc2)cc1
Reactant: O=C1C[C@H](C(=O)[O-])NCN1
Agent: C1OCOCO1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CN(Cc3ccccc3)C(=O)C[C@@H]2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
Benzyl 1-benzyl-3-1(4-methoxyphenyl)sulfonyl]-6oxo-hexahydro-pyrimidine-4(R)-carboxylate (1c): To the solution of N-benzyl-2(R)-[(4-methoxyphenyl)sulfonylamino]-succinamic acid benzyl ester as an oil (2.10 g, 4.4 mmol) in 200 mL of dichloromethane is added, with stirring, 1,3,5-trioxane (1.57 g, 17.4 mmol) followed by two drops of sulfuric acid. The reaction is heated at reflux for 3 hours at which time mass spectrometry (ES) indicates the reaction to be complete. The reaction is allowed to cool to room temperature, diluted with dichloromethane (250 mL), and washed with water (2x). The product is purified by flash silica gel chromatography (1:1 hexanes-ethyl acetate), to give benzyl 1-benyl-3-[(4-methoxyphenyl)sulfonyl]-6-oxo-hexahydro-pyrimidine4(R)-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:19]=1[NH2:20]>>[Cl:17][C:18]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:19]=1[NH:20][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: COc1ccc(Cl)c(N)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: COc1ccc(Cl)c(Nc2ccnc3[nH]c(=O)c4ccccc4c23)c1
Yield: 60.8 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2-chloro-5-methoxyaniline (109 mg, 0.56 mmol) to provide 208 (92 mg, 60% yield) as a white solid. LC-MS (M+H=352, obsd.=352).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br.[NH2:18][C:19]1[N:28]=[C:27]([NH2:29])[C:26]2[C:21](=[N:22][CH:23]=[C:24]([CH2:30]Br)[N:25]=2)[N:20]=1.CO>C1COCC1>[NH2:18][C:19]1[N:28]=[C:27]([NH2:29])[C:26]2[C:21](=[N:22][CH:23]=[C:24]([CH2:30][N:15]3[C:16]4[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=4[O:8][C:9]4[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:25]=2)[N:20]=1
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(N)c2nc(CN3c4ccccc4Oc4ccccc43)cnc2n1
Reaction time: 0.17 h

Procedure:
NaH (60% oil suspension containing 51 mg, 2.0 mmol) was added to a stirred solution of phenoxazine (147 mg, 0.784 mmol) in dry THF (10 mL) at 0° C. under N2. After 10 min. 2,4-diamino-6-bromomethylpteridine hydrobromide (100 mg, 0.392 mmol) was added and the reaction mixture was allowed to come to room temperature and left to stir for 2 days. The excess NaH was decomposed with MeOH (1 mL), and the mixture was concentrated to dryness by rotary evaporation. Flash chromatography on silica gel yielded the title compound, N-[(2,4-diaminopteridin-6-yl)methyl]phenoxazine, as a brown solid; yield 47 mg (34%); mp >250° C. dec. Anal. Calcd. for C19H15N7O0.4H2O: C, 62.60; H, 4.37. Found: C, 62.84; H, 4.10.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].[H-].[Na+].I[CH3:13]>C1COCC1>[CH3:13][O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4]
Reactant: CI
Reactant: CCCCC(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(OC)C(=O)O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
2-Hydroxy caproic acid (152 mg, 1.15 mmol) was dissolved in 3 mL anhydrous THF. Sodium hydride (95%, 61 mg, 2.41 mmol) was added and the mixture was stirred at room temperature for 40 min. Iodomethane (0.7 mL) was added and the mixture was stirred at room temperature overnight. It was quenched with water, stirred for 4 hours to hydrolyze the methyl ester, and then adjusted to pH 4 with 10% citric acid. The mixture was extracted with 5% methanol in dichloromethane, organic layer dried over sodium sulfate, filtered, and the filtrate was concentrated to give the crude 2-methoxy caproic acid which was used in next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1.C(N(CC)CC)C>ClCCl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Reactant: Cc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccc(C)cc3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
To the product from Example 137B (70 mg, 0.1505 mmol) was treated with p-toluidine (16 mg, 0.1505 mmol), triethylamine (0.025 mL, 0.1806 mmol) and dichloromethane (4 mL) following the procedure from Example 137C to provide the title compound as an off white solid after chromatography (64 mg, 80%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 2.27 (s, 3 H) 3.17-3.30 (m, 1 H) 3.78 (s, 3 H) 7.00 (d, J=8.82 Hz, 2 H) 7.14 (d, J=8.09 Hz, 2 H) 7.40 (d, J=8.82 Hz, 2 H) 7.62 (d, J=8.46 Hz, 1 H) 7.80 (d, J=8.09 Hz, 1 H) 7.99 (s, 1 H) 8.59 (s, 1 H) 8.86 (d, J=8.46 Hz, 1 H) 10.13 (s, 1 H) 10.20 (s, 1 H); MS (APCI) m/z 536 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:6]=2[C:7](=[O:10])[NH:8][CH:9]=1.I[CH3:25].O>CN(C)C=O>[Br:3][C:4]1[C:5]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:6]=2[C:7](=[O:10])[N:8]([CH3:25])[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)c[nH]c(=O)c32)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cn(C)c(=O)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Sodium hydride (0.875 g, 36.5 mmol, 1.46 g of a 60% in oil dispersion) was added to a stirring solution of 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (11.2 g, 30.4 mmol) in dimethylformamide (217 mL) under nitrogen. After 30 minutes, iodomethane (2.27 mL, 36.5 mmol) was added and the solution was stirred at room temperature for 3 h. Upon addition of water (250 mL) a precipitate formed. The precipitate was collected by vacuum filtration, rinsed with water (50 mL) and dried in a vacuum oven at 55° C. overnight to provide 11.2 g of 4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].CO>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8]
Reactant: COC(=O)CN(c1ccc(Cl)cc1C(=O)c1ccccc1F)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CN(c1ccc(Cl)cc1C(=O)c1ccccc1F)S(=O)(=O)c1ccc(N)cc1

Procedure:
The 5-chloro-2'-fluoro-2-[N-(methoxycarbonyl-methyl)-N-(4-nitrophenylsulfonyl)amino]benzophenone prepared in Example 2, step b, is dissolved in 100 ml of ethyl acetate and 5 ml of methanol and hydrogenated at ordinary pressure for 2 hours in the presence of 620 mg of 10% palladium-on-charcoal; the existence of 3 compounds (starting material, intermediate and expected product) is observed in TLC. The catalyst is filtered off, the solvent is evaporated off and the residue is chromatographed on silica gel. The expected compound is eluted with DCM containing 1% of methanol. After recrystallization from DCM/isopropyl ether, m.p.=168°-170° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]N=1>C(O)C>[N:12]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:11]=1[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: COC1=NCCCCC1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC1=NCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-tert-butoxycarbonyl-1,3-propanediamine (2 g; 11.48 mmol), described in Step a of Preparation A, in 1 ml of ethanol is added to a solution of 2-methoxy-4,5,6,7-tetrahydro-3H-azepine (1.46 g; 11.48 mmol; 1.7 ml) in 4 ml of absolute ethanol. After stirring for 8 hours at ambient temperature, the reaction mixture is concentrated to yield the expected product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:11][C:12]([NH2:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:15][NH2:16]>>[CH3:15][NH:16][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([NH2:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: NC(=O)Cc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: CN
Product: CNc1cc(CC(N)=O)ccc1[N+](=O)[O-]

Procedure:
2-(3-Methylamino-4-nitro-phenyl)-acetamide (727.0 mg) was prepared by following General Procedure A beginning with 2-(3-chloro-4-nitro-phenyl)-acetamide (1.0 g) in methylamine (2.0 M in THF, 20 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13](O)=[O:14])=[CH:4][C:3]=1[O:16][CH3:17].C(N(CC)CC)C.C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]([N:39]=[N+:40]=[N-:41])=[O:14])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cc(-c2ccsc2C(=O)O)ccc1Br
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(-c2ccsc2C(=O)N=[N+]=[N-])ccc1Br
Reaction time: 20 h

Procedure:
A stirred solution of 3-(4-bromo-3-methoxyphenyl)thiophene-2-carboxylic acid (2.23 g, 7.13 mmol) in benzene (28.5 mL) was treated with triethylamine (1.39 ml, 9.98 mmol) and diphenylphosphoryl azide (1.96 g, 7.13 mmol). The mixture was stirred for 20 h, then the volatiles were removed ant the residue was purified by column chromatography on silica gel (eluent: toluene) to afford the title (1.63 g, 68%). LCMS (ES+) m/z 310, 312 (M+H−N2)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14]CC)=[O:13])[C:6]=2[CH:23]=1.[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:27]([C:28](O)=[O:29])[C:26]=1[OH:36]>>[C:17]1([CH:10]([N:7]2[C:6]3[CH:23]=[C:2]([NH:1][C:28](=[O:29])[C:27]4[C:26]([OH:36])=[C:25]([Cl:24])[CH:33]=[C:32]([Cl:34])[C:31]=4[Cl:35])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH2:11][C:12]([OH:14])=[O:13])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1c(O)c(Cl)cc(Cl)c1Cl
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Product: O=C(O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3c(O)c(Cl)cc(Cl)c3Cl)cc21

Procedure:
Using a similar procedure to that described in Preparation 21, the title compound (19 mg) was prepared from ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and 3,5,6-trichlorosalicylic acid (HATU was substituted for TBTU), and purified by RP-HPLC. [LCMS (Method A, Mobile Phase I) RT=4.54 min, MH+ 506].
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([OH:10])[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].C(C1C=C(S(OO[CH:24]([CH2:26][CH3:27])[CH3:25])(=O)=O)C=CC=1C)C.[H-].[Na+]>>[C:1]([O:5][CH2:6][CH:7]([O:10][CH2:7][CH2:8][O:9][CH2:27][CH2:26][CH2:24][CH3:25])[CH2:8][O:9][CH2:2][CH2:1][O:5][CH2:25][CH2:24][CH2:26][CH3:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc(S(=O)(=O)OOC(C)CC)ccc1C
Reactant: CC(C)(C)OCC(O)CO
Agent: [H-]
Agent: [Na+]
Product: CCCCOCCOCC(COC(C)(C)C)OCCOCCCC

Procedure:
Compound 25 was prepared using a method similar to that described for 23. The o reagents used were as follows, compound 17 (25.5 g, 0.172 mol.), compound 19 (91.5 g, 0.336 mol.), sodium hydride (60% by wt. in mineral oil (14.0 g, 0.350 mol.). The final product was a colorless liquid (30.0 g 60%) (bpt. 100°-120 0° C., 0.06 torr.): 1H-NMR (CDCl3), d (ppm) 3.8-3.4 (m, 17H), 1.55 (m, 4H, CH2), 1.2 (s, 9H, C(CH3)3), 0.9 (t, 6H, --CH3). Mass spectroscopy, m/e 349 MH+.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([N:19]3[CH2:26][CH2:25][C:24]4([CH3:30])[C:27]([CH3:29])([CH3:28])[CH:20]3[CH2:21][C:22]3[CH:34]=[C:33]([C:35]([NH:37]O)=[NH:36])[CH:32]=[CH:31][C:23]=34)=[O:18])=[CH:16][C:11]=2[N:10]=[CH:9]1>CC1C=C(C)C=C(C)N=1>[NH:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([N:19]3[CH2:26][CH2:25][C:24]4([CH3:30])[C:27]([CH3:28])([CH3:29])[CH:20]3[CH2:21][C:22]3[CH:34]=[C:33]([C:35]5[N:36]=[C:5]([CH3:6])[O:7][N:37]=5)[CH:32]=[CH:31][C:23]=34)=[O:18])=[CH:16][C:11]=2[N:10]=[CH:9]1
Reactant: CC(=O)OC(C)=O
Reactant: CC12CCN(C(=O)c3ccc4[nH]cnc4c3)C(Cc3cc(C(=N)NO)ccc31)C2(C)C
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1nc(-c2ccc3c(c2)CC2N(C(=O)c4ccc5[nH]cnc5c4)CCC3(C)C2(C)C)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (0.1 mL) is added to a solution of 3-(1H-benzoimidazole-5-carbonyl)-N-hydroxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carboxamidine (0.15 g) in 2,4,6-trimethylpyridine (2 mL). The resulting solution is stirred at ambient temperature for 1 h and then at 120° C. for 3 h. After cooling to room temperature, the mixture is concentrated under reduced pressure and the residue is taken up in methanol (10 mL). Concentrated aqueous ammonia solution (1 mL) is added and the solution is stirred at ambient temperature for 1 h. The solution is concentrated under reduced pressure and the residue is purified by HPLC on reversed phase (water/MeCN) to give the title compound as a white foam-like solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@:6]1([NH:21]C(OC(C)(C)C)=O)[CH2:11][C@H:10]([O:12][C:13](=[O:15])[CH3:14])[C@@H:9]2[C@H:7]1[C@H:8]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O.ClCCl>[CH2:1]([O:3][C:4]([C@:6]1([NH2:21])[CH2:11][C@H:10]([O:12][C:13](=[O:15])[CH3:14])[C@@H:9]2[C@H:7]1[C@H:8]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](N)(C(=O)OCC)C[C@@H]2OC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.8 %

Procedure:
Dissolve (1S,2S,4S,5R,6R)-4-acetyloxy-2-(tert-butoxycarbonyl)aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester (1.25 g, 3.13 mmol, Preparation 19) in a solution of 95% TFA in dichloromethane (60 mL) and stir under nitrogen at room temperature for 5 minutes. After this time remove the TFA/dichloromethane in vacuo. Dissolve the crude product in a suspension of NaHCO3 (1.00 g) in dichloromethane (50 mL) and stir for 30 minutes. Filter the suspension, wash with dichloromethane (3×25 mL), and concentrate in vacuo to afford 916 mg (98%) of the product as a yellow oil.
Reaction SMILES: [Al:1].[Cl-:2].[Al+3].[Cl-].[Cl-].[C:6]1([C:8](=[CH:10][C:11](=[C:13]([CH:15]=1)[CH3:14])[CH3:12])[CH3:9])[CH3:7].[Ti:16](Cl)(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1>[Cl-:17].[Cl-:2].[Ti+2:16].[Cl-:17].[Al+3:1].[Cl-:17].[Cl-:17].[C:6]1([C:8](=[CH:10][C:11](=[C:13]([CH:15]=1)[CH3:14])[CH3:12])[CH3:9])[CH3:7]
Reactant: [Al]
Reactant: Cl[Ti](Cl)(Cl)Cl
Agent: Cc1cc(C)c(C)cc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: [Ti+2]
Temperature: 130 °C

Procedure:
20 g of aluminum power (BDH fine powder) and 27 g of aluminum chloride were introduced into a two liter flask. The mixture of solids was stirred and heated to a temperature of 130° C., which temperature was maintained for two hours. The mixture was then cooled, and a solution of 15.5 g of durene in one liter of toluene was added. The flask contents were stirred and heated to reflux temperature. 19.9 g of titanium tetrachloride in 100 ml of toluene were added dropwise over a period of 30 minutes. Heating was continued, at reflux temperature, for a further hour and the mixture was then allowed to cool. The mixture was then filtered and the filtrate was allowed to run directly into 2.5 liters of n-heptane. A dark-colored precipitate separated out and was filtered and then washed four times with 250 ml of n-heptane for each wash. The precipitate was then dried under vacuum (0.2 mm pressure) at ambient temperature (about 20° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17](=[O:21])[O:18][CH2:19][CH3:20])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.O[C:23]([C:26](O)(C)C)([CH3:25])[CH3:24].CC(C)=CB([O-])[O-].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>O>[CH3:25][C:23]([CH3:26])=[CH:24][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17](=[O:21])[O:18][CH2:19][CH3:20])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)NCCC1CCN(c2ccc(Br)cn2)CC1
Reactant: CC(C)(O)C(C)(C)O
Agent: CC(C)=CB([O-])[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)NCCC1CCN(c2ccc(C=C(C)C)cn2)CC1
Yield: 80.5 %

Procedure:
The process is performed according to the method described in Example 10 (step 10.5.). Starting with 1.00 g (2.81 mmol) of ethyl [2-(5′-bromo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)ethyl]carbamate, prepared in the preceding step, 0.61 g (3.37 mmol) of pinacol 2-methyl-1-propenylboronate (commercial), 2.74 g (8.42 mmol) of caesium carbonate, suspended in 18 mL of a 9/1 mixture of tetrahydrofuran and water, and 0.23 g (0.28 mmol) of PdCl2dppf.CH2Cl2, and after purifying on a column of silica gel, eluting with a 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.75 g of expected product is obtained in the form of a wax.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[N:11]([C:25](=[O:26])[C:24]3[C:23]([F:22])=[CH:31][CH:30]=[CH:29][C:28]=3[F:32])[C:10](=[O:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(=O)n(-c2cccc(Cl)c2)o1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1c(F)cccc1F)n1c(=O)on(-c2cccc(Cl)c2)c1=O
Reaction time: 24 h

Procedure:
2-(3-Chlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Difluorobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(3-chlorophenyl)-4-(2,6-difluorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.