Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:19])[CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[C:28]1[CH:38]=[C:37]([CH3:39])[C:31]2[N:32]=[C:33]([NH2:36])[N:34]=[N:35][C:30]=2[CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[C:28]1[CH:38]=[C:37]([CH3:39])[C:31]2[N:32]=[C:33]([NH:36][C:2]3[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:19])[CH2:12][CH2:13][N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)(=[O:10])=[O:9])=[CH:4][CH:3]=3)[N:34]=[N:35][C:30]=2[CH:29]=1
Reactant: Cc1cc(-c2c(Cl)cccc2Cl)cc2nnc(N)nc12
Reactant: CN(CCN1CCCC1)S(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(-c2c(Cl)cccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)N(C)CCN4CCCC4)cc3)nc12
Temperature: 100 °C
Yield: 76 %

Procedure:
4-bromo-N-methyl-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (1.0 equiv, 0.82 mmol), 7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (1.5 equiv, 1.23 mmol), Cs2CO3 (3.0 equiv, 2.46 mmol), Pd2(dba)3 (0.1 equiv, 0.082 mmol), and Xantphos (0.2 equiv, 0.1634 mmol) were dissolved in 15 mL dioxane and purged of air, then placed under an argon blanket and refluxed for 18 h at 100° C. The reaction was cooled to room temperature and filtered and condensed under reduced pressure. The residue that was recovered was dissolved in EtOAc and extracted with saturated bicarbonate and brine; the organics were then dried (Na2SO4) and concentrated to afford brown oil. Using EtOAc/hexanes (1:5 v/v) the residue was precipitated out to afford 4-[7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-N-methyl-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide, as a tan solid, (297.2 mg, 76% yield). 1H NMR (DMSO-d6): δ 1.95 (dm, 4H), 2.72 (s, 3H), 2.73 (s, 3H), 3.04 (q, J=7.5 Hz, 2H), 3.35 (dt, J=5.3 Hz, J=5.4 Hz, 4H), 3.58 (q, J=5.2 Hz, 2H), 7.52 (t, J=7.6 Hz, 1H), 7.67 (d, J=3.2 Hz, 2H), 7.79 (s, 1H), 7.87 (d, J=3.2 Hz, 2H), 8.18 (s, 1H), 8.31 (s, J=9.0 Hz, 2H), 10.51 (bs, 1H), 11.55 (s, 1H). MS (ES+) m/z=574, LC retention time 2.80 minutes.
Reaction SMILES: C1(C2(CCC3C=CC(C4(C#N)CC4)=C(F)C=3)CC(=O)C(CC3N=C4N=CC=CN4N=3)C(=O)O2)CCCC1.C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(=O)CC(=O)O2)CCCC1.[Cl:65][CH2:66][C:67]#[N:68].[NH2:69][C:70]1[CH:74]=[CH:73][S:72][C:71]=1[C:75]([O:77]C)=O.Cl>O1CCOCC1>[Cl:65][CH2:66][C:67]1[NH:68][C:75](=[O:77])[C:71]2[S:72][CH:73]=[CH:74][C:70]=2[N:69]=1
Reactant: N#CCCl
Reactant: COC(=O)c1sccc1N
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Agent: Cl
Agent: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)C(Cc4nc5ncccn5n4)C(=O)O3)cc2F)CC1
Solvent: C1COCCO1
Product: O=c1[nH]c(CCl)nc2ccsc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.4 %

Procedure:
This compound was prepared by a modification of a method reported for related fused pyrimidine-4(3H)-ones: (1) Shishoo, C. J.; Devani, M. B.; Pathak, U.S.; Ananthan, S.; Bhadti, V. S.; Ullas, G. V.; Jain, K. S.; Rathod, I. S.; Talati, D. S.; Doshi, N. H. J. Heterocyclic Chem. 1984, 21, 375, and (2) Gerecke, M.; Kyburz, E.; Borer, R.; Gassner, W. Heterocycles 1994, 39, 693). An oven-dried 1-L round bottomed flask was charged with chloroacetonitrile (21.86 g, 0.29 mol, 1.3 equiv), methyl 3-aminothiophene-2-carboxylate (35 g, 0.223 mol), and 4 M HCl in 1,4-dioxane (350 mL). The reaction mixture was stirred at room temperature for 1 d. The mixture was evaporated to dryness. The residue was dissolved in water (600 mL) and treated with aqueous 10% sodium bicarbonate to a pH of 8. The resulting slurry was filtered, and the cake washed with water and dried, affording 38.2 g (85%) of the title product.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:9]1[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:9]1[CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(C)n3Cc2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc2n1Cc1ccccc1

Procedure:
The desired product was prepared using a procedure similar to step 4 of example 3. Thus, 1,3-dibenzyl-5-(4-methoxy-phenyl)-2-methyl-1H-indole (0.692 g, 1.657 mmol) was reacted with BBr3 (2.0 ml of a 1M solution in CH2Cl2) to give the product (0.347 g, 0.860 mmol, 52%) as an off-white solid, mp 170-171° C. 1H NMR (DMSO-d6) δ 2.34 (s, 3H), 4.09 (s, 2H), 5.41 (s, 2H), 6.79 (d, J=8.5 Hz, 2H), 6.98 (d, J=7.3 Hz, 2H), 7.09-7.14 (m, 1H), 7.20-7.23 (m, 6H), 7.28 (t, J=7.1 Hz, 2H), 7.35-7.38 (m, 3H), 7.52 (d, J=1.3 Hz, 1H), 9.31 (s, 1H); IR (solid) 3530, 3020, 1600, 1480, 1260 and 11180 cm−1; [ESI(+)], m/z 404 (M+H)+; Anal. Calcd. for C29H25NO: C, 86.32; H, 6.24; N, 3.47; Found: C, 86.30; H, 5.99; N, 3.09.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cnc(-c3ccccc3)nc2n(CC)c1=O
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCCC2)c2cnc(-c3ccccc3)nc2n(CC)c1=O

Procedure:
To 0.7 g. (0.002 mole) of 5-chloro-8-ethyl-7,8-dihydro-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester in ethanol was added 0.14 g. (0.002 mole) of pyrrolidine and 0.21 g. (0.002 mole) of sodium carbonate and this mixture was refluxed 3 hours. At that point, the solid inorganic material was filtered and the filtrate allowed to stand several days. Pale yellow crystals of the title compound formed which were removed by filtration--m.p. 149°-153° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][CH2:13][CH2:14][N:15]([CH2:17][CH2:18][NH2:19])[CH3:16])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[Br:20][C:21]1[C:22]([OH:34])=[C:23]([CH:32]=O)[C:24]2[CH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[C:28]=2[CH:29]=1.[BH4-].[Na+].CCOCC>C(O)C.C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:10]([NH:12][CH2:13][CH2:14][N:15]([CH2:17][CH2:18][NH:19][CH2:32][C:23]2[C:22]([OH:34])=[C:21]([Br:20])[CH:29]=[C:28]3[C:24]=2[CH2:25][CH2:26][C:27]3([CH3:31])[CH3:30])[CH3:16])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: CC1(C)CCc2c1cc(Br)c(O)c2C=O
Reactant: CN(CCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCO
Product: CN(CCNCc1c(O)c(Br)cc2c1CCC2(C)C)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A mixture of 1.82 g (6.32 mmol) of 3,5-diamino-N-[2-[(2-aminoethyl)methylamino]ethyl]-6 -chloropyrazinecarboxamide (A) and 1.70 g (6.32 mmol) of 6-bromo-1,1-dimethyl-5-hydroxyindan-4-carboxaldehyde (B) in 70 ml of ethanol and 10 ml of methylene chloride was stirred at ambient temperature for 1 h. Sodium borohydride (0.29 g, 7.58 mmol) was added and the reaction mixture stirred for 15 min. The solution was evaporated and the residue was partitioned between water and methylene chloride The organic phase was dried and evaporated. The residue was chromatographed on silica gel (150 g) using 0.2:3:96.8 (v/v/v) ammonium hydroxide:methanol:methylene chloride as eluent. There was obtained 2.62 g (4.84 mmol, 77%) of the title compound after trituration with ether: mp 134°-136° C.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[C:12]([C:13](=[O:19])[C:14]=1[CH2:15][N:16]=[N+]=[N-])=[CH:11][CH:10]=[C:9]([Cl:20])[CH:8]=2)=[O:4].Cl>[Pt](=O)=O.C(Cl)Cl.C(OCC)(=O)C>[ClH:20].[CH3:1][N:2]([CH3:27])[C:3]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[C:12]([C:13](=[O:19])[C:14]=1[CH2:15][NH2:16])=[CH:11][CH:10]=[C:9]([Cl:20])[CH:8]=2)=[O:4]
Reactant: CN(C)C(=O)c1c(CN=[N+]=[N-])c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 147.1 %

Procedure:
In a 50 mL round-bottomed flask, 3-azidomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide (0.40 g, 1.05 mmol), platinum (IV) oxide (0.05 g, 0.204 mmol) and 4N HCl (0.1 mL) were added to 1:1 CH2Cl2/ethyl acetate (10 mL). The reaction was charged with 1 atm H2 using a balloon and stirred at room temperature for 4 hr. The catalyst was filtered off and washed with methanol. The filtrate was evaporated to afford 3-aminomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide hydrochloride salt (0.303 g, 74% yield). The intermediate was used in the next step without further purification. MS calcd. for C19H18ClN3O2 [(M+H)+] 356, obsd 356.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](O)[C:5]([I:9])=[C:4]([CH3:10])[N:3]=1.P(Cl)(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[Cl:13][C:6]1[C:5]([I:9])=[C:4]([CH3:10])[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(C)c(I)c(O)n1
Solvent: Cc1ccccc1
Product: Cc1nc(C)c(I)c(Cl)n1
Yield: 93.5 %

Procedure:
A mixture of 2,6-dimethyl-5-iodo-4-hydroxypyrimidine (24.5 g, 0.098 mol), phosphorus oxychloride (30.0 g, 0.196 mol) and toluene (200 mL) was heated under reflux for 1 h. The mixture was concentrated and ice water (100 mL) was added. The pH was adjusted to 5 with 2.5N NaOH and the mixture was extracted with CH2Cl2. The combined extracts were washed with brine, dried MgSO4), and concentrated to give 24.6 g of a brown solid. The crude product was combined with 26.0 g of similarly prepared material and filtered through a short column of silica gel eluted with CH2Cl2 to give 33.8 g (62%) of product as a yellow solid. An analytical sample was recrystallized from hexane/CH2Cl2, mp 62°-64° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C(OCC)(=O)C.O.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>O1CCCC1.C(N(CC)CC)C>[CH3:30][S:31]([O:1][CH2:2][CH2:3][CH2:4][C:5]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(CCCO)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(CCCOS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.7 g of 1-tert-butyl 4-ethyl 4-(3-hydroxypropyl)piperidine-1,4-dicarboxylate in 20 mL of tetrahydrofuran, 0.82 mL of triethylamine and 0.58 mL of methanesulfonyl chloride were added at 5° C., and the mixture was stirred at room temperature for 1 hour. Thereto were added ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.9 g of 1-tert-butyl 4-ethyl 4-(3-((methanesulfonyl)oxy)propyl)piperidine-1,4-dicarboxylate as a colorless oily substance.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:28]O>>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:28][NH:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(OCCN2CCCCC2)cc1
Reactant: O=C1Nc2ccc(F)cc2C1=CO
Product: O=C1Nc2ccc(F)cc2C1=CNc1ccc(OCCN2CCCCC2)cc1
Yield: 74.4 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-piperidin-1-yl-ethoxy)-phenylamine (600 mg, 1.2 equiv.) and 5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (407 mg, 2.27 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (644 mg, 74%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[NH:35][C:34]([SH:36])=[N:33][N:32]=4)[CH:26]=3)[O:18]C3CCCCO3)=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:37](=[O:39])[CH3:38].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[OH:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([OH:18])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[NH:35][C:34]([SH:36])=[N:33][N:32]=4)[CH:26]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:37](=[O:39])[CH3:38]
Reactant: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(-c4nnc(S)[nH]4)c3)cc2)c(C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(-c4nnc(S)[nH]4)c3)cc2)c(C)c1O

Procedure:
Stir a solution of 1-(2-hydroxy-4-{4-[[3-(5-mercapto-4H-[1,2,4]triazol-3-yl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzyloxy}-3-methyl-phenyl)-ethanone (1.12 g, 2.04 mmol) and p-toluenesulfonic acid (50 mg) in methanol (0.2M). Dilute with ethyl acetate and wash with water. Dry the organic layer and concentrate to afford the title compound (0.250 g, 0.551 mmol, 27% overall from acid chloride). 1H NMR (400 MHz, DMSO-d6) δ 2.02 (s, 3H), 2.50 (s, 3H), 5.21 (s, 2H), 5.76 (s, 1H), 6.05 (s, 1H), 6.71 (d, J=9.4 Hz, 1H), 7.39 (m, 6H), 7.53 (m, 1H), 7.73 (m, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.98 (s, 1H), 12.83 (s, 1H). MS (m/z): 460 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[CH2:12](Br)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:12]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reaction time: 6 h
Yield: 71.5 %

Procedure:
Methyl 4-hydroxybenzoate (7.6 g), geranyl bromide (10.9 g), and potassium carbonate (13.8 g) were refluxed in acetone (80 ml) with stirring for 6 hours. The reaction mixture, with water added thereto, was extracted with chloroform. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was dissolved in methanol (50 ml) and the resulting mixture, with potassium hydroxide (3.9 g) and water (10 ml) added thereto, was stirred overnight at room temperature. The reaction mixture was neutralized with hydrochloric acid and then extracted with chloroform. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol to yield 9.8 g of the aimed compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([O:19]C)=[O:18])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.O.[OH-].[Li+].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH3:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: COC(=O)c1cc2nc(-c3ccccc3)nn2cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cn2nc(-c3ccccc3)nc2cc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 129.3 %

Procedure:
A mixture of methyl 6-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (182 mg, 681 μmol) and lithium hydroxide monohydrate (114 mg, 2.72 mmol) in tetrahydrofurane (10 ml) and water (2 ml) is stirred for 4 hours at 25° C. The mixture is diluted with ethyl acetate, acidified to pH=0 with hydrochloric acid 37% and washed with water and brine. The organic layer is dried with magnesium sulfate and the solvent is evaporated to dryness affording 6-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (223 mg, 129%) as a light yellow solid. mp.: 228-233° C. MS: m/z=254.2 (M+H+).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]([F:24])([F:23])[C:18]([O:20]CC)=O)[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[Cl-].[NH4+]>C1COCC1>[CH2:1]([N:8]1[CH2:16][C:17]([F:23])([F:24])[C:18]([OH:20])=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(Cc1ccccc1)CC(F)(F)C(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(O)C(F)(F)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 126.6 %

Procedure:
To a solution of ethyl N-benzyl-N-(3-ethoxy-2,2-difluoro-3-oxopropyl)-β-alaninate (25.0 g) in anhydrous THF (200 mL) was added dropwise lithium diisopropylamide (2M, 72.8 mL) at −78° C. The reaction mixture was stirred at room temperature for 2 hr, and added to saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (27.4 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH3:19].[Br:21]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCOCC>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH2:19][Br:21]
Reactant: COC(=O)c1ccc(Oc2ccc(OC)cc2)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Oc2ccc(OC)cc2)cc1CBr
Temperature: 25 °C
Yield: 82.9 %

Procedure:
To a mixture of 4-(4-Methoxy-phenoxy)-2-methyl-benzoic acid methyl ester (2.8 grams, 10.3 mmol), N-bromosuccinimide (2.14 grams, 12 mmol) and carbon tetrachloride (12 mL) was added a crystal of benzoyl peroxide. The mixture was heated to reflux for 2 hours, and an additional 2.1 grams of N-bromosuccinimide was added. After refluxing for an additional 4 hours, the mixture was cooled to room temperature, diluted with ether, and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated, affording 3 grams of 2-Bromomethyl-4-(4-methoxy-phenoxy)-benzoic acid methyl ester as a colorless oil. 1H NMR (CDCl3, 500 MHz): δ 7.96 (d, 1H, J=8.8 Hz), 7.05-6.90 (m, 6H), 6.87 (dd, 1H, J=2.6, 8.3 Hz), 4.92 (s, 2H), 3.93 (s, 3H), 3.85(s, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[C:19]([NH2:21])=[O:20].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([S:29]([CH:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33](OC)=O)(=[O:31])=[O:30])[CH2:25][CH2:24]1.CC(C)([O-])C.[K+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:22][N:23]1[CH2:24][CH2:25][N:26]([S:29]([CH:32]([C:33]2[NH:21][C:19](=[O:20])[C:3]3[C:4]([CH2:17][CH3:18])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=3[N:1]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:31])=[O:30])[CH2:27][CH2:28]1
Reactant: COC(=O)C(c1ccccc1)S(=O)(=O)N1CCN(C)CC1
Reactant: CCCCCCC(CCC)n1nc(CC)c(C(N)=O)c1N
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CC)c2c(=O)[nH]c(C(c3ccccc3)S(=O)(=O)N3CCN(C)CC3)nc21
Yield: 38.6 %

Procedure:
6 mg (0.02 mmol) of 5-amino-3-ethyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.064 mmol) of methyl 4-N-methylpiperazinosulphonylphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic potassium tert-butoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate have been added, the phases are separated. Purification by chromatography gives 4.3 mg (38%) of a solid, Rf=0.50 (dichloromethane/methanol=15:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C(N(CC)CC)C.CN(C)C=O.[CH2:29](Br)[CH:30]=[CH2:31]>O>[CH2:31]([O:8][C:7]1[C:6]([Cl:9])=[CH:5][C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:3][C:2]=1[Cl:1])[CH:30]=[CH2:29]
Reactant: O=c1ccc(-c2cc(Cl)c(O)c(Cl)c2)n[nH]1
Reactant: C=CCBr
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCOc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a mixture of 4.9 g. of 6-(3,5-dichloro-4-hydroxyphenyl)-3-(2H)pyridazinone obtained in Example 5 and 2 g. of triethylamine in 30 ml. of dimethylformamide was added dropwise 2.4 g. of allyl bromide at 50° C. while stirring. The mixture was stirred at 50° C. for further 5 hours. After cooling, the reaction mixture was poured into 200 ml. of water and allowed to stand for a while. White solid substance thus formed was recovered by filtration, washed with water, dried to give 3.6 g. of crude crystalline substance, which was then recrystallized from methanol to give 3.2 g. of the desired product as colorless needles of m.p. 214° - 215° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8](O)([CH3:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.S(Cl)([Cl:19])=O.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]([Cl:19])([CH3:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cl)cc1C(C)(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1C(C)(Cl)C(F)(F)F
Temperature: 40 °C

Procedure:
2-(5-Chloro-2-methoxyphenyl)-1,1,1-trifluoropropan-2-ol (C45) (1.20 g, 4.71 mmol) was treated with thionyl chloride (4 mL, 50 mmol), followed by pyridine (19.1 μL, 0.236 mmol). The reaction mixture was heated at 40° C. for 16 hours, then poured into a mixture of ice and saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with dichloromethane (3×50 mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was determined by 1H NMR to be a mixture of product and an alkene side-product derived from elimination, in a roughly 4:1 ratio; this was used in the following step without additional purification. GCMS m/z 272 (M+). 1H NMR (400 MHz, CDCl3), product peaks only: δ 2.27 (br s, 3H), 3.86 (s, 3H), 6.90 (d, J=8.8 Hz, 1H), 7.33 (dd, J=8.8, 2.5 Hz, 1H), 7.69-7.73 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:15])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[N:8]2.[C-:16]#[N:17].[K+]>CN(C)C=O>[F:15][C:4]1[C:3]([CH2:2][C:16]#[N:17])=[C:12]2[C:7](=[CH:6][CH:5]=1)[N:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11]2
Reactant: COc1cnc2ccc(F)c(CBr)c2n1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cnc2ccc(F)c(CC#N)c2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
A mixture of 8-bromomethyl-7-fluoro-2-(methyloxy)quinoxaline (5.89 g, 20 mmol) and potassium cyanide (3.2 g, 49 mmol) in dimethylformamide (125 ml) was heated at 50° C. for approx. 40 h. More potassium cyanide (0.8 g) was added and heating continued at 60° C. for ˜8 h. The mixture was then evaporated and the residue was dissolved in dichloromethane and washed with water. The aqueous phase was extracted twice with dichloromethane and the combined organic fractions were dried and evaporated. Chromatography on silica (300 g), eluting with 0-25% ethyl acetate/hexane gave product (2.47 g, 57%).