Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:15])=[C:9]([C:11]([NH:13][NH2:14])=[O:12])[N:10]=2)[CH:7]=1.Cl.[N:17]([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:15])=[C:9]([C:11]([N:13]=[N+:14]=[N-:17])=[O:12])[N:10]=2)[CH:7]=1
Reactant: O=N[O-]
Reactant: Cc1c(C(=O)NN)nc2ccc(F)cn12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1c(C(=O)N=[N+]=[N-])nc2ccc(F)cn12
Temperature: 0 °C
Yield: 98.1 %

Procedure:
Compound 6-A (1.8 g, 8.65 mmol) was dissolved in 2N HCl (21.6 mL, 43.2 mmol) and cooled in an ice bath. A solution of NaNO2 (0.716 g, 10.4 mmol) in water (3 mL) was added dropwise over 5 minutes and the resultant solution was stirred on the ice bath for 25 minutes, then made basic with careful addition of a saturated aqueous solution of NaHCO3. A solid precipitate was collected by filtration, then dissolved in CH2Cl2 and dried over Na2SO4. The solvent was evaporated in vacuo to afford compound 6-B as a cream colored solid (1.86 g, 98%). 1H-NMR (CDCl3): δ 7.81-7.87 (m, 1H), 7.64 (dd, J=10.0, 5.2 Hz, 1H), 7.16-7.25 (m, 1H), 2.80 (s, 3H); MS: m/z 220.1 (MH+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][C:13]([F:16])([F:15])[F:14])=[C:8]([CH2:10][OH:11])[CH:9]=1.[CH3:17][O:18][CH2:19][CH2:20]Br>CCCCC.CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][C:13]([F:14])([F:15])[F:16])=[C:8]([CH2:10][O:11][CH2:20][CH2:19][O:18][CH3:17])[CH:9]=1
Reactant: COCCBr
Reactant: OCc1cc(Br)ccc1OC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: COCCOCc1cc(Br)ccc1OC(F)(F)F
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
In a 3-neck flask under argon, a 55-65% dispersion of NaH in oil (0.097 g, 2.44 mmol) is washed with n-pentane, the organics are removed and DMF (10 mL) is added. The mixture is cooled to 0-5° C., and a solution of (5-bromo-2-trifluoromethoxy-phenyl)-methanol (0.60 g, 2.21 mmol) in DMF (3.0 mL) is added dropwise. After warming to room temperature, stirring is continued for 1 h before this mixture is added to a solution of 2-bromoethyl methyl ether (0.312 mL, 3.32 mmol) in DMF (3mL). After 4 hrs at room temperature, the reaction is still incomplete by TLC. Another aliquot of NaH (1 equiv; oil dispersion washed with pentane) and 2-bromoethyl methyl ether (0.312 mL, 3.32 mmol) are added, followed by stirring for 18 hrs at room temperature. The mixture is poured into ice-water and extracted with AcOEt, the combined organics are dried (Na2SO4) and evaporated to dryness to give the title compound as yellowish oil. MS: 346.0/348.0 [M+H2l O]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.80 min. 1H-NMR (CDCl3): δ 3.49 (s, 3H), 3.64 (m, 2H), 3.72 (m, 2H), 4.69 (s, 2H), 7.13 (dd, 1H), 7.46 (dd, 1H), 7.77 (d, 1H) ppm.
Reaction SMILES: C([N:8]1[CH2:17][C:16]2[NH:15][C:14]3[CH2:18][O:19][CH2:20][C:21](=[O:22])[C:13]=3[CH:12]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Br:30])[CH:24]=3)[C:11]=2[C:10](=[O:31])[CH2:9]1)C1C=CC=CC=1.Cl[C:33]([O:35][CH:36]=[CH2:37])=[O:34]>C(Cl)Cl>[Br:30][C:25]1[CH:24]=[C:23]([CH:12]2[C:11]3[C:10](=[O:31])[CH2:9][N:8]([C:33]([O:35][CH:36]=[CH2:37])=[O:34])[CH2:17][C:16]=3[NH:15][C:14]3[CH2:18][O:19][CH2:20][C:21](=[O:22])[C:13]2=3)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: C=COC(=O)Cl
Reactant: O=C1COCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CN(Cc3ccccc3)CC1=O)N2
Solvent: ClCCl
Product: C=COC(=O)N1CC(=O)C2=C(C1)NC1=C(C(=O)COC1)C2c1ccc(F)c(Br)c1
Yield: 40.7 %

Procedure:
A solution of the product from Example 24A (0.29 g, 0.69 mmol) in methylene chloride (4 mL) was treated with vinyl chloroformate (0.10 mL, 1.2 mmol) and processed as in Example 2B. Purification by flash chromatography over silica gel (EtOAc) provided the title compound (0.13 g).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[C:32]([O:34]C)=[O:33])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.Cl.O1CCOCC1>C(O)CCC>[F:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]5[CH2:31][CH2:30][CH2:29][C@H:28]5[C:32]([OH:34])=[O:33])=[O:26])=[CH:21][CH:20]=4)=[CH:17][CH:18]=3)=[N:6][C:5]=2[CH:7]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Fc1ccc2sc(Cl)nc2c1
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)ccc4s3)cc2)cc1
Temperature: 90 °C

Procedure:
2-Chloro-5-fluoro-1,3-benzothiazole (29 mg, 0.16 mmol) and methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclopentanecarboxylate (50 mg, 0.16 mmol) were combined in 1-butanol. The solution was treated with 4 M HCl in dioxane (4 μL, 0.016 mmol) and heated at 90° C. for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was suspended in methanol, and the resulting solid was collected by filtration and dried in vacuo. The title compound was obtained as a pale yellow solid (55 mg, 77%); LC-MS m/z 475.3 (MH+), retention time 3.97 minutes.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[OH-:20].[Na+]>C(O)(=O)C>[O:13]([CH2:12][C:4]1[NH:3][C:2](=[O:20])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: Nc1nc(COc2ccccc2)nc2nccnc12
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]c(COc2ccccc2)nc2nccnc12

Procedure:
A mixture of 4.0 g (0.016 mole) of 4-amino-2-(phenoxymethyl)pteridine and 400 ml of 5% aqueous sodium hydroxide is brought slowly to 95° C. and maintained at this temperature for 2 hours. After cooling, the solution obtained is acidified with acetic acid to pH 5.5. The precipitate formed is isolated by filtration. It is purified by recrystallization from ethanol. Yld: 2.8 g (70%), m.p. 220°-221° C.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[N:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]([NH:6][C:7]1[N:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: Cc1ccc(N)nn1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NC(=O)CBr)nn1
Reaction time: 3.5 h

Procedure:
A solution of bromoacetyl bromide (0.22 mL) in dry CHCl3 (4 mL) was added slowly to a suspension of 3-amino-6-methylpyridazine (0.24 g) and triethylamine (0.47 mL) in dry CHCl3 (45 mL) at room temperature. The brown mixture was allowed to stir for 3.5 hr, then quenched with H2O (1.5 mL) and stirred for 20 mins before concentrating under reduced pressure to a brown solid. The crude product was purified by silica gel chromatography eluting with 1-2% MeOH/dichloromethane. The relevant fractions were combined and evaporated to give the title compound (0.20 g) as a pinkish/beige solid.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[F:5][C:6]([F:13])([F:12])[C:7](OCC)=[O:8]>CO>[CH2:1]([NH:4][C:7](=[O:8])[C:6]([F:13])([F:12])[F:5])[C:2]#[CH:3]
Reactant: C#CCN
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Product: C#CCNC(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h
Yield: 95.9 %

Procedure:
This compound has been prepared using a literature method (K. A. Cruickshank, D. L. Stockwell (1988) Tetrahedron Lett. 29, 5221). Propargylamine (90.9 mmol, 5 g, 6.227 mL) was added to methanol (90 mL) and the solution cooled to 0° C. Ethyl trifluoroacetate (1.3 equiv., 118.2 mmol, 16.8 g, 14.1 mL) was added and the mixture stirred at room temperature for 24 h. The solvent was evaporated, the residue diluted with 90 mL chloroform and washed with aqueous NaHCO3 solution (2×75 mL) and water (1×75 mL). The organic layer was evaporated and the orange residue distilled in vacuum to give N-propargyltrifluoroacetamide (13.171 g, 96%) as a colorless liquid which solidifies at -20° C. bp: 41° C./1.5 mm (bp ref.: 51° C./2.5 mm), mp: 31-33° C. 1H-NMR (CDCl3): 2.34 (m, 1H, CH), 4.15 (dd, 2H, CH2), 7.80 (br s, H, NH). 1H-NMR ref. (CDCl3): 2.34 (t, 1H), 4.16 (dd, 2H), 7.00 (br s, 1H). 13C-NMR (CDCl3): 29.4 (CH2), 72.4 (CH), 77.0 (C), 109.859, 113.673, 117.470, 121.276 (CF3, J=286.37 Hz), 156.748, 157.249, 157.750, 158.250 (CO, J=37.77 Hz).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].[CH:14]1[C:19]([CH:20]=O)=[CH:18][C:17]2[O:22][CH2:23][O:24][C:16]=2[CH:15]=1.[OH-].[Na+]>C(O)C>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[C:2](=[O:3])[CH:1]=[CH:20][C:19]1[CH:14]=[CH:15][C:16]2[O:24][CH2:23][O:22][C:17]=2[CH:18]=1
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)C=Cc2ccc3c(c2)OCO3)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a warm (40° C.) solution of 41.5 grams (0.23 mole) of 3,4-dimethoxyacetophenone and 40.5 grams (0.27 mole) of piperonal in 220 milliliters of ethanol was added 60 milliliters of 10 % aqueous sodium hydroxide. The mixture was warmed for 10 minutes at 40°-50° C; then stirred at room temperature for 2 hours. After standing overnight, the yellow crystalline produce was collected by filtration, washed with water (3 × 40 milliliters), and dried to give 72 grams (quantitative yield) of V, melting point 127°-129° c. An analytical sample was prepared by recrystallization of 1.6 gram of the product from 50 milliliters of ethanol, giving 1.4 gram of pure chalcone as yellow needles, melting point 131°-133° C.; λ (ethanol) 242 (log ε 4.23), 3.60 nm (4.53).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.O>C1(C)C=CC=CC=1>[C:12]1(=[O:17])[N:1]([CH2:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4]2)[C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCC1Cc2ccccc2N1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CC1Cc2ccccc2N1
Yield: 105.1 %

Procedure:
A mixture of 2-aminomethylindoline (6.0 g, 40.48 mmol) and phthalic anhydride (6.30 g, 42.51 mmol) in toluene (600 mL) was refluxed for 4 h, while water generated during the reaction was removed by azeotropic distillation by using Dean-Stark apparatus. The mixture was concentrated to give a crude 2-phthalimidomethylindoline (11.84 g), which was used for the next step without further purification: 1H NMR (270 MHz, CDCl3) δ7.82 (m, 2H), 7.71 (m, 2H), 7.03 (d, 1H, J=7 Hz), 6.95 (dt, 1H, J=1,7 Hz), 6.61 (m, 2H), 4.19 (m, 1H), 3.86 (d, 2H, J=6 Hz), 3.18 (dd, 1H, J=16, 9 Hz), 2.93 (dd, 1H, J=16, 6 Hz).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)[CH3:2].S1C=C[CH:13]=[C:12]1C(O)=O.ICCCC>>[CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)[CH2:2][CH2:12][CH3:13]
Reactant: O=C(O)c1cccs1
Reactant: CCc1ccc(C(=O)O)s1
Solvent: CCCCI
Product: CCCCc1ccc(C(=O)O)s1

Procedure:
The title compound is prepared in analogy to 5-ethyl-thiophene-2-carboxylic acid starting from 2-thiophenecarboxylic acid and 1-iodobutane; LC-MS: tR=0.92 min.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:11]=[N:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH:14]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=2)[NH2:33])[CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:13]2[CH:14]=[C:10]([C:6]3[C:5]4[N:4]([N:3]=[C:2]([NH:33][C:32]5[CH:34]=[CH:35][CH:36]=[C:30]([N:27]6[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]6)[CH:31]=5)[N:22]=4)[CH:9]=[CH:8][CH:7]=3)[CH:11]=[N:12]2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(-n2cc(-c3cccn4nc(Cl)nc34)cn2)cc1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5cnn(-c6ccc(F)cc6)c5)cccn4n3)c2)CC1

Procedure:
{8-[1-(4-Fluoro-phenyl)-1H-pyrazol-4-yl]-[1,2,4]triazolo[1,5-a]pyridine-2-yl}-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 2-chloro-8-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[1,2,4]triazolo[1,5-a]pyridine (Example 280a) and 3-(4-methylpiperazine-1-yl)aniline with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.055 g, 20%). MP=216-218° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.53 (s, 1H), 9.25 (s, 1H), 8.67 (d, 2H), 7.92 (m, 3H), 7.43 (m, 3H), 7.12 (m, 3H), 6.50 (m, 1H), 3.12 (m, 4H), 2.43 (m, 4H), 2.21 (s, 3H). MS=469 (MH)+.
Reaction SMILES: C(O[C@H]1C[C@@H](C2C=CN=CC=2)OC2(CCNCC2)C1)C.CCN=C=NCCCN(C)C.[CH:32]([O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][C:37]=1[CH3:45])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C>ClCCl>[CH:32]([O:35][C:36]1[CH:44]=[CH:43][C:39]([CH:40]=[O:41])=[CH:38][C:37]=1[CH3:45])([CH3:34])[CH3:33]
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CCO[C@H]1C[C@@H](c2ccncc2)OC2(CCNCC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C=O)ccc1OC(C)C
Reaction time: 16 h
Yield: 146.5 %

Procedure:
A solution of cis-8-ethoxy-10-(4-pyridyl)-11-oxa-3-azaspiro[5.5]undecane (50 mg, 0.18 mmol), EDCI (38 mg, 0.20 mmol) and 4-isopropoxy-3-methyl-benzoic acid (35 mg, 0.18 mmol) in dichloromethane (0.9 mL) was treated with DIPEA (94 μL, 0.54 mmol) and stirred for 16 h. The reaction mixture was filtered and purified by reverse phase HPLC (1-100% ACN/water) to afford cis-8-ethoxy-10-(2-pyridyl)-11-oxa-3-azaspiro[5.5]undecan-3-yl)(4-isopropoxy-3-methyl-phenyl)methanone (47 mg, 57.58%). ESI-MS m/z calc. 452.27, found 453.2 (M+1)+; Retention time: 1.059 minutes (3 min run).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[CH3:17]OC(OC)(C)C.Cl>CO.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[CH2:9][C:10]([CH3:14])([CH3:15])[C:11]([O:13][CH3:17])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)(CC(=O)c1ccc(Br)cc1)C(=O)O
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)CC(=O)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 22 h

Procedure:
To a solution of 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoic acid (8.33 g, 29.2 mmol) and 2,2-dimethoxypropane (3.95 g, 37.9 mmol) in methanol (100 mL) was added 1 M HCl in dioxane (2.0 mL). The reaction mixture was stirred at 50° C. for 22 h. The mixture was concentrated under reduced pressure. Toluene (2×60 mL) was added and the mixture concentrated again (2×) to afford methyl 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate as an off-white, semi-solid (8.60 g, 99%). This material was used in the next step without further purification. LC-MS: ret. time 3.23 min; m/z 298.8 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.34 (s, 6H), 3.28 (s, 2H), 3.67 (s, 3H), 7.58 (d, 2H), 7.78 (d, 2H).
Reaction SMILES: S(Cl)(Cl)=O.CC(CCCC)C(O)=O.CC(CCCC)C(Cl)=O.[CH3:23][CH:24]([CH2:30][CH2:31][CH2:32][CH3:33])[C:25]([N:27]=[C:28]=[S:29])=[O:26].[Cl:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1[O:42][C:43]1[C:52]2[C:47](=[CH:48][C:49]([O:55][CH3:56])=[C:50]([O:53][CH3:54])[CH:51]=2)[N:46]=[CH:45][CH:44]=1)[NH2:38]>C(O)C.C1(C)C=CC=CC=1>[Cl:34][C:35]1[CH:36]=[C:37]([NH:38][C:28]([NH:27][C:25](=[O:26])[CH:24]([CH3:23])[CH2:30][CH2:31][CH2:32][CH3:33])=[S:29])[CH:39]=[CH:40][C:41]=1[O:42][C:43]1[C:52]2[C:47](=[CH:48][C:49]([O:55][CH3:56])=[C:50]([O:53][CH3:54])[CH:51]=2)[N:46]=[CH:45][CH:44]=1
Reactant: CCCCC(C)C(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: CCCCC(C)C(=O)Cl
Agent: CCCCC(C)C(=O)O
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCC(C)C(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(Cl)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-methylhexanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-methylhexanoyl isothiocyanate was prepared using the resultant 2-methylhexanoyl chloride as a starting compound according to the description of the literature. 2-Methylhexanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 58%).
Reaction SMILES: C([O:4][C:5]1[C:10]2[C:11]([CH3:25])=[C:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[O:15])[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=O)C.Cl>CO.C([O-])([O-])=O.[K+].[K+].O>[OH:4][C:5]1[C:10]2[C:11]([CH3:25])=[C:12]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[O:15])[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1cccc2oc(C(=O)OCc3ccc(Cl)cc3)c(C)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)OCc2ccc(Cl)cc2)oc2cccc(O)c12
Reaction time: 8 h
Yield: 96 %

Procedure:
To the compound of Example 124 (0.2 g, 0.55 mmoles) dissolved in MeOH (10 ml) was added 2-3 drops K2CO3 10% w/v in H2O and the reaction mixture was stirred at 25° overnight. HCl (0.1N, 20 ml) was added and the mixture was filtered. The solid was air dried to give 0.170 g or 96% of the title compound, m.p. 202°-204° C.
Reaction SMILES: [CH3:1]I.[OH:3][CH:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].O>CN(C)C=O>[CH3:1][O:3][CH:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(O)c1ccccc1COC1CCCCO1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(OC)c1ccccc1COC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Methyl iodide (20.25 g, 143 mmol) was added to a solution of ethyl α-hydroxy-2-(tetrahydropyran-2-yloxymethyl)phenylacetate (14.00 g, 47.6 mmol) in N,N-dimethylformamide (40 ml), and the mixture was stirred at 0° C. 60% oily sodium hydride (1.90 g, 47.5 mmol) was added thereto. After 30 minutes, water (100 ml) was added, and the mixture was extracted with ether and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ ethyl acetate=4/1) to give the desired compound ethyl α-methoxy-2-(tetrahydropyran-2-yloxymethyl)phenylacetate (14.00 g, 95.5%) as an oil.
Reaction SMILES: [Si]([O:8][CH2:9][C@:10]1([CH3:34])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[O:30][CH:31]=[CH:32][N:33]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:34][C@@:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[O:30][CH:31]=[CH:32][N:33]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(-c5ncco5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: C[C@]1(CO)Cc2nnc(C3(c4ccc(-c5ncco5)cc4)CC3)n2CCS1
Yield: 88.4 %

Procedure:
A solution of the compound (674 mg, 1.36 mmol) obtained in Example 85-1) and 4 M hydrochloric acid (1,4-dioxane solution, 4 mL) in methanol (8 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, a 5 M aqueous sodium hydroxide solution (40 mL) was added to the residue, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=20:80) to obtain the title compound (460 mg, 88%) as a yellow solid.
Reaction SMILES: [Li].[C:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[C:16](=O)([O:19]C)[O:17]C>O1CCCC1>[C:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH2:15][C:16]([OH:19])=[O:17])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc(C(C)(C)C)ccc1C(=O)O
Reactant: COC(=O)OC
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)O)c(CC(=O)O)c1
Temperature: -40 °C
Reaction time: 4 h

Procedure:
An amount of 26 mL (198 mmol) of Lithium diiopropylamide (Aldrich) is added to a three neck flask cooled to −40° C. To this is added drops wise, a mixture of 4-tert-butyl-2-methyl-benzoic acid 1.9 g (9.9 mmol) and dimethyl carbonate 3.3 mL (39.6 mmol) in 5 mL of tetrahydrofuran, while keeping the temperature at −60° C. After the addition, the temperature is kept between −40° C. to −60° C. for four hours, then brought to 0° C. and quenched with 25 mL of water. The mixture is allowed to stir at room temperature for two hours and acidify to pH 2 with hydrogen chloride, extracted 3× with ethyl acetate, dried over magnesium sulfate and evaporated.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)[CH3:29]>>[CH2:28]([N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35]1[CH:41]=[CH:40][C:38]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:37][CH:36]=1)[CH3:29]
Reactant: CCn1ccnc1-c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: CCn1ccnc1-c1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(1-ethyl-imidazol-2-yl)-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol=10:1) C28H24N4O3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(OCC2CC2)c1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)c(OCC2CC2)c1
Temperature: 80 °C

Procedure:
1-chloro-2-cyclopropylmethoxy-4-nitro-benzene (2.3 g, 10 mmol) was dissolved in ethanol (30 ml) and water (30 ml), and then sodium dithionite was gradually added thereto. This was stirred at 80° C. for four and half hours. After cooling it to room temperature, an aqueous solution of 5 M hydrochloride (40 ml) was added to the reaction mixture. This was stirred at room temperature for one hour. Then, an aqueous solution (42 ml) of 5 M sodium hydroxide was added, and the solution was alkalinized and extracted with ethyl acetate. The extract was washed with water and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and concentration was performed. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. Thus, 4-chloro-3-cyclopropylmethoxy-phenylamine was obtained as a pale yellow gum-like material (1.4 g).