Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:18][C:19](OC(C)=O)=O>C1COCC1.N1C=CC=CC=1>[CH2:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:6][CH:7]=1)[CH3:19]
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
A solution of 1 g (3.86 mmol) of 2-(4-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 2 ml of THF and 5 mL of pyridine was treated with 0.44 mL (4.63 mmol) of Ac2O and stirred for 2 hrs at 60° C. The solvent was evaporated and the crude distributed between a diluted aqueous solution of HCl and Et2O. the combined organic phases were dried over Na2SO4 and the solvent evaporated. The residue was dissolved in 5 mL of THF, treated with 7.7 mL of a 1M BH3*THF-solution in THF and refluxed for 2 hrs. The solvent was evaporated and the residue distributed between a diluted aqueous solution of NaOH and Et2O. The aqueous phase was then acidified by addition of an aqueous solution of HCl to a pH of ca. 7 and extracted with Et2O. The combined organic phases were dried over Na2SO4 and the solvent evaporated to give 1.07 g (96%) of crude 2-(4-ethylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, light yellow solid, MS: 288 (MH+).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.[CH2:18]([O:25][CH2:26][N:27]1[N:31]=[N:30][C:29]([Sn](CCCC)(CCCC)CCCC)=[N:28]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([O:25][CH2:26][N:27]1[N:31]=[N:30][C:29]([C:2]2[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[O:9])=[C:5]([CH3:7])[N:6]=2)=[N:28]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(COCc2ccccc2)n1
Reactant: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2nnn(COCc3ccccc3)n2)sc1C(=O)NCc1cccnc1
Temperature: 85 °C
Yield: 48 %

Procedure:
To a mixture of 2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.10 g, 0.32 mmol), copper(I) iodide (0.002 g, 0.009 mmol), tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.009 mmol) in anhydrous toluene (3 mL) was added 2-(benzyloxymethyl)-5-(tributylstannyl)-2H-tetrazole (0.018 g, 0.39 mmol, prepared following the procedure described in Tetrahedron Letters, 41, (2000), 2805-2809) and the reaction mixture was heated at 85° C. in a sealed tube for 6 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:methanol, 10:1) to afford the title compound as a clear oil (0.065 g, 48%): 1H NMR (300 MHz, CDCl3) δ 8.53 (br s, 1H), 8.52-8.45 (m, 1H), 7.75-7.69 (m, 1H), 7.36-7.20 (m, 6H), 6.80 (t, J=5.8 Hz, 1H), 5.97 (s, 2H), 4.69 (s, 2H), 4.61 (d, J=5.8 Hz, 2H), 2.72 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.4, 160.3, 157.3, 153.3, 149.2, 149.1, 135.9, 135.3, 133.5, 128.7, 128.5, 128.2, 128.0, 123.8, 80.3, 72.4, 41.7, 17.5; MS (ES+) m/z 422.3 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8]
Reactant: C=CCOC(=O)c1cccc([N+](=O)[O-])c1
Solvent: CO
Product: C=CCOC(=O)c1cccc(N)c1

Procedure:
Reduction of the above nitro compound by the method of Example 2, except that the solvent was methanol, gave allyl 3-aminobenzoate. Nmr (CDCl3): δ 3.38 (br, 2H); 4.79 (dt, 2H); 5.24-5.44 (m, 2H); 5.93-6;09 (m, 1H); 6.86 (dm, 1H); 7.21 (t, 1H); 7.37 (t, 1H); 7.45 (dt, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11]C)=[O:10])=[C:5]([NH:15][C:16](=[O:34])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:19][CH:18]=2)[CH:4]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[C:5]([NH:15][C:16](=[O:34])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:19][CH:18]=2)[CH:4]=1
Reactant: COC(=O)COc1ccc(OC)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(OCC(=O)O)c(NC(=O)c2ccc(OCCCCc3ccccc3)cc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
In 25 ml of 90% methanol was suspended 0.54 g of methyl 4-methoxy-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Example 95. To the suspension wad added 10 ml of a 1N sodium hydroxide aqueous solution followed by stirring at 60° C. for 2 hours. The reaction mixture was diluted with 50 ml of water and the system was rendered acidic with 7 ml of 2N hydrochloric acid. Extraction was performed with ethyl acetate. After the organic layer was washed water and dried over anhydrous magnesium sulfate, the solvent was distilled off. The obtained solid was recrystallized from isopropyl alcohol to obtain 0.4 g of 4-methoxy-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[CH:3][C:2]=1[C:10]([OH:12])=O.Cl.[Cl:14][C:15]1[CH:16]=[C:17]([C:22]2[O:26][C:25]([CH2:27][CH2:28][NH2:29])=[CH:24][CH:23]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17]([C:22]2[O:26][C:25]([CH2:27][CH2:28][NH:29][C:10]([C:2]3[CH:3]=[C:4]4[N:9]=[CH:8][CH:7]=[CH:6][N:5]4[N:1]=3)=[O:12])=[CH:24][CH:23]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=C(O)c1cc2ncccn2n1
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: Cl
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc2ncccn2n1
Yield: 53.3 %

Procedure:
The title compound was prepared using the method of Example 20 but starting from pyrazolo[1,5-a]pyrimidinecarboxylic acid (82 mg; 0.5 mmol) and 2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine hydrochloride (146 mg; 0.5 mmol). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-20% DCM/MeOH) to obtain 107 mg of the title compound. The product was further purified by trituration in toluene to give 55 mg of pure product (27%). 1H-NMR (400 MHz; d1-CDCl3): δ 3.06 (t, 2H), 3.83 (m, 2H), 6.233 (d, 1H), 6.61 (d, 1H), 6.93 (dd, 1H), 7.35-7.41 (m, 2H), 7.44 (dd, 1H), 7.70 (d, 1H), 8.55 (dd, 1H), 8.57-8.60 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[O:9][N:8]=2)[NH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].[Cl:29][C:30]1[CH:35]=[C:34]([CH2:36]Cl)[CH:33]=[CH:32][N:31]=1>CN(C=O)C.O>[Cl:29][C:30]1[CH:35]=[C:34]([CH2:36][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[CH:11]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=4)[O:9][N:8]=3)=[N:5]2)[CH:33]=[CH:32][N:31]=1
Reactant: ClCc1ccnc(Cl)c1
Reactant: Cc1n[nH]c(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)nn1Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a mixture of 3-(5-methyl-2H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl)isoxazole (Example 96, Step 4, 400 mg, 1.3 mmol) and K2CO3 (445 mg, 3.3 mmol) in DMF (5 mL) was added 2-chloro-4-(chloromethyl)pyridine (210 mg, 1.3 mmol). The mixture was stirred at RT for 2 h, then diluted with H2O (30 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with H2O (20 mL) and concentrated under reduced pressure to afford the crude product, which was purified by silica gel chromatography (Petroleum ether:EA=1:3) to give the title compound as a light yellow solid (300 mg, 53.3%). MS (ES+) C19H13ClF3N5O2 requires: 435. found: 436 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1.C([BH3-])#N.[Na+]>C1COCC1.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)CC1
Temperature: 60 °C
Yield: 38.1 %

Procedure:
To a solution of 1-tert-butyloxycarbonylpiperazine (2.24 g, 12.0 mmol) in THF (20 ml) were added water (0.2 ml), cyclobutanone (1.35 ml, 18.1 mmol), acetic acid (2.20 ml) and sodium cyanoborohydride (18 ml of a 1M solution in THF, 18 mmol). The mixture was stirred at 60° C. over night, concentrated, and the residue was mixed with water (50 ml) and 1N aqueous hydrochloric acid (15 ml). The solution was washed with ethyl acetate (2×30 ml), made basic by addition of potassium carbonate, extracted (2×20 ml ethyl acetate), and the combined extracts were washed with brine, dried with magnesium sulphate, and concentrated. 1.1 g (38%) of the title compound was obtained as a colourless oil.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:20]=1[Cl:29])[C:10]([CH3:17])=[N:11]2.[OH-].[Na+]>CO>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:20]=1[Cl:29])=[C:8]2[CH3:30]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(S(C)(=O)=O)cc3Cl)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1Cc1ccc(S(C)(=O)=O)cc1Cl

Procedure:
A solution of [8-chloro-3-(2-chloro-4-methanesulfonylbenzyl)-2,4-dimethylquinolin-5-yloxy]acetic acid methyl ester (0.36 g), methanol (10 mL) and 1.0 M aqueous sodium hydroxide solution (4.0 mL) was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the pH of the residue adjusted to 5 by the addition of formic acid. Purification by preparative reverse-phase HPLC using a gradient of acetonitrile in water (50% to 65% of organic modifier) gave title compound as a white solid, 0.035 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28](OB(O)O)[CH:29]=[CH:30][CH:31]=1)=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:24]([O:23][CH3:22])=[O:25])[CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Clc1ccc(-c2ccc(OCC3CCCNC3)cc2)cc1
Product: COC(=O)c1cccc(N2CCCC(COc3ccc(-c4ccc(Cl)cc4)cc3)C2)c1
Yield: 58.2 %

Procedure:
Using 3-[(4′-chlorobiphenyl-4-yl)oxymethyl]piperidine (125 mg, 0.414 mmol) and 3-(methoxycarbonyl)phenylboric acid (149 mg, 0.828 mmol), the same procedure was followed as in Example 2 to give 105 mg (58%) of the desired compound as a colorless powder.
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][OH:4].CC([O:23]O)(C)C.CCOC(C)=O.CCCCCC>C(Cl)Cl.C1(C)C=CC=CC=1>[OH:4][CH2:3][C@@:2]1([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:1][O:23]1
Reactant: CC(C)(C)OO
Reactant: C=C(CO)CCCCCCCCCCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCC[C@]1(CO)CO1
Temperature: -20 °C
Reaction time: 0.58 h

Procedure:
A solution of Ti(O-t-Bu)4 (0.34 ml, 1.0 mmole) and (+)-DET (0.248 g, 1.2 mmole) in CH2Cl2 (10 ml) was prepared at room temperature. The solution was cooled to -20° C. in a CCl4 -Dry Ice bath and 2-methylenehexade-can-1-ol (22, 0.254 g, 1.0 mmole) was added. The mixture was allowed to warm slightly until the alcohol 22 completely dissolved after which the solution was cooled to -20° C. again. A solution of TBHP in toluene (0.6 ml of a 3.34M solution, 2.0 mmole) was added. The solution was stirred at -20° C. and after 2 hr TLC (30% acetonehexane, 30% EtOAc-hexane) showed some 22 remaining. The reaction was quenched after 4 hr by stirring with saturated aqueous Na2SO4 (1 ml) and ether (80 ml) for 35 min, filtering through Celite, and drying over MgSO 4. TLC now showed a main product, a minor product, several trace products and a trace of unreacted starting material. Chromatography, (11.5 g silica gel, 8% acetonehexane, 6 ml fractions) gave the desired major product (26b) in fractions 8-12, 0.140 g (0.518 mmole, 51%). 1H NMR identical to that of d,l-26.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]#[N:22])=[CH:16][N:15]=2)[C@H:11]([C:23]([O:25][CH3:26])=[O:24])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:28][OH:29].CCN(C(C)C)C(C)C>CCO.C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21](=[N:28][OH:29])[NH2:22])=[CH:16][N:15]=2)[C@H:11]([C:23]([O:25][CH3:26])=[O:24])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1c1ncc(C#N)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1c1ncc(C(N)=NO)cc1Cl
Yield: 101.4 %

Procedure:
A solution of methyl (2S,4R)-4-(tert-butyldimethylsilyloxy)-1-(3-chloro-5-cyanopyridin-2-yl)pyrrolidine-2-carboxylate (0.306 g; 0.77 mmol), hydroxylamine hydrochloride (0.064 g; 0.92 mmol) and DIEA (0.176 mL; 1.01 mmol) in EtOH/DCM (4 mL/2 mL) was stirred at ambient temperature for 96 hours. The solvent was evaporated in vacuo and the residue dissolved in DCM/water. The mixture was passed through a hydrophobic frit and the solvent evaporated in vacuo to afford the title product (0.335 g, 100%). 1H NMR (CDCl3, 400 MHz) δ 8.22 (1H, d, J=2 Hz), 7.76 (1H, d, J=1.6 Hz), 6.60 (1H, br s), 4.87-4.83 (1H, m), 4.73 (2H, br s), 4.54-4.53 (1H, m), 4.26-4.22 (1H, m), 3.75-3.67 (4H, m), 2.26-2.20 (1H, m), 2.09-2.02 (1H, m), 0.85 (9H, s), 0.05-0.08 (6H, m).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[S:9][CH:10]=[CH:11][C:4]=2[CH2:3]1.F[C:13]1[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=1>>[CH3:1][N:2]1[CH2:7][CH:6]([O:8][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:5]2[S:9][CH:10]=[CH:11][C:4]=2[CH2:3]1
Reactant: Fc1cccc(C(F)(F)F)c1
Reactant: CN1Cc2ccsc2C(O)C1
Product: CN1Cc2ccsc2C(Oc2cccc(C(F)(F)F)c2)C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 14) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-fluorobenzo trifluoride instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]([CH3:15])([CH3:14])[C:8]([O:10][CH2:11][CH2:12]Cl)=[O:9])=[CH:4][CH:3]=1.[C:18]([O-])(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21].[Na+]>CCOCC>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]([CH3:15])([CH3:14])[C:8]([O:10][CH2:11][CH2:12][O:26][CH2:18][C:19]2[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=2)[OH:21])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)OCCCl
Reactant: O=C([O-])c1ccccc1O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)OCCOCc1ccccc1O

Procedure:
50 g (0.18 mole) of 1-(2-p-chlorophenoxy-2-methylpropionyloxy)-2-chloro-ethane are mixed with 43.3 g (0.27 mole) of sodium salicylate. The mixture is heated to 195° for 8 hours. The products are taken up in ether, and NaCl is removed by filtration. The diester crystallizes quantitatively from the ether solution.
Reaction SMILES: I[C:2]1[C:3]([NH2:20])=[N:4][C:5]([S:18][CH3:19])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)#[CH:22].C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:29][C:26]1[N:27]=[CH:28][C:23]([C:21]#[C:22][C:2]2[C:3]([NH2:20])=[N:4][C:5]([S:18][CH3:19])=[N:6][C:7]=2[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:24][CH:25]=1
Reactant: CSc1nc(N)c(I)c(-c2cccc(C(F)(F)F)c2)n1
Reactant: C#Cc1ccc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nc(N)c(C#Cc2ccc(N)nc2)c(-c2cccc(C(F)(F)F)c2)n1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 850 mg (2.1 mmol) 5-iodo-2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ylamine, 1.5 g (12.4 mmol) 5-ethynyl-2-amino-pyridine, 39 mg (0.21 mmol) CuI, 145 mg (0.21 mmol) PdCl2(PPh3)2 and 2.9 mL triethylamine in 15 mL dry DMF. Yield after purification by RP-HPLC: 427 mg (52%).
Reaction SMILES: C([N:5]([CH2:9][CH:10](N)[CH3:11])[C:6](=[O:8])[OH:7])(C)(C)C.[CH:13]1[CH:14]=[CH:15][C:16]([NH:23][C:24]2[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=2[Cl:30])=[C:17]([CH2:19][C:20]([OH:22])=[O:21])[CH:18]=1.CCN=C=NCCCN(C)C.Cl.C(OCC)(=O)C>ClCCl.CN(C1C=CN=CC=1)C>[C:6]([N-:5][CH2:9][CH2:10][CH3:11])([O:7][C:17]([CH3:19])([CH3:18])[CH3:16])=[O:8].[CH:13]1[CH:14]=[CH:15][C:16]([NH:23][C:24]2[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:31])=[C:17]([CH2:19][C:20]([OH:22])=[O:21])[CH:18]=1
Reactant: CC(N)CN(C(=O)O)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC[N-]C(=O)OC(C)(C)C
Reaction time: 1.17 h

Procedure:
In 3 ml of dichloromethane, 338.4 mg (1.94 mmol) of tert-butyl N-(2-aminopropyl)carbamic acid (manufactured by Tokyo Kasei Kogyo) and 694.4 mg (2.34 mmol) of diclofenac were dissolved, and under ice-cooling, 59.0 mg (0.483 mmol) of DMAP and 505.3 mg (2.64 mmol) of WSCI.HCl were added thereto, followed by stirring for 70 minutes and then stirred at room temperature for 90 minutes. Ethyl acetate was added thereto, followed by separation by washing with 5% aqueous citric acid solution, 5% aqueous sodium hydrogen carbonate solution and saturated brine consecutively. After dehydration with sodium sulfate, ethyl acetate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 835.5 g (95%) of the titled compound. The structure was identified by 1H-NMR.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:3]1.O[N:30]=[C:31]([NH2:34])[CH2:32][CH3:33]>>[CH2:32]([C:31]1[N:34]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:4]3[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]3)=[O:8])[CH2:10]2)[O:28][N:30]=1)[CH3:33]
Reactant: CCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)C2)C1
Product: CCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)C3)C2)n1

Procedure:
200 mg (0.50 mmol) of the compound from Example 112A and 67 mg (0.75 mmol) of N′-hydroxypropanimidamide were reacted according to the General Method 2. Yield: 17 mg (7% of theory).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([NH:24][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nc1
Reactant: NN1CCOCC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN2CCOCC2)nc1
Yield: 49 %

Procedure:
As described for example 4c, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using N-aminomorpholine instead of N,N-dimethylhydrazine, to the title compound (62 mg, 49%) which was obtained as a light yellow oil. MS: m/e=395.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6]3[CH2:23][CH2:22][CH2:21][C:7]=3[CH:8]=2)[N:3]=1.[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH:21]1[C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=2[CH2:23][CH2:22]1)[N:3]=[C:2]([CH3:1])[N:11]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[C:10]3=[O:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)CCC3
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Br)CC3
Temperature: 0 °C

Procedure:
A mixture of 2-methyl-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]-quinazolin-4-one (50 g), N-bromosuccinimide (31.2 g), benzoyl peroxide (0.1 g) and carbon tetrachloride (500 ml) was stirred and heated to reflux for 90 minutes. The mixture was cooled to 0° C. The mixture was filtered and the filtrate was evaporated. The residue was triturated under diethyl ether (400 ml). The mixture was cooled to 0° C. The precipitate was isolated, washed with diethyl ether and dried. The solid so obtained was purified by column chromatography using a 1:1 mixture of hexane and ethyl acetate as eluant. There was thus obtained 6-bromo-2-methyl-3-pivaloyloxy-methyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (21 g), m.p. 98° C. (decomposes);
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:19][CH2:20][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>ClCCl>[C:21]1([CH:18]2[C:12]3[C:11]4=[C:16]([CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:8][CH2:9][N:10]4[CH2:20][CH2:19]2)[CH:15]=[C:14]([NH:17][C:36](=[O:37])[N:35]([CH3:39])[CH3:34])[CH:13]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
To a solution 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-amine (Intermediate 4), (106 mg, 0.31 mmol) in dichloromethane (10 mL) was added triethyl amine (0.130 mL, 0.933 mmol) followed by dimethylcarbamic chloride (0.043 mL, 0.46 mmol), under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The mixture was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 10 to 15% EtOAc:Hexane to give 3-(1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)-1,1-dimethylurea, (405), (63 mg 49%). 1H NMR (300 MHz, CDCl3) ppm 2.01-2.16 (m, 2H) 2.20-2.37 (m, 2H) 2.85 (s, 6H) 3.00-3.15 (m, 4H) 4.12-4.25 (m, 2H) 5.78 (s, 1H) 6.62 (s, 2H) 7.10-7.22 (m, 5H) 7.23-7.34 (m, 5H)