Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@H:15]3[S@@:14](=O)[C:13]2([CH3:33])[CH3:32])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:36]([N:39]=[C:40]=[O:41])(=[O:38])[CH3:37].S1[C@@H]2CC(=[O:49])N2CC1>O1CCOCC1>[N+:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@H:15]3[S:14][C@:13]2([CH2:33][O:41][C:40](=[O:49])[NH:39][C:36](=[O:38])[CH3:37])[CH3:32])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC1(C)[C@H](C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2[S@]1=O
Reactant: O=C1C[C@H]2SCCN12
Reactant: CC(=O)N=C=O
Solvent: C1COCCO1
Product: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 40.2 %

Procedure:
A solution of (1S,3S,5R,6R) 2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxide p-nitrobenzyl ester (25.18 g, 50.0 mmol), acetyl isocyanate (8.50 ml, 9.53 g, 112 mmol), and dioxane (250 ml) was refluxed under nitrogen for 5 hours, cooled and concentrated in vacuo to a yellow foam. The foam was chromatographed on silica gel (1.7 Kg) with methylene chloride:acetone; 9:1; v:v to give four products; the 3-methyl-Δ3 -cephem; starting sulfoxide, the title penam, and the cephem (in order of elution). The penam fractions were concentrated to a colorless foam in 40.2% yield (11.80 g). Re-chromatography of a portion gave an analytical sample: m.p. 83°-85°; nmr 100 MHz (CDCl3) ppm 8.40 (1,s, ##STR59## 8.20 (2, d, J=8.5, 1/2 aromatic AB pNB), 7.56 (3, d, J=8.5 over m, 1/2 AB, pNB and C6 --NH), 7.5 (2, m) and 6.9 (3, m, O--Ph--H's), 5.7 (2, m's, C5 --C6 --H's), 5.32 (2, br s, pNB methylene), 4.88 (1, s, C3 --H), 4.56 (2, s, ##STR60## 4.26 and 4.06 (2, d's,J=11.5, AB of C2 --CH2O), 2.22 (3, s, ##STR61## and 1.47 (3, s, C2 --CH3); nmr 13C 4 carbonyls ca 170 ppm, carbamate carbonyl C 157.0, C2 singlet at 67.4, while C2 --CH2O is t at 72.3, and C2 --CH3 is q at 21.7.
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:11][CH:10]=[N:9][C:8]=1[O:12][CH2:13][CH:14]1[CH2:16][O:15]1.[CH3:17][CH:18]([Si:20](Cl)([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH3:19]>C1COCC1>[CH:18]([Si:20]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[C:10]1[S:11][C:7]2[CH:14]([CH2:16][OH:15])[CH2:13][O:12][C:8]=2[N:9]=1)([CH3:19])[CH3:17]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1scnc1OCC1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](c1nc2c(s1)C(CO)CO2)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
At −78° C., a soln. of n-BuLi in hexanes (2.18 M, 16.7 mL, 36.4 mmol) was added over 30 min to a soln. of 5-bromo-4-(oxiran-2-ylmethoxy)thiazole (7.17 g, 30.4 mmol) in THF (564 mL). The mixture was stirred at −78° C. for 2 h, then, TIPSCl (6.63 mL, 31.0 mmol) was added, the mixture was allowed to warm to RT and stirred at RT for 30 min. Subsequently, the mixture was cooled to −78° C. and treated with a soln. of n-BuLi in hexanes (2.18 M, 13.9 mL, 30.4 mmol). The mixture was stirred at 0° C. for 2 h, then, it was quenched with aq. sat. NaHCO3 and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. The residue was purified by means of CC (5-50% EtOAc/Hept) to provide a yellow oil.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[N:9][N:8]2[CH2:11][CH2:12][NH:13][C:7]=12)=O)C.[H-].COCCO[Al+]OCCOC.[Na+].[H-].O1CCCC1>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[CH3:4][C:6]1[CH:10]=[N:9][N:8]2[CH2:11][CH2:12][NH:13][C:7]=12
Reactant: CCOC(=O)c1cnn2c1NCC2
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cnn2c1NCC2
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of 2,3-dihydro-7-ethoxycarbonyl-1H-imidazo[1,2-b]pyrazole (5 g) in xylene (27 ml) was added dropwise 3.4M solution (27 ml) of sodium bis(2-methoxyethoxy)aluminum hydride in toluene under ice-cooling. The mixture was stirred at room temperature and then stirred at 140° C. for 3.5 hours. The reaction mixture was cooled at 5° C. and poured into a mixture of ice-water (100 ml) and tetrahydrofuran (100 ml). The insoluble material was filtered off and the filtrate was separated. The aqueous layer was extracted with tetrahydrofuran. The organic layer and extract were combined and dried over magnesium sulfate. The solvent was evaporated to give 2,3-dihydro-7-methyl-1H-imidazo[1,2-b]pyrazole (2.04 g).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11])[C:4]=2[CH2:3][O:2]1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=1>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][C:14]([NH:13][S:10]([C:9]2[C:4]3[CH2:3][O:2][CH2:1][C:5]=3[CH:6]=[CH:7][CH:8]=2)(=[O:12])=[O:11])=[O:15])[N:19]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1cccc2c1COC2
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2COC3)n1
Reaction time: 1.75 h

Procedure:
A 7.0 ml portion of the methylene chloride solution of 1,3-dihydrobenzo[c]furan-4-sulfonyl isocyanate prepared in Example 4 was added to a stirred suspension of 0.78 g of 4-methoxy-6-methylpyrimidin-2-amine in 20 ml of methylene chloride. After several minutes the amine dissolved, followed by formation of a precipitate. After stirring for 1.75 hours, the solid was collected, washed with methylene chloride and 1-chlorobutane, then dried to give 1.4 g of 1,3-dihydro-N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]benzo[c]furan-4-sulfonamide, m.p. 190°-194° (d).
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[C@H:3]([NH:31][C:32](=[O:35])[O:33][CH3:34])[C:4](=[O:30])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1.Br[C:38]1[CH:39]=[C:40]2[C:63](=[CH:64][CH:65]=1)[C:44]1[NH:45][C:46]([C@@H:48]3[CH2:52][C@H:51]([CH2:53][O:54][CH3:55])[CH2:50][N:49]3[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[N:47][C:43]=1[CH:42]=[CH:41]2.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:34][O:33][C:32]([NH:31][C@@H:3]([CH:2]([CH3:36])[CH3:1])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:38]3[CH:39]=[C:40]4[C:63](=[CH:64][CH:65]=3)[C:44]3[NH:45][C:46]([C@@H:48]5[CH2:52][C@H:51]([CH2:53][O:54][CH3:55])[CH2:50][N:49]5[C:56]([O:58][C:59]([CH3:62])([CH3:60])[CH3:61])=[O:57])=[N:47][C:43]=3[CH:42]=[CH:41]4)=[CH:19][CH:20]=2)=[CH:13][N:14]=1)=[O:30])=[O:35]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(Br)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc(-c6cnc([C@@H]7CCCN7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc5)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 85 °C
Yield: 49.7 %

Procedure:
Methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (260 mg, 0.524 mmol), (2S,4S)-tert-butyl 2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (201 mg, 0.437 mmol), Pd(PPh3)4 (50 mg, 0.0437 mmol) and K2CO3 (2 M in H2O, 0.55 mL, 1.1 mmol) were combined in DME (4 mL). The reaction mixture was degassed with bubbling N2, then heated to 85° C. for 5 h. Upon completion, the reaction mixture was cooled to RT, diluted with 5 mL MeOH, filtered and concentrated. The crude residue was purified by silica column chromatography (0% to 45% MeOH/EtOAc) to afford (2S,4S)-tert-butyl 2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (163 mg, 50%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:20][C:21](OC(C)=O)=[O:22].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[C:21](=[O:22])[CH3:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: CC(=O)OC(C)=O
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)n1ncc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.6 %

Procedure:
6-nitroindazole (1 g, 6.13 mmol) was dissolved in dimethylformamide (15 mL), and added with triethylamine (1.7 mL, 12.2 mmol), Ac2O (0.69 mL, 7.4 mmol) and 18-Crown-6 (0.38 g, 1.23 mmol). The reaction solution was stirred for about 4 hours at room temperature. The reaction mixture was added with distilled water, and further stirred for about 1 hour. The resulting solid was filtered under reduced pressure, and washed with distilled water. The filtered solid was dried with warm wind in an oven (40° C.) for 3 hours or more to obtain the title compound (0.9 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][C:6]([F:17])=[CH:5][CH:4]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([OH:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][C:6]([F:17])=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3cc(F)ccc13)CCCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c2c(nc3cc(F)ccc13)CCCC2O
Reaction time: 1 h

Procedure:
To a cooled suspension of 5.0 of 9-amino-3,4-dihydro-6-fluoroacridin-1(2H)-one in 85 ml of tetrahydrofuran was added 22 ml of 1M solution of lithium aluminum hydride in tetrahydrofuran. This was stirred for 1 hour and then quenched with 8 ml of saturated ammonium chloride solution. The inorganics were filtered and rinsed with ethyl acetate, and the combined organics were dried over anhydrous magnesium sulfate. This was filtered and concentrated to obtain 5.0 g of a powder, mp 203°-206° C. d. This was recrystallized from tetrahydrofuran/hexane to obtain 3.95 g of an analytically pure powder, mp 207°-209° C. d.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][CH2:13][Br:14])=[C:6]([CH2:15][CH2:16][CH3:17])[C:5]=1[OH:18])(=[O:3])[CH3:2].[C:19]1([P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br-:14].[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][CH2:13][P+:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:6]([CH2:15][CH2:16][CH3:17])[C:5]=1[OH:18])(=[O:3])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1c(SCCCBr)ccc(C(C)=O)c1O
Product: CCCc1c(SCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)ccc(C(C)=O)c1O
Product: [Br-]

Procedure:
The title compound is prepared analogously to Example 1 from 3-(4-acetyl-3-hydroxy-2-propylphenylthio)-propyl bromide and triphenylphosphine.
Reaction SMILES: [Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[N:6]([C@H:9]3[CH2:14][C@H:13]([OH:15])[C@@H:12]([CH2:16][OH:17])[O:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.CN(C=O)C.N1C=CN=C1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>O>[Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[N:6]([C@H:9]3[CH2:14][C@H:13]([OH:15])[C@@H:12]([CH2:16][O:17][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[O:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H]1OC[C@@H](n2cnc3cc(Cl)c(Cl)cc32)C[C@@H]1O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1OC[C@@H](n2cnc3cc(Cl)c(Cl)cc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a stirred suspension of (3S,5S,6R)-5,6-dichloro-1-(tetrahydro-5-hydroxy-6-(hydroxymethyl)-2H-pyran-3-yl)-1H-benzimidazole (example 36, 1.50 g, 4.73 mmol) in 15 ML of dry DMF at 0° C. was added imidazole (0.40 g, 5.68 mmol) followed by tert-butyldimethylsilyl chloride (0.81 g, 5.20 mmol). The reaction was allowed to warm to room temperature, stirred overnight then diluted with water (100 ML) and extracted with chloroform (100 ML). The organic layer was dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. Purification by flash chromatography on silica gel 60 eluting with 50% ethyl acetate-hexanes afforded the title compound as a white solid (1.00 g, 50%) along with 0.40 g recovered starting material; m.p. 143-155° C.; 1H-NMR (DMSO-d6, 200 MHz) δ: 8.51, 8.09, 8.00 (s, each 1H), 4.90 (d, J=5.6 Hz, 1H), 4.89 (m, 1H), 4.26 (m, 1H), 3.91 (m, 1H), 3.86 (m, 1H), 3.55-3.42 (m, 1H), 3.32-3.24 (m, 2H), 2.29-2.19 (m, 1H), 1.97-1.83 (m, 1H), 0.91 (s, 9H), 0.97, 0.78 (s, each 3H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[N:8]=1)=[O:6].[H-].[Na+].Br[CH2:29][CH2:30][F:31]>CN(C=O)C.C(OCC)(=O)C>[F:31][CH2:30][CH2:29][S:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[N:8]=1)=[O:6]
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NCCS)c1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NCCSCCF)c1
Reaction time: 1 h

Procedure:
1.0 g (0.0027 mol) of N-(2-mercaptoethyl)-4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxamide (compound No. I-91) was dissolved in DMF, and the obtained solution was mixed with 0.12 g (ca. 60% in mineral oil; 0.0027×1.1 mol) of NaH and then with 0.68 g (0.0027×2.0 mol) of 1-bromo-2-fluoroethane, followed by stirring the solution for about one hour. The reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water and then washed with saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([SH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH:15]1[CH2:20][CH2:19][O:18][C:16]1=[O:17].Cl>O.C(OC(=O)C)(=O)C.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:15]3([C:9](=[O:11])[C:8]=2[CH:12]=1)[CH2:20][CH2:19][O:18][C:16]3=[O:17])([O-:3])=[O:2]
Reactant: O=C1OCCC1Br
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1OCCC12Sc1ccc([N+](=O)[O-])cc1C2=O

Procedure:
In 200 ml of water was dissolved 4.45 g of dipotassium salt of 5-nitrothiosalicylic acid, and 3.55 g of α-bromo-γ-butyrolactone was added dropwise to the solution under ice-cooling with stirring. After stirring the solution at room temperature for 3.5 hours, 10 ml of concentrated hydrochloric acid was added to the solution to acidify, and the solution was subjected to extraction with ethyl acetate. The extract was washed with water, dried and evaporated to dryness under reduced pressure, resulting in α-[(2-carboxy-4-nitrophenyl)thio]-γ-butyrolactone. The crude product was dissolved in 50 ml of acetic anhydride and 10 ml of triethylamine, and heated under a stream of nitrogen at 130° C. for 30 minutes. The reaction solution was evaporated to dryness under reduced pressure, and the residue was chromatographed on a column of activated carbon and silica gel. Recrystallization from ethanol of the resultant crude crystals yielded pale yellow needles of 5-nitro-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2' -dione. Melting point: 190.5°-193.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:11][OH:12].O[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH:18]([C:17]1[CH:20]=[CH:21][C:14]([O:12][CH2:11][C:3]2[N:2]([CH3:1])[C:6]3[C:5]([N:4]=2)=[CH:10][CH:9]=[CH:8][N:7]=3)=[CH:15][CH:16]=1)=[O:19]
Reactant: O=Cc1ccc(O)cc1
Reactant: Cn1c(CO)nc2cccnc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(C=O)cc2)nc2cccnc21
Yield: 45.2 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 500 mg of 3-methylimidazo-[5,4-b]pyridin-2-ylmethanol (prepared as described in Preparation 15), 374 mg of 4-hydroxybenzaldehyde, 0.76 ml of tributylphosphine, 773 mg of 1,1'-(azodicarbonyl)dipiperidine and 12 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 50:1 by volume as the eluent, to give 0.37 g of the title compound, melting at 124-125° C.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][N:35]=[CH:34]3)O1>>[NH:36]1[C:37]2[C:33](=[CH:32][C:31]([C:2]3[C:3]([F:22])=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]4=[O:21])=[CH:39][CH:38]=2)[CH:34]=[N:35]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4[nH]ncc4c3)c(F)cn2c1=O
Yield: 78.9 %

Procedure:
Ethyl 8-(1H-indazol-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A′ from ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (50 mg, 0.15 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (45.2 mg, 0.19 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (48 mg, 77%).
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)[CH3:4].[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11].[CH3:17]N(P(N(C)C)(N(C)C)=O)C.C(I)CCC>C1COCC1>[CH3:11][C:10]([CH3:17])([CH2:12][CH2:2][CH2:3][CH3:4])[C:9]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C(C)C
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [Li+]
Solvent: CCCCI
Solvent: C1CCOC1
Product: CCCCC(C)(C)C(=O)OCC
Reaction time: 1 h

Procedure:
To LDA prepared at -78° C. in the usual manner was added ethyl isobutyrate (45 g) in THF, and stirred for 1 h. A dry HMPA solution of butyl iodide (107 g) was added, and the mixture was stirred at -78° C. for 1 h and then at room temperature for additional 1 h.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN([CH2:23][CH3:24])CC.[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29](C)(C)[CH3:30])=O>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:26](=[O:25])[O:28][CH2:29][CH2:30][CH2:23][CH3:24])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccc(Nc2ccnc(Cl)c2)c1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCOC(=O)N(c1cccc([N+](=O)[O-])c1)c1ccnc(Cl)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
To a stirring solution of 2-Chloro-N-(3-nitrophenyl)pyridine-4-amine (2.70 g, 10.82 mmol) in THF (45 mL) was added Et3N (6.32 mL, 45.3 mmol). The mixture was cooled to 0° C., and DMAP (0.0135 g, 0.110 mmol) and BOC2O (2.84 g, 12.99 mmol) were added. The mixture was warmed to rt and stirred for 18 h. The mixture was quenched with ice and diluted with water. Extracted with EtOAc (3×200 mL), washed with brine and water, dried (MgSO4), and concentrated. A dark oil was afforded, which was passed through a pad of silica gel, eluting with 1:1 EtOAc/hexanes. Concentrated and dried under high vacuum to afford ten-Butyl 2-chloropyridin-4-yl(3-nitrophenyl)carbamate (3.65 g, 96.5% yield).
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16].[NH2:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][N:37]=1)[C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH2:28]([NH:27][C:25](=[O:26])[C:24]1[CH:35]=[CH:36][N:37]=[C:22]([NH:21][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([F:11])[CH:13]=2)[CH:23]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Reactant: O=C(Cl)c1cccc(F)c1
Agent: O=C(Cl)c1ccccc1F
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2cccc(F)c2)c1
Yield: 44 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 3-fluorobenzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(3-fluorobenzamido)isonicotinamide was obtained as a colorless solid in 44% yield: mp 140-143° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.71 (s, 1H), 8.60 (s, 1H), 8.41-8.39 (m, 1H), 7.70-7.55 (m, 3H), 7.51-7.44 (m, 1H), 7.37-7.25 (m, 6H), 6.76-6.66 (m, 1H), 4.65 (d, J=5.8 Hz, 2H); MS (ES+) m/z 350.5 (M+1).
Reaction SMILES: [N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]4[O:20][C:19]([CH2:21][CH2:22][OH:23])=[CH:18][C:17]=4[CH:24]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>C(Cl)Cl>[N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]4[O:20][C:19]([CH2:21][CH2:22][O:23][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:18][C:17]=4[CH:24]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a room temperature solution of 2-[5-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzofuran-2-yl]-ethanol (200 mg, 0.91 mmol) in CH2Cl2 (10 ml) was added triethylamine (303 mg, 3 mmol) and methanesulfonyl chloride (525 mg, 4.56 mmol). The mixture was stirred at room temperature for 30 minutes. Water was added to the reaction and the organic layer separated. The aqueous layer was extracted with CH2Cl2 and the combined organic extracts were dried and concentrated to give methanesulfonic acid 2-[5-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzo-furan-2-yl]-ethyl ester, which was used in the next reaction without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][C:16]([C:19](=[O:23])[N:20]([CH3:22])[CH3:21])([CH3:18])[C:15]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1.[H][H].[C:33](OC(=O)C)(=[O:35])[CH3:34]>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:33](=[O:35])[CH3:34])[C:11]([N:13]2[CH2:17][C:16]([C:19](=[O:23])[N:20]([CH3:22])[CH3:21])([CH3:18])[C:15]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)C(=O)C1(C)CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C(=O)N1CC(C)(C(=O)N(C)C)C(c2ccc(Cl)cc2)=N1)c1ccc(Cl)cc1
Reaction time: 0.08 h

Procedure:
In a 50 ml round bottomed flask was placed 0.45 g of 60% sodium hydride (0.011 mole). The sodium hydride was washed twice with hexane and suspended in 15 ml of tetrahydrofuran. A solution of 2.0 g (0.005 mole) of N,3-bis-(4-chlorophenyl)-4-dimethylcarbamoyl-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide in 5 ml of tetrahydrofuran was added slowly. When hydrogen evolution ceased, 1 ml of acetic anhydride was added and the mixture was stirred for 5 minutes. The reaction was partitioned between ethyl ether and brine, dried, concentrated, and chromatographed yielding 1.6 g of N,3-bis-(4-chlorophenyl)-4-dimethylcarbamoyl-4-methyl-N-acetyl-4,5-dihydro-1H-pyrazole-1-carboxamide, an oil. NMR and IR data were consistent with the structure.