Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.I[CH2:7][C:8]12[CH2:25][N:24]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:23][C:9]1([CH2:36]I)[CH2:10][N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:12]2.CCCCC>C1COCC1>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:11]2[CH2:10][C:9]34[CH2:36][CH2:7][C:8]3([CH2:25][N:24]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)(=[O:28])=[O:27])[CH2:23]4)[CH2:12]2)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC3(CI)CN(S(=O)(=O)c4ccc(C)cc4)CC3(CI)C2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1ccc(S(=O)(=O)N2CC34CCC3(C2)CN(S(=O)(=O)c2ccc(C)cc2)C4)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
t-Butyl lithium (1.7 M pentane) (1.05 mL, 1.76 mmol) was added dropwise to a stirring solution of 3a,6a-bis(iodomethyl)-2,5-bis((4-methylphenyl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole (0.50 g, 0.71 mmol) in THF (10 mL) at −78° C. The resulting orange mixture was stirred at −78° C. for 30 minutes. After this time, additional t-Butyl lithium 1.7 M in pentane (1.05 mL, 1.76 mmol) was added to the reaction mixture at −78° C. After 10 minutes of additional stirring at −78° C., the reaction was quenched with the addition of sat. NH4Cl (aq) (10 mL). The mixture was warmed to r.t., diluted with EtOAc (15 mL) and the layers were separated. The aq. layer was then extracted with EtOAc (3×20 mL) and once with CH2Cl2. The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give 2,5-bis((4-methylphenyl)sulfonyl)tetrahydro-1H,4H-3a,6a-ethanopyrrolo[3,4-c]pyrrole (0.308 g, 0.690 mmol, 97% yield) as a white crystaline solid. LCMS: m/e=447 (M+H)+. LCMS retention time: 2.39 min. (Column: SunFire C18 5u 4.6×50 mm. Solvent A=90% Water/10% Acetonitrile/0.1% TFA. Solvent B=10% Water/90% Acetonitrile/0.1% TFA. Start % B=0. Final % B=100. Gradient Time=3 min. Flow Rate=4 mL/min.). Structure was verified via single crystal X-ray diffraction. 1H NMR (400 MHz, CHLOROFORM-d) □ ppm 7.67 (4 H, d, J=8.28 Hz), 7.34 (4 H, d, J=8.03 Hz), 3.36 (4 H, d, J=9.79 Hz), 2.73 (4 H, d, J=9.79 Hz), 2.47 (6 H, s), 2.00 (4 H, s).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][C:31]1[CH:39]=[CH:38][C:34]2=[N:35][O:36][N:37]=[C:33]2[CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[N:35]1[O:36][N:37]=[C:33]2[CH:32]=[C:31]([CH2:30][N:19]3[C:14]4[C:15](=[O:18])[N:16]([CH3:17])[C:11]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH3:10])=[O:8])=[C:12]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)[C:13]=4[CH:21]=[CH:20]3)[CH:39]=[CH:38][C:34]=12
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Reactant: BrCc1ccc2nonc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2ccn(Cc3ccc4nonc4c3)c2c(=O)n1C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (10 mg, 0.026 mmol) and 5-(bromomethyl)benzo[c][1,2,5]oxadiazole (22.28 mg, 0.105 mmol) in Acetonitrile (1 mL) was treated with cesium carbonate (34.1 mg, 0.105 mmol) and the resultant was stirred at 70° C. for 2 hours. The mixture was cooled to ambient temperature, water was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was used crude in the next step without further purification. LC/MS (m/z) ES+=515 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([O:18][C:19](=[O:25])[C:20](OCC)=[O:21])[CH3:17].[O-]CC.[Na+]>C(O)C>[CH2:16]([O:18][C:19](=[O:25])[C:20](=[O:21])[CH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])[CH3:17]
Reactant: CCOC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1ccc(C(=O)OCC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
To a solution of ethyl 4-methyl-3-nitrobenzoate (80 g, 0.38 mol) and oxalic acid diethyl ester (57 mL, 0.42 mol) in ethanol (1000 mL) is added sodium ethoxide (430 mL, 1.15 mol, 21% in ethanol). The resulting brown solution is stirred at room temperature for 16 h. The reaction is quenched with 3N HCl to neutral pH and diluted with water (2000 mL). The resulting white precipitate is filtered and dried in vacuum to afford the title compound (91 g, 77%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C@@H:21]2[O:39][C:24]3=[CH:25][N:26]=[C:27]([C:29]4[CH2:30][CH2:31][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:33][CH:34]=4)[CH:28]=[C:23]3[CH2:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>[CH3:38][S:35]([N:32]1[CH2:31][CH:30]=[C:29]([C:27]2[CH:28]=[C:23]3[CH2:22][C@H:21]([CH:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)[O:39][C:24]3=[CH:25][N:26]=2)[CH2:34][CH2:33]1)(=[O:36])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (2 mL) is added to a solution of (R)-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.0 g) in dichloromethane (10 mL) at room temperature. The solution is stirred at room temperature overnight and then diluted with dichloromethane, 2 N aqueous NaOH solution, and saturated aqueous Na2CO3 solution. The resulting mixture is vigorously stirred for 20 min and then extracted with dichloromethane. The combined extract is dried (Na2SO4) and concentrated to give the title compound. Mass spectrum (ESI+): m/z=364 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([CH2:12][CH2:13][S:14][CH2:15][CH3:16])[C:6](=[O:17])[C:5]2([CH3:19])[CH3:18].CS[C:22](SC)=[N:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH2:15]([S:14][CH2:13][CH2:12][N:7]1[C:8]2[CH:9]=[C:10]3[NH:11][C:22]([NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:1][C:2]3=[CH:3][C:4]=2[C:5]([CH3:18])([CH3:19])[C:6]1=[O:17])[CH3:16]
Reactant: CCSCCN1C(=O)C(C)(C)c2cc(N)c(N)cc21
Reactant: CSC(=NC(=O)c1ccccc1)SC
Solvent: CN(C)C=O
Product: CCSCCN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4ccccc4)[nH]c3cc21
Yield: 71.2 %

Procedure:
A solution of B30 (0.73 g) and N-(bis-methylsulfanyl-methylene)-benzamide (0.72 g; 2.70 mmol) in dry N,N-dimethylformamide (35 ml) is stirred at 80° C. for 18 h. The mixture is evaporated to dryness and the residue is purified by preparative RP-MPLC eluted with MeCN/water to yield the desired compound (0.76 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:21])[C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[N+:18]([O-])=O)=[CH:5][CH:4]=1.[C:22]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:18][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]=2[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:21])=[O:31])=[CH:33][CH:34]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(NC(=O)c2c(C)cccc2[N+](=O)[O-])cc1
Product: COc1ccc(NC(=O)c2c(C)cccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 16.5 %

Procedure:
Using the procedure described in Example 93, Part B, N-(4-methoxyphenyl)-2-nitro-6-methylbenzamide (1.05 mmol) was reduced to the corresponding amine. Using the procedure described in Example 93, Part A, the amine was reacted with 4-tert-butylbenzoyl chloride (1.05 mmol) to yield 72 mg (17%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH:18]=O)[CH:14]=1)=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:26]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH2:18][NH:33][CH2:32][CH2:31][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:14]=1)=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCN1CCCC1
Reactant: O=Cc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1cc(CNCCN2CCCC2)no1
Yield: 53 %

Procedure:
From 5-(6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl)-isoxazole-3-carboxaldehyde and 2-pyrrolidin-1-yl-ethylamine according to procedure 24. Yield 53%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:27][C:28]([C:31]56OCC(C)(C[O:36]5)[CH2:33][O:32]6)=[CH:29][CH:30]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH3:33][O:32][C:31]([C:28]1[O:27][C:26]([C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][N:17]=[C:16]3[NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)=[CH:30][CH:29]=1)=[O:36]
Reactant: CC12COC(c3ccc(-c4ccc5ncnc(Nc6ccc(OCc7ccccc7)cc6)c5c4)o3)(OC1)OC2
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4-Benzyloxy-phenyl)-(6-(5-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)-furan-2-yl)-quinazolin-4-yl)-amine (0.680 g, 1.30 mmol) was dissolved in THF (10 ml) and 2N aqueous HCl (10 ml) was added. The mixture was stirred at room temperature for 2 hours. The THF was removed in vacuo and the residue diluted with water to preciptate the intermediate (partial hydrolysis) 5-(4-(4-benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carboxylic acid (3-methyloxetan-3-yl)methyl ester which was collected by filtration and washed with water and acetone; δH [2H6]DMSO 12.10 (1H,s), 9.50 (1H,s), 8.87 (1H,s), 8.43 (1H,s), 8.00 (1H,s), 7.66 (2H,d), 7.58 (1H, d), 7.30-7.54 (6H,m), 7.13 (2H,d), 5.16 (2H,s), 4.14 (2H,s), 3.28-3.41 (4H,m), 0.88 (3H,s). This solid was suspended in a mixture of MeOH (15 ml) and NaOH (2N, 15 ml), and the mixture was stirred at room temperature for 2 hours. The reaction was diluted with water to give the title product as a yellow solid, which was collected by filtration (0.375 g, 0.831 mmol, 64%); δH [2H6]DMSO 10.06 (1H,s), 8.91 (1H,s), 8.48 (1H,s), 8.21 (1H,d), 7.80 (1H,d), 7.63 (2H,d), 7.25-7.52 (7H,m), 7.05 (2H,d), 5.10 (2H,s), 3.85 (3H,s); m/z (M+1+) 452.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1>>[CH:18]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][C:5](=[O:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:17][CH2:16][CH2:15][CH:14]=[CH:13]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Reactant: C1=CCCCC1
Product: CC1(C)CC(=O)CC(C)(C)N1OC1C=CCCC1
Temperature: 85.5 °C
Yield: 10.3 %

Procedure:
A mixture of 25.0 g (0.15 mol) of 1-oxyl-4-oxo-2,2,6,6-tetramethylpiperidine and 162.2 g (1.97 mol) of cyclohexene is heated under a nitrogen atmosphere at 85-86° C. for 56 hours. The reaction mixture is filtered to remove the hydroxylamine, and the solvent is removed in vacuo. The residue is dissolved in heptane and washed with 5% ascorbic acid (2×50 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous magnesium sulfate and the volatiles removed in vacuo. The residue is eluted through a silica gel column with heptane/ethyl acetate (9/1) to give 3.9 g (21% yield) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][N:17]=[C:18]=[O:19].N1C=CC=CC=1>C(O)C>[CH3:16][NH:17][C:18](=[O:19])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: CN=C=O
Solvent: c1ccncc1
Solvent: CCO
Product: CNC(=O)Nc1ccc(C2=NNC(=O)NC2C)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.5 g), methyl isocyanate (0.48 ml) and pyridine (40 ml) was stirred at room temperature for 4.5 hours, and ethanol (5 ml) was added. The solvent was then distilled off under reduced pressure. To the oily residue was added 10% HCl, and the thus-produced crystals were collected by filtration, washed with water, dried and recrystallized from aqueous dimethylformamide to give 6-[4-(3-methylureido)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.43 g).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][O:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=3)=[C:2]([CH3:1])[S:6][C:5]=2[CH:7]=1
Reactant: BrCCCCBr
Reactant: Cc1sc2cc(O)ccc2c1-c1ccc(C(F)(F)F)cc1
Product: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 27.1, 2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-ol and 1,4-dibromobutane were converted to yield 6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene as colorless oil, MS: 443 (MH+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:18]3[CH2:17][N:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[C:15](=[O:28])[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42](O)=[O:43])[C:37]2=[O:45])=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[CH2:17][C:18]3[C:9]([O:8][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:42]([C:38]5[C:37](=[O:45])[N:36]([C:33]6[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=6)[CH:41]=[CH:40][CH:39]=5)=[O:43])=[N:7][CH:6]=4)=[CH:10][CH:11]=[N:12][C:13]=3[NH:14][C:15]2=[O:28])=[CH:21][CH:22]=1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(CN2Cc3c(Oc4ccc(N)nc4)ccnc3NC2=O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(Oc4ccc(NC(=O)c5cccn(-c6ccc(F)cc6)c5=O)nc4)ccnc3NC2=O)cc1
Yield: 31.8 %

Procedure:
A solution of 5-[(6-aminopyridin-3-yl)oxy]-3-(4-methoxybenzyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one (100.00 mg; 0.26 mmol; 1.00 eq.), 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (67.97 mg; 0.29 mmol; 1.10 eq.), pybop (179.26 mg; 0.34 mmol; 1.30 eq.), DMF (4.00 ml), and N,N-diisopropylethylamine (0.13 μl; 0.79 mmol; 3.00 eq.) was stirred at room temperature under N2 for 14 hours. The reaction was concentrated, redissolved in DMSO, and purified via prep HPLC to afford 49 mg (26%) of 282 as a peach-colored solid. LC-MS (M+H=593, obsd.=593).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[N+:9]([C:12]1[CH:13]=[C:14]([C:21](Cl)=[O:22])[C:15](=[CH:19][CH:20]=1)[C:16](Cl)=[O:17])([O-:11])=[O:10]>CCO>[N+:9]([C:12]1[CH:13]=[C:14]2[C:15](=[CH:19][CH:20]=1)[C:16](=[O:17])[C:8]1[C:1]([OH:2])=[CH:3][CH:4]=[C:5]([OH:6])[C:7]=1[C:21]2=[O:22])([O-:11])=[O:10]
Reactant: Oc1ccc(O)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1C(=O)Cl
Solvent: CCO
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)c2c(O)ccc(O)c21
Yield: 75 %

Procedure:
The method was similar to that in Example 1 but using 11.0 g (0.1 mols) of hydroquinone and 24.7 g (0.1 mols) of 4-nitrophthalic acid dichloride. The product was 21.4 g (75% yield) of 6-nitro-1,4-dihydroxy-9,10-anthraquinone (5), m.p.=226°-228° C. (EtOH). The compound had the following characteristics:
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([NH:12][C:13]([C:15]2[CH:45]=[CH:44][C:18]3[N:19]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[C:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:26]=[N:25]5)=[N:21][C:17]=3[CH:16]=2)=[O:14])[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H](C(O)=O)CC1C=CC([OH:55])=CC=1>>[CH:38]1([N:19]2[C:18]3[CH:44]=[CH:45][C:15]([C:13]([NH:12][CH:8]([CH2:7][C:1]4[CH:6]=[CH:5][C:4]([OH:55])=[CH:3][CH:2]=4)[C:9]([OH:11])=[O:10])=[O:14])=[CH:16][C:17]=3[N:21]=[C:20]2[C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=[N:25]3)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(NC(CC1CCCCC1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Product: O=C(NC(Cc1ccc(O)cc1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 36 %

Procedure:
The general procedure described for Compound 242 was used with Fmoc-Tyr Wang resin (125 mg, 0.8 mmol/g), producing 22 mg of the title compound (36% yield). MS: 610.22 (M−H+) HPLC Procedure A, retention time=16.14 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]([OH:17])[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]([O:17][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: On1c(-c2ccncc2)c(-c2ccc(F)cc2)c2ncccc21
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2c(-c3ccncc3)n(OCCN3CCCCC3)c3cccnc23)cc1
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1-hydroxy-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine (0.20 g, 0.65 mmol) and 2-chloroethylpiperidine hydrochloride (0.24 g, 1.31 mmol) in dimethylformamide (5 ml) was added sodium hydride (100 mg, 6.56 mmol, 60% in oil). The reaction mixture was stirred overnight and quenched with water (2 ml). The pH was adjusted to pH=11-12 by the addition of saturated sodium carbonate solution and the product was extracted into ethyl acetate. The combined extracts were dried over anhydrous MgSO4 and concentrated in vacuo to give an oil. Purified by flash column chromatography (50%-80% ethyl acetate/hexanes, followed by 95/5% methylene chloride/methanol gradient) gave 3-(4-fluorophenyl)-1-[2-(piperidin-1-yl)ethoxy]-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine as a yellow solid (182 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37]O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>C(Cl)Cl>[I:25][CH2:37][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=1
Reactant: II
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCI)cc1

Procedure:
To a 0° C. solution of triphenylphosphine (1.9 g, 7.2 mmol) and imidazole (489 mg, 7.18 mmol) in DCM (20 ml) was added iodine (1822 mg, 7.18 mmol) to form a solution. Small portions of 2-(4-nitrophenyl)ethanol (1.0 g, 6.0 mmol) was added to the suspension. TLC showed conversion to the desired product quickly. Hexane was added to the reaction to precipitate side products which were filtered off. The filtrate was concentrated in vacuo to obtain crude 1-(2-iodoethyl)-4-nitrobenzene, which was purified by silica gel flash chromatography using Hexane and EtOAc system. 1H-NMR (500 MHz, CD3Cl) δ 8.22 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 3.41 (t, J=7.0 Hz, 2H), 3.32 (t, J=7.0 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]3)[C:8]([CH2:12]Cl)=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[CH2:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][N:16]4[CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Br)cc2nc(CCl)n1CC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=c1c2ccc(Br)cc2nc2n1CC1CCCCN1C2
Temperature: 25 °C

Procedure:
A solution of 7-bromo-2-(chloromethyl)-3-(piperidin-2-ylmethyl)quinazolin-4(3H)-one and K2CO3 (1 g, 7.2 mmol) in CH3CN was stirred at reflux for 1.5 h. After it was cooled to room temperature, the mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4, and the crude product was purified by column chromatography to give the desired product. MS (ESI): 334, 336 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:7]=[C:8]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[CH:9]=1)(=[O:3])[CH3:2].[Br:23]Br>C(O)(=O)C.O>[Br:23][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:19])[F:20])[CH:7]=[C:8]([S:10]([F:14])([F:15])([F:13])([F:12])[F:11])[CH:9]=1)=[O:3]
Reactant: CC(=O)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C(CBr)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(3-Acetyl-5-pentafluorosulfanylphenyl)-2,2,2-trifluoroacetamide (20 mg) was initially introduced dissolved in glacial acetic acid (1 ml), and bromine (9 mg) dissolved in glacial acetic acid (90 μl) was slowly added dropwise. After stirring at RT for 30 min, the mixture was warmed at 60° C. for 1 h. After cooling to RT, the glacial acetic acid was diluted with a large quantity of water and extracted three times with ethyl acetate. The combined extracts were washed with sodium hydrogencarbonate solution until acid-free, dried over magnesium sulfate, filtered and concentrated. The crude product obtained (24 mg) was employed in the next stage without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH2:27][CH3:28])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[NH:30]([CH2:34][CH2:35][N:36]1[C:40]([SH:41])=[N:39][N:38]=[N:37]1)[C:31]([NH2:33])=[NH:32]>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH2:27][CH3:28])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][S:41][C:40]4[N:36]([CH2:35][CH2:34][NH:30][C:31]([NH2:33])=[NH:32])[N:37]=[N:38][N:39]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: N=C(N)NCCn1nnnc1S
Reactant: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=N)N)CS[C@H]12)c1csc(N)n1
Yield: 53.7 %

Procedure:
To a solution of 467 mg of sodium 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-ethoxyiminoacetamido]-3-hydroxymethyl -3-cephem-4-carboxylate and 374 mg of 1-(2-guanidinoethyl) -5-mercapto-1H-tetrazole in 10 ml of DMF was added 500 mg of ethyl o-phenylenephosphate at -20° C. under stirring. The reaction mixture was stirred at -20° C. to 0° C. for 60 minutes, and was subjected to a column chromatography on silica gel (100 g), being washed with acetonitrile and eluted with a (5:1) mixture of acetonitrile and water. The eluate was concentrated under reduced pressure, and then subjected to a column chromatography on XAD-II (150 ml), being washed with water and eluted with 20% aqueous ethanol. The eluate was concentrated under reduced pressure and then lyophilized to give 333 mg of the title compound as a colorless powder.