Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]3[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=3)[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[O:17])[CH2:10][CH2:9][C:7]=2[N:8]=1>C(O)C.[Ni]>[N:8]1[C:7]2[CH2:9][CH2:10][N:11]([C:13]3[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=3)[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[CH:20]=3)=[O:17])[CH2:12][C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Agent: [Ni]
Solvent: CCO
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(N2CCc3ncncc3C2)c1
Reaction time: 18 h

Procedure:
A suspension of 3-[2-(methylthio)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-N-[3-(trifluoromethyl)phenyl]benzamide 3 (150 mg, 0.337 mmol) in ethanol (15 ml) was treated with Raney Nickel (˜150 mg, slurry in water) and the reaction mixture was stirred under 1 atm. H2 at 60° C. for 18 hours. The catalyst was filtered off (celite) and the filtrate was concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, EtOAc) gave the title compound as a yellow oil which solidified to a glass (84 mg, 63%).
Reaction SMILES: [C:1]([C:3]1[CH:37]=[CH:36][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:27]([N:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[O:28])=[C:18]([CH:26]=2)[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:39][OH:40].[O-]CC.[Na+]>C(O)C>[NH2:2][C:1](=[N:39][OH:40])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:27](=[O:28])[N:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:31])[CH3:32])=[C:18]([CH:26]=2)[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:36][CH:37]=1
Reactant: CCOC(=O)COc1cc(OCCCCCOc2ccc(C#N)cc2)ccc1C(=O)N(C(C)C)C(C)C
Reactant: NO
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)COc1cc(OCCCCCOc2ccc(C(N)=NO)cc2)ccc1C(=O)N(C(C)C)C(C)C
Reaction time: 8 h

Procedure:
A stirred solution of ethyl 5-[5-(4-cyanophenoxy)pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxyacetate (970 mg, 1.9 mmol) in 20 mL of anhydrous ethanol is treated with hydroxylamine hydrochloride (400 mg, 5.7 mmol) and 21% sodium ethoxide solution in ethanol (2.1 mL, 5.7 mmol) and stiffed at 50° C. overnight. The reaction is concentrated in vacuo and purified by chromatography on silica gel (20 g) with 80-100% ethyl acetate/hexane followed by 0-10% methanol/ethyl acetate as the eluent to afford (a) ethyl 2-[5-[5-[4-[amino(hydroxyimino)methyl]phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxy]acetate as a colorless foam;
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]([O:13][CH3:14])[NH:8][CH:9]=[C:10]([C:11]#[N:12])[C:5]=2[N:4]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([C:33]([NH2:35])=[O:34])[S:31][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[C:11]([C:10]1[C:5]2[N:4]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:3]=[C:2]([C:28]3[CH:29]=[C:30]([C:33]([NH2:35])=[O:34])[S:31][CH:32]=3)[C:6]=2[C:7]([O:13][CH3:14])=[N:8][CH:9]=1)#[N:12]
Reactant: COC1NC=C(C#N)c2c1c(Br)cn2C1CCCC1
Reactant: CC1(C)OB(c2csc(C(N)=O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ncc(C#N)c2c1c(-c1csc(C(N)=O)c1)cn2C1CCCC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A mixture of 3-bromo-1-cyclopentyl-4-methoxy-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (400 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxamide (553 mg) obtained in Step B of Example 33, (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (102 mg), 2M aqueous sodium carbonate solution (1.24 mL) and DME (3.5 mL) was stirred under microwave irradiation at 120° C. for 1 hr 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (310 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[C:9]([Cl:17])[CH:8]=2)=[O:4].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH2:15][Br:24])=[CH:11][CH:10]=[C:9]([Cl:17])[CH:8]=2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A solution of 7-chloro-3-methyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (1.6 g, 4.88 mmol), N-bromosuccinimide (869 mg, 4.88 mmol) and benzoyl peroxide (118 mg, 488 μmol) in carbon tetrachloride (50 mL) was heated at 100° C. for 5 h. At this time, the reaction was cooled to 25° C. The resulting solids were collected by filtration to afford 3-bromomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (1.7 g, 85.6%) as a white solid. The material was used without further purification.
Reaction SMILES: O[C:2]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=1)=[CH:3][C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:23][NH:24][NH2:25]>C(O)C>[CH3:23][N:24]1[C:2]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[CH:3][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N:25]1
Reactant: CCOC(=O)C(=O)C=C(O)c1cc(OC)c(OC)c(OC)c1
Reactant: CNN
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cc(OC)c(OC)c(OC)c2)n(C)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Ethyl 4-hydroxy-2-oxo-4-(3,4,5-trimethoxyphenyl)-3-butenoate (3.0 g) was dissolved in ethanol (30 mL), and to the solution methylhydrazine (468 mg) was added, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.[CH3:18][C:19]([CH3:24])([CH2:22]O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:9][S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:21][CH2:20][C:19]([CH3:24])([CH3:22])[CH2:18][O:17]2)=[CH:4][CH:3]=1
Reactant: CC(C)(CO)CO
Reactant: CCOC(=O)CSCC(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CSCC1(c2ccc(Cl)cc2)OCC(C)(C)CO1
Yield: 31.3 %

Procedure:
Ethyl {[2-(4-chlorophenyl)-2-oxoethyl]thio}acetate (8.15 g, 29.9 mmol) was dissolved in toluene (165 ml). 2,2-Dimethyl-1,3-propanediol (24.8 g, 238 mmol) and p-toluene sulfonic acid (300 mg) were added. The mixture was stirred at reflux in a Dean-Stark apparatus for 2.5 h and concentrated under reduced pressure. The crude product was dissolved in CH2Cl2. The mixture was washed with H2O (3×), brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash-chromatography (Hexane:EtOAc 9:1) to give 3.36 g (31%) of the title compound as an yellow oil. MS (CI) M/z: 381.0 (M++Na, 100), 382.0 (15), 383.0 (30), 384 (5)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 127 %

Procedure:
In a 15 mL round-bottomed flask, 3-(tert-butoxycarbonylamino)pyrrolidine (0.50 g, 2.68 mmol) was dissolved in CH2Cl2 (5 mL). Triethylamine (0.45 mL, 3.22 mmol) was added and the reaction mixture was cooled to 0° C. Methanesulfonyl chloride (0.25 mL, 3.22 mmol) was added dropwise and the reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was diluted with CH2Cl2 (20 mL) and quenched with 1.0 M aqueous HCl (5 mL). The aqueous layer was extracted with CH2Cl2 then the combined organics were dried over Na2SO4, filtered and concentrated to afford 0.90 g of (1-methanesulfonyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester as a light brown solid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][NH2:35])[CH:32]=2)[CH:27]=[CH:26][CH:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([NH:35][CH2:34][C:31]3[CH:32]=[C:33]4[C:28]([CH:27]=[CH:26][CH:25]=[N:24]4)=[CH:29][CH:30]=3)=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NCc1ccc2cccnc2c1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc4cccnc4c3)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylic acid (17 mg, 0.055 mmol) in N,N-dimethylformamide (0.5 mL) were added quinolin-7-ylmethanamine (34 mg, 0.22 mmol) (WO 2008/130481), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (80 mg, 0.21 mmol) and N,N-diisopropylethylamine (80 μL, 0.46 mmol). The reaction mixture was stirred at 50° C. for 16 hours. LC-MS indicated the reaction was complete. The reaction mixture was purified by preparative HPLC to afford the titile compound.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[C:13](=[CH:17][CH:18]=1)[C:14]([OH:16])=O>O1CCCC1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:19](=[O:20])[O:21][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)O)c(C(=O)O)c1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)OC2=O
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Acetic anhydride (40 ml) was added to a mixture of 4-methoxyphthalic acid (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99%) as an off white solid. 1H NMR (DMSO-d6) 8.02 (1H, d), 7.59 (1H, d), 7.49 (1H, dd), 3.97 (3H, s). MS: [M+H]+ 179.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:37][O:38][CH3:39])[C:10]([NH:12][CH:13]2[C:35](=[O:36])[N:15]3[C:16]([C:21]([O:23][CH:24]([CH2:30][O:31][CH:32]([CH3:34])[CH3:33])[CH2:25][O:26][CH:27]([CH3:29])[CH3:28])=[O:22])=[CH:17][CH2:18][S:19](=O)[C@H:14]23)=[O:11])[N:8]=1)=[O:2].[I-].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC(C)=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:37][O:38][CH3:39])[C:10]([NH:12][CH:13]2[C:35](=[O:36])[N:15]3[C:16]([C:21]([O:23][CH:24]([CH2:25][O:26][CH:27]([CH3:28])[CH3:29])[CH2:30][O:31][CH:32]([CH3:33])[CH3:34])=[O:22])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(COC(C)C)COC(C)C)=CCS(=O)[C@H]12)c1csc(NC=O)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(COC(C)C)COC(C)C)=CCS[C@H]12)c1csc(NC=O)n1
Temperature: 0 °C
Reaction time: 1.2 h
Yield: 88.6 %

Procedure:
To a stirred solution of 2-isopropoxy-1-isopropoxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate-1-oxide (syn isomer, 6.5 g) and sodium iodide (5 g) in dried acetone (130 ml) was dropwise added trifluoroacetic anhydride (7 g) at -2° C. over 16 minutes, and stirred at 0° to 5° C. for 1.2 hours. The resultant mixture was poured into ice water (650 ml), and then extracted with ethyl acetate (200 ml). The extract was washed with an aqueous solution of sodium sulfite (50 ml) and a saturated aqueous solution of sodium chloride (50 ml) in turn. The solution was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was triturated with diethylether (100 ml). The precipitates were collected by filtration to give 2-isopropoxy-1-isopropoxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 5.6 g).
Reaction SMILES: [CH:1]1([CH:4]([C:17]2[CH:27]=[CH:26][C:20]3[O:21][C:22]([F:25])([F:24])[O:23][C:19]=3[CH:18]=2)[C:5]2[C:13]3[C:8](=[C:9]([CH2:14][S:15][CH3:16])[CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH2:3][CH2:2]1.ClC1C=CC(C(C2CC2)C2C3C(=C(CS(C)=[O:47])C=CC=3)NC=2)=CC=1>>[CH:1]1([CH:4]([C:17]2[CH:27]=[CH:26][C:20]3[O:21][C:22]([F:25])([F:24])[O:23][C:19]=3[CH:18]=2)[C:5]2[C:13]3[C:8](=[C:9]([CH2:14][S:15]([CH3:16])=[O:47])[CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH2:2][CH2:3]1
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Reactant: CSCc1cccc2c(C(c3ccc4c(c3)OC(F)(F)O4)C3CC3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(c3ccc4c(c3)OC(F)(F)O4)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 100 mg (0.26 mmol) of the compound from Example 231 in analogy to the synthesis of the compound from Example 235. 92 mg (88% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=2/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC(=O)c1ccc(Br)c(/C=C/c2ccc(OC(F)(F)F)cc2)c1
Reactant: C1CCNC1
Product: NC(=O)c1ccc(N2CCCC2)c(/C=C/c2ccc(OC(F)(F)F)cc2)c1

Procedure:
The captioned compound was synthesized from 4-bromo-3-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-benzamide and pyrrolidine by the same procedure as in Example 2-5-2.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.[CH:15](OCC)(OCC)OCC>>[Cl:1][C:2]1[C:11]2[N:10]([CH:15]=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2
Reactant: CCOC(OCC)OCC
Reactant: NNc1nc2cc(F)ccc2nc1Cl
Product: Fc1ccc2nc(Cl)c3nncn3c2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 10 g. (0.047 mole) of 2-chloro-6-fluoro-3-hydrazinoquinoxaline and 80 ml. (0.47 mole) of triethyl orthoformate was heated under a nitrogen atmosphere with mechanical stirring in a preheated oil bath at 100° C. overnight (~16 hours). The resulting mixture was cooled to room temperature, and the precipitate which formed was subsequently recovered by means of suction filtration, washed with three-50 ml. portions of ethanol and air-dried to constant weight to ultimately afford 9.42 g. (91%) of pure 4-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 310°-312° C. (decomp.).
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([C:31](O)=[O:32])[CH:30]=1)[NH:27][CH:26]=[CH:25]2.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][N:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:31]([C:29]2[CH:30]=[C:22]([Cl:21])[CH:23]=[C:24]3[C:28]=2[NH:27][CH:26]=[CH:25]3)=[O:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccncc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccncc2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Yield: 47.1 %

Procedure:
268 mg (1 mmol) of (4-tert-butyl-benzyl)-(2-pyridin-4-yl-ethyl)-amine, 196 mg (1 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 217 mg (1.1 mmol) of EDC.HCl were stirred over night at rt in 20 ml DCM. The product was purified by column chromatography (silica gel; EtOAc) to yield 210 mg (47%) product as a colorless oil. MS (ISP) 446.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:15][CH2:16][CH2:17][CH:18]=[O:19])[CH2:12][CH:13]=[CH2:14]>C1C=CC=CC=1>[CH2:11]([N:15]([CH2:16][CH2:17][CH:18]=[O:19])[C:9]([NH:8][C:6]1[S:7][C:3]([O:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH2:12][CH:13]=[CH2:14]
Reactant: C=CCCNCCC=O
Reactant: COc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C=CCCN(CCC=O)C(=O)Nc1nnc(OC)s1

Procedure:
A mixture of 5-methoxy-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the diethyl acetyl of 3-but-3-enylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield the desired product the diethyl acetal of 3-[1-but-3-enyl-3-(5-methoxy-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: C(OC[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:20][N:21]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=3)[CH2:22][C:23]#[CH:24])[CH:16]=2)[N:11]=[CH:10]1)(=O)C(C)(C)C.[N+:34]([C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40][NH2:41])([O-:36])=[O:35]>>[O:19]=[C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:20][N:21]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:41][CH2:40][C:39]4[CH:42]=[CH:43][CH:44]=[C:37]([N+:34]([O-:36])=[O:35])[CH:38]=4)=[O:31])=[CH:27][CH:26]=3)[CH2:22][C:23]#[CH:24])[CH:16]=2)[N:11]=[CH:10][NH:9]1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: C#CCN(Cc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)O)cc1
Product: C#CCN(Cc1ccc2nc[nH]c(=O)c2c1)c1ccc(C(=O)NCc2cccc([N+](=O)[O-])c2)cc1
Yield: 56 %

Procedure:
Using the procedure described in Example 10, p-[N-(3,4-dihydro-3-pivaloyloxymethyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzoic acid was reacted with 3-nitrobenzylamine to give p-[N-(3,4-dihydro-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]-N-(3-nitrobenzyl)benzamide (containing 1 equivalent of water, 56%), m.p. 197°-199° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:12]([O-:13])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Na+].[OH-].[K+]>>[C:4]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[OH:13])[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: [O-]c1ccccc1-c1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccccc1-c1ccccc1
Yield: 92.2 %

Procedure:
Starting from 7.35 g of potassium o-phenyl-phenate, obtained "in situ" by salifying 6 g of o-phenyl-phenol with KOH, and from 4.2 g of acetophenone (molar ratio = 1:1), it was possible to obtain, by operating as in Example 1, 0.5 g of benzoylacetic acid. Under the same conditions, potassium p-phenyl-phenate did not cause any sensible reaction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](F)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.CN(C)C=O>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(F)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(-c2nc(-c3ccccn3)no2)cc(-n2ccnc2)c1

Procedure:
In a screw cap vial equipped with stir bar added 3-(2-Pyridyl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (20 mg, 0.08 mmol), potassium carbonate (20.8 mg, 0.15 mmol), imidazole (7.7 mg, 0.11 mmol) and dimethylformamide (1 ml). Stirred the resulting mixture at 120° C. for 2 h. The reaction mixture was diluted with chloroform (30 ml) and washed with water (30 ml). The aqueous phase was re-extracted with chloroform (30 ml) and the combined organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was purified on silica gel using 2% methanol in dichloromethane to isolate the free base of the desired compound as a white solid. The free base was converted to it's hydrochloride salt (10.0 mg), white solid. 1H-NMR (DMSO), δ (ppm): 9.85 (s, 1H), 8.86 (m, 4H), 8.49 (s, 1H), 8.23 (d, 1H), 8.13 (t, 1H), 7.95 (s, 1H), 7.73 (dd, 1H).
Reaction SMILES: ON1C(=O)CCC1=O.N1C=CC=CC=1.[CH2:15]([O:22][CH2:23][C@@:24]1([N:49]2[CH:57]=[C:55]([CH3:56])[C:53](=[O:54])[NH:52][C:50]2=[O:51])[O:48][C@H:28]([CH2:29][O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:26]([OH:27])[CH2:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:58]1[CH:63]=[CH:62][C:61]([O:64][C:65](Cl)=[S:66])=[CH:60][CH:59]=1>C1(C)C=CC=CC=1>[CH2:15]([O:22][CH2:23][C@@:24]1([N:49]2[CH:57]=[C:55]([CH3:56])[C:53](=[O:54])[NH:52][C:50]2=[O:51])[O:48][C@H:28]([CH2:29][O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@@H:26]([O:27][C:65]([O:64][C:61]2[CH:62]=[CH:63][CH:58]=[CH:59][CH:60]=2)=[S:66])[CH2:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: S=C(Cl)Oc1ccccc1
Agent: O=C1CCC(=O)N1O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](OC(=S)Oc3ccccc3)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 75.1 %

Procedure:
N-hydroxysuccinimide (3.9 g, 34 mmol) and pyridine (24.3 mL, 300 mmol) were added to a solution of the alcohol 3 (90.0 g, 150 mmol) in 1 L of toluene. The mixture was warmed up to 80° C. and stirred for 10 min. Phenyl chlorothionoformate (30 g, 174 mmol) was added to the solution and the resultant reaction mixture was stirred at 80° C. for 8 h. The hot toluene solution was decanted from solids. The solids were rinsed with AcOEt (2×30 mL) and the combined toluene solution and AcOEt washes were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes/AcOEt 9:1 then 3:1) to give 83.0 g (75.2%) of the title compound, 17, as a light yellow foam. Rf (hexanes/AcOEt 9:1) 0.24. 13C-NMR (CDCl3): 12.97 (5-CH3), 19.49 (2'-C), 27.16 (Me3C), 38.32 (Me3C), 64.87 (O--C-Ph), 70.75 (N--C--O), 72.28 (5'-C), 84.21 (4'-C), 84.90 (3'-C), 85.39 (1'-C), 110.82 (5-C), 121.95, 126.94, 127.72, 128.27, 128.40, 129.81 (Ar--C), 130.35 (6-C), 131.93, 132.79, 133.76, 135.38, 135.76, 138.30 (Ar--C), 151.05 (2-C), 153.42 (Ar--C), 163.40 (4-C), 194.36 (thioformate-C).