Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.Br[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]2[CH2:27][O:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:13])=[CH:7][CH:6]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.O>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]3[CH2:27][O:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[O:13])=[CH:9][CH:10]=2)=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc(Br)cc2)C(COc2cccnc2)C1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(NC(=O)N3CCN(C(=O)OC(C)(C)C)CC3COc3cccnc3)cc2)cc1
Temperature: 80 °C

Procedure:
[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (8.3 mg, 0.010 mmol) was added to a mixture of tert-butyl 4-(4-bromophenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (100 mg, 0.204 mmol, prepared as in Example 2, Step 1), (4-methoxyphenyl)boronic acid (61.9 mg, 0.407 mmol) and sodium carbonate (42.4 mg, 0.407 mmol) in toluene (4 mL), 1,4-dioxane (1 mL), and water (1 mL). The reaction mixture was heated to 80° C. for 3 h. Upon cooling to room temperature, the reaction mixture was filtered though Celite®, concentrated under reduced pressure, and purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). This gave 114.9 mg (89%, ˜90% pure) of the TFA salt of the desired product as a thick, brownish oil. LC-MS: RT=8.69 min, [M+H]+=519.2.
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[N:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:3]=1.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1COCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:23]([O:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:4]3[CH:3]=[C:2]([C:32]4[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)[N:6]([CH3:7])[N:5]=3)=[O:9])[CH2:11][CH2:12]2)[CH:21]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)COc1cc(N2CCN(C(=O)c3cc(I)n(C)n3)CC2)ncn1
Reactant: COc1ccc(B(O)O)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(C(=O)N3CCN(c4cc(OCC(C)C)ncn4)CC3)nn2C)cn1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
A mixture of (5-iodo-1-methyl-1H-pyrazol-3-yl) (4-(6-isobutoxypyrimidin-4-yl)piperazin-1-yl)methanone (20 mg, 0.043 mmol), (6-methoxypyridin-3-yl)boronic acid (8.5 mg, 0.055 mmol), palladium acetate (1.9 mg), triphenylphosphine (4.5 mg), and sodium carbonate (18 mg, 0.17 mmol) in dioxane-THF-water (1.6 mL, 1:0.3:0.3) was stirred at 150° C. for 10 min under microwave irradiation. After cooling to rt, the mixture was poured onto water, and the aqueous layer was extracted with EtOAc (three times). The combined organic layer was concentrated in vacuo. The residue was purified by preparative LC-MS to give 6.5 mg (34% yields) of the title compound.
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:17]([CH2:18][CH2:19][O:20][CH2:21][C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)[C:16]3[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+].C(O)(C)C>O>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[CH2:21][O:20][CH2:19][CH2:18][N:17]1[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=2[N:14]=[C:13]1[N:9]1[CH2:10][CH2:11][CH2:12][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCCN(c2nc3ccccc3n2CCOCc2ccco2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: c1coc(COCCn2c(N3CCCNCC3)nc3ccccc32)c1
Reaction time: 18 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1 mmol), potassium hydroxide (1.2 mmol), and isopropanol (20 mL). Heat to reflux. After 18 hours, evaporate in vacuo to give a residue. Combine the residue and water. Extract with dichloromethane. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [I:1]Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[NH2:7].O.O.O.C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Cl:3][C:4]1[C:10]([C:11]([F:12])([F:13])[F:14])=[CH:9][C:8]([I:1])=[C:6]([CH:5]=1)[NH2:7]
Reactant: ClI
Reactant: Nc1ccc(C(F)(F)F)c(Cl)c1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(C(F)(F)F)cc1I

Procedure:
Iodine monochloride (1.5 g) was added in one portion to a mixture of 3-chloro-4-trifluoromethylaniline (1.7 g), sodium acetate trihydrate (2.2 g), and acetic acid (10 ml) at room temperature. After 30 min aqueous sodium bicarbonate/sodium sulfite was added and the mixture extracted with diethyl ether. The organic phase was dried over Na2SO4, filtered and evaporated. The residue was purified by chromatography (ethyl acetate-hexane) to afford the title compound, 2.2 g.
Reaction SMILES: [Na].C(O[CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:25])[CH:11]2[NH:15][C:16](=[O:24])[CH2:17][C:18]2[S:19][C:20](=[O:23])[S:21][CH:22]=2)[C:8]=1[C:26]([OH:28])=[O:27])(=O)C.[S-]C#N.[K+].C(=O)(O)[O-].[Na+].[CH3:38][N:39]1[N:43]=[N:42][C:41](=[S:44])[NH:40]1.Cl.C(OC(C)C)(C)C>O.O1CCCC1>[C:26]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][S:44][C:41]1[N:42]=[N:43][N:39]([CH3:38])[N:40]=1)[CH:11]([NH:15][C:16](=[O:24])[CH2:17][C:18]1[S:19][C:20](=[O:23])[S:21][CH:22]=1)[C:10]2=[O:25])([OH:28])=[O:27]
Reactant: Cn1nnc(=S)[nH]1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Agent: Cl
Agent: N#C[S-]
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: Cn1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4csc(=O)s4)C3SC2)n1
Temperature: 60 °C
Yield: 74 %

Procedure:
The sodium salt of 3-acetoxymethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (6.1 g.) is dissolved in water (20 cc.). Potassium thiocyanate (26.6 g.), sodium bicarbonate (1.38 g.) and 2-methyl-5-thioxo-1,2,3,4-tetrazoline (1.9 g.) are added to this solution and the mixture is heated to 60° C. for 5 hours. After cooling, the reaction mixture is diluted with water (100 cc.), acidified to pH 5.8 by adding 4 N hydrochloric acid and washed with ethyl acetate (50 cc.). The aqueous phase is acidified to pH 1.6 by adding 4 N hydrochloric acid in the presence of ethyl acetate (200 cc.). After decanting the organic phase, the aqueous phase is extracted twice with ethyl acetate (a total of 200 cc.). The organic extracts are combined, washed twice with an 0.1 N hydrochloric acid solution (a total of 140 cc.) and then twice with water (a total of 200 cc.), dried over sodium sulphate, treated with decolourising charcoal, filtered and then concentrated to dryness under reduced pressure (20 mm Hg). The residue obtained is dissolved in tetrahydrofuran (25 cc.) and this solution is then added dropwise to isopropyl ether (300 cc.). A product precipitates which is isolated by filtration and dried under reduced pressure (0.1 mm Hg). 2-Carboxy-3[(2-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (5.1 g.) is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CNc2ccc(O)c(C(=O)O)c2)cc1
Yield: 49.9 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (1.00 g, 6.53 mmole) and 4-methoxybenzyl chloride (1.23 g, 7.84 mmole), 890 mg (50% yield) of 5-(4-methoxybenzyl)aminosalicylic acid was obtained as a white solid.: mp 205-206° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(C(OC)=O)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:14]([O-:16])=[O:15])[CH2:6]1)=[O:4].[Cl-].[Li+].O>CS(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:14]([O-:16])=[O:15])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C(=O)OC)Cc2cccc([N+](=O)[O-])c2C1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C1Cc2cccc([N+](=O)[O-])c2C1
Temperature: 160 °C
Yield: 67.7 %

Procedure:
A mixture of dimethyl-4-nitroindane-2,2-dicarboxylate (4.84 g, 0.0167 mol), lithium chloride (0.84 g, 0.0198 mol), 1.11 mL water, and 18 mL dimethylsulfoxide was heated to 160° C. under nitrogen for two hours. It was then allowed to cool and the dimethylsulfoxide was removed under high vacuum. The residue was purified on silica (10%-100% CH2Cl2 in hexanes) to give 2.5 g white solid (65%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10](Br)[CH:11]=[CH2:12].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH:11]=[CH2:10]
Reactant: N#Cc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.7 %

Procedure:
4-Hydroxybenzonitrile (30.0 g, 252 mmol), allyl bromide (39.6 g, 327 mmol), and Cs2CO3 (98.5 g, 302 mmol) were dissolved in DMF (900 mL), and water (1 mL) was added. After stirring for 12 h at rt, the reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with EtOAc (2×). The combined organic layers were washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure yielding 40 g (100%) of the title compound as a white crystalline solid. 1H NMR (400 MHz, CDCl3): δ 4.60 (d, 2H), 5.34 (d, 1H), 5.43 (d, 1H), 6.03 (m, 1H), 6.96 (d, 2H), 7.58 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([OH:17])[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].Br[CH2:21][CH:22]=[CH2:23]>CN(C)C=O>[CH2:23]([O:17][C:9]1([CH2:8][N:5]2[C:6]([CH3:7])=[C:2]([Br:1])[CH:3]=[N:4]2)[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[CH2:10]1)[CH:22]=[CH2:21]
Reactant: Cc1c(Br)cnn1CC1(O)CCCC(C)(C)C1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(Cn2ncc(Br)c2C)CCCC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of EXAMPLE 185B (3.63 g) in N,N-dimethylformamide (25 mL) was added NaH (0.964 g, 60% dispersion in mineral oil), and the reaction was stirred for 30 minutes. 3-Bromoprop-1-ene (1.529 mL) was added. The cooling bath was removed, and the reaction was warmed to room temperature. The reaction mixture was heated to 50° C., whereupon a significant evolution of gas occurred. After 2 hours, the reaction mixture was diluted with diethyl ether (75 mL), washed with water (2×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography, eluting with a gradient of 1.5% to 15% ethyl acetate in hexanes, gave the title compound.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([NH:19]C(=O)OC(C)(C)C)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:8][CH:7]=1)=[N+:2]=[N-:3].FC(F)(F)C(O)=O>ClCCl>[N:1]([CH2:4][C@@H:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:8][CH:7]=1)[NH2:19])=[N+:2]=[N-:3]
Reactant: CCCC(C)COc1ccc([C@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)COc1ccc([C@@H](N)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of t-butyl (1R)-2-azido-1-(4-(2-methylpentyloxy)phenyl)ethylcarbamate (14.2 g, 39.2 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (18.1 mL, 235 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated and the residue was transferred to a separatory funnel containing saturated aqueous K2CO3 solution. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford (1R)-2-azido-1-(4-(2-methylpentyloxy)phenyl)ethanamine (9 g, 88% yield) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.6 Hz, 2 H), 3.96 (t, J=6.4 Hz, 1H), 3.80 (dd, J=9.1, 5.5 Hz, 1H), 3.71 (dd, J=9.2, 6.7 Hz, 1H), 3.29-3.39 (m, 2H), 2.59-2.75 (m, 2H), 1.86 (dq, J=12.8, 6.5 Hz, 1H), 1.25-1.48 (m, 3H), 1.12-1.22 (m, 1H), 0.95 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.1 Hz, 3H); HRMS (ESI) m/e 263.1860 [(M+H)+, calcd for C14H23N4O 263.1872].
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH3:22])[CH:16]=2)[CH2:9]1)C1C=CC=CC=1.C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(OC(C)(C)C)=O.ClC(OC(Cl)C)=O>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:16][C:17]=1[CH3:22]
Reactant: Cc1cc(CC2CN(Cc3ccccc3)CCO2)ccc1F
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Agent: CC(Cl)OC(=O)Cl
Product: Cc1cc(CC2CNCCO2)ccc1F

Procedure:
Example 71 was prepared as described for example 27, but using N-benzyl-2-(4-fluoro-3-methylbenzyl)-morpholine, intermediate (a) and 1-chloroethyl chloroformate. Example 71 was isolated as a colorless oil (13.7 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].S([O-])([O-])=O.[Na+].[Na+].[C:20](=O)(O)[O-].[Na+].BrCC(O)=O>O>[F:9][C:5]1[CH:4]=[C:3]([S:10]([CH3:20])(=[O:12])=[O:11])[C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: O=C([O-])O
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Agent: O=C(O)CBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1cc(F)c(F)cc1F
Temperature: 150 °C
Yield: 66.5 %

Procedure:
2,4,5-Trifluorophenyl sulfonyl chloride (279 mg) was added to a solution of sodium sulfite (306 mg) and sodium bicarbonate (153 mg) in water (4 mL). The mixture was heated to 150° C. in a sealed microwave vial for 400 seconds and allowed to cool. The mixture was treated with bromoacetic acid (253 mg) in water (1 mL), and heated to 150° C. for 300 seconds then allowed to cool, following which the precipitate was removed by filtration and dried in vacuo to give the desired compound (169 mg). The material was used without further purification. 1H NMR δ (d6-DMSO): 3.35 (s, 3H), 7.87-8.01 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:19][CH2:18][C:11]2([NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:22](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([NH:15][C:14](=[O:16])[N:13]([CH3:22])[C:12]2=[O:17])[CH2:18][CH2:19]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)NC2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: CN1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.2 %

Procedure:
To a solution of 2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (3.60 g, 13 mmol) in DMSO (30 ml), MeI (2.27 g, 16 mmol) and potassium carbonate (2.40 g, 17 mmol) are added at ambient temperature. The mixture is stirred for 18 h at ambient temperature. The reaction mixture is quenched with water and extracted with AcOEt. The combined extracts are washed with brine, dried over magnesium sulfate, filtrated and evaporated to afford 3.8 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccnc3ccc(Br)cc23)CC1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of 485 mg 6-bromo-4-chloroquinoline, 1.1 mL N-methyl piperazine, 415 mg potassium carbonate and 10 mL N,N-dimethylformamide was stirred at 130° C. for 8 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with water and brine and dried over an hydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 502 mg of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([OH:18])=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2].S(O[CH2:30][CH2:31][Cl:32])(C1C=CC(C)=CC=1)(=O)=O>O>[C:1]([NH:4][C:5]1[C:6]([O:18][CH2:30][CH2:31][Cl:32])=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COc1c(NC(C)=O)c(O)c(OC)c2occc12
Solvent: O
Product: COc1c(NC(C)=O)c(OCCCl)c(OC)c2occc12

Procedure:
A solution of 25.1 g (0.1 mole) of 5-acetamido 4,7-dimethoxy 6-hydroxy benzofuran in 15 ml of a 50% aqueous solution of soda was brought to 90° C. and 21 g (0.1 mole) of 2-chloro ethanol tosylate was slowly added, it was ketp at 90° C. for 2 hours, diluted in 1 l of water, filtered and recrystallized in ethanol.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)[N:12]=1)([CH3:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O>>[CH3:6][C:2]([S:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][CH2:14][N:16]([CH3:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:12]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CN(C(=O)Cc1csc(SC(C)(C)C(=O)O)n1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ccccc1
Reaction time: 2 h

Procedure:
To the resin obtained using 2-methyl-2-[(4-{2-[methyl(phenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)thio]propionic acid resin obtained in Example 487-1 as a starting material and by an operation similar to that of Example 461-6 was added trifluoroacetic acid (2.0 mL), and the mixture was left standing as it was for 2 hr. Then the resin was removed by filtration from the reaction mixture, and the filtrate was concentrated by blowing a nitrogen gas, vacuum dried, and purified by preparative HPLC to give the title compound (30 mg) as a pale-brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[OH:24][CH2:25][CH2:26][N:27]1[C:31](=[O:32])[CH2:30][S:29][C:28]1=[O:33]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:30]4/[C:31](=[O:32])[N:27]([CH2:26][CH2:25][OH:24])[C:28](=[O:33])[S:29]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:21])([F:22])[F:23])[CH:3]=1
Reactant: O=C1CSC(=O)N1CCO
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCO

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylene)-3-(2-hydroxyethyl)thiazolidine-2,4-dione was prepared from [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) and 3-(2-hydroxyethyl)thiazolidine-2,4-dione following General Procedure E.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][C:26]=1[OH:34].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][C:26]=1[O:34][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Oc1cc2cc[nH]c2cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3F)ncnc2cc1OCCCN1CCOCC1
Temperature: 90 °C
Yield: 37.4 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (110 mg, 0.325 mmol), (prepared as described for the starting material in Example 1), and 6-fluoro-5-hydroxyindole (59 mg, 0.39 mmol), (prepared as described for the starting material in Example 242), in DMF (1.8 ml) containing potassium carbonate (67 mg, 0.487 mmol) was heated at 90° C. for 2 hours. After cooling, water was added. The solid was separated and triturated with methanol. Water was added and the solid was filtered, washed with water and dried under vacuum to give 4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (55 mg, 41%).
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][C:22]=2[C:31]([F:34])([F:33])[F:32])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[CH3:35][NH:36][CH2:37][C:38]([OH:40])=[O:39]>>[OH:30][C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11]([CH:10]=[C:6]4[S:5][C:4]([N:36]([CH2:37][C:38]([OH:40])=[O:39])[CH3:35])=[N:8][C:7]4=[O:9])=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:31]([F:33])([F:32])[F:34])[CH:23]=1)([CH3:29])[CH3:28]
Reactant: CNCC(=O)O
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(C)(C)O)cc3C(F)(F)F)c2)S1
Product: CN(CC(=O)O)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(C)(C)O)cc3C(F)(F)F)c2)S1

Procedure:
[(5-{1-[4-(1-Hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-4-oxo-4,5-dihydro-thiazol-2-yl)-methyl-amino]-acetic acid was prepared from 2-Ethylsulfanyl-5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-thiazol-4-one and N-Methyl Glycine following General Procedure C.
Reaction SMILES: [CH2:1]([N:3]1[C:7](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC)=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:3]1[C:7](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4cncn4CC)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCn1cncc1/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(CC(=O)O)cc3)oc2C)c(OC)c1
Yield: 72.9 %

Procedure:
A mixture of ethyl {4-[4-({4-[({4-[(E)-2-(1-ethyl-1H-imidazol-5-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (156 mg), 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was heated under reflux for 30 min. After cooling, the reaction mixture was neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the obtained crystal from ethyl acetate-hexane gave {4-[4-({4-[({4-[(E)-2-(1-ethyl-1H-imidazol-5-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as colorless crystals (109 mg, yield 73%). melting point: 149-150° C.