Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:3]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([N:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH2:33][CH2:32]2)[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][C:2]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([N:31]3[CH2:32][CH2:33][N:34]([C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])[CH2:35][CH2:36]3)[CH:26]=2)[N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[N:8]=2)[N:3]=1.[CH3:1][C:2]1[N:3]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[N:8]=2)[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([N:31]3[CH2:32][CH2:33][N:34]([C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])[CH2:35][CH2:36]3)[CH:26]=2)[N:6]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2cc(CCl)ccn2)CC1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n(Cc2ccnc(N3CCN(C(=O)OCc4ccccc4)CC3)c2)n1
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccnc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %
Yield: 8 %

Procedure:
To a solution of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (311 mg, 1.0 mmol) and benzyl 4-(4-(chloromethyl)pyridin-2-yl)piperazine-1-carboxylate (690 mg, 2.0 mmol) in DMF (15 mL), Cs2CO3 (820 mg, 2.5 mmol) was added at RT. The mixture was stirred at RT overnight, then diluted with H2O (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=1:2) to give benzyl 4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazine-1-carboxylate (350 mg, 56%) as a yellow oil and benzyl 4-(4-((3-methyl-5-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazine-1-carboxylate as a white solid (50 mg, 8%). MS (ES+) C30H27F3N8O4 requires: 620. found: 621[M+H]+.
Reaction SMILES: [CH2:1]([Li])CCC.[NH2:6][C:7]1[N:8]=[C:9]([CH:30]=[CH2:31])[C:10]([C:20]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:21]=2[CH:22]=O)=[N:11][C:12]=1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[NH2:6][C:7]1[C:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:11][C:10]([C:20]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:21]=2[CH:22]=[CH2:1])=[C:9]([CH:30]=[CH2:31])[N:8]=1
Reactant: C=Cc1nc(N)c(Cc2ccccc2)nc1-c1ccc(OC)cc1C=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(OC)ccc1-c1nc(Cc2ccccc2)c(N)nc1C=C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
Under an argon atmosphere, to a suspension of methyltriphenylphosphonium bromide (1.29 g, 3.61 mmol) in anhydrous THF (5 mL) was gradually dropwise added n-butyl lithium (1.65 M in n-hexane) (1.70 mL, 2.81 mmol) at 0° C. The mixture was stirred at 0° C. for 15 minutes as it was. To the mixture was added 2-(5-amino-6-benzyl-3-vinylpyrazin-2-yl)-5-methoxybenzaldehyde (8) (871 mg, 2.52 mmol) at 0° C. After elevating to room temperature, stirring was continued for 1.5 hours. After to this was added water, the product was extracted with ethyl acetate (×3). The combined organic extract was washed successively with water (×1) and brine (×1), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=3/1) to give 2-amino-3-benzyl-5-(4-methoxy-2-vinylphenyl)-6-vinylpyrazine (9) (570 mg, 1.66 mmol, 65.8%) as a white solid. TLC Rf=0.37 (n-hexane/ethyl acetate=3/1); 1H NMR (500 MHz, CDCl3) δ 3.88 (s, 3H), 4.16 (s, 2H), 4.39 (s, 2H), 5.18 (dd, 1H, J=1.0, 10.5 Hz), 5.30 (dd, 1H, J=2.0, 10.5 Hz), 5.67 (dd, 1H, J=1.0, 17.5 Hz), 6.25 (dd, 1H, J=2.0, 17.5 Hz), 6.47 (dd, 1H, J=10.5, 17.5 Hz), 6.50 (dd, 1H, J=10.5, 17.5 Hz), 6.90 (dd, 1H, J=2.5, 8.0 Hz), 7.20-7.26 (m, 5H), 7.29-7.35 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 41.2, 55.6, 110.5, 113.8, 115.4, 119.3, 127.2, 128.7 (2C), 129.2 (2C), 129.8, 132.1, 133.0, 135.1, 137.0, 138.3, 140.3, 141.9, 144.8, 151.4, 159.8.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[CH3:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: COCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
Triethylamine (2.91 g, 28.86 mmol) was added to the stirred solution of 4-methoxy-1-butanol (1.00 g, 9.62 mmol) in dichloromethane (15 mL) at 0° C. and stirred for 15 min. p-Toluene sulfonyl chloride (1.83 g, 9.62 mmol) was added and the mixture was warmed to ambient temperature and stirred for 2 h. The reaction mixture was quenched with ice-water and the organic layer was separated. The aqueous layer was extracted with dichloromethane (3×5 mL) and the combined organic layers were washed with saturated sodium bicarbonate, water, and brine; dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product was purified by column chromatography over silica gel (60-120 mesh) with 0% to 20% ethyl acetate in petroleum ether as eluent to afford 4-methoxybutyl-4-methylbenzenesulfonate (800 mg, 32%) as a liquid.
Reaction SMILES: [CH:1]([OH:14])([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>O1CCCC1.ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:14][CH:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C1=COCCC1
Reactant: CCCCCCCCCCCC(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(O)OC1CCCCO1
Temperature: 25 °C
Yield: 25 %

Procedure:
Dodecanediol (23.000 g) was dissolved in 230 ml of dry tetrahydrofuran and 40 ml of dichloromethane, and 10 mg of p-toluenesulfonic acid and 9,578 g of dihydropyran were added thereto. The mixture was stirred at room temperature for a day. Triethylamine (1.0 ml) was added thereto to stop the reaction and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 8.132 g of dodecanediol monotetrahydropyranyl ether.
Reaction SMILES: [CH2:1]([C:8]1([C:23]([O-])=O)[C:12](=[O:13])[N:11]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:10](=[O:22])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[Cl:27][C:28]1[CH:29]=[C:30]([NH2:35])[C:31]([NH2:34])=[CH:32][CH:33]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C@:8]1([C:23]2[NH:35][C:30]3[CH:29]=[C:28]([Cl:27])[CH:33]=[CH:32][C:31]=3[N:34]=2)[NH:9][C:10](=[O:22])[N:11]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:12]1=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: C[C@H](c1ccccc1)N1C(=O)NC(Cc2ccccc2)(C(=O)[O-])C1=O
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](c1ccccc1)N1C(=O)N[C@](Cc2ccccc2)(c2nc3ccc(Cl)cc3[nH]2)C1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To the product from Step D (200 mg, 0.581 mmol), 4-chlorobenzene-1,2-diamine (91 mg, 0.639 mmol) in N,N-dimethylformamide (2.5 ml) was added N,N-diisopropylethylamine (0.152 mL, 0.871 mmol) and O-(7-azabensotriazol-1yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (265 mg, 0.697 mmol) sequentially. The reaction mixture was stirred for 16 h, diluted with ethyl acetate (50 mL), washed with water (2×10 mL), saturated aqueous brine (1×10 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo. LC/MS 463.0 (M+1). The crude residue was dissolved in acetic acid (5 ml) and heated at 80° C. for 1 h. The mixture was cooled and the solvent removed in vacuo. The residue was purified by column chromatography (silica gel 40 g column) eluting with ethyl acetate/hexane (gradient from 0% to 100%) to give a mixture of diastereomers as a brown amorphous solid. The isomers were separated via chiral HPLC (ChiralPak AS-H; 40% 2:1 methanol:acetonitrile/carbon dioxide) to afford the first eluting isomer (5R)-5-benzyl-5-(6-chloro-1H-benzimidazol-2-yl)-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione (1.9 minutes) and the second eluting isomer (5S)-5-benzyl-5-(6-chloro-1H-benzimidazol-2-yl)-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione (2.97 minutes) as colorless amorphous solids. LC/MS 445.0 (M+1). IC50 value=C rating
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.I[C:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=2)[N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:18]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:17]3[C:25]4[C:20](=[CH:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=4)[N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:18]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: C=Cc1ccc(N2CCN(C)CC2)nc1
Product: CN1CCN(c2ccc(/C=C/c3nn(COCC[Si](C)(C)C)c4cc(C=O)ccc34)cn2)CC1
Temperature: 90 °C

Procedure:
The title compound was synthesized according to the method of Example A15A, utilizing 1-methyl-4-(5-vinylpyridin-2-yl)piperazine (65 mg, 0.32 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (100 mg, 0.25 mmol), with heating in a sealed tube at 90° C. overnight instead of with microwave irradiation. Purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound to as a pale orange material (46 mg, 39%). 1H NMR (400 MHz, CD3OD) δ ppm 10.14 (s, 1 H), 8.34 (d, J=2.26 Hz, 1.0H), 8.24-8.28 (m, 2H), 8.00 (dd, J=8.91, 2.38 Hz, 1H), 7.80 (d, J=8.78 Hz, 1H), 7.51 (d, J=16.56 Hz, 1H), 7.36 (d, J=16.56 Hz, 1H), 6.97 (d, J=9.29 Hz, 1H), 5.85 (s, 2H), 3.77-3.87 (m, 4H), 3.63 (t, J=7.91 Hz, 2H), 3.06-3.15 (m, 4H), 2.75 (s, 3H), 0.88 (t, J=8.03 Hz, 2H), −0.09 (s, 9H); MS ESI 478.3 [M+H]+, calcd for [C26H35N5O2Si+H]+ 478.7.
Reaction SMILES: O1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH:8]1([NH2:11])[CH2:10][CH2:9]1>CN(C)C=O>[CH:8]1([N:11]2[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]2)[CH2:10][CH2:9]1
Reactant: O=c1ccocc1
Reactant: NC1CC1
Solvent: CN(C)C=O
Product: O=c1ccn(C2CC2)cc1
Temperature: 100 °C
Yield: 158 %

Procedure:
990 mg of 4H-pyran-4-on and 1.5 g of cyclopropylamine were dissolved in 15 ml of N,N-dimethylformamide, and reacted by heating in a sealed tube at 100° C. for 6 hours. The reaction mixture was concentrated to dryness, dissolved in 80 ml of chloroform and washed with 40 ml of water. The chloroform layer was concentrated to obtain 2.2 g of 1-cyclopropyl-4-pyridone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[NH:17][CH:16]=[CH:15]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[N:17]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH:16]=[CH:15]2
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1[nH]ccc2cc(F)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc3cc(F)ccc3c2=O)cc1
Reaction time: 2 h

Procedure:
169 μL of p-methoxybenzylchloride were added to a suspension of 200 mg of 6-fluoro-isoquinolinone (8) and 368 mg (1.36 mmol, 1.2 eq) of Cs2CO3 in 3 mL of DMF. The mixture was stirred for 2 h and then poured on ice. The precipitate was filtered, washed with water and dried to yield 300 mg of the title compound. Rt=1.76 min (Method B). Detected mass: 284.14 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].C(N(CC)CC)C>CCOCC>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[Cl:20]
Reactant: COC(=O)CCCCCCCNc1cccc(Cl)c1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CCCCCCCN(C(=O)c1ccccc1Cl)c1cccc(Cl)c1

Procedure:
As described in example 3(b), the reaction is carried out with 10 g (35 mmol) of 8-(3-chlorophenylamino)-caprylic acid methyl ester, 6.2 g (35 mmol) of 2-chlorobenzoic acid chloride, 3.9 g (39 mmol) of triethylamine and 100 cc. of ether. Reaction time: 24 hours, reaction temperature: 25° C. The crude product is further purified chromatographically on silicic acid gel using chloroform as eluant.
Reaction SMILES: C([BH3-])#N.[Na+].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH2:16][N:17]1[C:28](=[O:29])[C@@H:27]([NH:30][C:31](=[O:35])[C@@H:32]([NH2:34])[CH3:33])[C:21]3([CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[O:20][C:19]3[CH:36]=[CH:37][CH:38]=[CH:39][C:18]1=3)=[C:11]([O:40][CH3:41])[CH:10]=[CH:9]2.[CH2:42]1OC(O)C[O:44][CH:43]1O.C(O)(=O)C>CO.Cl.O>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH2:16][N:17]1[C:28](=[O:29])[C@@H:27]([NH:30][C:31](=[O:35])[C@@H:32]([NH:34][CH2:42][CH2:43][OH:44])[CH3:33])[C:21]3([CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[O:20][C:19]3[CH:36]=[CH:37][CH:38]=[CH:39][C:18]1=3)=[C:11]([O:40][CH3:41])[CH:10]=[CH:9]2
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N)C2(CCOCC2)Oc2ccccc21
Reactant: OC1COC(O)CO1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)NCCO)C2(CCOCC2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 163.3 %

Procedure:
Sodium cyanoborohydride (5.14 mg, 81.8 μmol, Eq: 1.50) was added to a solution of (S)-N-((S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-yl)-2-amino-propanamide (31 mg, 54.5 μmol, Eq: 1.00), glycolaldehyde dimer (3.6 mg, 30.0 μmol, Eq: 0.55) and acetic acid (3.27 mg, 3.15 μl, 54.5 μmol, Eq: 1.00) in MeOH (1 mL) and the mixture was stirred at RT overnight. The mixture was diluted with 1 N HCl and H2O/1 N NaOH was added to adjust the pH to ˜8-9. The mixture was extracted with EtOAc, the combined extracts were washed with brine, dried over Na2SO4 and concentrated. The resulting material was purified by flash chromatography to afford the title compound (30 mg, 90% yield). MS m/z 613.8 (MH+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[CH3:14][C:15]1[C:16]([NH2:30])=[N:17][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH2:29])[CH:27]=3)[O:22][CH2:21][CH2:20]2)[N:19]=1>>[NH2:30][C:16]1[C:15]([CH3:14])=[N:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH:29][C:9](=[O:11])[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:8][N:7]=4)[CH:27]=3)[O:22][CH2:21][CH2:20]2)[N:17]=1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Product: CC1=NC2(CCOc3ccc(NC(=O)c4ccc(C(F)(F)F)cn4)cc32)N=C1N
Yield: 47.4 %

Procedure:
The title compound (44 mg, 46% yield) was prepared as described for Example 13a starting from 5-(trifluoromethyl)picolinic acid (45 mg, 0.23 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 54 mg, 0.23 mmol): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85-1.98 (m, 2H), 2.24 (s, 3H), 4.30-4.50 (m, 2H), 6.56 (s, 2H), 6.81 (d, 1H), 7.02-7.10 (m, 1H), 7.62-7.71 (m, 1H), 8.28 (d, 1H), 8.46 (dd, 1H), 9.01-9.10 (m, 1H), 10.57 (s, 1H); MS (APCI+) m/z 404 [M+H]+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:28][C:15]=1[O:16][C:17]1[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=1.[C:46]([O:50][CH3:51])(=[O:49])[CH2:47]O.CN(C)C=O>O>[Cl:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:28][C:15]=1[O:16][C:17]1[C:18]([O:23][CH2:24][C:25]([O:27][CH2:47][C:46]([O:50][CH3:51])=[O:49])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CO
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccnc3OCC(=O)O)c(Cl)cc2F)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1.5 h
Yield: 52.3 %

Procedure:
First, 0.13 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added to a mixture of 0.30 g of [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetic acid (compound a-2), 60 mg of methyl glycolate, and 2 ml of N,N-dimethylformamide at room temperature, and the mixture was stirred for 1.5 hours. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.18 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetoxyacetate (compound a-32).
Reaction SMILES: [C:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=O.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[NH2:27])=[CH:22][C:21]=1[NH:29][C:30](=[O:48])[CH2:31][CH:32]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][C:39]=1[O:46][CH3:47])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:19])([CH3:18])[CH3:17]>C(#N)C.C(OCC)(=O)C>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:27][C:4](=[O:6])[CH2:3][CH2:2][C:1]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[O:28])=[CH:22][C:21]=1[NH:29][C:30](=[O:48])[CH2:31][CH:32]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][C:39]=1[O:46][CH3:47])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(=O)CCC(=O)OCc2ccccc2)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15 %

Procedure:
810 mg (5.0 mmol) of N,N'-carbonyldiimidazole were added to a solution of 1.04 g (5.0 mmol) of benzyl hydrogen succinate in 10 ml of acetonitrile, and the resulting mixture was stirred for 15 minutes, after which 565 mg (1.22 mmol) of N-(2-t-butyl-5-carbamoylphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Example 2) and 610 mg (5.0 mmol) of 4-N,N-dimethylaminopyridine were added. The mixture was then heated under reflux for 4 days, after which the reaction mixture was allowed to cool to room temperature. The reaction mixture was then diluted with ethyl acetate, and the diluted solution was washed with 2 N aqueous hydrochloric acid and with 2 a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 15 g of silica gel using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 3:1 to 1:1 by volume as the eluent, to give a crude product containing the title compound. The product was further purified by column chromatography through silica gel under the same conditions as above, to give the title compound as a viscous substance in a 15% yield.
Reaction SMILES: Cl[C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][C:3]=1[CH:9]=O.C(N(CC)CC)C.[SH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>ClCCl>[CH3:8][C:5]1([CH3:7])[CH2:6][C:2]2[S:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9][C:3]=2[CH2:4]1
Reactant: CCOC(=O)CS
Reactant: CC1(C)CC(Cl)=C(C=O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(s1)CC(C)(C)C2

Procedure:
To a solution of 131b (33.0 g, crude) in dichloromethane (400 mL) and triethylamine (60 g, 600 mmol) was added ethyl 2-mercaptoacetate (19.2 g, 160 mmol). See FIG. 15. The reaction mixture was heated at reflux for 6 h. It was then concentrated under reduced pressure. The residue was dissolved in ethanol (400 mL) and triethylamine (60 g, 600 mmol). The mixture was heated at reflux for 12 h. It was concentrated again under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 40:1 petroleum ether/ethyl acetate to 131c as a yellow solid (18.0 g, 32%, over two steps). MS-ESI: [M+H]+ 225.3. 1H NMR (500 MHz, DMSO-d6) δ 7.49 (s, 1H), 4.32 (q, J=7.0 Hz, 2H), 2.72 (s, 2H), 2.56 (s, 2H), 1.35 (t, J=7.0 Hz, 3H), 1.22 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[C:11]([CH2:13][NH:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=O)[CH:10]=[CH:9][N:8]=1.[NH2:24][C:25]1[CH:26]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:29][CH:30]=1.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[C:11]([CH2:13][NH:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)=[O:19])[CH:10]=[CH:9][N:8]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccccc1NCc1ccnc(N2CCCC2=O)c1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1NCc1ccnc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
156 mg (0.5 mmol) of 2-{[2-(2-oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-benzoic acid is mixed in 5 ml of dimethylformamide with 0.12 ml (1 mmol) of 3-aminobenzotrifluoride, 228 mg (0.6 mmol) of HATU (N-dimethylamino-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethane ammonium hexafluorophosphate-N-oxide) and 0.14 ml of N-methylmorpholine, and it is stirred overnight at room temperature. It is diluted with ethyl acetate and washed in succession with saturated sodium bicarbonate solution, water and saturated common salt solution. The organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on Isolute as a mobile solvent. 95 mg (42% of theory) of 2-{[2-(2-oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamide is obtained. (MS: m/e 454)