Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:14][C:15]1[C:16]2[C:36](=[O:37])[N:35]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH2:34][C:17]=2[C:18]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=2)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(C1C=CC=CC=1)C1C=CC=CC=1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].C([SiH](CC)CC)C>ClCCl>[CH2:32]([O:31][C:28]1[CH:27]=[CH:26][C:25]([C:18]2[C:17]3[CH2:34][N:35]([CH2:38][C:39]4[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=4)[C:36](=[O:37])[C:16]=3[C:15]([OH:14])=[C:24]3[C:19]=2[CH:20]=[CH:21][CH:22]=[N:23]3)=[CH:30][CH:29]=1)[CH3:33].[C:48]([OH:50])([C:47]([F:52])([F:51])[F:46])=[O:49]
Reactant: CCOc1ccc(-c2c3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(-c2c3c(c(O)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9-benzhydryloxy-5-(4-ethoxy-phenyl)-7-(4-fluoro-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 275 (8 mg, 0.013 mmol) dissolved in dichloromethane (1 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was triturated with diethyl ether/hexane (1/1) to afford 5-(4-ethoxy-phenyl)-7-(4-fluoro-benzyl)-9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 276, TFA salt, (1.8 mg, 0.003 mmol, 25%) as a yellow solid: 1H NMR (CDCl3) δ 9.0 (d, 1H), 8.1 (d, 1H), 7.7 (m, 2H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.2 (dd, 2H), 7.1 (t, 2H), 4.7 (s, 2H), 4.2(s, 2H), 4.1 (m, 2H), 1.5 (t, 3H); MS: 429 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1>O1CCCC1>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][CH2:11]2)=[S:27])=[CH:21][CH:20]=1
Reactant: NCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Reactant: Cc1ccc(N=C=S)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=S)NCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-1-piperazineethanamine (0.01 mol) and 4-methyl-1-isothiocyanatobenzene (0.01 mol) in tetrahydrofuran (300 ml) was stirred at room temperature for 1 hour. The solvent was evaporated. The residue was recrystallized from DIPE. The precipitate was filtered off and dried. The product was used without further purification, yielding 4.2 g N-(4-methylphenyl)-N'-[2-[4-(3,4-dichlorophenyl)-1-piperazinyl]ethyl]thiourea (interm. 6).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][N:10]=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][CH:26]=1.CC([O-])(C)C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH3:8][C:6]1[CH:5]=[C:4]([N:9]([C:34]2[CH:35]=[CH:36][C:31]([C:28]3[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=3)=[CH:32][CH:33]=2)[N:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: Cc1cc(C)cc(NN=C(c2ccccc2)c2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(N(N=C(c2ccccc2)c2ccccc2)c2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 66 %

Procedure:
N-(3,5-Dimethylphenyl)benzophenone hydrazone (1.0 equiv., 0.5 mmol, 150 mg), 4-bromobiphenyl (1.0 equiv., 0.5 mmol, 117 mg), Pd(OAc)2 (0.01 equiv, 0.005 mmol, 2 mg), DPE-phos (0.01 equiv, 0.005 mmol, 3 mg), and toluene (1 mL) were added to an oven dried test tube and stirred at room temperature for 2 minutes. NaOtBu (1.4 equiv., 0.7 mmol, 67 mg) and an additional 1 mL toluene were then added. The test tube was then capped with a septum, briefly purged with argon (˜1 min.) and then heated to 100° C. under argon for 14 hours. The reaction solution was then cooled to room temperature, diluted with Et2O, filtered through Celite, and concentrated under vacuum to give the crude product as a brown oil. Purification by flash column chromatography (2% EtOAc/Hex) gave the title product as a yellow solid (149 mg, 0.33 mmol, 66% yield).
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[CH3:14])[C:4](=O)[CH3:5])#[N:2].O.[NH2:16][NH2:17].C(O)(=O)C>C1(C)C=CC=CC=1>[NH2:2][C:1]1[NH:17][N:16]=[C:4]([CH3:5])[C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[CH3:14]
Reactant: NN
Reactant: CC(=O)C(C#N)c1ccc(C)cc1C
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2c(C)n[nH]c2N)c(C)c1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
A mixture of 1-cyano-1-(2,4-dimethylphenyl)propan-2-one (43.8 g, 0.23 mol), hydrazine-hydrate (22 mL, 0.46 mol), glacial acetic acid (45 mL, 0.78 mol) and toluene (500 mL) were stirred at reflux temperature for 18 hours in an apparatus fitted with a Dean-Stark trap. The reaction mixture was cooled to ambient temperature and solvent was removed in vacuo. The residue was dissolved in 6N HCl and the resulting solution was extracted with ether three times. A concentrated ammonium hydroxide solution was added to the aqueous layer until pH=11. The resulting semi-solution was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. Solvent was removed in vacuo to give a pale brown viscous oil (34.6 g, 75% yield): NMR (CDCl3, 300 MHz): 7.10 (s, 1H), 7.05 (d, 2H, J=1), 2.37 (s, 3H), 2.10 (s, 3H); CI-MS: 202 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[CH:11]12[O:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][NH:13][CH2:12]2.[OH-].[Na+]>O>[C:1]([N:13]1[CH2:12][CH:11]2[O:18][CH:15]([CH2:16][CH2:17]2)[CH2:14]1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)Cl
Reactant: C1CC2CNCC1O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCC(=O)N1CC2CCC(C1)O2
Reaction time: 2 h

Procedure:
Heptanoyl chloride (14.86 grams, 0.1 mole) was slowly added to a mixture of 8-oxa-3-azabicyclo(3.2.1)octane hydrochloride product of Example 3 (14.96 grams, 0.1 mole) and sodium hydroxide (10 grams) in 300 ml water, at 10° C. After the addition of heptanoyl chloride, the reaction mixture was stirred for 2 hours and then left overnight at room temperature. The product was extracted from the reaction mixture with diethyl ether and treated with DARCO G60 (activated carbon) After the removal of the diethyl ether, the product 3-heptanoyl-8-oxa-3-azabicyclo (3.2.1)octane was obtained as a clear liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)=[C:9]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:4][CH:3]=1>CCO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of ethyl(RS)-1-(4-fluorophenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (40 mg, 0.10 mmol) in EtOH (3 ml) was added 10% palladium on activated carbon (45 mg). The resulting suspension was stirred under an atmosphere of H2 overnight, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the title compound (40 mg, 100%), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5](F)=[N:6][CH:7]=1.[C@H:10]1([NH2:17])[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11]1>CS(C)=O>[Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5]([NH:16][C@H:13]2[CH2:14][CH2:15][C@H:10]([NH2:17])[CH2:11][CH2:12]2)=[N:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cc(I)c(Cl)cn1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(I)c(Cl)cn2)CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A mixture of 5-chloro-2-fluoro-4-iodopyridine (1000 mg, 3.88 mmol), DMSO (7 ml), and trans-cyclohexane-1,4-diamine (2661 mg, 23.31 mmol) reaction mixture was stirred at about 85° C. for 2 hours, followed by LCMS. The crude reaction mixture then was mixed with 5 ml DMSO, filtered and purified by prep LC. After lyapholization, 1.17 grams of the title compound was obtained as a TFA salt. LCMS (m/z): 352.1 (MH+), retention time=0.50 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][C:4]=1OCC)#[N:2].[CH3:16]C1C=C([N+]([O-])=O)C=CC=1C#N>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:10])=[O:11])=[CH:5][C:4]=1[CH3:16])#[N:2]
Reactant: Cc1cc([N+](=O)[O-])ccc1C#N
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Product: Cc1cc(S(=O)(=O)Cl)ccc1C#N

Procedure:
The titled compound was prepared analogously to 4-cyano-3-ethoxy-benzenesulfonyl chloride (Intermediate 127c) by replacing 2-ethoxy-4-nitro-benzonitrile with 2-methyl-4-nitro-benzonitrile.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:13][NH2:14])[CH:6]=[CH:7][C:8]=1[S:9](=[O:12])(=[O:11])[NH2:10].[F:15][C:16]([F:35])([F:34])[C:17](=O)[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)=[C:23]([CH3:32])[CH:22]=1)=O>>[F:2][C:3]1[CH:4]=[C:5]([N:13]2[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:28][CH:29]=[CH:30][CH:31]=4)=[C:23]([CH3:32])[CH:22]=3)=[CH:18][C:17]([C:16]([F:35])([F:15])[F:34])=[N:14]2)[CH:6]=[CH:7][C:8]=1[S:9]([NH2:10])(=[O:11])=[O:12]
Reactant: NNc1ccc(S(N)(=O)=O)c(F)c1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1ccco1
Agent: Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(N)(=O)=O)c(F)c2)ccc1-c1ccco1

Procedure:
The title compound was prepared according to the procedure of Example 60 using 3-fluoro-4-sulfamoylphenylhydrazine hydrochloride instead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride and 4,4,4-trifluoro-1-[4-(2-furyl)-3-methylphenyl]butane-1,3-dione instead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione in step 2.
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.Cl[CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O.O>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:12]=[C:3]([CH:2]([CH3:1])[C:15]([O:17][CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[O:16])[CH:4]=[CH:5]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CCN(CC)C(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Reaction time: 8 h
Yield: 87.4 %

Procedure:
Naproxen (1.07 g, 5 mmole) and 2-chloro-N,N-diethyl-acetamide (0.90 g, 6 mmole) were dissolved in 7 ml of N,N-dimethylformamide and triethylamine (1.4 ml, 10 mmole) and sodium iodide (76 mg) were added. The mixture was refluxed for 2 h, cooled and poured into 35 ml of water. The precipitate formed after standing overnight at 4° C. was collected by filtration, washed with water and recrystalized from 95% ethanol, yielding 1.5 g (92%) of the title compound. Mp 89°-89.5° C.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH3:19])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH2:20](I)C>>[CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH2:19][CH3:20])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(OC)c2ccn(C3CC3)c2c1
Reactant: CCI
Product: CCOC(=O)c1cc(OCC)c2ccn(C3CC3)c2c1

Procedure:
The compound was prepared according to the procedure for ethyl 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylate but using EtI in place of MeI.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]1)[C:14](=[O:27])[N:13]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)[C:12]2=[O:39])C1C=CC=CC=1>C(O)=O>[CH3:38][O:37][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[O:35][CH3:36])[CH2:28][N:13]1[C:12](=[O:39])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[N:15]([CH:19]2[CH2:20][CH2:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24]2)[C:14]1=[O:27]
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCS(=O)(=O)CC3)c2=O)cc1OC
Solvent: O=CO
Product: COc1ccc(Cn2c(=O)c3cc(O)ccc3n(C3CCS(=O)(=O)CC3)c2=O)cc1OC

Procedure:
A mixture of 0.42 g of the compound obtained in Step 18.1 and 3.66 g of formic acid is irradiated in a microwave field for 10 minutes at 180° C. The reaction mixture is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture from (100/0, v/v) to (90/10, v/v), to give the expected product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)([OH:15])[CH2:11][CH2:10]2)[N:3]=1.[OH-:23].[Na+]>>[Cl:1][C:2]1[NH:7][C:6](=[O:23])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)([OH:15])[CH2:11][CH2:10]2)[N:3]=1
Reactant: OC1(c2ccc(F)cc2)CCN(c2nc(Cl)nc(Cl)n2)CC1
Reactant: [OH-]
Agent: [Na+]
Product: O=c1nc(N2CCC(O)(c3ccc(F)cc3)CC2)nc(Cl)[nH]1
Yield: 58.5 %

Procedure:
1-(4,6-Dichloro-1,3,5-triazin-2-yl)-4-(4-fluorophenyl)piperidin-4-ol (304 mg, 0.89 mmol) synthesized in Reference Synthesis Example 12 and 1 M sodium hydroxide aqueous solution (1.80 mL, 1.80 mmol) were used to obtain the title compound (169 mg, yield 59%) by synthesis in a similar manner to Reference Synthesis Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:16]([NH:17][CH2:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccn1
Reactant: Nc1cccc2nc(-c3cccc(Cl)c3)oc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Clc1cccc(-c2nc3cccc(NCc4ccccn4)c3o2)c1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a stirred suspension of 2-(3-chlorophenyl)-7-amino-benzoxazole (1.10 g, 0.0045 mol) in 10 ml of methanol, 2.5 ml of 1 N HCl in methanol, was added. 2-pyridinecarboxaldehyde(0.043 g, 0.0040 mol) was added to this suspension followed by sodium cyanoborohydride (0.32 g, 0.0051 mol) and the pH was adjusted to 6 using 1 N HCl in methanol. After 1 hour, 1 N sodium hydroxide was added to bring the pH to 10 and the reaction was extracted with 3×50 ml of ethyl acetate. The combined ethyl acetate extractions were washed with water, dried and evaporated to give 1.3 g of yellow solid. This solid was purified by flash chromatography over silica gel using 50:50 CH2Cl2 in hexane to give 0.25 g of recovered starting material, followed by 0.90 g of product when the eluting solvent was CH2Cl2. This solid was recrystallized from 100 ml of hexane to give 0.78 g of the title compound, mp 115-116° C.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]1(C)[S:20]CN=[N:17]1)=[C:7]2[C:11]([OH:13])=[O:12].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[K+].[NH2:32][CH:33]1C(=O)N2[CH:34]1SCC(CSC1SC(C)=NN=1)=C2C(OC(C1C=CC=CC=1)C1C=CC=CC=1)=O>O.O1CCCC1>[CH3:34][C:33]1[N:17]=[C:16]([S:15][CH2:14][C:6]2[CH2:5][S:4][CH:3]3[N:8]([C:9](=[O:10])[CH:2]3[NH2:1])[C:7]=2[C:11]([OH:13])=[O:12])[S:20][N:32]=1
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Reactant: CC1(SCC2=C(C(=O)O)N3C(=O)C(N)C3SC2)N=NCS1
Agent: O=C([O-])O
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nsc(SCC2=C(C(=O)O)N3C(=O)C(N)C3SC2)n1
Reaction time: 0.5 h

Procedure:
18 g. of 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are suspended in 350 ml. of tetrahydrofuran. 4.1 ml. of 70% perchloric acid are added dropwise. After 30 minutes, a slightly turbid solution forms. This solution is filtered and to the filtrate is added dropwise with stirring 12 g. of diphenyldiazomethane and 20 ml. of tetrahydrofuran. After three hours, the reaction mixture is poured into 2 liters of absolute ether. The solid, light brown precipitate, which is the perchloric acid salt of the desired product, is dried over Kieselgel in a desiccator. To obtain the base, the perchloric acid salt is dissolved in water and treated with the calculated equivalent of potassium bicarbonate. The aqueous solution obtained is extracted with chloroform. The chloroform phase is treated with activated carbon and sodium sulfate to obtain the 10 g. of the product, 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2 -ene-2-carboxylic acid, diphenylmethyl ester, as a light brown powder, m.p. 157°-159°. The product is recrystallized from tetrahydrofuran/petroleum ether. The isomeric thiadiazolyl derivative is similarly obtained from the product of Example 20.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH:15](O)[CH2:14]2)[CH2:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(N(S(F)(F)[F:37])CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH:15]([F:37])[CH2:14]2)[CH2:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(C2CC(=O)N(Cc3ccccc3)C2)CC(O)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(C2CC(=O)N(Cc3ccccc3)C2)CC(F)C1
Reaction time: 20 h
Yield: 80 %

Procedure:
A 495 mg (1.56 mmol) portion of 1-benzyl-4-[3-(ethoxycarbonyl)-1-hydroxycyclobutan-3-yl]-2-pyrrolidone (Isomer A) was dissolved in a mixed solvent consisting of 12 ml of toluene and 6 ml of dichloromethane to which, while cooling in an ice bath with stirring, was then added 839 μl (6.24 mmol) of diethylaminosulfur trifluoride, subsequently carrying out 20 hours of stirring at 40° C. While cooling in an ice bath with stirring, the reaction solution was alkalified by slowly adding saturated sodium bicarbonate aqueous solution and then mixed with chloroform to carry out separation of layers, and the resulting organic layer was washed with saturated brine. The aqueous layer was again extracted with chloroform, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure and the resulting residue was purified by a silica gel column chromatography (n-hexane:ethyl acetate=2:1) to give 400 mg (80.0%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]([NH2:16])=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:15]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
4-Amino-1H-pyrazole-3-carboxylic acid (4-fluorophenyl)-amide (500 mg; 2.27 mmol) was dissolved in 5 ml of pyridine, treated with acetic anhydride (240 μl, 2.5 mmol) then stirred at room temperature overnight. The solvent was removed by evaporation then dichloromethane (20 ml) and 2M hydrochloric acid (20 ml) were added. The undissolved solid was collected by filtration, washed with more dichloromethane and water then dried under vacuum. The product was isolated as an off white solid (275 mg). (LC/MS: Rt 2.96, [M+H]+262.91).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[NH:16][C:17](=O)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=1)[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl.O.[OH-].[NH4+]>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]2[N:6]([CH2:5][CH2:4][N:3]([CH2:29][CH3:30])[CH2:1][CH3:2])[C:7]3[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=3[N:16]=2)=[CH:20][CH:21]=1)[CH3:27]
Reactant: CCOc1ccc(CC(=O)Nc2cc([N+](=O)[O-])ccc2NCCN(CC)CC)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3n2CCN(CC)CC)cc1
Temperature: 25 °C

Procedure:
N-[2-(2-Diethylamino-ethylamino)-5-nitro-phenyl]-2-(4-ethoxy-phenyl)-acetamide 6a (295 mg, 0.712 mmol), Phosphorous pentachloride (148.3 mg, 0.712 mmol) were dissolved in anhydrous chloroform (10 mL) in a small, argon purged flask fitted with a condenser and magnetic stirbar. The solution was heated to reflux in an oil bath for 4 hours and cooled to room temperature overnight. The mixture was diluted with H2O and chloroform and 2M ammonium hydroxide solution added to adjust pH to 9-10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with chloroform and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated to afford crude. The product was purified using dry silica gel column chromatography eluting with 25 mL portions of solvent system (2.5% 2M NH3 in methanol/95% dichloromethane) to afford a yellow residue. Recrystallization from diethyl ether/hexanes at 0° C. yielded a pale yellow solid 7a {2-[2-(4-Ethoxy-benzyl)-5-nitro-benzoimidazol-1-yl]-ethyl}-diethyl-amine. Yield: 177 mg (62.7%). 1H NMR (DMSO) : 0.71 (t, 6H, J=7.0), 1.29 (t, 3H, J=7.0), 2.37 (q, 4H, J=7.1), 2.50 (m, 2H), 3.98 (q, 2H, J=6.9), 4.25 (m, 2H), 4.32 (s, 2H), 6.87 (d, 2H, J=8.4), 7.19 (d, 2H, J=8.4), 7.71 (d, 1H, J=8.9), 8.14 (dd, 2H, J=8.9, 2.1), 8.45 (d, 1H, J=2.1); MS (ESI): 397 (MH+, 100%)
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]12[CH:13]([CH2:14][N:15]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[C:25]([F:35])[CH:24]=3)[C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[O:17])[CH:12]1[CH2:11][NH:10][CH2:9]2.[CH:36](=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH2:36]([N:10]1[CH2:11][CH:12]2[CH:8]([CH:13]2[CH2:14][N:15]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[CH2:9]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(c1cccs1)N(CC1C2CNCC21)c1ccc(N2CCOCC2)c(F)c1
Reactant: O=Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cccs1)N(CC1C2CN(Cc3ccccc3)CC21)c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of the Thiophene-2-carboxylic acid (3-aza-bicyclo[3.1.0]hex-6-ylmethyl)-(3-fluoro-4-morpholin-4-yl-phenyl)-amide trifluoroacetic acid salt prepared above (100 mg, 0.16 mmol) in 4 mL of CH2Cl2 at room temperature was added benzaldehyde (0.02 mL, 0.24 mmol) and NaHB(OAc)3 (50 mg, 0.24 mmol). The reaction stirred at room temperature for 2 hours. The reaction was quenched by the addition of saturated NaHCO3, the layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting crude material was purified via flash chromatography with 75% EtOAc/hexanes. The product containing fractions were collected and concentrated to yield 32 mg of the desired product. 400 MHz 1H NMR (CDCl3) δ 7.17-7.29 (m, 6H), 6.94-6.98 (m, 4H), 6.78-6.80 (m, 1H), 3.86-3.88 (m, 4H), 3.65 (d, J=7.47 Hz, 2H), 3.52 (brs, 2H), 3.09-3.12 (m, 4H), 2.86-2.88 (m, 2H), 2.26-2.28 (m, 2H), 1.63 (brs, 1H), 1.47 (brs, 1H), 1.21-1.25 (m, 1H); MS (M+1) 492.2.