Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.BrC1C=C(C#N)[CH:29]=[N:30]C=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:29]#[N:30])[CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccnc2)ccn1
Product: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cncc(C#N)c2)ccn1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide (example 5) in accordance with the general method of example 20 using 5-Bromo-3-cyanopyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a light yellow crystalline solid, MS (ISP): m/e=345.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][N:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:7][CH2:6][N:5]1[CH2:29][C:30]([NH:32][C:33]1[C:38]([Cl:39])=[CH:37][C:36]([CH2:40][NH:41]C(=O)OC(C)(C)C)=[CH:35][C:34]=1[Cl:49])=[O:31])=[O:3].CO.Cl>CC(O)C>[NH2:1][C:2]([CH:4]1[CH2:9][N:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:7][CH2:6][N:5]1[CH2:29][C:30]([NH:32][C:33]1[C:38]([Cl:39])=[CH:37][C:36]([CH2:40][NH2:41])=[CH:35][C:34]=1[Cl:49])=[O:31])=[O:3]
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)c(NC(=O)CN2CCN(CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2C(N)=O)c(Cl)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: NCc1cc(Cl)c(NC(=O)CN2CCN(CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2C(N)=O)c(Cl)c1
Yield: 44.9 %

Procedure:
A mixture of 8.7 parts of (1,1-dimethylethyl) [[4-[[2-[2-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-1-piperazinyl]acetyl]amino]-3,5-dichlorophenyl]methyl]carbamate, 120 parts of methanol and 24 parts of 2-propanol, saturated with hydrogen chloride was stirred for 30 minutes at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The whole was treated with an ammonium hydroxide solution and the product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (93:7 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.34 parts (44.9%) of 2-(aminocarbonyl)-N-(4-(aminomethyl)-2,6-dichlorophenyl]-4-[5,5-bis(4-fluorophenyl)pentyl]-1-piperazineacetamide; mp. 160.8° C. (compound 100 ).
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=1Br.[I:17]I>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=1[I:17]
Reactant: COC(=O)c1cc(Br)c(Br)s1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(I)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
At −78° C., nBuLi (2.05 mL, 5.13 mmol) was added to a solution of methyl 4,5-dibromo-2-thiophenecarboxylate (1.4 g, 4.67 mmol) in THF (10 mL). After the mixture was stirred for 30 min, I2 (1.185 g, 4.67 mmol) was added in 3 mL THF. After the resulting solution was stirred at −78° C. for 1 h, it was quenched with Na2S2O3 at −78° C., and warmed to RT. The reaction mixture was extracted with DCM, dried over Na2SO4, and concentrated. The crude product was purified on silica (EtOAc/Hex, 0-10%) to give the title compound (1.3 g, 56%) as a yellow solid: LC-MS (ES) m/z 348(M+H)+.
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[C:8]2[CH2:9][CH2:10][N:11]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=3)[C:12](=[O:19])[C:13]=2[C:14]=1[O:15]C(=O)C)(=O)C.C[O-].[Na+].Cl>CO>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[F:27])[CH2:20][N:11]1[CH2:10][CH2:9][C:8]2[C:7]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[N:6][C:5]([OH:4])=[C:14]([OH:15])[C:13]=2[C:12]1=[O:19]
Reactant: CC(=O)Oc1nc(C(=O)N(C)C)c2c(c1OC(C)=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)C(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O

Procedure:
6-(3-Chloro-4-fluorobenzyl)-1-[(dimethylamino)carbonyl]-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-3,4-diyl diacetate (30 g, 62.7 mmol) was dissolved in 500 mL MeOH and treated with a 30% by weight solution of NaOMe in MeOH (45.2 mL, 251 mmol 4 equivalents was sufficient to get the pH of the reaction to 9) for 1 hour at 40° C. LCMS showed the cleavage of the acetate groups was complete. The reaction was neutralized with 1N HCl and the volume reduced to remove the MeOH and the residue was diluted with water and acidified to pH 3. The cloudy aqueous layer was diluted with an equal volume (800 mL) of chloroform. After shaking, the product began to crystallize out of the solutions and gathered at the miniscus. The total contents of the funnel were filtered and the collected solids were washed with water until no more salts appeared to remain. The solid was dried in vacuo for 16 hours to give a cinnamon colored solid. The organic layer from the filtered extraction was collected, washed with water and dried over Na2SO4, filtered and evaporated. The residue was crystallized from methanol to give product. The crude material was quite insoluble but was crystallized from DMF, then boiled in MeOH, filtered and dried under vacuum to give product.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1.[CH:24](OCC)=[O:25]>C1COCC1>[Cl:16][C:17]1[C:22]([CH:24]=[O:25])=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CCOC=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ncc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To THF (200 mL) at −30° C. under N2 is added n-butyllithium (2.5 M in hexane, 8 mL, 20 mmol), followed by 2,2,6,6-tetramethylpiperidine (3.5 mL, 20.5 mmol). The mixture is warmed to room temperature and stirred at this temperature for 10 minutes. After the mixture is cooled to −78° C., 2,6-dichloropyrazine (2.5 g, 16.75 mmol) in THF (25 mL) is added and the mixture is stirred at this temperature for 1 hour. To the mixture is added ethyl formate (2 mL, 24.4 mmol) and the mixture is stirred at this temperature for an additional 2 hours. The reaction is quenched with saturated NH4Cl (25 mL), warmed to room temperature, and diluted with ethyl acetate (200 mL). The organic layer is separated and dried, and solvent removed. Column chromatography on silica gel (15% ethyl acetate in hexane) gives 2.4 g of 3,5-dichloro-pyrazine-2-carbaldehyde as an oil.
Reaction SMILES: [F:1][C:2]1[C:16]([N+:17]([O-])=O)=[CH:15][C:5]([C:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1>[Fe].C(O)(=O)C>[CH3:14][C:13]1[C:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:16]([NH2:17])[CH:15]=2)=[O:7])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cccnc1C(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1cccnc1C(=O)c1ccc(F)c(N)c1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To a mixture of 2-(4-fluoro-5-nitrobenzoyl)-3-methylpyridine (7.13 g, 0.0258 mol) and glacial acetic acid at 70-80° C. is added iron powder (7.76 g, 0.130 mol) in three portions. The resultant mixture is stirred overnight at 70-80° C., cooled to room temperature and extracted three times with ethyl acetate. The combined organic layers are filtered through Celite, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a tan solid (4.36 g, 69.8%) which is identified by NMR spectral analysis.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[S:25]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:27])(=[O:26])[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:10]=1
Reactant: NCc1cc(F)ccc1S(=O)(=O)Nc1ccccc1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)ccc1S(=O)(=O)Nc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
(Step 2) A suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.26 g), 2-(aminomethyl)-4-fluoro-N-phenylbenzenesulfonamide hydrochloride obtained in Step 1 (0.37 g) and potassium carbonate (0.45 g) in ethanol (20 ml) was stirred overnight at 70° C. The reaction solution was filtered through celite, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.12 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[CH:20]=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(OC(C)C)(C)C>CO.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[CH2:20][OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C=O)c2cccc(OCc3ccccc3)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(CO)c2cccc(OCc3ccccc3)c2n1
Yield: 82.7 %

Procedure:
To a suspension of 8-benzyloxy-4-formyl-2-methylquinoline (300 mg) in a mixture of methanol (3 ml) and tetrahydrofuran (2 ml) was added sodium borohydride (20.6 mg) portionwise in an ice bath. The suspension was stirred for half an hour, then quenched with saturated sodium chloride. The mixture was extracted with chloroform and the organic layer was dried over anhydrous magnesium sulfate. After being concentrated in vacuo the residue was chromatographed on silica gel eluting with ethyl acetate-n-hexane to give an amorphous solid which was solidified with diisopropyl ether to afford 8-benzyloxy-4-hydroxymethyl-2-methylquinoline (250 mg) as a colorless solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[NH2:58][CH:59]1[CH2:64][CH2:63][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:61][CH2:60]1>ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:22]([CH3:32])=[C:21]([C:33]([NH:58][CH:59]4[CH2:60][CH2:61][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:63][CH2:64]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2ncnc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[5-(Cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid from example D.c1 (3.98 g; 8.0 mmol), triethylamine (2.43 g; 24.0 mmol) and HOBt (1.08 g; 8.0 mmol) is stirred in dry dichloromethane (40 mL) for 30 min, before addition of EDC (1.84 g; 9.6 mmol). The reaction mixture is stirred for one hour at ambient temperature. After addition of tert-butyl 4-amino-piperidine-1-carboxylate hydrochloride (2.27 g; 9.6 mmol) the reaction mixture is stirred at ambient temperature until the starting material is consumed according to LC-MS and chromatographed on silica gel (ethylacetate/cyclohexane—1:1) to yield the title compound as colorless foam.
Reaction SMILES: C(Cl)CCl.[C:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([OH:21])=O)[CH2:14][CH2:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][NH2:30])=[N:27][CH:28]=1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:8]([O:7][C:5]([N:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]([NH:30][NH:29][C:26]2[CH:25]=[CH:24][C:23]([F:22])=[CH:28][N:27]=2)=[O:21])[CH2:16][CH2:17]1)=[O:6])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Reactant: NNc1ccc(F)cn1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)NNc2ccc(F)cn2)CC1
Yield: 80 %

Procedure:
EDC (543 mg, 2.83 mmol) was added portionwise to a solution of 2-(4-Boc-1-piperazinyl)acetic acid (576 mg, 2.36 mmol), 5-fluoro-2-hydrazinyl-pyridine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 0.30 g, 2.36 mmol) and HOBt (32 mg, 0.24 mmol) in dry DCM (15 mL) at RT and stirred for 16 h. The solution was diluted with DCM (20 mL), washed with water (2×20 mL) and dried (Na2SO4). The solvent was evaporated to give the title compound as an off-white solid (667 mg, 80%). LCMS (Method 1): Rt 1.99 min, m/z 354 [MH+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:10](N1[C@H](C)[C@H](C2C=CC=CC=2)OC1=O)=[O:11])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].OO.[O-:38]S([O-])=O.[Na+].[Na+]>C1COCC1.O.CCOC(C)=O>[C:1]([O:5][C:6]([NH:7][CH2:8][C@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:10]([OH:11])=[O:38])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S([O-])[O-]
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](CNC(=O)OC(C)(C)C)Cc1ccc(Cl)cc1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@H](Cc1ccc(Cl)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of [(2S)-2-(4-Chlorobenzyl)-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-3-oxo-propyl]-carbamic acid tert-butyl ester (300 mg, 0.63 mmol) in THF/H2O (30/10 mL) at 0° C. was added LiOH (80 mg, 1.9 mmol) and H2O2 (30% by volume, 3.0 mL, 0.63 mmol) and stirred at 0° C. for 30 minutes. Then Na2SO3 (saturated solution, 10 mL) was added slowly & cautiously. Diluted with EtOAc (100 mL) and extracted into water (2×100 mL) The aq. layer was acidified (1N HCl) and extracted into EtOAc (3×100 mL) Dried over Na2SO4 and concentrated in vacuo to give (S)-2-(tert-Butoxycarbonylamino-methyl)-3-(4-chlorophenyl)-propionic acid (150 mg, 75%.) LCMS (APCI−) m/z 322 [M-Boc+H]−; Rt: 2.23 min
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)OCCc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OCCc1cccc(N)c1
Reaction time: 1 h

Procedure:
To a solution of acetic acid 2-(3-nitro-phenyl)-ethyl ester (15 g, 71.7 mmol) (from Example 3a supra) in ethyl acetate (150 mL), was added 10% palladium on carbon (1.5 g) (Aldrich). This mixture was hydrogenated at room temperature on the Parr apparatus at 50 psi for one hour. The reaction mixture was filtered over a bed of Celite® and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give acetic acid 2-(3-amino-phenyl)-ethyl ester. (Yield 12.81 g, 71.48 mmol, 99%).
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C:11]1([CH2:14][N:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:16]2=[O:26])[CH2:13][O:12]1.C(=O)([O-])O.[Na+].[H-].[Na+]>O.C(O)C>[CH3:13][C:11]1([CH2:14][N:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:17][C:16]2=[O:26])[O:12][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CC1(Cn2nc(-c3ccccc3)oc2=O)CO1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(Cn2nc(-c3ccccc3)oc2=O)Cn2cc([N+](=O)[O-])nc2O1
Yield: 41.1 %

Procedure:
A mixture of 2-chloro-4-nitro-1H-imidazole (170 mg, 1.15 mmol), 3-(2-methyloxiran-2-ylmethyl)-5-phenyl-3H-[1,3,4]oxadiazol-2-one (310 mg, 0.9 mmol), sodium hydrogencarbonate (120 mg, 1.43 mmol) and ethanol (2 ml) was stirred under reflux for 2.5 hours. The reaction mixture was allowed to return to room temperature, then diluted with water. The solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, the residue was dissolved in 1,4-dioxane (10 ml). To the solution, sodium hydride (55 mg, 1.38 mmol) was added followed by stirring at room temperature for 1 hour and then stirring under reflux for 1.5 hours. The reaction mixture was allowed to return to room temperature. To the solution, water was added, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to afford 3-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethyl)-5-phenyl-3H-[1,3,4]-oxadiazol-2-one (127 mg, yield 32%) as a light brown powder.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1>C1C=CC=CC=1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:14])=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(Cc1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of aluminum chloride (2.64 g, 19.8 mmol) in dry benzene (40 ml) was added a solution of 4-bromophenylacetyl chloride (4.63 g, 19.8 mmol) in 15 ml benzene over a period of 25 minutes under nitrogen. The resulting dark yellow solution was refluxed for six hours, and cooled to room temperature. Ice water (100 ml) was added, and the layers separated. The aqueous layer was extracted with benzene (1×50 ml). The combined organic portions were washed with water (2×60 ml), 10% NaOH (1×60 ml), water (1×60 ml), and brine (1×60 ml), and dried over magnesium sulfate. After filtration, concentration of the filtrate in vacuo afforded the ketone as 5.06 g of a white microcrystalline solid (93% yield). NMR indicated good purity. A portion was recrystallized from boiling petroleum ether/ethanol to give the ketone as colorless plates: m.p. 147.5°-149.0° C. (lit. m.p. 146°-147° C.; Huttel, R. et al., J. Chem. Ber. 93:1433 (1960)); 1H NMR δ8.02 (d, J=7.1 Hz, 2H), 7.63-7.46 (m, 5H), 7.16 (d, J=8.3, 2H), 4.27 (s, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:10][C:11]1[CH:12]=[C:13]([C@H:17]2[O:19][C@@H:18]2[CH2:20][OH:21])[CH:14]=[CH:15][CH:16]=1>C(OCC)(=O)C>[N:1]1([C@@H:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=2)[C@H:18]([OH:19])[CH2:20][OH:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: OC[C@H]1O[C@@H]1c1cccc(F)c1
Solvent: CCOC(C)=O
Product: OC[C@@H](O)[C@H](c1cccc(F)c1)N1CCc2ccccc21
Temperature: 125 °C
Yield: 74.6 %

Procedure:
A mixture of indoline (1.42 g, 11.89 mmol) and [(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (2.0 g, 11.89 mmol) was heated at 125° C. for 5 hours in a sealed reaction vial. Upon cooling, the crude product was dissolved in ethyl acetate, absorbed on Fluorocil, and purified by Biotage chromatography (FlasH40i, silica, 0-55% EtOAc/hexane) to give 2.55 g (75%) of (2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol as a colorless oil. MS (ESI) m/z 288.1 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]3[C:12](=[NH:23])[NH:11][C:10](=N)[C:9]2=3)=[CH:4][CH:3]=1.Cl.[N:26]1([C:31]2[S:32][CH2:33][C:34](=[NH:36])[N:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1.N=C1C2CCCCC=2C(=N)N1.Cl.N=C1NC(=N)CS1>>[NH:23]=[C:12]1[C:13]2[CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][CH2:16][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[C:9]=2[C:10](=[C:33]2[S:32][C:31]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:35][C:34]2=[NH:36])[NH:11]1
Reactant: N=C1NC(=N)C2=C1C(c1ccccc1)CCC2c1ccc(Br)cc1
Reactant: N=C1CSC(N2CCCC2)=N1
Agent: Cl
Agent: N=C1CSC(=N)N1
Agent: N=C1NC(=N)C2=C1CCCC2
Product: N=C1N=C(N2CCCC2)SC1=C1NC(=N)C2=C1C(c1ccc(Br)cc1)CCC2c1ccccc1

Procedure:
When equivalent amounts of 4-(p-bromophenyl)-7-phenyl-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-pyrrolidino-4-imino-2-thiazoline hydrochloride are substituted for the 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2,4-diiminothiazolidine hydrochloride respectively, in the procedure described in Example 10, part A above, there is obtained as the product 1-imino-4-(p-bromophenyl)-7-phenyl-4,5,6,7-tetrahydro-3-(2-pyrrolidino-4-imino-2-thiazolin-5-ylidene)isoindoline.
Reaction SMILES: [ClH:1].Cl.Br[C:4]1[CH:5]=[C:6]([N:10]2[CH:16]3[CH2:17][N:13]([CH2:14][CH2:15]3)[CH2:12][CH2:11]2)[CH:7]=[N:8][CH:9]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[ClH:1].[ClH:1].[C:18]1([C:4]2[CH:5]=[C:6]([N:10]3[CH:16]4[CH2:17][N:13]([CH2:14][CH2:15]4)[CH2:12][CH2:11]3)[CH:7]=[N:8][CH:9]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cncc(N2CCN3CCC2C3)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cncc(N3CCN4CCC3C4)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 157.7 %

Procedure:
4-(5-Bromo-pyridin-3-yl)-1,4-diaza-bicyclo[3.2.1]octane dihydrochoride (50 mg, 0.15 mmol) was added to a mixture of phenylboronic acid (25 mg, 0.20 mmol), tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.006 mmol), sodium carbonate (63 mg, 0.60 mmol) in EtOH (5 mL) and water (5 mL). The reaction mixture was placed in an oil bath at 80° C. for 3 h, and then 60° C. for 18 h. The mixture was cooled to RT, diluted with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was dissolved in EtOH (10 mL) and conc. HCl (0.2 mL) was added. The mixture was concentrated and EtOH (10 mL) was added and the solution was concentrated. This procedure was repeated three times and the resulting solid was triturated in EtOAc. The remaining solids were collected via filtration to give 40 mg (78%) of the title compound: (data for free base) 1H NMR (CD3OD, 400 MHz) δ 8.55 (br s, 1H), 8.50 (br s, 1H), 8.33 (br s, 1H), 7.83-7.81 (m, 2H), 7.60-7.53 (m, 3H), 5.12 (br s, 1H), 4.06-4.04 (m, 1H), 3.70-3.59 (m, 5H), 3.54-3.51 (m, 2H), 2.51-2.47 (m, 1H), 2.26-2.23 (m, 1H); APCI MS m/z 266.2 (M+1).