Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CSC[N:4]1C(S)=NN=N1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)CN)C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)CCN)C1C=CC=CC=1.C([O:64][C:65]([CH2:67][N:68]1[C:72]([SH:73])=[N:71][N:70]=[N:69]1)=O)C1C=CC=CC=1.N>>[C:65]([CH2:67][N:68]1[C:72]([SH:73])=[N:71][N:70]=[N:69]1)(=[O:64])[NH2:4]
Reactant: O=C(Cn1nnnc1S)OCc1ccccc1
Reactant: CSCn1nnnc1S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Agent: NCC(=O)OCc1ccccc1
Product: NC(=O)Cn1nnnc1S

Procedure:
The reactions described in Reference Example 10 (1) and (2) were carried out using glycine benzyl ester p-toluenesulfonate in lieu of β-alanine benzyl ester p-toluenesulfonate to prepare 1-benzyloxycarbonylmethyl-1H-tetrazole-5-thiol, which was then converted with alcoholic ammonia into the captioned compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])/[C:12](=[CH:15]/[CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)/[CH2:11][C:10]2=[O:22])=[C:4]([CH3:23])[CH:3]=1>CO.[Pd]>[CH:16]1([CH2:15][CH:12]2[CH2:11][C:10](=[O:22])[CH:9]([C:5]3[C:6]([CH3:8])=[CH:7][CH:2]=[CH:3][C:4]=3[CH3:23])[C:13]2=[O:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)C/C(=C\C2CCCCC2)C1=O
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C)c1C1C(=O)CC(CC2CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
To a solution of 2-(4-bromo-2,6-dimethyl-phenyl)-4-[1-cyclohexyl-meth-(E)-ylidene]-cyclopentane-1,3-dione (250 mg, 0.844 mmol) in methanol (25 ml) was added 10% palladium on carbon (50 mg, 20%) and stirred at room temperature under hydrogen balloon pressure for 7-8 hours. The reaction mixture was filtered through celite bed, concentrated under high vacuum. Compounds were separated by auto prep purification system to give 4-cyclohexylmethyl-2-(2,6-dimethyl-phenyl)-cyclopentane-1,3-dione.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]=1[OH:18])=[O:3].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:27]([C:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][CH2:32][CH2:33]Br)#[N:28]>CN(C)C=O.O>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:2][CH:1]=2)=[O:3])=[C:5]([O:18][CH2:33][CH2:32][CH2:31][CH2:30][C:29]([CH3:36])([C:27]#[N:28])[CH3:35])[CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C#N)CCCCBr
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C#N)CCCCOc1cc(OCc2ccccc2)ccc1C(=O)c1ccccc1
Yield: 111 %

Procedure:
A solution of 4-benzyloxy-2-hydroxyacetophenone (2.45 g), potassium carbonate (3.25 g), potassium iodide (0.42 g), and 5-cyano-5-methyl-1-bromohexane (2.6 g) in dimethylformamide (40 mL) was heated at 90° C. for 22 hours under nitrogen. The slurry was cooled, poured into water (150 mL) and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4), filtered, and concentrated under reduced pressure to an orange oil. This was purified by flash chromatography (ethyl acetate:hexane) to afford the product (2.4 g) as a clear oil. NMR(CDCl3): 1.37, s (6H); 1.64, m (4H); 1.89, m (2H); 2.58, s (3H); 4.03, t (3H); 5.09, s (2H); 6.50, s (1H); 6.58, d (1H); 7.37, m (5H); 7.81, d (1H). Mass Spec (GC-MS) m/z=365 (M).
Reaction SMILES: [ClH:1].C[O:3][C:4]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@H:9]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[C:27](=[O:28])[C:26]4=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]4[C:24]3=[O:33])[C:8]=2[CH:7]=[CH:6][CH:5]=1.B(Br)(Br)Br.[OH-].[Na+].C(=O)([O-])O.[Na+].Cl>C(Cl)Cl.C(O)C.O>[ClH:1].[OH:3][C:4]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@H:9]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[C:24](=[O:33])[C:25]4=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]4[C:27]3=[O:28])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCCCN1C(=O)c2ccccc2C1=O
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCCCN1CC[C@@H]2c3cccc(O)c3CC[C@@H]21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.1 %

Procedure:
A solution of 1.80 g (0.004 mol) of rac-cis-N-[6-(1,2,3a, 4,5,9b-hexahydro-6-methoxy-3H-benzo[e]indol-3-yl)hexyl]phthalimide hydrochloride in 100 ml of methylene chloride was treated dropwise with a solution of 1.8 ml (0.019 mol) of boron tribromide in 10 ml of methylene chloride. The mixture was stirred at room temperature for 1.5 hours, subsequently treated dropwise with 25 ml (0.05 mol) of 2N sodium hydroxide solution while cooling with an ice bath and then poured into water, whereupon aqueous sodium hydrogen carbonate solution was added until a pH of 8 had been reached. The mixture was extracted with chloroform, the extracts were dried over sodium sulphate and the solvent was distilled off in a vacuum. The residue was chromatographed over silica gel with methylene chloride/methanol (20:1). The oil obtained was dissolved in ethanol and treated with ethanolic HCl. Distillation of the solvent and recrystallization from methanol gave 0.93 g (53%) of rac-cis-N-[6-(1,2,3a,4,5,9b-hexa-hydro-6 -hydroxy-3H-benzo[e]indol-3-yl)-hexyl]phthalimide hydrochloride as white crystals with m.p. 218°.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[N:24]([CH2:25][C:26]([NH2:28])=[O:27])[N:23]=[N:22][N:21]=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[N:24]([CH2:25][C:26](=[O:27])[NH2:28])[N:23]=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: NC(=O)Cn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(=O)Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 1 h

Procedure:
7-Aminocephalosporanic acid (5.44 g., 20 mmole) and 5-Mercapto-1H-tetrazol-1-ylacetamide (3.50 g., 2.2 mmole) were suspended in 50% aqueous acetone (200 ml) and solid sodium bicarbonate added until a clear solution was obtained, ~pH 7.0. The solution was heated at 60° for 6 hours, uncovered for the final hour which allowed most of the acetone to evaporate, then acidified to pH 4.0 and stirred in an ice bath for one hour. The solid product was collected, washed with a little cold water and dried in vacuo, 3.22 g (43.4%), δ(CF3CO2H) 4.00 (2H,bs, C2 methylene), 4.69 (2H,bs, --CH2S--), 5.56 (4H,s, --CH2CO2NH2 and β-lactam protons), 7.4-7.8 (2H,m, --CONH2).
Reaction SMILES: [C:1](/[C:3](=[C:5]1/[C:6]2[CH:19]=[CH:18][C:17]([C:20](OC)=[O:21])=[CH:16][C:7]=2[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]/1=2)/[CH3:4])#[N:2].[BH4-].[Li+].Cl>C1COCC1>[OH:21][CH2:20][C:17]1[CH:18]=[CH:19][C:6]2=[C:7]([CH:16]=1)[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[C:5]/2=[C:3](/[CH3:4])\[C:1]#[N:2]
Reactant: COC(=O)c1ccc2c(c1)OCc1ccccc1/C2=C(/C)C#N
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C(C#N)=C1/c2ccccc2COc2cc(CO)ccc21
Temperature: 50 °C
Reaction time: 6 h
Yield: 83.8 %

Procedure:
[step 2] Methyl (E)-11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepine-3-carboxylate (6.40 g, 21.0 mmol) was suspended in THF (105 mL), and the solution was added with lithium borohydride (2.29 g, 105 mmol), followed by stirring at 50° C. for 6 hr. Ice was added to the reaction mixture, and the mixture was neutralized with 1 mol/L hydrochloric acid to pH 2, and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70) to give the title compound (4.89 g, 17.6 mmol, 84.1%).
Reaction SMILES: Br[C:2]1[C:3]([O:20][CH:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:4][C:5]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:19])[C:11]3[C:6]=2[C:7]=1[CH:8]=[CH:9][CH:10]=3.C(=O)([O-])[O-].[Na+].[Na+].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[SH:43].CN(C=O)C>O>[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43][C:2]1[C:3]([O:20][CH:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:4][C:5]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:19])[C:11]3[C:6]=2[C:7]=1[CH:8]=[CH:9][CH:10]=3
Reactant: CC(C)CC(CC(C)C)Oc1cc2c3c(cccc3c1Br)C(=O)c1ccccc1-2
Reactant: Nc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(CC(C)C)Oc1cc2c3c(cccc3c1Sc1ccccc1N)C(=O)c1ccccc1-2
Temperature: 125 °C

Procedure:
A 500 ml three neck round bottom flask was equipped with a mechanical stirrer, heating mantle and condenser. To the flask was added 52.5 g (0.11 mole) of 3-bromo-2-(1-isobutyl-3-methylbutoxy)-7H-benzo[de]anthracene-7-one (4), 9.2 g (0.087 mole) sodium carbonate, 16.0 g (0.13 mole) 2-aminothiophenol and 170 g DMF. The mixture was agitated well and heated at 120-130° C. for three hours. The reaction was cooled to 25° C. and 300 g water was added. The reaction mixture was extracted twice with 250 g chloroform. The organic layers were combined and washed twice with 250 g water. The solvent was removed on a rotary evaporator. The yield of crude product was 55 g of a dark brown oil which was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:28][CH2:27][CH2:26][C@:8]3([C:12](=[O:13])[NH:11][C:10](=[O:14])[N:9]3C(=O)N[C@@H](C3C=CC=CC=3)C)[C:6]=2[CH:7]=1.C[O-].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:28][CH2:27][CH2:26][C@:8]3([C:12](=[O:13])[NH:11][C:10](=[O:14])[NH:9]3)[C:6]=2[CH:7]=1
Reactant: C[C@@H](NC(=O)N1C(=O)NC(=O)[C@]12CCOc1ccc(F)cc12)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: O=C1NC(=O)[C@]2(CCOc3ccc(F)cc32)N1
Yield: 36 %

Procedure:
In like manner, when pure (4R)-6-fluoro-2,3dihydro-3'-[(R)-1-phenylethylcarbamoyl]spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione [the (R) (R)-diastereomer product of Example 1] and sodium methoxide were reacted together in accordance with this same procedure (using the same molar proportions as before), there was eventually obtained (after work-up) a 36% yield of pure (4R)-(-)-6-fluoro-2,3-dihydro-spiro-[4H-1-benzopyran-4,4'-imidazolidine]2',5'-dione in the form of a white crystalline solid melting at 235°-237° C.; [α]D25° -54.1° (c=1 in methanol). This product was also substantially identical in every respect with the corresponding final product first reported as 1-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione m.p. 241°-243° C.; [α]D25° -54.8° (c=1 in methanol)] by R. Sarges in Example I of U.S. Pat. No. 4,130,174.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:12][N:13]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].O.NN>CCO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:12][NH2:13])[CH2:9][CH2:10][CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC[C@H](CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Agent: NN
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCC[C@H](CN)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of [(R)-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-butyl]-carbamic acid tert-butyl ester (1.2 g, 3.61 mmol) and hydrazine monohydrate (1.0 mL, 20.6 mmol) in EtOH (25 mL) and DCM (75 mL) is stirred at RT for 48 h. The precipitated solid is removed by filtration and washed with DCM. The filtrate is concentrated in vacuo to afford the title compound as white solid that is used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:24][N:25]1[CH:29]=[C:28]([C:30]2[CH:31]=[C:32]([C:36]3[N:41]=[CH:40][C:39]([C:42]4[CH:43]=[N:44][NH:45][CH:46]=4)=[CH:38][N:37]=3)[CH:33]=[CH:34][CH:35]=2)[CH:27]=[N:26]1>CC(N(C)C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:44]2[CH:43]=[C:42]([C:39]3[CH:38]=[N:37][C:36]([C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([C:28]5[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=5)[CH:31]=4)=[N:41][CH:40]=3)[CH:46]=[N:45]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cn[nH]c4)cn3)c2)cn1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(CC5CN(C(=O)OC(C)(C)C)C5)c4)cn3)c2)cn1
Yield: 131.9 %

Procedure:
A solution of 3-Methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester (Matrix scientific, 200 mg; 0.68 mmol; 1.0 eq.), cesium carbonate (442 mg; 1.36 mmol; 2.0 eq.) and 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1H-pyrazol-4-yl)pyrimidine (example 3, 205 mg; 0.68 mmol; 1.0 eq.) in dry DMA (3 mL) was heated at 100° C. O/N. The reaction mixture was then diluted with water and extracted with EtOAc (three times). Combined organic phases were washed with brine (three times), dried over magnesium sulfate, filtered and concentrated. The crude was dissolved in DMSO and precipitated by addition of acetonitrile. It was filtered, rinced with acetonitrile and dried under vacuum to give the title compound as a yellow powder (423 mg, quantitative). MS (ESI+): 472.3.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH2:33][C:34]1[CH:39]=[C:38]([CH2:40][OH:41])[CH:37]=[C:36]([CH2:42][OH:43])[CH:35]=1.[C:44]([OH:47])(=[S:46])[CH3:45]>C1COCC1>[C:44]([S:46][CH2:33][C:34]1[CH:39]=[C:38]([CH2:40][OH:41])[CH:37]=[C:36]([CH2:42][OH:43])[CH:35]=1)(=[O:47])[CH3:45]
Reactant: CC(O)=S
Reactant: OCc1cc(CO)cc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SCc1cc(CO)cc(CO)c1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 33.5 %

Procedure:
To a solution of triphenylphosphine (577 mg, 2.2 mmol) in anhydrous THF (5 mL) was added diethyl azodicarboxylate (2.2 M in toluene, 791 μL, 1.7 mmol) dropwise at 0° C. After stirred at 0° C. for 50 minutes, a solution of 1,3,5-tri(hydroxymethyl)benzene (269 mg, 1.6 mmol, prepared by reduction of trimethyl 1,3,5-benzenetricarboxylate with lithium aluminum hydride in THF, co-evaporated with dry benzene and dried on high vacuum for couple hours before use) and thioacetic acid (108 μL, 1.45 mmol) in dry THF (4 mL) was added dropwise. After 1 hour, the ice/water bath was removed and the reaction was stirred at room temperature for 15 hours. The solvents were removed by rotary evaporation in vacuo. The residue was purified by flash chromatography to give 5-acetylthiomethyl-1,3-bis(hydroxymethyl)-benzene as colorless solid (110 mg). 1H NMR (400 Hz, CDCl3): δ 7.13-6.99 (m, 3H), 4.45 (apt, J=20.4 Hz, 4H), 3.98 (apt, J=20.4 Hz, 4H), 3.73 (bs, 2H), 2.24 (apt, J=20.4 Hz, 3H); MS (ESI): m/z 249.0 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][CH:14]=[N:13][C:12]=2[N:11](COCC[Si](C)(C)C)[CH:10]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+].C(N)CN>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][CH:14]=[N:13][C:12]=2[NH:11][CH:10]=1
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(-c3ccccc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: COc1ccccc1-c1c[nH]c2ncnc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(2-methoxyphenyl)-4-phenyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (60 mg, 0.13 mmol) in DCM (1.0 mL) was added TFA (0.964 mL, 12.5 mmol) and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was redissolved in MeOH (1.0 mL). 10 M aqueous NaOH (0.088 mL, 0.88 mmol) and ethylenediamine (17 μL, 0.25 mmol) were then added and the reaction was stirred for 30 minutes at room temperature. The reaction mixture was then acidified with TFA and purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The combined fractions with the desired product were concentrated until only the water layer remained. The water layer was neutralized with 2 M aqueous potassium bicarbonate and the mixture was extracted with ethyl acetate (×5). The combined organic fractions were dried with sodium sulfate, filtered and concentrated under reduced pressure to give 5-(2-methoxyphenyl)-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine. LRMS (ESI) calc'd for C19H16N3O [M+H]+: 302, found 302. 1H NMR (600 MHz, DMSO-D6) δ 12.34 (s, 1H); 8.83 (s, 1H); 7.57 (d, 1H, J=2.3 Hz); 7.31 (m, 3H); 7.22 (m, 2H); 7.07 (t, 2H, J=7.6 Hz); 6.93 (t, 1H, J=7.6 Hz); 6.52 (d, 1H, J=8.2 Hz); 3.33 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@H:17]3[CH3:26])=[CH:12][N:11]=2)=[CH:5][C:4]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([N:33]3[C:45](=[O:46])[C:44]4[S:43][C:42]5[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=5[C:36]=4[CH:35]=[N:34]3)[C:28]=2[CH:47]=[O:48])=[CH:3]1.[BH4-].[Na+]>CO>[OH:48][CH2:47][C:28]1[C:29]([N:33]2[C:45](=[O:46])[C:44]3[S:43][C:42]4[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=4[C:36]=3[CH:35]=[N:34]2)=[N:30][CH:31]=[CH:32][C:27]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:23][O:24][CH2:25]4)[CH2:18][C@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
A mixture of 154a (150 mg, 0.23 mmol), NaBH4 (35 mg, 0.92), and methanol (10 mL) was stirred at room temperature for 1 h. The mixture was then quenched with water (8 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×10 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 154 (29 mg, 19%). MS-ESI: [M+H]+ 667. 1H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J=2.5 Hz, 1H), 8.56 (d, J=5.0 Hz, 1H), 8.49-8.47 (m, 2H), 7.85 (d, J=3.0 Hz, 1H), 7.53 (d, J=5.0 Hz, 1H), 7.48 (d, J=2.5 Hz, 1H), 7.38-7.36 (m, 1H), 7.24 (d, J=8.5 Hz, 1H), 4.85 (t, J=9.5 Hz, 1H), 4.57-4.54 (m, 2H), 4.43-4.36 (m, 4H), 3.69-3.68 (m, 1H), 3.60 (s, 3H), 3.40-3.36 (m, 1H), 3.11-3.07 (m, 1H), 2.97-2.86 (m, 6H), 2.33-2.31 (m, 2H), 2.16 (t, J=8.5 Hz, 1H), 1.89-1.86 (m, 4H), 0.92 (d, J=6.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[N:21]([CH3:36])[C:20]1=[O:37]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]([CH3:36])[C:20]2=[O:37])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (prepared as described in Bock M. G.; DiPardo, R. M.; Evans, B. E.; Rittle, K. E.; Veber, D. F.; Freidinger, R. M.; Hirshfield, J.; Springer, J. P. J. Org. Chem. 1987, 52, 3232), the title compound was prepared as a solid having a melting point of 152-160° C. The reaction was monitored by tlc on silica gel (Rf=0.15 in 50% ethyl acetate/hexanes) and purification was by silica gel chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1.O>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH2:10][O:11][Si:16]([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(CO)cc1Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COc1ccc(CO[Si](C)(C)C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.8 %

Procedure:
To a solution of 98.8 g of the compound obtained in Step 204-1 in DMF (455 ml) was added 72.0 g of TBSCl and 62.0 g of imidazole under ice cooling, and the reaction mixture was stirred for 10 minutes. The solution was warmed to room temperature then stirred for two hours, water and Et2O were added and liquid separation was performed. The organic layer was washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. n-hexane was used on the obtained solid residue for a recovery by filtration to obtain 152 g of the title compound.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[NH:12][C:11]3=[O:19])=[CH:4][C:3]=2[O:2]1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[C:11]1=[O:19])(=[O:22])[CH3:21]
Reactant: O=c1[nH]c2cccnc2n1-c1ccc2c(c1)OCO2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)n1c(=O)n(-c2ccc3c(c2)OCO3)c2ncccc21

Procedure:
A suspension of 500 mg. of 1,3-dihydro-3-(3,4-methylenedioxyphenyl)imidazo[4,5-b]pyridin-2-one in 15 ml. of acetic anhydride was heated on a steam bath overnight. The solution was evaporated in vacuo leaving a crystalline residue which was recrystallized from 20 ml. of benzene to give 1-acetyl-3-(3,4-methylenedioxyphenyl)-1,3-dihydroimidazo[4,5-b]pyridin-2-one, m.p. 211°-212° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[S:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][O:20][CH2:21][C:22]([OH:24])=[O:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:19]([CH3:18])[O:20][CH2:21][C:22]([OH:24])=[O:23])=[S:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOCC(=O)O
Reactant: S=C=Nc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(OCC(=O)O)C(=S)Nc1ccc(Oc2ccccc2)cc1
Yield: 101.2 %

Procedure:
A mixture of 4-phenoxyphenyl-isothiocyanate (11.35 g), N-methyl aminooxy acetic acid hydrochloride (7.1 g), triethylamine (10.5 g) and chloroform (300 mL) was heated at reflux for three hours, then evaporated to dryness. The residue was dissolved in ethyl acetate (600 mL) and washed with 2N HCl (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness to give (16.8 g) of [[[[(4-phenoxyphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as an oil. 1H-NMR (DMSO-d6; 300 Mhz) δ13.10 (br s, 1H), 10.50 (s, 1H), 7.50 (m, 2H), 7.38 (m, 2H), 7.12 (t, 1H), 6.98 (m, 4H), 4.63 (s, 2H), and 3.52 ppm (s, 3H). The acid (16.8 g) was dissolved in benzene (300 mL). Phosphorus pentachloride (10.4 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (600 mL) and washed with sodium bicarbonate saturated solution (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (40% methylene chloride in hexane). The title compound (8.6 g) was obtained as a solid, m.p. 159-160° C. Mass spectrum (El, M.+) m/z 314. 1H-NMR (DMSO-d6; 400 MHz) δ7.43 (m, 2H), 7.19 (m, 3H), 7.09 (m, 2H), 7.00 (m, 2H), 5.07 (s, 2H), and 3.68 ppm (s, 3H).