Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[F:31][C:32]([F:52])([F:51])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]([F:46])([F:45])[F:44])=[CH:37][C:36]=1[S:47](Cl)(=[O:49])=[O:48]>>[F:52][C:32]([F:31])([F:51])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]([F:44])([F:45])[F:46])=[CH:37][C:36]=1[S:47]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]2[C:26]([N:28]([CH3:29])[CH3:30])=[O:27])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[C:6]1=[O:11])(=[O:49])=[O:48]
Reactant: O=S(=O)(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: COc1ccccc1C1(N2CCCC[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(N2CCCC[C@H]2C(=O)N(C)C)C(=O)N(S(=O)(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)c2ccc(Cl)cc21
Yield: 66.6 %

Procedure:
With 200 mg of (2S)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide, which is the compound described in Preparation 3.49 (Isomer B) of the brochure No. WO01/98295, and 183 mg of 2,5-bis(2,2,2-trifluoroethoxy)benzene sulfonyl chloride as starting materials, 238 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]([F:24])([F:23])[CH:7]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH:8]([OH:13])[C:9](OC)=[O:10].Br.[CH3:26][NH:27][C:28](NC)=[NH:29].C(O)(=O)C>C(O)C>[NH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([CH:7]([CH:8]2[O:13][C:28]([NH:27][CH3:26])=[N:29][C:9]2=[O:10])[C:6]([F:24])([F:23])[F:5])=[CH:15]1
Reactant: CNC(=N)NC
Reactant: COC(=O)C(O)C(c1c[nH]c2ccccc12)C(F)(F)F
Agent: Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CNC1=NC(=O)C(C(c2c[nH]c3ccccc23)C(F)(F)F)O1
Temperature: 0 °C
Yield: 20.5 %

Procedure:
Sodium ethoxide (580 mg) was added to a solution of methyl 4,4,4-trifluoro-2-hydroxy-3-(indol-3-yl)butyrate (980 mg) and N,N′-dimethyl guanidine hydrogen bromide (630 mg) in ethanol (2.5 ml). The mixture was refluxed for 1.5 hours and then cooled. To the cooled reaction mixture was added ice water (20 ml). After the pH of the mixture was adjusted to 7 using acetic acid, the whole was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and then dried over magnesium sulfate. Concentration of the solution under the reduced pressure gave residue, which was subjected to silica gel chromatography. Eluent with ethyl acetate-hexane was collected and concentrated to provide the titled compound (218 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[Cl:40][C:41]1[CH:42]=[N:43][NH:44][CH:45]=1.N1C=CC=CC=1>O>[CH3:1][O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:43]3[CH:42]=[C:41]([Cl:40])[CH:45]=[N:44]3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: Clc1cn[nH]c1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2cc(Cl)cn2)cc1
Temperature: 50 °C
Yield: 97.4 %

Procedure:
A mixture of {4-difluoromethoxy-2-ethyl-8-fluoro-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid methyl ester (0.14 g), 4-chloro-1H-pyrazole (0.053 g), cuprous acetate (0.093 g) and pyridine (3 mL) was heated at 50° C. for 116 hours. The mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and then concentrated under reduced pressure. Purification of the residue by column chromatography silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 7:3 by volume) gave title compound as a colourless oil (0.13 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:18])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:18])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:30])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(C)c(Br)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C)N1C(=S)COc2cc(C)c(Br)cc21
Yield: 80.9 %

Procedure:
To a solution of 2-(6-bromo-7-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (23.6 g, 69 mmol) in toluene (300 mL) was added Lawesson's reagent (30.7 g, 76 mmol) and the reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature water (300 mL) was added. The organic phase was separated and the aqueous portion was extracted with EtOAc (3×100 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5% EtOAc in petroleum ether) to give 2-(6-bromo-7-methyl-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as solid (20.0 g, 81%). 1H NMR (DMSO-d6, 400 MHz): δ 7.41 (s, 1H), 7.16 (s, 1H), 6.03 (m, 1H), 4.90 (s, 2H), 4.14 (m, 2H), 2.29 (s, 3H), 1.61 (d, J=6.8 Hz, 3H), 1.08 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[OH:11].C(=O)([O-])[O-].[Cs+].[Cs+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[O:11][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.6 %

Procedure:
4-Methoxy-3-hydroxy-benzaldehyde (1.0 mg, 7.5 mmoles) is dissolved in DMF (20 mL). Cesium carbonate (2.45 g, 7.5 mmoles) and 1-fluoro-4-nitro-benzene (1.75 mL, 7.5 mmoles) are added and the resulting mixture is stirred at room temperature for 20 hours. The reaction mixture is then quenched by addition of 1N HCl and extracted with AcOEt. The organic layer is dried over Na2SO4 and the solvent is evaporated. The crude mixture is purified by chromatography on SiO2 (eluent:hexane:AcOEt=9:1) to yield 2.0 g of the pure title compound.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[C:10]=1[CH3:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:36](O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[C:1]([C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]([CH3:19])[C:16]([O:18][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:17])[C:10]=1[CH3:20])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: Cc1cc(C(=O)c2ccccc2)c(C)n1C(C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)c2ccccc2)c(C)n1C(C)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 62.7 %

Procedure:
In 5 ml of methylene chloride was dissoved 2-(3-benzoyl-2,5-dimethylpyrrol-1-yl)propionic acid (500 mg, 1.85 mmoles), and 257 μl (1.85 mmoles) of triethylamine was added. The mixture was stirred at -15° C. for 5 minutes. Isobutyl chloroformate (243 μl, 1.85 mmoles) was added to the solution, and the mixture stirred at -15° C. for 10 minutes. Then, 190 μl (1.85 mmoles) of benzyl alcohol was added. The mixture was stirred at room temperature for 20 hours, and 50 ml of methylene chloride was added. The organic layer was washed with water, dilute hydrochloric acid and an aqueous solution of sodium hydrogen carbonate in this order, dried, and concentrated to afford 543 mg of a crude product. The product was chromatographed on a column of silica gel using benzene/ethyl acetate as an eluent to afford compound (720)(421 mg, 1.16 mmoles, 63%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:17]=[CH:16][C:15]([S:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CSc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(SC[C@@H]2CCCN2)cc1
Reaction time: 3.5 h
Yield: 30.2 %

Procedure:
A solution of 2.55 g of N-tert-butyloxycarbonyl-(2S)-2-(4-trifluoromethylphenylthiomethyl)-pyrrolidine in 5.64 ml of trifluoroacetic acid is stirred for 1 hour at 0° C. and then for 3.5 hours at room temperature. The reaction mixture is poured onto 10% sodium bicarbonate solution, extracted with ethyl acetate, washed twice with 2 M hydrochloric acid, the water phase is extracted with ether, made basic with sodium bicarbonate, extracted three times with ethyl acetate, washed with common salt solution, dried on sodium sulfate and concentrated by evaporation. 557 mg of (2S)-2-(4-trifluoromethylphenylthio-methyl)-pyrrolidine is obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].[CH2:13]([C:17]([NH2:19])=[O:18])[C:14]#[C:15]C>O1CCOCC1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]1[C:14]([CH3:15])=[C:13]([C:17]([NH2:19])=[O:18])[N:7]=[N:6]1
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: CC#CCC(N)=O
Solvent: C1COCCO1
Product: Cc1c(C(N)=O)nnn1Cc1c(F)cccc1F

Procedure:
16.9 g (0.1 mole) of 2,6-difluorobenzyl azide and 8.3 g (0.1 mole) of but-2-ynecarboxamide are heated in 20 ml of dioxane for 16 hours to 100° C. After removing the dioxane by evaporation, the desired isomer is separated by column chromatography, to give 1-(2,6-difluorobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide with a melting point of 208°-210° C. (recrystallisation from methanol).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH:11](O)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[C:12]1([CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:7]2[CH:8]=[C:2]([C:1]([NH2:10])=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)c1ccccc1O
Reactant: OC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: NC(=O)c1cc(C(c2ccccc2)c2ccccc2)ccc1O

Procedure:
A mixture of 25 g (0.182 mol) of salicylamide, 30 g (0.163 mol) of benzhydrol, 30 g (0.158 mol) of p-toluenesulfonic acid and 200 ml of acetic acid was refluxed for 3 hours with heating. After cooling, the precipitated white crystals were separated by filtration and washed with water to obtain 5-diphenylmethylsalicylamide. Thereafter 40 g of sodium hydroxide in 100 ml of water were added and the mixture was heated on a steam bath for 6 hours with stirring. After being allowed to cool, the mixture was acidified using diluted hydrochloric acid to obtain 40 g of a crude product comprising 5-diphenylmethylsalicylic acid, Compound (2). When the crude product was recrystallized using diluted methanol, it had a melting point of 190° to 191.5° C. The resulting Compound (2) was converted into the zinc salt by the same process as that described in Synthesis Example 2.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[C:10]2[C:14]1[C:15](=[O:30])[NH:16][C:17](=[O:29])[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[N:26]([CH3:28])[CH:25]=[CH:24]2.O1CCCC1.C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:59]>C(Cl)Cl>[Br:59][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[C:10]2[C:14]1[C:15](=[O:30])[NH:16][C:17](=[O:29])[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[N:26]([CH3:28])[CH:25]=[CH:24]2
Reactant: Cn1ccc2cccc(C3=C(c4c[nH]c5c(CCCO)cccc45)C(=O)NC3=O)c21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5c(CCCBr)cccc45)C(=O)NC3=O)c21
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a solution of 3-[7-(3-hydroxypropyl)-1H-indol-3-yl]-4-(1-methyl-1H-indol-7-yl)pyrrole-2,5-dione (505 mg, 1.27 mmol) in 1:1 tetrahydrofuran/methylene chloride (60 mL) was added triphenylphosphine (330 mg, 1.25 mmol) followed by carbon tetrabromide (418 mg, 1.26 mmol). After one hour, additional triphenylphosphine (332 mg, 1.27 mmol) and carbon tetrabromide (414 mg, 1.25 mmol) was added. After 1 h, triphenylphosphine (330 mg, 1.26 mmol) and carbon tetrabromide (430 mg, 1.30 mmol) was added and stirred for 1 h. The reaction mixture was diluted with methylene chloride (100 mL), washed with saturated aq NaHCO3 (100 mL), brine (100 mL), dried (MgSO4) and concentrated. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (462 mg, 91%) as a red solid. 1H NMR (CDCl3) 8.93 (m, 1H), 8.66 (m, 1H), 8.07–7.87 (m, 4H), 6.64 (m, 1H), 6.49 (m, 2H), 3.72 (s, 3H), 3.41 (m, 2H), 2.96 (m, 2H), 2.21 (m, 2H). MS (electrospray, m/z) 464/462 (C24H20BrN3O2+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>>[F:1][C:2]([F:21])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(C(=O)O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A mixture of diethyl 2-(4-(trifluoromethoxy)phenyl)malonate (5.6 g, 17.486 mmol, Intermediate 13: step a) and an aqueous 3 M NaOH solution was stirred in a 100° C. oil bath for 1 hour, cooled to room temperature, poured into ice water and acidified with 6 N aqueous HCl. The aqueous mixture was extracted with EtOAc. The EtOAc extract was dried over Na2SO4, filtered, and evaporated in vacuo to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[C:16]4[CH3:22])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:42][CH:43]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:42][CH:43]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:45][CH2:44]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (1.00 g, 3.11 mmol), (prepared as described for the starting material in Example 271), potassium carbonate (1.288 g, 9.33 mmol) and 4-(4-methylphenylsulphonyloxymethyl)-1-tert-butoxycarbonylpiperidine (1.264 g, 3.42 mmol), (prepared as described for the starting material in Example 10), in DMF (35 ml) was stirred at 80° C. for 2 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the solvent removed in vacuo. The residue was purified by silica column chromatography, 5% methanol/95% dichloromethane and the product was recrystallised from ethanol to give 6-methoxy-4-(3-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)quinazoline (1.011 g, 63%).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li][CH2:12]CCC>C1COCC1>[CH3:12][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Brc1cc2ccccc2[nH]1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The 2-bromoindole derivative 19-1 (1.009 g, 3.00 mmol, prepared as described in Example 12 of WO 03/010141) was dissolved in anhydrous THF (25 mL) under an argon atmosphere and the solution cooled to −78° C. n-BuLi (2.0 M in hexane, 1.60 mL, 3.20 mmol) was added dropwise and the mixture stirred for 15 min. Mel (0.37 mL, 2.00 mmol) was added and stirring was continued for an additional 30 min. The reaction mixture was then warmed up to RT and volatiles removed under reduced pressure. The residue was dissolved in TBME (100 mL) and the solution washed with brine (2×25 mL). The extract was dried (MgSO4), concentrated under reduced pressure and the residue purified by flash chromatography using 0-15% EtOAc in hexane as eluent. The desired 2-methylindole derivative 20-1 was obtained as a waxy solid (0.658 g, 80% yield): MS-ES m/z 272.1 (MH+). The methyl ester 20-1 was saponified in the usual way (NaOH/DMSO) to give the corresponding carboxylic acid 20-2 in 96% yield: MS-ES m/z 258.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15](O)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([NH:37][S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NS(=O)(=O)c1ccccc1)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.3 %

Procedure:
To a solution of 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)-methyl]-2-pyridinecarboxylic acid (81 mg) in dichloromethane (2 ml) and tetrahydrofuran (2 ml) was added benzenesulphonamide (50 mg), 4-dimethyl-aminopyridine (3.5 mg) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (61 mg) and the mixture stirred at ambient temperature for 5 hours. Solvent was removed in vacuo and water (5 ml) added. The mixture was extracted with ether (2×5 ml) and the combined extracts dried (MgSO4) and concentrated in vacuo. The residue was purified by mass-directed autopreparation to afford the title compound (46 mg, 42%) as a white solid. LC/MS [MH+]=545/547, Rt=3.89 min.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([C:8]1[S:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:23]
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc2c(-c3ccccc3)c(C(=O)c3cccc(Cl)c3)sc2c1
Temperature: 0 °C

Procedure:
To 200 ml. of 1,2-dichloroethane were added 10.0 g. (0.042 mole) of 3-phenyl-6-methoxybenzothiophene and 6.5 g. (0.042 mole) of 3-chlorobenzoyl chloride. The mixture was stirred and cooled to 0° C., and 5.73 g. (0.042 mole) of aluminum chloride were added. The mixture was stirred for about one hour and ice then was added. The resulting organic layer was separated from the aqueous. The aqueous layer was washed with chloroform, and the chloroform was separated and added to the organic layer. The organic layer then was evaporated, and to the resulting residue were added 250 ml. of methanol and 15 ml. of 5N sodium hydroxide. The mixture was refluxed for 30 minutes and evaporated. The residue was recrystallized from methanol to obtain the title compound, m.p. 105° C.
Reaction SMILES: Cl.[OH:2][C:3]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:4][C:5]1[N:14]2[CH2:15][CH2:16][N:17]=[C:13]2[C:12]2[CH:11]=[CH:10][C:9]([OH:18])=[C:8]([O:19][CH3:20])[C:7]=2[N:6]=1.Cl[CH:28]([CH2:33][CH3:34])[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:2][C:3]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:4][C:5]1[N:14]2[CH2:15][CH2:16][N:17]=[C:13]2[C:12]2[CH:11]=[CH:10][C:9]([O:18][CH2:34][CH2:33][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:8]([O:19][CH3:20])[C:7]=2[N:6]=1
Reactant: COc1c(O)ccc2c1N=C(C=C(O)c1cccnc1)N1CCN=C21
Reactant: CCC(Cl)C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCOc1ccc2c(c1OC)N=C(C=C(O)c1cccnc1)N1CCN=C21
Temperature: 120 °C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
A mixture of 5-(2-hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol hydrochloride (Example 1-4) 50.4 mg (0.14 mmol), methyl chloro-butyrate 22.2 mg (0.16 mmmol) and potassium carbonate 186.9 mg (1.35 mmmol) in N,N-dimethylformamide 1 mL was stirred at 120° C. for 4 hours. The reaction mixture was poured into water and extracted into dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtrated and the solvent was evaporated. The residue was washed by diethyl ether to give the title compound 35.0 mg as yellow solid. Yield 59.3%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([Cl:9])=[CH:6][C:7]=1[NH2:8].O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl.[OH-].[Na+]>[Cl:9][C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][C:4]=1[C:10]([F:13])([F:11])[F:12])[NH:1][C:17](=[O:18])[C:16](=[O:20])[NH:8]2
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(C(F)(F)F)cc2[nH]c1=O
Temperature: 25 °C
Yield: 59.3 %

Procedure:
A mixture of 3,4-diamino-6-chlorobenzotrifluoride (185 mg, 0.88 mmol) and oxalic acid dihydrate (117 mg, 0.93 mmol, used as received) in 2N HCl (4 mL) was refluxed at 170°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed twice by cold water (2×2 mL), collected by filtration, and dried at 60° C. with reduced pressure for 2 h, affording 180 mg of crude title compound (77.3%) as a light yellow powder. The crude product was dissolved in 1N NaOH (6 mL) and filtered. The filtrate was acidified to pH=6, affording 138 mg of title compound. It was recrystallized from DMSO/H2O twice to give 102 mg of pure compound (43.9%) as yellow microcrystals. mp:>360° C. (dec. from 295° C.). IR (KBr, cm-1) 3425, 3200, 1731, 1706, 1625; 1400. 1H NMR (DMSO-d6): δ7.274 (s, 1H); 7.478 (s, 1H); 12.145 (s, 2H). HRMS: calcd for C9H4ClF3N2O2 (M+) m/z: 263.9912; found: 263.9919.