Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C@@H:35]3[CH2:43][CH2:42][CH2:41][C:40]4[N:39](S(C5C=CC(C)=CC=5)(=O)=O)[N:38]=[CH:37][C:36]3=4)[N:14]=[C:15]([C:16]3[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=4)=[O:21])=[CH:18][CH:17]=3)[C:8]=12>C(O)(C(F)(F)F)=O>[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C@@H:35]3[CH2:43][CH2:42][CH2:41][C:40]4[NH:39][N:38]=[CH:37][C:36]3=4)[N:14]=[C:15]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=4)=[O:21])=[CH:33][CH:34]=3)[C:8]=12
Reactant: COc1ccc(CNc2ncnc3c2c(-c2ccc(C(=O)Nc4cc(C(F)(F)F)ccn4)cc2)nn3[C@@H]2CCCc3c2cnn3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(C(=O)Nc3cc(C(F)(F)F)ccn3)cc1)nn2[C@@H]1CCCc2[nH]ncc21
Yield: 53 %

Procedure:
A solution of (R)-4-(4-((2,4-dimethoxybenzyl)amino)-1-(1-tosyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (90 mg, 0.109 mmol) in TFA (3 mL) was stirred for 3 h at 100° C. Removed the solvent and purified by preparative HPLC to give the title compound (30 mg, yield 52.8%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:28][CH3:29])=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:37][CH3:38]>CN(C=O)C>[CH2:37]([O:18][C:17](=[O:19])[C:16]1[CH:20]=[C:21]([O:28][CH3:29])[C:22]([C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:23][C:15]=1[C:14]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:38]
Reactant: CCI
Reactant: COc1cc(C(=O)O)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OC)c(C(C)(C)C)cc1-c1cccnc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
step 1—To a solution of 76 (100 mg, 0.26 mmol) in DMF (3 mL) were added Cs2CO3 (101 mg, 0.31 mmol) and iodoethane (25 μL, 0.31 mmol). The reaction mixture was stirred at RT overnight then quenched with H2O and thrice extracted with EtOAc. The combined organics were washed with H2O (3×), dried (MgSO4), filtered and concentrated under reduced pressure to afford 109 mg (99%) of 2-(2-benzyloxypyridin-3-yl)-4-tert-butyl-5-methoxybenzoic acid ethyl ester (78) as a pale yellow foam.
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:11]([N:12]=[CH:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C.[H][H]>C(O)C>[N:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: [H][H]
Reactant: c1ccc2c(c1)ncc1nnnn12
Solvent: CCO
Product: c1ccc2c(c1)NCc1nnnn1-2
Reaction time: 2 h
Yield: 45 %

Procedure:
A 1 g. portion of tetrazolo[1,5-a]quinoxaline was dissolved in 200 ml. of ethanol. The solution was placed in a Parr hydrogenator on a shaking apparatus and 100 mg. of 5 percent palladized charcoal was added. The bomb was pressurized to about 2 atmospheres with hydrogen and was shaken for 2 hours. The reaction mixture was then removed and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from ethanol-water to obtain the product, 4,5-dihydrotetrazolo[1,5-a]quinoxaline, m.p. 149°-51°C., in 45 percent yield. The product was identified by nuclear magnetic resonance analysis and by elemental microanalysis, with the following results.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)=[CH:5][C:4]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[N:3]1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)[CH:5]=2)=[CH:12][N:11]=1)=[O:24]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cc1nc(-c2cc(-c3ccc(N)nc3)n(C)n2)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cc(-c3ccc(NC(=O)c4ccccc4Cl)nc3)n(C)n2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.7 %

Procedure:
To a solution of crude 5-[1-methyl-3-(5-methyl(1,2,4-oxadiazol-3-yl))pyrazol-5-yl]-2-pyridylamine (74) (27 mg, 0.1 mmol) in 2 ml DCM was added 2-chlorobenzoyl chloride (25 μl, 2 eq) followed by addition of DIEA (70 μl). The resulting solution was stirred at r.t. for 3 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (250 μl) at r.t. for 1 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 7 mg (2-chlorophenyl)-N-{5-[1-methyl-3-(5-methyl(1,2,4-oxadiazol-3-yl))pyrazol-5-yl](2-pyridyl)}carboxamide (75) as light yellow solid. (yield: 17.7%, purity>95%).
Reaction SMILES: O[CH:2]([C:10]1[C:15]2[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=2[C:13]([O:21][CH3:22])=[CH:12][CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:22][O:21][C:13]1[C:14]2[O:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]=2[C:10]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(C(O)Cc2ccncc2)c2c1OC(C)(C)C2
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CCc2ccncc2)c2c1OC(C)(C)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
Under an argon atmosphere, a solution (7 ml) of Compound 46a (0.2 g) obtained in Step A in methylene chloride was cooled to −78° C., and then boron trifluoride ether complex (0.17 ml) and triethylsilane (0.33 ml) were successively added thereto, followed by stirring at 0° C. for 2 hours. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to give Compound 46 (0.11 g, 58.1%) as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[C:3]2[S:22][CH2:21][CH2:20][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[CH2:23]([NH2:26])[CH2:24][CH3:25]>O>[C:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([CH2:25][CH2:24][CH2:23][NH2:26])[C:3]4[S:22][CH2:21][CH2:20][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCN
Reactant: Clc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Solvent: O
Product: NCCCc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Yield: 76 %

Procedure:
0.83 g (2.5 mmol) of 4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (V) is combined with 8.3 mL of n-propylamine, reacted for 0.2 hours at 130° C. in the microwave. Then the reaction mixture is added to water and extracted with dichloromethane. The organic phase is concentrated by evaporation, the residue is crystallized. The aqueous phase is extracted with ethyl acetate, the organic phase evaporated to dryness. The solids are combined and stirred with methanol. 0.68 g of the product (76%) is obtained as a powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([Mg]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[CH:18]2[Si:23]([CH:26]1[C:34]2[C:29](=[C:30](Br)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[CH3:36])([CH3:25])[CH3:24]>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([CH3:37])[CH:18]3[Si:23]([CH:26]2[C:34]3[C:29](=[C:30]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[CH:31]=[CH:32][CH:33]=3)[CH:28]=[C:27]2[CH3:36])([CH3:25])[CH3:24])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1=Cc2c(Br)cccc2C1[Si](C)(C)C1C(C)=Cc2c(Br)cccc21
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc2C1[Si](C)(C)C1C(C)=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc21
Reaction time: 1 h

Procedure:
In an argon atmosphere, to a solution of 15 mL of THF with 29.0 ml of 0.5 M ZnCl2 (14.5 mmol) in THF, 13.0 ml of 1.0 M 4-(tert-butyl) phenylmagnesium bromide (13.0 mmol) in THF was added at ambient temperature. This mixture was stirred for 1 hour, and, then, 10.0 ml of 0.02 M Pd(PtBu3)2 (0.20 mmol, 4 mol. %) in THF and 2.37 g (5.0 mmol) of 1 were added. The resulting mixture was stirred for 5 hours at reflux. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 30 mm, l 100 mm; eluent: hexanes). Yield 2.85 g (98%) of white solid of ca. 1 to 1 mixture of rac- and meso-compounds.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[CH2:12][CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[C:17]1([C:15]23[CH2:14][CH2:13][CH2:12][N:1]2[C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[O:5]3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: Nc1ccccc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: O=C1OC2(c3ccccc3)CCCN2c2ccccc21

Procedure:
A mixture of 26.1 g of 2-aminobenzoic acid, 36.5 g of 4-chloro-1-phenyl-1-butanone, 0.5 g of p-toluenesulfonic acid and 250 ml of xylene were refluxed with a water trap. After the reaction was complete, the solvent was removed by distillation and the remaining solid was recrystallized from ethanol. Yield: 41.1 g (81.5%), melting point 152° C.
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[N:25]([C@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29]([O-:31])=[O:30])=[C:26]=[O:27].[N-]=C=O.COC(=O)[C@H](CC1C=CC=CC=1)N>>[O:1]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][O:16][C:26]([NH:25][CH:28]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]([OH:31])=[O:30])=[O:27])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CCOc2ccccc2)cc1
Reactant: O=C=N[C@H](Cc1ccccc1)C(=O)[O-]
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Product: O=C(NC(Cc1ccccc1)C(=O)O)OCc1ccc(CCOc2ccccc2)cc1

Procedure:
4-(2-phenoxy-ethyl)-benzoic acid (387 mg) was further reduced with LiAlH4, condensed with (R)-2-isocyanato-3-phenyl-propionate of formula 5 and hydrolyzed as described for example in Example 1, Steps 2–4, to yield about 550 mg of 2-[4-(2-phenoxy-ethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid 73 mp. 150.2–152.4° C.
Reaction SMILES: C([NH:8][C:9]1[C:14]([N+:15]([O-])=O)=[C:13]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>CO.Cl.[Pd]>[NH2:8][C:9]1[C:14]([NH2:15])=[C:13]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:12]=[CH:11][N:10]=1
Reactant: COCCOc1ccnc(NCc2ccccc2)c1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COCCOc1ccnc(N)c1N
Yield: 78.8 %

Procedure:
1.87 g of 2-benzylamino-4-(2-methoxyethoxy)-3-nitropyridine (starting material J2) are dissolved in a mixture of 30 ml of methanol and 6.16 ml of 2N aqueous hydrochloric acid and hydrogenated over 500 mg of 10% strength Pd on carbon at 50° C. for 5 hours. After filtration and addition of 6.16 ml of 2N aqueous sodium hydroxide solution the mixture is evaporated to dryness and the residue is chromatographed on silica gel (dichloromethane/methanol 25:1+1% triethylamine). Concentration of the pure fractions and drying in vacuo gives 0.89 g of the title compound as a brownish oil. The mass spectrum shows the molecular peak M+ at 184.0 Da.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CCN)cc1
Product: COc1ccc(CCNC(C)=O)cc1

Procedure:
In close analogy to the procedure described above, 2-(4-methoxy-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27].C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[NH:23][CH2:24][CH2:25][CH2:26][OH:27])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(C1=CCOc2c(F)ccc(F)c21)c1ccc(Cl)cc1
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)cc1)C1c2c(F)ccc(F)c2OCC1NCCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(4-Chloro-benzenesulfonyl)-5,8-difluoro-2H-chromene (0.3 g, 0.88 mmole) was dissolved in 15 ml THF and 3-aminopropanol (1 ml) was added. The mixture was stirred at room temperature for 30 minutes. 50 saturated Na2CO3 solution and 50 ml EtOAc were added. The organic layer was washed with water (50 ml), brine (50 ml), dried over Na2SO4 and concentrated. The product was purified by column (EtOAc/hexane from 50/50 to 100/0 in 45 minutes). Yield: 0.31 g, 84%. 1H NMR (CDCl3 400 MHz) δ 7.69 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.1 Hz), 6.99 (td, J=9.5, 5.1 Hz, 1H), 6.38 (td, J=9.5, 3.7 HZ, 1H), 4.80 (dd, J=12.5, 2.9 Hz, 1H), 4.53 (s, 1H), 4.43 (d, J=11.8 Hz, 1H), 3.78 (s, 1H), 3.61 (t, J=5.9 Hz, 2H), 2.86-2.71 (m, 2H), 2.25 (bs, 1H), 1.57 (p, J=5.9 Hz, 2H).
Reaction SMILES: C([O:14][C:15]([CH2:17][C:18]([NH:20][C:21]1[N:22]2[CH:25]([S:26][CH2:27][C:28]=1[C:29]1[S:33][C:32]([NH:34][C:35](=[S:47])[CH2:36][CH2:37][CH2:38][NH:39]C(OC(C)(C)C)=O)=[N:31][CH:30]=1)[CH:24]([S:48][C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[C:51]([Cl:56])[CH:50]=1)[C:23]2=[O:57])=[O:19])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH2:39][CH2:38][CH2:37][CH2:36][C:35]([NH:34][C:32]1[S:33][C:29]([C:28]2[CH2:27][S:26][CH:25]3[N:22]([C:23](=[O:57])[CH:24]3[S:48][C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[C:51]([Cl:56])[CH:50]=3)[C:21]=2[NH:20][C:18](=[O:19])[CH2:17][C:15]([OH:16])=[O:14])=[CH:30][N:31]=1)=[S:47]
Reactant: CC(C)(C)OC(=O)NCCCC(=S)Nc1ncc(C2=C(NC(=O)CC(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(Sc4ccc(Cl)c(Cl)c4)C3SC2)s1
Solvent: O=CO
Product: NCCCC(=S)Nc1ncc(C2=C(NC(=O)CC(=O)O)N3C(=O)C(Sc4ccc(Cl)c(Cl)c4)C3SC2)s1
Yield: 96.8 %

Procedure:
A solution of 2-benzhydryloxycarbonyl-3-[2-(2-t-butoxycarbonylamino-ethylthioacetamido)-thiazol-5-yl]-7-(3,4-dichlorophenylthio)-acetamido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.7 g) in formic acid (50 cc) is heated at 50° C. for 30 minutes and then concentrated to dryness under reduced pressure (2 mm Hg; 0.27 kPa) at 40° C. The oil which remains is taken up in acetone (20 cc), which is concentrated to dryness under reduced pressure (40 mm Hg; 5.3 kPa) at 50° C.; this operation is repeated once more and the residue is then taken up in boiling acetone (20 cc). The mixture is filtered hot and the solid collected is washed with acetone (20 cc) and ethyl ether (20 cc), to give 3-[2-(2-aminoethylthioacetamido)-thiazol-5-yl]-2-carboxy-7-(3,4-dichlorophenylthio)-acetamido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.15 g) in the form of a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1.[CH2:22]([NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[C:30]([F:43])[CH:29]=1)=[O:26])[CH3:23].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.O.COCCOC>[CH2:22]([NH:24][C:25](=[O:26])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:3]=[C:4]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]3[CH3:21])[C:5]3[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=3[N:7]=2)=[C:30]([F:43])[CH:29]=1)[CH3:23]
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: COC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OC)C3)c(F)c1
Yield: 4.2 %

Procedure:
A solution of (S)-methyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 26) (98 mg, 0.313 mmol), 1-ethyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 28) (110 mg, 0.357 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (13 mg, 0.0157 mmol) and sodium carbonate (93 mg, 0.876 mmol) in 2 ml of a 7:3:1 mixture of DME:H2O:EtOH respectively was heated in the microwave at 115° C. for 45 minutes. The reaction was concentrated in vacuo and the residue was re-dissolved in a mix of H2O and EtOAc. The aqueous phase was extracted into EtOAc and the organic extracts were combined and concentrated in vacuo. The sample was then purified via preparative HPLC at low pH and then triturated in MeOH and filtered to yield the title compound (6 mg, 4%).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:24]([O-:26])=[O:25])=[C:9]([CH:23]=1)[O:10][C:11]1[CH:22]=[CH:21][C:14]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1.COCOC1C=CC([N+]([O-])=O)=C(C=1)OC1C=CC=CC=1OCC(OC)=O>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([N+:24]([O-:26])=[O:25])=[C:9]([CH:23]=1)[O:10][C:11]1[CH:22]=[CH:21][C:14]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1
Reactant: COCOc1ccc([N+](=O)[O-])c(Oc2ccc(OCC(=O)OC)cc2)c1
Agent: COCOc1ccc([N+](=O)[O-])c(Oc2ccccc2OCC(=O)OC)c1
Product: COC(=O)COc1ccc(Oc2cc(O)ccc2[N+](=O)[O-])cc1

Procedure:
Using essentially the same procedure, but subtituting methyl {p-[5-(methoxymethoxy)-2-nitrophenoxy]phenoxy}acetate for methyl {o-[5-(methoxymethoxy)-2-nitrophenoxy]phenoxy}acetate, methyl [p-(5-hydroxy-2-nitrophenoxy)phenoxy]acetate is obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39]N>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:34]=1[NH:39][C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:20]2[CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:29])[CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: COc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: COc1cccc2c(CCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccccc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(4-oxo-4-phenylbutyl)-4-piperidinyl]phenyl}propanamide and 1-(2-methoxyphenyl)hydrazine hydrochloride: ESMS m/e: 496.2 (M+H)+.
Reaction SMILES: [N:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6])=O.C(OC(=O)C)(=O)C>>[C:8]1([N+:3]2[N-:1][O:6][C:5](=[O:7])[CH:4]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=NN(CC(=O)O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=c1c[n+](-c2ccccc2)[n-]o1

Procedure:
N-phenyl sydnone was prepared by dehydration of the above prepared N-nitrosophenylglycine with acetic anhydride, using the method described in Organic Syntheses, Coll. Vol. 5, p. 962 (1973); Vol. 45, p. 96 (1965).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][OH:22])[CH:14]=3)=[CH:11][C:10]([C:23]([O:25]CC)=[O:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][OH:22])[CH:14]=3)=[CH:11][C:10]([C:23]([OH:25])=[O:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(OCCO)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C(O)c1cc(-c2cccc(OCCO)c2)n(-c2cccc(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 66A in analogy to the synthesis of the compound of Example 71A. 11 mg (82% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:9][CH:10](Cl)[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:13].[Na+]>C(#N)C>[C:1]([O:9][CH:10]([I:13])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(Cl)OC(=O)c1ccccc1
Agent: [Na+]
Solvent: CC#N
Product: CC(I)OC(=O)c1ccccc1
Temperature: 60 °C
Yield: 39 %

Procedure:
1-Chloroethyl benzoate (6.30 g, 34.12 mmol) and sodium iodide (23.0 g, 153.56 mmol) were combined in acetonitrile (150 mL) and heated to 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. Diethyl ether and dichloromethane were added to the residue and the solids were filtered off and the filtrate was concentrated under reduced pressure. After silica gel chromatography using ethyl acetate in hexanes the residue was combined with sodium iodide (4.70 g, 31.39 mmol) in acetonitrile (50 mL) and heated to 60° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure. Diethyl ether was added, the solids were filtered off and the filtrate was concentrated under reduced pressure. Chromatography on silica gel using ethyl acetate in hexanes provided 1-iodoethyl benzoate as a pale yellow oil (3.67 g, 39% yield).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([OH:13])=[O:12])[CH2:3][CH2:2]1.[C:14](Cl)(=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]([C:11]([OH:13])=[O:12])[CH2:3][CH2:2]2)=[O:23])=[CH:16][CH:17]=1
Reactant: O=C(O)C1CCNc2ccccc21
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2CCC(C(=O)O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
1,2,3,4-Tetrahydro-quinoline-4-carboxylic acid (305 mg, 1.89 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Anisoyl chloride (644 mg, 3.78 mmol) was added followed by diisopropylethylamine (733 mg, 1.01 mL, 15.67 mmol). The reaction was stirred at room temperature for 7 days. The mixture was concentrated and partitioned between chloroform and sodium hydroxide (1 M, aqueous). The chloroform extract was set aside. The aqueous phase was acidified with concentrated hydrochloric acid (pH=3-4). The aqueous phase was then extracted with ethyl acetate (three times). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was used without further purification. MS m/z: 312 (M+1).