Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:9][CH:8]=1)(C)(C)C.[OH-].[Na+].CCOC(C)=O>C1COCC1>[CH3:27][O:26][C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]([OH:28])=[O:5])=[CH:12][CH:11]=1)=[O:25]
Reactant: COC(=O)CCCCCCCCCCCc1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCCCCCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(11-Methoxycarbonylundecyl)benzoic acid tert-butyl ester (185 mg, 0.47 mmol) was dissolved in THF (2 ml), and 1 N NaOH (0.497 mmol) was added over 1 min. The mixture was stirred for 16 h at rt. AcOEt (50 ml) was added and the solution was washed with 5% AcOH (2×25 ml), dried over MgSO4 and concentrated under vacuum to the product (153 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=1.[ClH:26]>>[ClH:26].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=1
Reactant: CCOC(=O)CCCCCc1c(-c2cccnc2)[nH]c2ccccc12
Agent: Cl
Product: O=C(O)CCCCCc1c(-c2cccnc2)[nH]c2ccccc12

Procedure:
A solution of 7.46 g of 2-(3-pyridyl)-3-[5-(ethoxycarbonyl)-pentyl]-indole in 2N aqueous hydrochloric acid (275 ml) is heated at reflux for 20 hours. The hot reaction mixture is filtered, and the filtrate on cooling gives yellow crystals which are collected by filtration and dried to yield 2-(3-pyridyl)-3-(5-carboxypentyl)-indole hydrochloride, m.p. 220°-222°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[N:5][C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:3]1.[Cl-].[CH3:16][C:17]1[N:22]2[N:23]=[C:24]([CH2:26][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:25]=[C:21]2[C:20]([CH3:46])=[N:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:16][C:17]1[N:22]2[N:23]=[C:24](/[CH:26]=[CH:7]/[C:6]3[N:2]([CH3:1])[N:3]=[C:4]([N:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)[N:5]=3)[N:25]=[C:21]2[C:20]([CH3:46])=[N:19][CH:18]=1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: Cn1nc(N2CCCCC2)nc1C=O
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1ncc(C)n2nc(/C=C/c3nc(N4CCCCC4)nn3C)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.6 %

Procedure:
A mixture of 1-methyl-3-(piperidin-1-yl)-1H-1,2,4-triazole-5-carbaldehyde (60 mg, 309 μmol, Eq: 1.00), ((5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphonium chloride (142 mg, 309 μmol, Eq: 1.00) and DBU (51.7 mg, 51.2 μl, 340 μmol, Eq: 1.1) in tetrahydrofuran (15 ml) was stirred for 18 hours at 25° C. under argon. The crude material was applied on silica gel and purified by flash chromatography over a 20 g silica gel column using ethyl acetate/methanol 0-7% as eluent affording 5,8-dimethyl-2-[(E)-2-(2-methyl-5-piperidin-1-yl-2H-[1,2,4]triazol-3-yl)-vinyl]-[1,2,4]triazolo[1,5-a]pyrazine (56 mg, 53.6%) as a yellow solid. MS: m/z=339.5 (M+H+), MP: 186-188° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[Si](C)(C)[CH3:18]>CO>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH2:12][C:13]([O:15][CH3:18])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1ccc2cccc(CC(=O)O)c2n1
Solvent: CO
Product: COC(=O)Cc1cccc2ccc(C)nc12
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 2-(2-methylquinolin-8-yl)acetic acid (1.45 g, 7.21 mmol) in dry MeOH (100 mL) was added chlorotrimethylsilane (1.82 mL, 14.4 mmol) dropwise at 0° C. After addition, the reaction mixture was stirred at reflux for 2 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate (20 mL). The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give methyl 2-(2-methylquinolin-8-yl)acetate (1.35 g, 87.0%) as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:14])=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[CH2:15]([O:17][C:18]1[C:22]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][N:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[N:19]=1)[CH3:16].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:15]([O:17][C:18]1[C:22]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][N:20]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:2][C:3]3[C:4]([CH3:14])=[N:5][N:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:7]=3)=[CH:35][CH:36]=2)[N:19]=1)[CH3:16]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Reactant: Cc1nn(-c2ccccn2)cc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn(-c4ccccn4)nc3C)cc2)nc1OCC
Temperature: 80 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
A mixture of 2-(4-chloromethyl-3-methyl-1H-pyrazol-1-yl)pyridine (350 mg), ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (500 mg), potassium carbonate (500 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethoxy]benzyl]-1H-pyrazol-4-yl]propionate (700 mg, yield: 91%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: Cl.[CH2:2]([N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=O)=[C:21]([CH:30]=[CH2:31])[CH:20]=1)[CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(N(CCOC1C=CC(CCC(=O)[C:58]([F:61])([F:60])[F:59])=CC=1)C)CCCCCCCCCCC>>[CH2:2]([N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](=[O:29])[C:58]([F:61])([F:60])[F:59])=[C:21]([CH:30]=[CH2:31])[CH:20]=1)[CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: C=Cc1cc(OCCN(C)CCCCCCCCCCCC)ccc1CCC(=O)O
Reactant: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Agent: Cl
Product: C=Cc1cc(OCCN(C)CCCCCCCCCCCC)ccc1CCC(=O)C(F)(F)F
Yield: 54 %

Procedure:
3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-vinylphenyl]propanoic acid, hydrochloride (830 mg, 1.83 mmol) was reacted by the general procedure as described in the preparation of 4-[4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]-1,1,1-trifluoro-2-butanone. The residue was chromatographed on silica gel (ethyl acetate) to afforded the title compound (0.46 g, 54%) as a pale purple oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][NH2:15])[C:7]=2[CH:6]=[CH:5][CH:4]=1.BrC1C=CC(S(O[CH2:27][C@@H:28]2[O:42][C:32]3=[C:33]4[C:38](=[CH:39][CH:40]=[C:31]3[O:30][CH2:29]2)[N:37]=[C:36]([CH3:41])[CH:35]=[CH:34]4)(=O)=O)=CC=1>CS(C)=O.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][NH:15][CH2:27][CH:28]3[O:42][C:32]4=[C:33]5[C:38](=[CH:39][CH:40]=[C:31]4[O:30][CH2:29]3)[N:37]=[C:36]([CH3:41])[CH:35]=[CH:34]5)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: COc1cccc2c(CCCN)coc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc2c(CCCNCC3COc4ccc5nc(C)ccc5c4O3)coc12
Temperature: 50 °C

Procedure:
To a stirred solution of 3-(7-methoxy-benzofuran-3-yl)-propylamine (770 mg, 3.75 mmol) in 5 mL of anhydrous DMSO was added [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (563 mg, 1.25 mmol). The reaction mixture was heated to 50° C. overnight. The reaction was diluted with saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. Flash chromatography on SiO2 (5% MeOH/CH2Cl2) afforded 120 mg (23%) of the (S)-enantiomer of the title compound as a yellow oil. The fumarate salt was prepared, yielding 132 mg of a beige solid, m.p. 155-160° C.; MS (ESI) m/z 419 [M+H]+.
Reaction SMILES: O.C(NC1CC(=O)[N:8]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])N=1)(=O)C>C(O)C>[Cl:18][C:17]1[CH:16]=[C:15]([Cl:19])[CH:14]=[C:13]([Cl:20])[C:12]=1[NH2:8]
Reactant: CC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Solvent: O
Solvent: CCO
Product: Nc1c(Cl)cc(Cl)cc1Cl
Yield: 57 %

Procedure:
The procedure was repeated using a mixture of 20% water and 80% ethanol as the solvent instead of the anhydrous ethanol used above. This time the yield of 3-acetamido-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one was very poor, i.e., only 8%, while a 57% yield of 2,4,6-trichloroaniline was obtained. This illustrates that, in contrast to the excellent yields produced in an organic medium, very poor yields are obtained when the rearrangement is run in an aqueous medium.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1.C1CCCCC1.C1(N)CCCCC1>C(OCC)(=O)C.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: O=C(O)CCCc1ccc(-c2ccc(F)cc2F)cc1
Yield: 39 %

Procedure:
Prepared analogous to Example 1 from 4-(2',4'-difluoro-4-biphenylyl)-4-oxo-butyric acid. Yield: 39% of theory; m.p. 76°-77° C. (from cyclohexane). Melting point of the cyclohexylamine salt: 127°-128° C. (from ethyl acetate/methanol 9:1).
Reaction SMILES: [CH:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH2:3][CH3:4])[CH3:2].[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17]>>[CH3:17][C:11]1[CH:10]=[C:15]([CH:14]=[CH:13][CH:12]=1)[O:16][CH2:6][CH:7]([OH:9])[CH2:8][NH:5][CH:1]([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)N1CC(O)C1
Reactant: Cc1cccc(O)c1
Product: CCC(C)NCC(O)COc1cccc(C)c1

Procedure:
1-(sec.-butyl)-3-azetidinol and m-cresol were reacted in the same manner as in Example 6 to yield 1-(3-methylphenoxy)-3-(sec.-butylamino)-2-propanol. A hydrochloric acid gas was blown to yield 1-(3-methylphenoxy)-3-(sec.-butylamino)-2-propanol hydrochloride melting at 159°-160° C. The yield was 69%.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[NH2:10].[F:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:13]=1[C:14](O)=[O:15].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1.CCOC(C)=O>[F:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:13]=1[C:14]([NH:10][C:2]1[S:1][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=1)=[O:15]
Reactant: Nc1nc2cnccc2s1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1nc2cnccc2s1)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.2 %

Procedure:
A mixture of thiazolo[4,5-c]pyridin-2-amine (Milestone Pharm Tech USA Inc.) (1.35 g, 8.93 mmol), 2-fluoro-5-(trifluoromethyl)benzoic acid (2.23 g, 10.72 mmol) and triethylamine (2.71 g, 26.8 mmol) in THF (30 mL) was treated drop wise with 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate) (6.82 g, 10.72 mmol). The mixture was stirred at room temperature for 12 hrs. The reaction mixture was diluted with EtOAc, and washed with saturated NaHCO3. The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was triturated with Et2O and hexane to afford the title compound (2.2 g, 72%) as a brown solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.66 (t, J=9.46 Hz, 1H) 8.07 (m, 1H) 8.12 (d, J=4.88 Hz, 1H) 8.26 (dd, J=6.10, 2.14 Hz, 1H) 8.44 (d, J=5.49 Hz, 1H) 9.07 (s, 1H); MS (DCI/NH3) m/z 342 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:15][N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][C:21](F)=[C:22]([F:27])[CH:23]=2)[N:18]([CH2:29][CH3:30])[C:17]1=[O:31])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:8]([O:15][N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][C:21]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[C:22]([F:27])[CH:23]=2)[N:18]([CH2:29][CH3:30])[C:17]1=[O:31])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN1CCNCC1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Yield: 84.9 %

Procedure:
4-Methylpiperazine (0.08 mL, 0.72 mmol) was added to a solution of 3-benzyloxy-1-ethyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example C, 0.2 g, 0.6 mmol) and DBU (0.09 mL, 0.6 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 100 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with water brine, and dried over magnesium sulfate. The solution was concentrated to give 0.21 g of a solid. The solid was purified by column chromatography (chloroform/methanol 99:1). The appropriate fractions were combined to give 0.14 g of the title compound as a solid, mp 134-136° C.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:53][O:54][CH:55]([CH3:57])[CH3:56])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])([CH3:4])[CH3:3].C(O)(=O)C.C(O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:53][O:54][CH:55]([CH3:57])[CH3:56])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])([CH3:4])[CH3:3]
Reactant: CC(C)OCc1nc(C(C)(C)O)c(C(=O)OC(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)OCc1nc(C(C)(C)O)c(C(=O)OC(C)C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 95.9 %

Procedure:
A solution of 609 mg of isopropyl 4-(1-hydroxy-1-methylethyl)-2-isopropoxymethyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] in 10 ml of a 25% v/v aqueous solution of acetic acid was stirred at 60° C. for 2.5 hours. 10 ml of water were then added, after which the mixture was cooled with ice. The trityl alcohol which appeared as crystals was filtered off. The filtrate was concentrated by distillation under reduced pressure, and then acetic acid and water were distilled off as azeotropic mixtures with benzene, to give 398 mg of the title compound as an amorphous powder.
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C1CCN2C(=NCCC2)CC1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:22][C:21]1[O:20][C:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:18][C:17]=1[CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]=[CH:2][C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1
Reactant: COC(=O)C(Br)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of methyl 2-bromo-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionate (15.0 g), 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) (6.2 g) and toluene (200 ml) was stirred for 2 hours at 70° C. The reaction mixture was poured into ethyl acetate (200 ml), which was washed with 2N HCl and a saturated aqueous saline solution, followed by drying (MgSO4). The solvent was distilled off under reduced pressure to leave methyl 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]cinnamate (10.8 g, 88%). Recrystallization from ethyl acetate--hexane colorless needles, m.p.114°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[NH2:11][CH:12]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[CH2:13]O.C(N(CC)CC)C.S(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH2:13][CH:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[N:11]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cc1ccc(CC(N)CO)cc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccc(CC2COC(c3cccc(Cl)c3)=N2)cc1
Temperature: 25 °C

Procedure:
A solution of 1.75 g (10 millimoles) of 3-chlorobenzoyl chloride in 15 ml of tetrahydrofuran was added with ice cooling and stirring to a 100 ml egg-plant-shaped flask containing 1.61 g (10 millimoles) of 2-amino-3-(4-methyl-phenyl)-1-propanol, 1.01 g (10 millimoles) of triethylamine and 30 ml of tetrahydrofuran over the course of 30 minutes. The mixture was further stirred at 20° C. for 3 hours. The resulting triethylamine hydrochloride was removed by a glass filter, and the filtrate was concentrated under reduced pressure. Thionyl chloride (5 ml; 68 millimoles) was added all at once to a 100 ml eggplant-shaped flask containing this concentrate and 30 ml of benzene. With stirring, the mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The concentrate was dissolved in 100 ml of ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A 100 ml eggplant-shaped flask containing this concentrate and 30 ml of ethanol was heated to 70° C. over an oil bath with stirring, and 15 ml of a 3 % aqueous solution of sodium hydroxide was added over 10 minutes. The mixture was further stirred at 70° C. for 20 minutes, and concentrated under reduced pressure. Benzene (100 ml) was added to the concentrate, and the mixture was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate=7/3) to give 2-(3-chlorophenyl)-4-(4-methylbenzyl) -2-oxazoline (compound No. 108) as a yellow viscous oil. Yield 1.7 g (59.5 %).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[Na+].CO>[Pd].C(OCC)(=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCOC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reaction time: 15 h
Yield: 77.1 %

Procedure:
A mixture of 208 mg of 1-Bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (0.5 mmol), 49 mg of sodium acetate (0.6 mmol), 50 mg of 10 wt % palladium on charcoal, 10 ml of methanol, and 5 ml of ethyl acetate was stirred under hydrogen at 1 atm for 15 h. Then the mixture was filtered by suction through a pad of celite and was concentrated in vacuo. The residue was partitioned between 2 ml of half concentrated aqueous bicarbonate solution and 8 ml of ethyl acetate. The organic phase was dried over MgSO4. Evaporation in vacuo gave 130 mg of the title compound; 1H NMR (CDCl3): δ=11.89 (bs, 1H), 8.61 (s, 1H), 8.36 (d, 1H), 7.10 to 7.53 (m, 7H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: N[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[S:17])=[CH:11][C:10]=2[F:29])[CH:3]=1.F[C:31]1C=CC(CC(N=C=S)=O)=CC=1>C(Cl)Cl>[NH2:5][C:6]1[CH:31]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[S:17])=[CH:11][C:10]=2[F:29])[CH:3]=[CH:2][N:7]=1
Reactant: Nc1cc(Oc2ccc(NC(=S)NC(=O)Cc3ccc(F)cc3)cc2F)ncn1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Solvent: ClCCl
Product: Nc1cc(Oc2ccc(NC(=S)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 38.6 %

Procedure:
4-Fluorophenylacetylchloride (Aldrich, 0.017 mL, 0.126 mmol, 2.5 eq) was added to a solution of sodium thiocyanate (0.014 g, 0.176 mmol, 3.5 eq) in ethyl acetate (1.0 mL) at room temperature and the reaction mixture was stirred for 1.5 h to afford a 2-(4-fluorophenyl)ethanoyl isothiocyanate solution (0.126 M). 4-(4-Amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 0.011 g, 0.050 mmol, 1.0 eq) was dissolved in CH2Cl2 (1.0 mL) and 2-(4-fluorophenyl)ethanoyl isothiocyanate (0.126 M, 0.50 mL, 0.063 mmol, 1.3 eq) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by silica gel flash chromatography (Merck, 40-63 μM, 230-240 mesh, eluting 0-6% MeOH in CHCl3) to afford the title compound (0.008 g, 38%) as a solid. 1H NMR (CD3OD) δ 7.85-7.95 (m, 1H), 7.67-7.69 (m, 1H), 7.13-7.28 (m, 4H), 6.95-7.00 (m, 2H), 6.05-6.15 (m, 1H), 5.90-5.91 (m, 1H), 3.65 (s, 2H); MS (ESI+) m/z 415 (M+H)+; HRMS (ESI+) calculated: 415.1040. found: 415.1041.
Reaction SMILES: [CH2:1]([N:4]1[C:9]2[CH:10]=[C:11]([C:14](=[O:26])[CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[Cl:25])[CH3:16])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:27])[CH:2]=[CH2:3].[F:28][C:29]([Si](C)(C)C)([F:31])[F:30]>>[CH2:1]([N:4]1[C:9]2[CH:10]=[C:11]([C:14]([OH:26])([C:29]([F:31])([F:30])[F:28])[CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[Cl:25])[CH3:16])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:27])[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=CCN1C(=O)COc2ccc(C(=O)C(C)c3ccc(OC)cc3Cl)cc21
Product: C=CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(OC)cc3Cl)C(F)(F)F)cc21

Procedure:
In analogy to Example 56, step 3, 4-allyl-6-[2-(2-chloro-4-methoxy-phenyl)-propionyl]-4H-benzo[1,4]oxazin-3-one (7.2 g) was reacted with (trifluoromethyl)-trimethylsilane. The product was purified by crystallization with heptane/AcOEt (4:1) to give the title compound (4.45 g) as an off-white solid. MS (m/e)=456.3 [M+H+].
Reaction SMILES: C=[O:2].S(=O)(=O)(O)O.O.[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=NO)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:2])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C=O
Reactant: CCOC(=O)C(CCCCCCl)=NO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(=O)CCCCCCl

Procedure:
The solution of ethyl 7-chloro-2-hydroxyiminoheptanoate [III-1] in toluene obtained in Example 9 (without being concentrated) is added dropwise into 36% aqueous formalin solution, and thereto is added sulfuric acid. The mixture is warmed, and further thereto is added water. The organic layer is separated, neutralized, washed with water, and concentrated under reduced pressure to give ethyl 7-chloro-2-oxoheptanoate [I-1].