Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[C:6]1[CH3:30].O1CCCC1.[OH-].[Na+].Cl>CO>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:31])=[O:2])[C:6]([CH3:30])=[C:7]2[CH2:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[S:21]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22]
Reactant: COC(=O)Cn1c(C)c(Cc2ccsc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cc2ccsc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A mixture of [5-fluoro-3-(2-benzenesulfonylthiophen-3-ylmethyl)-2-methylindol-1-yl]acetic acid methyl ester (0.18 g), tetrahydrofuran (4.0 mL) and methanol (2.0 mL) was treated with 1.0 M aqueous sodium hydroxide solution (2.0 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid solution and concentrated to low bulk under reduced pressure. The resulting precipitate was collected by filtration, washed with water and dried to afford the title compound as a white solid (0.16 g).
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:51][CH2:52][CH2:53][OH:54]>O1CCCC1.C(#N)C>[OH:54][CH2:53][CH2:52][NH:51][C:18](=[O:20])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[N:16][CH2:15]1
Reactant: NCCO
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(c1cccc2cc(C3=NCC(CC(=O)NCCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a solution of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (200 mg), 1H-1,2,3-benzotriazol-1-ol (150 mg) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (190 mg) in tetrahydrofuran (3 mL) and acetonitrile (3 mL) was added 2-aminoethanol (100 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (124 mg, yield 56%) as white crystals from a fraction eluted with ethyl acetate:hexane=50:50. melting point 214° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[CH:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:16]1[S:17][CH:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:20]=1>CN(C=O)C.C(N(CC)CC)C.C(OCC)(=O)C.[Cu](I)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>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]#[C:14][C:16]2[S:17][CH:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:20]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: C#Cc1cc(OC)c(OC)c(OC)c1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(C#Cc2cc(OC)c(OC)c(OC)c2)n1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
3,4,5-Trimethoxyphenylacetylene (1.34 g), ethyl 2-bromothiazole-4-carboxylate (1.98 g) and copper iodide (53 mg) were dissolved in a mixed solvent of DMF (3 mL) and triethylamine (6 mL), and to the solution dichlorobis-(triphenylphosphine)palladium (II) (99 mg) was added, and the mixture was stirred at 45° C. for 4 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed with 2 M hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate. After concentrating the reaction mixture under reduced pressure, the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1 to 3:1) to obtain the title compound.
Reaction SMILES: [CH:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].C([Li])CCC.C(C([O:19][N+:20]([O-])=[O:21])=O)(F)(F)F>O1CCCC1.[N+]([O-])([O-])=O.[K+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[N+:20]([O-:21])=[O:19])=[O:2]
Reactant: O=C(O[N+](=O)[O-])C(F)(F)F
Reactant: O=Cn1ccnc1
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: O=Cn1ccnc1[N+](=O)[O-]
Reaction time: 0.03 h
Yield: 62 %

Procedure:
1-formyl-imidazole (about 0.100 grams) was dissolved in 1 mL of tetrahydrofuran at room temperature. Immediately, 1 equivalent (eq.) of n-butyl lithium in about 1.6 M (molar) hexanes was added to the reaction mixture, followed by 1.2 eq. of freshly prepared 1:1 molar mixture of potassium nitrate (KNO3) and trifluoroacetic anhydride (TFAA) in tetrahydrofuran as solvent at about 0° C. to about 4° C. The active nitrating species (CF3C(O)ONO2), thus, was generated in situ and the reaction mixture was stirred further for about 1.5 minutes. The 1-formyl-2-nitro-1H-imidazole product was isolated and purified by flash column chromatography to yield the pure product (i.e., about 95% purity) in about 62% yield. The structure of the 1-formyl-2-nitro-1H-imidazole product was confirmed by 1H NMR spectroscopy. 1H NMR (CDCl3): δ 2.8 (s, 3H), 7.20 (d, 1H), 7.74 (d, 1H).
Reaction SMILES: C([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]([C:25]([OH:27])=O)=[C:17]2[CH2:28][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:30](=[O:31])[C:16]=12)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:40][C:41]1[S:42][CH:43]=[CH:44][N:45]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[S:42]1[CH:43]=[CH:44][N:45]=[C:41]1[NH:40][C:25]([C:18]1[C:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:24]=2[C:15]([OH:14])=[C:16]2[C:30](=[O:31])[N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:28][C:17]=12)=[O:27]
Reactant: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.6 %

Procedure:
9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 (0.02 g, 0.0386 mmol) was dissolved in 0.3 mL of dimethylformamide. To this was added 2-aminothiazole (0.0077 mL, 0.0772 mmol), diisopropylethylamine (0.027 mL, 0.1544 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at room temperature. After 15 hours, starting material was consumed. Purified by reverse phase HPLC (0.1% TFA, H2O/ACN) to give 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid thiazol-2-ylamide 319 (0.01 g, 0.023 mmol, 60%.) 1H NMR (CDCl3) δ 9.02 (dd, 1H), 8.61 (d, 1H), 7.65 (dd, 1H), 7.55 (d, 1H), 7.38 (dd, 2H), 7.21 (d, 1H), 7.07 (dd, 2H), 4.78 (s, 2H), 4.67 (s, 2H.) MS: 435 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([CH3:19])[CH:11]=2)=[N:8][N:9]=1)([CH3:4])[CH3:3]>[Zn].CN(C)C=O.O>[CH3:4][C:2]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([CH3:19])[CH:11]=2)=[N:8][N:9]=1)([CH3:1])[CH3:3]
Reactant: Cc1cc(-c2nnc(C(C)(C)C)o2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2nnc(C(C)(C)C)o2)ccc1N
Temperature: 100 °C

Procedure:
A mixture of 2-(1,1-dimethylethyl)-5-(3-methyl-4-nitrophenyl)-1,3,4-oxadiazole (1.6 g), FeCl3.6H2O (5 g) and zinc powder (4 g) in a dimethylformamide/water mixture (1/1, 25 ml) is heated at 100° C. for 30 minutes and then filtered through Celite. After dilution with saturated aqueous sodium carbonate solution, the reaction mixture is extracted with diethyl ether. Drying over magnesium sulphate and evaporation of the organic phase gives the title aniline.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=2)=[CH:16][C:15]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:28][CH2:27]2)=[CH:14][N:13]=1.[NH2:36][C:37]1[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1.C1COCC1>>[CH3:44][O:43][C:40]1[N:39]=[CH:38][C:37]([NH:36][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=3)=[CH:16][C:15]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:28][CH2:27]3)=[CH:14][N:13]=2)=[CH:42][CH:41]=1
Reactant: COc1ccc(N)cn1
Reactant: Cc1ncnc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2ncnc(C)n2)cn1
Reaction time: 1 h
Yield: 17.1 %

Procedure:
LiHMDS (1.0 M in THF, 557 μL, 0.557 mmol) was added to a stirred solution of 2-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-4-methyl-1,3,5-triazine (68.0 mg, 0.186 mmol) and 3-amino-6-methoxypyridine (Aldrich) (34.6 mg, 0.278 mmol) in THF (928 μL, 0.186 mmol) at 0° C. and the mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with water (10 mL) and diluted with ethyl acetate (10 mL). The separated aqueous layer was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (DCM to 5% MeOH in DCM) followed by washing with iPrOH to give N-(6-methoxypyridin-3-yl)-3-(4-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-amine (15 mg, 17%) as a yellow solid. LCMS (API-ES) m/z 471 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 11.44 (s, 1H) 9.29 (s, 1H) 8.81 (s, 1H) 8.51 (br. s., 1H) 8.29 (br. s., 1H) 8.11 (d, J=9.19 Hz, 1H) 6.85 (d, J=9.19 Hz, 1H) 3.85 (s, 3H) 3.53 (s, 2H) 3.11 (br. s., 4H) 2.87 (s, 3H) 2.75 (s, 3H) 2.34-2.49 (m, 4H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12](=[O:18])[CH2:13][NH:14][CH2:15][CH2:16][OH:17])([CH3:10])([CH3:9])[CH3:8].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O1CCOCC1.O>[C:7]([O:11][C:12](=[O:18])[CH2:13][N:14]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:15][CH2:16][OH:17])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)CN(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Potassium carbonate (33.0 g; 0.19 mol) is added to a solution of the product from Example 4 (32.15 g; 0.18 mol) in dioxane (1.0 l) and water (0.5 l). A solution of benzyl chloroformate (27.3 ml; 0.19 mol) in dioxane (0.2 l) is slowly added dropwise at room temperature. The solution is stirred at room temperature for 3.5 h and subsequently concentrated. The residue is taken up in dichloromethane (3.0 l) and extracted by shaking with water (1.0 l). The aqueous phase is re-extracted five times with dichloromethane. The organic phases are combined, dried (magnesium sulphate) and concentrated. Yield: 24.47 g (43%), pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3ccccn3)ccc12
Yield: 1.8 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (153 mg, 0.590 mmol), 2-(aminomethyl)pyridine (0.066 mL, 0.646 mmol), Pd2(dba)3 (49 mg, 0.0535 mmol), rac-BINAP (113 mg, 0.181 mmol) and NaOtBu (160 mg, 1.665 mmol) in DMA (5 mL) was heated at 85° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-[(pyridin-2-ylmethyl)-amino]-2H-phthalazin-1-one (3 mg) as a yellow brown solid, 1H (400 MHz, d6-DMSO) δ: 4.53 (d, 2H), 6.84 (s, 1H), 7.18 (dd, 1H), 7.28 (m, 1H), 7.38 (d, 1H), 7.75 2H), 7.92 (d, 1H), 8.55 (d, 1H), 12.35 (s, 1H) ppm; m/z (M+1) 286.99.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:16](=[O:19])[NH:17][CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.[ClH:21].O1CCOCC1>>[ClH:21].[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]([NH:17][CH3:18])=[O:19]
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)[C@@H](N)Cc1ccccc1

Procedure:
[((1S)-1-Methylcarbamoyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (2.35 g, 8.45 mmol) was dissolved in 4 M HCl-dioxane (20 ml) at 25° C. for 2 hours. The mixture was concentrated and the residue triturated with ether, and dried. Yield 1.70 g, 94%.
Reaction SMILES: [C:1]1([OH:8])[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[N:9]([CH2:12][CH3:13])=[C:10]=[O:11].C(N(CC)CC)C>O1CCOCC1>[OH:7][C:4]1[CH:5]=[CH:6][C:1]([O:8][C:10](=[O:11])[NH:9][CH2:12][CH3:13])=[CH:2][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCN=C=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCNC(=O)Oc1ccc(O)cc1

Procedure:
Benzene-1,4-diol Compound 25a was reacted with isocyanato-ethane and a catalytic amount of triethylamine in 1,4-dioxane at room temperature to provide ethyl-carbamic acid 4-hydroxy-phenyl ester Compound 25b.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10].[C:17]([C:19]([OH:26])([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])#[CH:18]>>[F:10][C:9]([F:12])([F:11])[C:8]([NH:7][CH2:6][CH2:5][C:4]1[CH:14]=[CH:15][CH:16]=[C:2]([C:18]#[C:17][C:19]([OH:26])([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH:3]=1)=[O:13]
Reactant: C#CC(O)(CCC)CCC
Reactant: O=C(NCCc1cccc(Br)c1)C(F)(F)F
Product: CCCC(O)(C#Cc1cccc(CCNC(=O)C(F)(F)F)c1)CCC
Reaction time: 17 h

Procedure:
N-(3-Bromophenethyl)-2,2,2-trifluoroacetamide was coupled with alkynol 20 following the procedure described in Example 18 except that the reaction was run for 17 h to give 2,2,2-trifluoro-N-(3-(3-hydroxy-3-propylhex-1-ynyl)phenethyl)-acetamide as a brown oil after purification by flash chromatography (10% to 50% EtOAc in hexanes gradient). Yield (0.975 g, 66%). 1H NMR (400 MHz, CDCl3) δ 7.32 (dt, J=7.8, 1.2 Hz, 1H), 7.24-7.29 (m, 2H), 7.10-7.15 (m, 1H), 6.27 (br.s, 1H), 3.61 (q, J=6.7 Hz, 2H), 2.86 (t, J=7.0 Hz, 2H), 1.95 (s, 1H), 1.66-1.74 (m, 4H), 1.52-1.64 (m, 4H), 0.99 (t, J=7.2 Hz, 6H).
Reaction SMILES: Br[CH2:2][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)([F:5])[F:4].[N-:13]=[N+:14]=[N-:15].[Na+]>CS(C)=O>[N:13]([CH2:2][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)([F:5])[F:4])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cccc(C(F)(F)CBr)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC(F)(F)c1cccc(F)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a solution of 14 (2.4 g, 10 mmol) in anhydrous DMSO (15 mL) was added NaN3 (1.0 g, 15.7 mmol). The reaction solution turned purple upon heating. After being stirred at 110° C. for 8 h, the reaction mixture was cooled to room temperature and partitioned between EtOAc (300 mL) and H2O (200 mL). The organic layer was washed with H2O (200 mL), brine (200 mL), and dried over Na2SO4. The solvents were removed by rotary evaporation. The crude product was purified by flash column chromatography (EtOAc/hexanes, 1:9) to yield azide 15 (1.7 g, 88%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 3.60-3.75 (m, 2H), 7.00-7.15 (m, 2H), 7.15-7.35 (m, 1H), 7.40-7.60 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 55.8, 56.1, 56.4, 112.95, 113.01, 113.06, 113.14, 113.19, 113.25, 117.89, 117.90, 118.06, 118.07, 118.08, 119.78, 119.81, 121.25, 121.28, 121.30, 121.33, 121.35, 121.38, 130.8, 130.9, 136.7, 161.9, 163.9; GC-MS calcd for C8H6F3N3 201. found 201. 2,2-Fifluoro-2-(3-fluorophenyl)ethanamine (4d). To a solution of 15 (2.0 g, 10.0 mmol) in EtOH (30 mL) was added 1 N HCl (15 mL) and Pd(OH)2/C (20%, 200 mg). The reaction mixture was allowed to stir under one atmosphere of H2 for 24 h. The catalyst was removed by filtration and the solvent was evaporated. The resulting yellowish solid was partitioned between diethyl ether (200 mL) and 1 N HCl (200 mL). The aqueous layer was washed with diethyl ether (200 mL) then concentrated to yield amine 4d as a white solid (1.6 g, 91%): 1H NMR (500 MHz, D2O) δ 3.60-4.66 (t, J=15.0 Hz, 2H), 7.17-7.30 (m, 3H), 7.40-7.45 (m, 1H); 13C NMR (125 MHz, D2O) δ 44.6, 44.8, 45.0, 112.6, 112.8, 118.5, 118.7, 121.3, 131.4, 131.5, 161.6, 163.6; LCQ-MS (M+H+) calcd for C8H9F3N 176. found 176; LC-TOF (M+H+) calcd for C8H9F3N 176.06816. found 176.06843.
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:39])[C:5](=O)[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=1.[NH3:40]>C(O)C>[NH2:40][C:5]1[C:4](=[O:39])[C:3](=[O:2])[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[NH:15][CH2:16][CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:9]=1
Reactant: N
Reactant: COc1ccc(C(NCC(c2ccccc2)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Solvent: CCO
Product: COc1ccc(C(NCC(c2ccccc2)c2ccccc2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1

Procedure:
In a similar manner to that described in Example (1d), 3-methoxy-4-{3-[(4-methoxyphenyl)-(2,2-diphenylethylamino)methyl]phenylamino}-3-cyclobutene-1,2-dione (1.35 g) [prepared as described in step (c) above] and a solution of ammonia in ethanol (2N, 5.2 ml) were reacted, to give the title compound (1.36 g) as a pale yellow solid.
Reaction SMILES: NC1C=CC=CC=1.CC/C=C\C/C=C\C/C=C\CCCCCCCC(O)=[O:26].ClC(Cl)=C(Cl)Cl.[C:34]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:36])[CH3:35]>C(O)CCC>[C:34]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:36])[CH2:35][OH:26]
Reactant: CCCCOC(C)=O
Reactant: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Solvent: ClC(Cl)=C(Cl)Cl
Solvent: Nc1ccccc1
Solvent: CCCCO
Product: CCCCOC(=O)CO
Temperature: 100 °C
Reaction time: 3 h

Procedure:
87.7 parts of an epoxide obtained from 2,2-bis-(4'-hydroxyphenyl)-propane and epichlorohydrin (0.05 epoxy group equivalent, the epoxide containing 0.57 epoxy group equivalent/kg) are dissolved in 27.5 parts of butyl acetate and 5 parts of n-butanol. 2.3 parts of aniline (0.025 mol) and 7.25 parts of a technical mixture of about 75% of C36 dimerised acid and about 25% of C54 trimerised acid, based on linoleic acid and linolenic acid (0.025 acid equivalent, the mixture containing 3.45 acid equivalents/kg) are added to this solution. The reaction mixture is heated to 100° C. and kept at this temperature for 3 hours. Dilution with 65.5 parts of perchloroethylene and 47.8 parts of butyl glycolate gives a clear, viscous solution of the reaction product, the solution having a solids content of 40% and an acid number of 17.
Reaction SMILES: [CH:1]1([C:4]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:18](Br)=[CH:17][N:16]=2)=[O:14])([C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH3:5])[CH2:3][CH2:2]1.Cl.[F:29][C:30]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31]1>>[CH:1]1([C:4]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:18]([N:32]3[CH2:33][CH2:34][C:30]([F:35])([F:29])[CH2:31]3)=[CH:17][N:16]=2)=[O:14])([C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(Br)cn2)C2CC2)no1
Reactant: FC1(F)CCNC1
Agent: Cl
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(N3CCC(F)(F)C3)cn2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 78h, using 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 78g) and 3,3-difluoropyrrolidine hydrochloride (CAN 163457-23-6) as starting materials and isolated (17 mg, 32%) as a white solid; MS (ESI, m/z): 476.4 (M+H+).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:34]=[CH:33][CH:32]=[CH:31][C:4]=1[C:5]([C:7]1[N:8]([CH2:12][CH:13]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:14][CH2:15][O:16]C2CCCCO2)[CH:9]=[CH:10][N:11]=1)=[O:6].Cl>CO>[Cl:30][C:25]1[CH:24]=[C:23]([CH:13]([CH2:12][N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[C:5](=[O:6])[C:4]2[CH:31]=[CH:32][CH:33]=[CH:34][C:3]=2[C:2]([F:1])([F:35])[F:36])[CH2:14][CH2:15][OH:16])[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: O=C(c1ccccc1C(F)(F)F)c1nccn1CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CO
Product: O=C(c1ccccc1C(F)(F)F)c1nccn1CC(CCO)c1ccc(Cl)c(Cl)c1
Reaction time: 4 h
Yield: 71.4 %

Procedure:
1-[2-(2-Trifluoromethylbenzoyl)imidazol-1-yl]-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butane (0.68 g) (see Preparation 59) was dissolved in methanol (15 ml), which had been previously saturated with hydrogen chloride gas, and left to stand for 4 hours. The solvent was then removed under reduced pressure to give a residue which was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate solution (the pH of the aqueous layer was kept at 8-9). The organic phase was separated and the aqueous phase extracted (twice) with dichloromethane. The organic phases were then combined, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give 3-(3,4-dichlorophenyl)-4-[2-(2-trifluoromethylbenzoyl)imidazol-1-yl]butan-1-ol (0.41 g) as a white foam.
Reaction SMILES: CC1N=C(C2C=CC([CH:13]3[O:19][CH2:18][CH2:17][N:16]([C:20]4[N:25]([CH3:26])[C:24](=[O:27])[CH:23]=[C:22]([C:28]5[CH:33]=[CH:32][N:31]=[CH:30][N:29]=5)[N:21]=4)[CH2:15][CH2:14]3)=CC=2)ON=1.Cl.[O:35]1[C:39]([C:40]2[CH:45]=[CH:44][C:43](C3COCCNC3)=[CH:42][CH:41]=2)=[N:38][CH:37]=[N:36]1>>[CH3:26][N:25]1[C:24](=[O:27])[CH:23]=[C:22]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][N:29]=2)[N:21]=[C:20]1[N:16]1[CH2:15][CH:14]([C:43]2[CH:42]=[CH:41][C:40]([C:39]3[O:35][N:36]=[CH:37][N:38]=3)=[CH:45][CH:44]=2)[CH2:13][O:19][CH2:18][CH2:17]1
Reactant: c1noc(-c2ccc(C3CNCCOC3)cc2)n1
Reactant: Cc1noc(-c2ccc(C3CCN(c4nc(-c5ccncn5)cc(=O)n4C)CCO3)cc2)n1
Agent: Cl
Product: Cn1c(N2CCOCC(c3ccc(-c4ncno4)cc3)C2)nc(-c2ccncn2)cc1=O

Procedure:
1-Methyl-2-[6-(4-[1,2,4]oxadiazol-5-yl-phenyl)-[1,4]oxazepan-4-yl]-1H-[4,4′]bipyrimidinyl-6-one was prepared by the same procedure as that of 2-{7-[4-(3-Methyl-[1,2,4]-oxadiazole-5-yl)phenyl]-[1,4]-oxazepane-4-yl}-3-methyl-6-pyrimidin-4-yl-3H-pyrimidin-4-one except for utilizing 6-(4-[1,2,4]Oxadiazol-5-yl-phenyl)-[1,4]oxazepane hydrochloride instead of 7-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-[1,4]oxazepane hydrochloride. 1-Methyl-2-[6-(4-[1,2,4]oxadiazol-5-yl-phenyl)-[1,4]oxazepan-4-yl]-1H-[4,4′]bipyrimidinyl-6-one (A080) was obtained as white solid (0.02 g, 0.04 mmol, 50%).