Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:21]12CC(C=C1)C=[CH:22]2.CCN(CC)CC>C1(C)C=CC=CC=1>[F:18][C:17]([F:20])([F:19])[O:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH:22]=[CH:21][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]2)=[CH:11][CH:12]=1
Reactant: C1=CC2C=CC1C2
Reactant: CCOC(=O)C(Cl)=NNc1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccn(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 70 °C
Yield: 78.5 %

Procedure:
A stirred mixture of hydrazonoyl chloride 65 (1.55 g, 4.99 mmol), bicyclo[2.2.1]hepta-2,5-diene (1.25 mL, 24.6 mmol) and Et3N (2.0 mL, 14.3 mmol) in toluene (10 mL) was heated to 70° C. for 1 h. The mixture was cooled and filtered, the filter cake was washed with toluene (10 mL) and the organic fractions were combined and evaporated. The residue was refluxed in xylenes (30 mL) for 2 h. Column chromatography on silica gel, eluting with hexanes, firstly gave xylenes, and then further elution with CH2Cl2 gave ethyl 1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole-3-carboxylate (66) (1.176 g, 79%) as a white solid: mp 76-78° C.; 1H NMR (CDCl3) δ 7.91 (d, J=2.5 Hz, 1H), 7.79 (d, J=8.9 Hz, 2H), 7.33 (d, J=8.9 Hz, 2H), 7.00 (d, J=2.5 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). APCI MS m/z 301 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[CH:5]2.[Se](=O)=[O:13]>CO>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:1]=[O:13])=[CH:11][CH:10]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=[Se]=O
Reactant: Cc1ccc2ncncc2c1
Solvent: CO
Product: O=Cc1ccc2ncncc2c1
Temperature: 160 °C
Yield: 43.7 %

Procedure:
The mixture of 6-methyl-quinazoline (5.0 g, 34.7 mmol) and selenium dioxide (7.7 g, 69.4 mmol) was heated at 160° C. for 12 hours. After cooling to room temperature, methanol was added with stirring. After removal of solid by filtration, the filtrate was concentrated. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-30% ethyl acetate in hexane in 30 min) afforded 6-quinazolinecarboxaldehyde (2.4 g, 43.7%) as a white solid: LC-MS m/e 159 (MH+).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][N:17]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27]C(O)=O.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([N:8]([CH3:27])[CH2:9][CH2:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][N:17]=2)=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: NC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)nc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(CCc1ccc(Oc2ccc(C(N)=O)cn2)cc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine amine (65 mg, 0.20 mmol) from example 1, AcOH (70 μL, 1.2 mmol), formaldehyde (0.6 mmol) and NaBH(OAc)3 (0.40 mmol) in 1,2-DCE (2 mL). Stir the mixture at room temperature overnight. Dilute the mixture with CH2Cl2 and wash with NaHCO3 sat. Extract the aqueous layer with CH2Cl2, combine the organic layers and dry over Na2SO4. Purify by flash chromatography on silica gel (eluent: EtOAc). Electrospray MS M+1 ion=362, 1H-NMR (CDCl3, 400 MHz): 8.58 (d, 1H, J=2.6 Hz), 8.15 (dd, 1H, J=2.6 and 8.6 Hz), 7.32-7.22 (m, 7H), 7.06-7.04 (m, 2H), 6.95 (d, 1H, J=8.6 Hz), 3.61 (bs, 2H), 2.91-2.84 (m, 2H), 2.74-2.66 (m, 2H), 2.32 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([O-:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[NH2:15][CH:16]1[C:27](=[O:28])[N:18]2[C:19]([C:24]([OH:26])=[O:25])=[C:20]([CH3:23])[CH2:21][S:22][C@H:17]12>>[C:11]([CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([NH:15][CH:16]1[C:27](=[O:28])[N:18]2[C:19]([C:24]([OH:26])=[O:25])=[C:20]([CH3:23])[CH2:21][S:22][C@H:17]12)=[O:10])([OH:13])=[O:12]
Reactant: O=C([O-])C(C(=O)O)c1ccccc1
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: [Na+]
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)O)c3ccccc3)[C@H]2SC1

Procedure:
The process was carried out in the same manner as in Example 21 using 2.2 g of mono-sodium phenylmalonate and 2.14 g of 7-amino-3-methyl-3-cephem4-carboxylic acid. 7-(α-Carboxyphenylacetamido)-3-methyl-3-cephem-4-carboxylic acid was afforded in a yield of 2.1 g (56%).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH:22]3[CH2:27][CH2:26][SiH:25](Cl)[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C@H:22]3[CH2:27][CH2:26][Si@H:25]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: CCCCCBr
Reactant: Clc1ccc(OC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc1
Product: CCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](COc3ccc(Cl)cc3)CC2)CC1

Procedure:
The general procedure of Example 30 was repeated using n-pentyl bromide and 4-(trans-4-(4-chlorophenyloxymethyl)cyclohexyl)-1-chloro-1-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:17]1([CH:14]2[C:15]3[C:10](=[N:9][C:8]4[C:3]([C:2]=3[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:11][CH2:12][CH2:13]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1c2c(nc3ccccc13)CCCC2N1CCCC1

Procedure:
9-Amino-1,2,3,4-tetrahydroacridin-1-ol (5.36 g) was refluxed overnight in 250 ml of toluene that contained pyrrolidine (7.10 g) and p-toluenesulfonic acid monohydrate (9.5 g). At the end of this time the reaction mixture was washed with an aqueous K2CO3 solution and then the organic phase was concentrated. The residue obtained in this manner was purified by flash chromatography (5% Et3N, toluene) to give, after recrystallization from benzene/pentane, 2.91 g, m.p. 201°-203°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2cc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3ncc(Cl)cc32)cc1
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a solution of 6-chloro-1H-pyrrolo[3,2-b]pyridine (5.0 g, 32.8 mmol) in THF (150 mL) in an ice bath was added NaH (1.57 g, 60% in mineral oil, 39.3 mmol). After stirring in an ice bath for 30 min, 4-toluenesulfonyl chloride (6.87 g, 36.1 mmol) was added. The mixture was stirred at RT overnight. The reaction mixture was quenched with water (50 mL) at 0° C. and extracted with EtOAc (300 mL). The extract was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 chromatography eluting with petroleum ether/EtOAc gradient (8:1 to 2:1) to afford 6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridine as a yellow solid (8.5 g, 84%). MS (ESI): m/z=307.0 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:16]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:19]([CH2:22]I)=[CH:18][CH:17]=1>>[C:16]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:17]=[CH:18][C:19]([CH2:22][O:1][C:2]2[CH:9]=[C:8]([CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:20][CH:21]=1
Reactant: ICc1ccc(-c2ccccc2)cc1
Reactant: N#Cc1ccc(Cn2ccnc2)cc1O
Product: N#Cc1ccc(Cn2ccnc2)cc1OCc1ccc(-c2ccccc2)cc1

Procedure:
Following the procedure described in Example 2, Step E but using 2-hydroxy-4-imidazol-1-ylmethyl-benzonitrile (as described in Step F) and biphenyl-4-ylmethyl iodide as starting materials, the title compound was obtained as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: C1COCCN1
Solvent: O
Product: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Temperature: 25 °C
Yield: 96 %

Procedure:
As shown in Scheme 3 above, a mixture of 2,6-dichloropurine (1.90 g, 10 mmol) and morpholine (2.34 g, 30 mmol) in water (25 mL) was heated under reflux for 15 min. Solidified reaction mixture was cooled to room temperature. Solid was filtered out and washed with water, methanol and ether. The 2-chloro-6-morpholin-4-yl-9H-purine was obtained in 96% yield (2.30 g). A mixture of 2-chloro-6-morpholin-4-yl-9H-purine (1.92 g, 8 mmol) and 2-(3,4-dimethoxyphenyl)ethylamine (4.35 g, 24 mmol) in sealed tube and under nitrogen was stirred at 190-195° C. for 1 hour. The reaction mixture turned to clear solution initially and then formed a slurry. The reaction mixture was cooled to room temperature diluted with methanol (8 mL) and the solid was collected by filtration, washed with methanol and Et2O and dried to afford 2.30 g (74% yield) of [2-(3,4-dimethoxy-phenyl)-ethyl]-(6-morpholin-4-yl-9H-purin-2-yl)amine.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[C:11]=2[CH:12]([CH3:14])[CH3:13])[C:3]1=[O:22].[CH2:23]([C:25]1[NH:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=1)[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([N:26]4[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[N:29]=[C:25]4[CH2:23][CH3:24])[C:3]3=[O:22])[CH:8]=[N:9]2)=[CH:16][CH:17]=1
Reactant: CCc1nc(C(F)(F)F)c[nH]1
Reactant: CC(C)c1c(N2CCC(Br)C2=O)cnn1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc(C(F)(F)F)cn1C1CCN(c2cnn(-c3ccc(Cl)cc3)c2C(C)C)C1=O
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 1.3 %

Procedure:
A mixture of 3-bromo-1-[1-(4-chlorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.200 g, 0.52 mmol), 2-ethyl-4-(trifluoromethyl)-1H-imidazole (0.060 g, 0.36 mmol) and K2CO3 (0.080 g, 0.58 mmol) in DMF (1.5 mL) was stirred at 65° C. for 1.5 hrs. The mixture was then cooled to room temperature, quenched with water (30 mL), extracted with EtOAc (50 mL), and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to yield the title compound (0.0022 g, TFA salt, 1.0%). 1H NMR (TFA salt) (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.49 (m, 2H), 7.35 (m, 2H), 7.21 (s, 1H), 5.03 (dd, J=10.4, 8.8 Hz, 1H), 3.88 (m, 1H), 3.81 (m, 1H), 3.03 (heptet, J=7.0 Hz, 1H), 2.88 (m, 2H), 2.30 (m, 2H), 1.40 (t, J=7.4 Hz, 3H), 1.23 (m, 6H); MS: (ES) m/z calculated for C22H23ClF3N5O [M+H]+ 466.1. found 466.1.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:8])[CH2:6][SH:7])(=[O:3])[CH3:2].[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5](=[O:8])[CH2:6][S:7][C:16](=[O:17])[CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(=O)CS
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)NC(=O)CSC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 0.10 mole of N-acetyl-2-mercapto acetamide in 150 ml. of chloroform is added 0.1 mole of phenyl acetylchloride followed by 0.1 mole of triethylamine. The reaction mixture is stirred at ambient temperature for 1 hour and then concentrated to dryness. Chromatograph of the residue on 500 g. of silica gel eluting with ethylacetate in hexane (25-75%) gives N-acetyl-2-(phenylacetylthio) acetamide.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15]C(=O)OC(C)(C)C)[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]1[N:35]=[N:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[C:32]([CH3:40])[C:31]=1[CH3:41].C(N(CC)C(C)C)(C)C>C(#N)CCC>[NH2:15][C:11]1([C:8]2[CH:9]=[CH:10][C:5]([C:3]3[N:29]=[C:30]4[C:31]([CH3:41])=[C:32]([CH3:40])[C:33]([C:36]([O:38][CH3:39])=[O:37])=[N:34][N:35]4[C:2]=3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:6][CH:7]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1nnc(N)c(C)c1C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC#N
Product: COC(=O)c1nn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c(C)c1C
Temperature: 125 °C
Yield: 16 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that was prepared in a manner analgous to that described for Intermediate Example Int-1-A] (630 mg, ˜90% purity, 1.28 mmol, 1.0 eq), methyl 6-amino-4,5-dimethylpyridazine-3-carboxylate [that was prepared in a manner analgous to that described for Intermediate Example Int-34] (257 mg, 1.28 mmol, 1.0 eq), N,N-diisopropylethylamine (220 μL, 1.28 mmol, 1.0 eq) in butyronitrile (2.6 mL) was heated for 17 hours at 125° C. On cooling the mixture was partitioned between DCM and water, stirred vigorously and filtered through a silicone coated filter paper. The filtrate was concentrated in vacuo. The crude mixture was purified via preparative reversed phase HPLC to give 89 mg (16% yield) of the title compound directly as the free amine.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])[C:12]1=[O:27])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])[C:12]1=[O:27])[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2C(F)(F)F)C1=O)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2C(F)(F)F)C1=O
Yield: 73 %

Procedure:
A solution of Example 138B in dichloromethane (1.5 mL) was treated with trifluoroacetic acid (1.5 mL) at 25° C. for 16 h. The solvents were evaporated, and the crude residue was purified using reverse phase chromatography eluting with a gradient of 95% water (0.1% trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give the title compound (0.121 g, 73%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][N:4]=1.[NH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[NH2:12]>CCO>[CH3:1][S:2][C:3]1[N:8]=[C:7](/[CH:9]=[N:12]/[NH:11][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(C=O)n1
Reactant: NNc1ccccn1
Solvent: CCO
Product: CSc1nccc(/C=N/Nc2ccccn2)n1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A mixture of 2-methylsulfanyl-pyrimidine-4-carbaldehyde (1.00 g) (U.S. Pat. No. 6,218,537) and 2-hydrazinopyridine (0.71 g) in EtOH (20 mL) was heated to reflux for 24 h, then cooled to RT and the resulting solid collected by filtration to give N-[1-(2-methylsulfanyl-pyrimidin-4-yl)-meth-(E)-ylidene]-N′-pyridin-2-yl-hydrazine (1.26 g). A mixture of this material and DCM (20 mL) was gently heated, and a second aliquot of DCM (10 mL) and chloroform (5 mL) added to facilitate solubilization. Iodobenzene diacetate (1.65 g) was added, and the resulting mixture stirred at RT under N2 for 17 h. The reaction mixture was then evaporated under reduced pressure and the crude residue was triturated with hot Et2O. Once the mixture cooled to RT, the solid was collected by filtration to afford 3-(2-methylsulfanyl-pyrimidin-4-yl)-[1,2,4]triazolo-[4,3-a]pyridine (1.12 g).
Reaction SMILES: N12CCCN=C1CCCCC2.CO[C:14](=[O:30])[C:15]1[C:16](=[C:21]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19]C)=O.Cl.[NH2:32][CH:33]1[CH2:39][CH2:38][C:37](=[O:40])[NH:36][C:34]1=[O:35]>CN(C=O)C>[O:35]=[C:34]1[CH:33]([N:32]2[C:17](=[O:19])[C:16]3[C:15](=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:25][NH:26][C:27](=[O:29])[CH3:28])[C:14]2=[O:30])[CH2:39][CH2:38][C:37](=[O:40])[NH:36]1
Reactant: NC1CCC(=O)NC1=O
Reactant: COC(=O)c1cccc(CNC(C)=O)c1C(=O)OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 120 °C
Yield: 22.8 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.93 g, 6 mmol) was added dropwise to a stirred suspension of 3-(acetylamino-methyl)-phthalic acid dimethyl ester (1.61 g, 6.0 mmol) and aminoglutarimide hydrochloride (1.0 g, 6.0 mmol) in DMF (15 ml). The mixture was then heated to 120° C. for 24 hours. The cooled mixture was concentrated in vacuo and the residue was stirred with water (25 ml) and dichloromethane (20 ml). The resulting slurry was filtered to give 0.45 g (22%) of the product as a gray solid. Recrystallization from methanol gave a white solid: mp 177-179° C.; 1H NMR (DMSO-d6) 6 (11.02 (s, 1H), 8.36 (t, J=5.8 Hz, 1H), 7.74-7.55 (m, 3H), 5.05-4.98 (dd, J=5.3 and 12.5 Hz, 1H), 4.57 9D, j=5.9 Hz, 2H), 2.84-2.70 (m, 1H), 2.51-2.34 (m, 2H), 1.95-1.91 (m, 1H), 1.79 (s, 3H); 13C NMR (DMSO-d6) 6 (172.85, 169.89, 169.81, 167.56, 167.05, 139.37, 134.83, 133.35, 131.58, 127.14, 121.94, 48.91, 37.84, 30.98, 22.54, 22.05; Anal. Calcd. For C16H15N3O5+0.96 water: C, 55.45; H, 4.92; N, 12.12. Found: C, 55.27; H, 4.82; N, 12.00.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.[H-].[Na+].[CH3:20][O:21][CH2:22]Br>CN(C=O)C.O>[CH3:1][C:2]1[N:11]([CH2:20][O:21][CH3:22])[C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Cc1ccc2ccc3nc(C)[nH]c(=O)c3c2c1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1c(C)nc2ccc3ccc(C)cc3c2c1=O
Reaction time: 0.58 h

Procedure:
To a suspension of 3,9-dimethylbenzo[f]quinazolin-1(2H)-one (1.0 g, 4.5 mmol) in DMF (25 ml) was added 80% NaH (0.15 g, 5.0 mmol) (Aldrich) portion wise and the mixture was stirred 35 minutes. Bromomethyl methyl ether (0.39 ml, 4.8 mmol) (Aldrich) was added in one portion and the solution was stirred at room temperature overnight. The solution was then diluted with water (100 ml) and extracted twice with methylene chloride (100, 40 ml). The combined methylene chloride extracts were washed with a small volume of water, dried (K2CO3), and concentrated in vacuo. The residue was purified by silica gel (4 0 g) chromatography eluting with ethyl acetate:methylene chloride (0 to 1:19) to give 3,9-dimethyl-2-methoxymethylbenzo[f]quinazolin-1(2H)-one and the corresponding O-alkylated material in a 4:1 ratio as determined by NMR (0.79 g). 1H NMR (DMSO-d6, 300 MHz) for major isomer δ: 2.57 (s, 3H, C9 -CH3), 2.68 (s 3.38 (s, 3H, OCH3), 5.62 (s, 2H, NCH2O), 7.51 (dd, J=8,2 Hz, 1H, Ar), 7.56 (d, J=9 Hz, 1H, Ar), 7.96 (d, J=8 Hz, 1H, Ar), 8.24 (d, J=9 Hz, 1H, Ar), 9.63 (s, 1H, Ar). Anal. Calculated for C16H16N2O2 : C, 71.62; H, 6.01; H, 10.44. Found: C, 71.55; H, 6.03; H, 10.43.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[C:2]([O:4]C)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1.C[O-].[Na+].Cl>CO>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH2:17][C:2](=[O:4])[C:1]([O:7][CH3:8])=[O:6])=[CH:12][CH:11]=1
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccc(F)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethyl oxalate (18.80 g, 0.159 mol) and 4'-fluoroacetophenone (20.0 g, 0.145 mol) were charged to a 1000 mL round-bottom flask and diluted with methanol (400 mL). The reaction flask was placed in a sonication bath (Bransonic 1200), and sodium methoxide (25% in methanol, 70 mL) was added over 25 minutes. The reaction was sonicated at 45° C. for 16 hours. The reaction became an insoluble mass during this time. The solid was mechanically broken up, then poured into a hydrochloric acid solution (1N, 500 mL). A magnetic stirrer was added, and the white suspension was stirred vigorously at room temperature for 60 minutes. The suspension was cooled to 0° C. and held for 30 minutes. The solid was filtered, and the filter cake was then washed with cold water (100 mL). Upon drying, methyl 4-[4-fluorophenyl]-2,4-diketobutanoate was obtained (22.91 g, 70.6%) as the enol: 1H NMR (CDCl3 /300 MHz) 8.03 (ddd, J=8.86 Hz, J=8.66 Hz, J=5.03 Hz, 2H), 7.19 (dd, J=8.86 Hz, J=8.66 Hz, 2H), 7.04 (s, 1H), 3.95(s, 3H). 19F NMR (CDCl3 /282.2 MHz) -103.9(m).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]([F:14])[C:5]([F:13])=[C:6]2C(=O)[O:10][C:8](=[O:9])[C:7]=12.O.[OH-].[Li+].[CH2:19]([OH:21])[CH3:20]>O>[CH2:19]([O:21][C:3]1[C:2]([F:1])=[C:7]([CH:6]=[C:5]([F:13])[C:4]=1[F:14])[C:8]([OH:10])=[O:9])[CH3:20]
Reactant: CCO
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCOc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 140 °C
Yield: 77.5 %

Procedure:
4.4 g (20 mmol) of tetrafluorophthalic anhydride are dissolved in 3 g of water and 30 g of ethanol, 4.2 g of lithium hydroxide hydrate are added, and the mixture is heated at reflux for 48 hours. Then 50 g of water are added and an ethanol/water mixture (31.9 g) is distilled off until a head temperature of 100° C. is reached. Subsequently a pH of 0.6 is established by adding 19 g of 30% strength hydrochloric acid, and the mixture is extracted using a mixture of 20 g of 1,2-dichlorobenzene and 10 g of Hostarex A327. The organic phase is dried over MgSO4, heated at 140° C. for one hour until the evolution of gas comes to an end (decarboxylation) and then adjusted at 25° C. to a pH of 14 using 12.1 g of 35% strength sodium hydroxide solution. The mixture is extracted three times with in each case 50 g of dichloromethane, and the aqueous phase is adjusted to a pH of 0.7 by adding 9.4 g of 30% strength hydrochloric acid and extracted with MTBE. The mixture is dried over MgSO4 and filtered, and removal of the solvent leaves 3.4 g (15.5 mmol, corresponding to 77%) of yellowish 3-ethoxy-2,4,5-trifluorobenzoic acid (purity by GC>95%).
Reaction SMILES: [C:1]([O:10]C1C=CC=CC=1)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([NH:17][C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[OH:4])=[CH:19][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Product: N#Cc1ccc(NC(=O)c2ccccc2O)cc1

Procedure:
The 4′-cyano-salicylanilide was prepared by condensing phenyl salicylate with 4-amino-benzonitrile then purified as described in Example 2a. The ligand mixture was then prepared from 4′-cyano-salicylanilide and 1,1′-bi-2-naphthol using the procedure described in Example 5a. 31P NMR (121.77 MHz): several peaks between 116.4-117.7 ppm.
Reaction SMILES: [SH2:1].[CH2:2]([O:4][C:5]([NH:7][CH2:8][C:9]#[N:10])=[O:6])[CH3:3].N1C=CC=CC=1.C(N(CC)CC)C>>[CH2:2]([O:4][C:5]([NH:7][CH2:8][C:9]([NH2:10])=[S:1])=[O:6])[CH3:3]
Reactant: CCOC(=O)NCC#N
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)NCC(N)=S
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stream of H2S is passed into a mixture of 27.5 g of ethoxycarbonylaminoacetonitrile (210 mmol), pyridine (21ml, 210 mmol) and triethylamine (14.5 ml, 105 mmol) according to the procedure of Example 23. After stirring for 4 hours at room temperature and washing with water, a beige precipitate is obtained which is filtered off to give 6.6 g of ethoxycarbonylaminothioacetamide, which is a beige powder melting at 116° C.