Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[K+].[K+].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:35][CH2:34][C@@H:33]4[CH2:36][N:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:38][C@H:32]34)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[N:44]1[NH:45][C:46](=[O:50])[CH:47]=[CH:48][CH:49]=1>CN(C)C=O.[Cu]I>[O:50]=[C:46]1[N:45]([C:28]2([N:31]3[CH2:35][CH2:34][C@@H:33]4[CH2:36][N:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:38][C@H:32]34)[CH:29]=[CH:30][C:25]([C:22]3[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=3)=[CH:26][CH2:27]2)[N:44]=[CH:49][CH:48]=[CH:47]1
Reactant: CCOC(=O)N1C[C@H]2CCN(c3ccc(-c4ccc(Br)cc4)cc3)[C@H]2C1
Reactant: O=c1cccn[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CN(C)C=O
Product: CCOC(=O)N1C[C@H]2CCN(C3(n4ncccc4=O)C=CC(c4ccccc4)=CC3)[C@H]2C1
Temperature: 140 °C
Yield: 81.9 %

Procedure:
A mixture of 1.98 g of copper (I) iodide (10.4 mmole, 0.10 eq.), 1.66 g of 8-hydroxyquinoline (11.44 mmole, 0.11 eq.), 4.0 g of potassium carbonate (28.94 mmole, 0.29 eq.) in 18.8 g of dimethylformamide (DMF) was mixed at ambient temperature. The mixture was added to another flask containing 41.6 g of the product of Example 41D (100.16 mmole, 1.00 eq.), 23.6 g of potassium carbonate (170.75 mmole, 1.70 eq.), and 14.4 g of pyridazinone (149.86 mmole, 1.50 eq.). Additional DMF (226 g) was used to transfer the catalyst slurry. The resulting mixture was deoxygenated then heated to 140° C. for about 18 hours. After cooling to ambient temperature the mixture was diluted with 567 g of THF and 384 g of 10% sodium chloride solution. The mixture was filtered to remove excess salts and the aqueous phase was separated and back extracted with an additional 177 g of THF. The combined organic phases were then washed with 10% sodium chloride solution (3×384 g). The organic phase was concentrated under reduced pressure and methanol (253 g) was added and the contents were concentrated under reduced pressure After adding additional methanol (158 g) the contents were cooled to 0° C., filtered, and washed with cold methanol. The resulting solids were transferred to a vacuum oven to yield 35.31 g (81.9% yield). Mass Spectroscopy. 431.5 (m w. 430.5). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (s, 3H), 1.78-1.88 (m, 1H), 2.10 (ddd, J=12.49, 6.17, 6.04 Hz, 1H), 3.03 (s, 1H), 3.24-3.35 (m, 5H), 3.53 (ddd, J=9.23, 6.86, 6.69 Hz, 2H), 3.67 (s, 1H), 4.00 (s, 2H), 4.22 (s, 1H), 6.63 (d, J=8.51 Hz, 2H), 7.07 (dd, J=9.47, 1.51 Hz, 1H), 7.48 (dd, J=9.47, 3.84 Hz, 1H), 7.53-7.60 (m, 4H), 7.68 (d, J=8.64 Hz, 2H), 8.06 (dd, J=3.84, 1.51 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 14.79 (CH3), 28.89 (CH2), 47.71 (CH2), 60.24 (CH2), 112.34 (CH), 124.87 (CH), 125.27 (CH), 126.02 (C), 126.89 (CH), 130.05 (CH), 131.69 (CH), 136.87 (CH), 138.78 (C), 139.31(C), 145.61(C), 153.53(C), 158.64 (C).
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)([CH2:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)C1=O)CCC.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:30](=[O:39])[C:29]2=[O:40].C(C1C=CC=CN=1)(=O)C>>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:30](=[O:39])[C:29]2([OH:40])[CH2:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CC(C)CN1C(=O)C(=O)c2cc(Cl)ccc21
Reactant: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Agent: CC(=O)c1ccccn1
Product: CC(C)CN1C(=O)C(O)(CC(=O)c2ccccn2)c2cc(Cl)ccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-chloro-1-isobutylindoline-2,3-dione and commercially available 2-acetyl pyridine (purchased from Fisher Scientific). 1H-NMR δ 8.71 (ddd, 1H), 8.13 (dd, 1H), 7.93 (dd, 1H), 7.56 (ddd, 1H), 7.31 (d, 1H), 7.28-7.26 (m, 2H), 6.78 (d, 1H), 3.74 (dd, 1H), 3.56-3.40 (m, 3H), 2.13 (m, 1H), 0.96 (d, 6H). calculated mass for C19H19ClN2O3, 358.11, observed, 359.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O.Cl.[NH2:23][C:24]1([CH3:32])[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[C:16](=[O:18])[N:23]([C:24]1([CH3:32])[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:10]2=[O:12]
Reactant: CC1(N)CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(NCc2cccc(Cl)c2)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: CC1(N2C(=O)c3cccc(NCc4cccc(Cl)c4)c3C2=O)CCC(=O)NC1=O
Yield: 40.7 %

Procedure:
To a stirred solution of 3-(3-Chloro-benzylamino)-phthalic acid (4 mmol) in pyridine (50 ml) was added 3-amino-3-methyl-piperidine-2,6-dione hydrochloride (0.71 g, 4 mmol). The reaction mixture was heated to reflux for 18 h. The solvent was evaporated in vacuo and the residue dissolved in methylene chloride (150 ml). The methylene chloride mixture was washed with water (2×100 ml), 0.1N HCl (2×100 ml), brine (1×100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated in vacuo to give a yellow semi-solid. The residue was purified by preparative HPLC (Symmetry C18, isocratic, 50% acetonitrile/water) to give 0.67 g (41%) of product as a yellow solid: mp 199–201° C.; 1H NMR (DMSO-d6) δ δ 10.99 (s, 1H), 7.52–7.28 (m, 6H), 6.97–6.89 (m, 2H), 4.54 (d, J=6.1 Hz, 1H), 2.78–2.50 (m, 3H), 2.08–1.98 (m, 1H), 1.89 (s, 3H); 13C NMR (DMSO-d6) δ 172.42, 172.19, 169.62, 167.92, 145.59, 141.82, 136.02, 133.14, 132.06, 130.35, 126.91, 126.78, 125.60, 117.23, 110.42, 109.49, 58.37, 44.74, 29.27, 28.62, 21.02; Anal. Calcd. For C21H18ClN3O4: C, 61.24; H, 4.41; N, 10.20. Found: C, 61.30; H, 4.28; N, 9.97.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]Br)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([N:19]2[C:27](=[O:28])[CH:22]3[CH2:23][NH:24][CH2:25][CH2:26][N:21]3[C:20]2=[O:29])[CH:15]=[C:16]([Cl:18])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(C(C)=O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:24]2[CH2:25][CH2:26][N:21]3[C:20](=[O:29])[N:19]([C:14]4[CH:15]=[C:16]([Cl:18])[CH:17]=[C:12]([Cl:11])[CH:13]=4)[C:27](=[O:28])[CH:22]3[CH2:23]2)=[CH:4][CH:3]=1
Reactant: O=C1C2CNCCN2C(=O)N1c1cc(Cl)cc(Cl)c1
Reactant: BrCCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)C(C)C
Product: O=C1C2CN(CCc3ccc(Br)cc3)CCN2C(=O)N1c1cc(Cl)cc(Cl)c1

Procedure:
A mixture of 1-bromo-4-(2-bromoethyl)benzene (101 mg, 0.38 mmol, prepared as described in Synth.Commun [1996], 26, pp. 1467-1472), 2-(3,5-dichlorophenyl)-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dione (100 mg, 0.33 mmol, Prep. 19), potassium carbonate (48 mg, 0.35 mmol) and sodium iodide (10 mg, 0.06 mmol) in methyl isopropyl ketone (2 mL) was heated at 100° C. for 48 h. The precipitate was discarded and the filtrate was concentrated under vacuum and chromatographed over silica gel (CH2Cl2). The obtained oil was treated with Et2O/HCl to yield the hydrochloride of 7-[2-(4-bromophenyl)ethyl]-2-(3,5-dichlorophenyl)-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dione as a white solid (60 mg). 1H NMR (CDCl3) of the free base: 7.25-7.4 (5H, m), 7.00 (2H, d, J=8.3Hz), 4-4.15 (2H, m), 3.32 (1H, dd, J1=4.1 Hz, J2=11.1 Hz), 3.09 (1H, dt), 2.87 (1H, br d), 2.5-2.8 (4H, m), 1.95-2.15 (2H, m)
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]=[C:13]3[CH3:37])[CH:10]=2)[O:5][C:4]([CH3:39])([CH3:38])[CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:54]([CH:61]([CH3:63])[CH3:62])([CH:58]([CH3:60])[CH3:59])[CH:55]([CH3:57])[CH3:56])(=O)=O>ClCCl.C(OCC)(=O)C>[CH3:39][C:4]1([CH3:38])[CH2:3][CH:2]([O:1][Si:54]([CH:61]([CH3:63])[CH3:62])([CH:58]([CH3:60])[CH3:59])[CH:55]([CH3:57])[CH3:56])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]=[C:13]3[CH3:37])[CH:10]=2)[O:5]1
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCCc1nc(C)n(-c2ccc3c(c2)C(O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4′-{[1-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (3.1 g) and 2,6-lutidine (2.1 mL) in dichloromethane (30 mL) was added triisopropylsilyl trifluoromethanesulfonate (3.2 mL), and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (4.1 g, 100%) as a solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.CO.[OH-].[NH4+]>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)nc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
To a solution of N-tert-butyl-2-(5-methylpyridin-2-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (162 mg, 356 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (813 mg, 549 μL, 7.13 mmol) and the mixture stirred at room temperature for 16 h. The mixture was then concentrated in vacuo and the residue obtained was dissolved in dichloromethane (3 mL), methanol (1 mL) and ammonium hydroxide (0.6 mL) and the mixture stirred at room temperature for 30 min. The yellow precipitate formed was collected by filtration and dried. The mother liquor was purified by chromatography (silica, 5-25% of a 1:4 methanol:dichloromethane solution in dichloromethane) and combined with the solid to give N-tert-butyl-2-(5-methylpyridin-2-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (77 mg, 237 μmol, 67%) as an off-white solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.37 (s, 1H), 9.88 (s, 1H), 8.38 (s, 1H), 8.13 (d, J=2.5 Hz, 1H), 8.04 (d, J=3.2 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.74 (s, 1H), 7.51 (dd, J=8.2, 2.3 Hz, 1H), 2.25 (s, 3H), 1.47 (s, 9H); MS (EI/CI) m/z: 325.1 [M+H].
Reaction SMILES: Cl.N[N:3]1[CH2:7][CH2:6][N:5]([C:8]([NH2:10])=[O:9])[C:4]1=[O:11].C(N(CC)CC)C.[C:19]([O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][C:33](=[O:35])[CH3:34])[C:26](Cl)=[O:27])(=[O:21])[CH3:20]>ClCCl>[C:19]([O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][C:33](=[O:35])[CH3:34])[C:26]([N:3]1[CH2:7][CH2:6][N:5]([C:8]([NH2:10])=[O:9])[C:4]1=[O:11])=[O:27])(=[O:21])[CH3:20]
Reactant: NC(=O)N1CCN(N)C1=O
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C(=O)N2CCN(C(N)=O)C2=O)cc1OC(C)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 314.9 %

Procedure:
3-Amino-2-oxo-1-imidazolidinecarboxamide, monohydrochloride (12 g 0.006 mol) was suspended in 300 ml of dichloromethane. The suspension was cooled to 0° C. and 29.2 ml of triethylamine (0.198 mol) was added; the mixture was stirred for another 20 minutes. [3,4-Bis(acetyloxy)benzoyl]chloride (10.5 g) dissolved in 200 ml of dichloromethane was added dropwise with stirring at 0° C. and the mixture was stirred overnight at room temperature, filtered and treated with 50 ml of water. After stirring for 5 minutes, 3-[3,4-bis(acetyloxy)benzoyl]-2-oxo-1-imidazolidinecarboxamide crystallized out (7.2 g) contaminated with some triethylamine hydrochloride. The impurity was removed by treatment with water to yield 6.6 g of 3-[3,4-bis(acetyloxy)benzoyl]-2-oxo-1-imidazolidinecarboxamide, melting point 222°-224° C.
Reaction SMILES: Cl.[CH2:2](N=C=NCCCN(C)C)[CH3:3].Cl.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[N:24]1[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1.C(O)C>CN(C1C=CN=CC=1)C.ClCCl>[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[N:24]1[CH2:25][CH2:26][CH:27]([C:30]([O:32][CH2:2][CH3:3])=[O:31])[CH2:28][CH2:29]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C1CCN(c2ccc3ccccc3n2)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.79 g, 9.34 mmol) was added to a solution of 1-(quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride (1.14 g, 3.89 mmol), N,N-dimethyl-4-aminopyridine (1.42 g, 11.6 mmol), and ethanol (546 μL, 9.34 mmol) in dichloromethane (20 mL), and the mixture was stirred overnight at room temperature. Then, the solvent in the reaction solution was distilled off under reduced pressure. A solution of the obtained residue in ethyl acetate was washed with water twice and brine once and dried over anhydrous sodium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=95/5-60/40 (gradient)] to obtain the title compound (1.07 g, yield: 96%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1)[O:6][CH2:5]2.[Li]CCCC.CN([CH:29]=[O:30])C>C1COCC1>[CH:29]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1)[O:6][CH2:5]2)=[O:30]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(Br)ccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=O)ccc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
To a stirred solution of tert-butyl 5′-bromo-3′H-spiro[azetidine-3,1-isobenzofuran]-1-carboxylate (Intermediate 1, 2 g, 5.879 mmol, 1 eq) in dry THF (40 mL) was added n-BuLi (6.42 mL, 7.054 mmol, 1.2 eq) at −78° C. under nitrogen atmosphere. Reaction mixture was stirred for 10 minutes at −78° C. under nitrogen atmosphere. At −78° C., DMF (0.678 mL, 8.818 mmol, 1.5 eq) was added in drop wise manner over period of 10 minutes. Resulting reaction mixture was allowed to warm to −20° C. and stirred for 3 hours under nitrogen atmosphere. After complete consumption of starting material, reaction was quenched with 10% NH4Cl solution (5 mL) followed by water (70 mL) and extracted with ethyl acetate (3×30 mL). Combined organic phase was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound as pale yellow thick oil (1.5 g, crude). Crude compound was used as such for next reaction. (m/z): 290.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][CH3:33])[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][CH3:33])[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: CCCCn1cc(Br)cn1
Product: CCCCn1cc(-n2c(C)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-Bromo-1-butyl-1H-pyrazole
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[OH:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]>CN(C=O)C.O>[C:18]([C:17]1[CH:16]=[C:15]([CH:22]=[CH:21][CH:20]=1)[CH2:14][N:13]([CH2:12][CH2:11][OH:10])[CH2:3][CH2:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])#[N:19]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: N#Cc1cccc(CNCCO)c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCN(CCO)Cc1cccc(C#N)c1
Temperature: 80 °C

Procedure:
Tert-butyl acrylate (3.56 ml, 29 mmol) was added into a solution of 3-{[(2-hydroxyethyl)amino]methyl}benzonitrile (4.9 g, 28 mmol) in anhydrous DMF (5 mL) under nitrogen atmosphere. The resulting mixture was heated at 80° C. for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.50 (m, 1H), 4.36 (t, 1H), 3.62 (s, 2H), 3.43 (m, 2H), 2.69 (t, 2H), 2.47 (m, 2H), 2.34 (t, 2H), 1.38 (s, 9H).
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][O:8]/[N:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:21][C:20]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)([C:22]([F:25])([F:24])[F:23])[O:19][N:18]=2)=[CH:13][C:12]=1[CH3:34])(C)(C)C.C(O)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:33][C:28]1[CH:27]=[C:26]([C:20]2([C:22]([F:24])([F:23])[F:25])[O:19][N:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11](/[CH:10]=[N:9]/[O:8][CH2:7][C:6]([OH:35])=[O:5])=[C:12]([CH3:34])[CH:13]=3)[CH2:21]2)[CH:31]=[C:30]([Cl:32])[CH:29]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1/C=N/OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=CO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1/C=N/OCC(=O)O
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of [1-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-phenyl}-meth-(E)-ylideneaminooxy]-acetic acid tert-butyl ester (i.e the product of Step 1, 531 mg) in CH2Cl2 (20 mL) was treated with formic acid (0.25 mL, 0.30 g) and stirred at room temperature over night. Trifluoroacetic acid (0.50 g) was added and the mixture stirred until tlc (thin layer chromatography) indicated completion of the reaction. The organic layer was washed with water three times, dried (Na2SO4) and evaporated to give the title compound (502 mg, 80%) that was used in the next step without further purification. NMR indicated the absence of the tert butyl ester.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10](=[O:17])[O:11][C:12]([CH3:16])=[CH:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.C(O)(=[O:22])C>C1(C)C=CC=CC=1.C(O)C>[CH2:1]([S:8]([C:9]1[C:10](=[O:17])[O:11][C:12]([CH3:16])=[CH:13][C:14]=1[OH:15])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(O)c(SCc2ccccc2)c(=O)o1
Reactant: CC(=O)O
Agent: OO
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(O)c(S(=O)Cc2ccccc2)c(=O)o1
Yield: 69 %

Procedure:
3-Benzylthio-4-hydroxy-6-methyl-2-pyrone (7.45 g., 0.0282 mol) and 30% hydrogen peroxide (3.7 g., 0.033 mol) were combined in 30 ml. glacial acetic acid and stirred at room temperature for 20 hours. The solution was then diluted with a mixture of toluene and ethanol (5:1) and warmed in vacuo to codistil the acetic acid. The recovered tan solid was recrystallized from toluene (DARCO) to give 5.4 g. (69 percent) of the desired product: m.p. 150°-153°C. One additional recrystallization from toluene gave the pure compound: m.p. 155°-156°C.
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:22]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:71])[C@H:30]([CH3:70])[CH2:31][C@H:32]([O:62][Si](C(C)(C)C)(C)C)[C@@H:33]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:34][C@@H:35]([CH:51]([CH3:53])[CH3:52])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:38]=1)(=[O:24])[NH2:23]>CN(C)C=O>[C:22]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:71])[C@H:30]([CH3:70])[CH2:31][C@H:32]([OH:62])[C@@H:33]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:34][C@@H:35]([CH:51]([CH3:53])[CH3:52])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:38]=1)(=[O:24])[NH2:23]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](C)C(=O)NCCCC(N)=O)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCC(N)=O)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
50 mg of tetrabutylammonium fluoride trihydrate are added to 115 mg of 5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid [N-(3-carbamoyl-propyl)]-amide in 4 ml of dimethylformamide at 0° C. The reaction mixture is stirred for a further 5 hours at room temperature and then concentrated by evaporation. 20 ml of sainted sodium hydrogen carbonate solution are added to the evaporation residue and the mixture is extracted repeatedly with ethyl acetate. The organic phases are washed with saturated sodium chloride solution and concentrated by evaporation. The residue is purified by means of FC (18 g of silica gel, dichloromethane/methanol=9:1). The title compound is obtained: Rf (dichloromethane/methanol=9:1)=0.24.
Reaction SMILES: C(C1C=CC(O)=CC=1)(C)C.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](C)([CH3:27])[CH3:26])=[CH:21][C:20]=1[C:29]([CH3:38])([CH3:37])[CH2:30][C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([CH3:26])[CH3:27])=[CH:21][C:20]=1[C:29]([CH3:38])([CH3:37])[CH2:30][C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)c1ccc(OCc2ccccc2)c(C(C)(C)CC(=O)C(F)(F)F)c1
Agent: CC(C)c1ccc(O)cc1
Product: CC(C)c1ccc(OCc2ccccc2)c(C(C)(C)CC(=O)C(F)(F)F)c1

Procedure:
4-(2-Benzyloxy-5-isopropylphenyl)-1,1,1-trifluoro-4-methylpentan-2-one was prepared from 4-isopropylphenol in the same manner as described in the synthesis of 4-(2-benzyloxy-5-tert-butylphenyl)-1,1,1-trifluoro-4-methylpentan-2-one.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]#[N:23])=[CH:19][CH:20]=3)[C:15]([CH3:24])=[C:14]2[C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[CH:6][CH:5]=1.[OH-].[Li+].Cl>CO>[C:22]([C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[N:13]([CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[CH:5][CH:6]=1)[C:14]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[C:15]2[CH3:24])#[N:23]
Reactant: COC(=O)c1ccc(OCCn2c(-c3cccnc3)c(C)c3cc(C#N)ccc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(-c2cccnc2)n(CCOc2ccc(C(=O)O)cc2)c2ccc(C#N)cc12

Procedure:
A flask is charged with 4-[2-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acid methyl ester (Example 61, 0.150 g, 0.36 mmol) in MeOH (5 mL). Aqueous lithium hydroxide (1 M, 0.912 mL, 0.912 mmol) is added and the mixture is refluxed overnight. The reaction mixture is then acidified to pH 1 using 1 M aqueous HCl solution and the methanol is removed in vacuo. The resulting solution is extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (dichloromethane-methanol, 9:1) to afford 4-[2-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acid as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 2.27 (s, 3H), 4.22 (t, J=5.1 Hz, 2H), 4.60 (t, J=5.2 Hz, 2H), 6.72 (d, J=8.8 Hz, 2H), 7.57 (dd, J=8.6, 1.5 Hz, 1H), 7.62-7.72 (m, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.86 (d, J=8.6 Hz, 2H), 8.02 (d, J=7.8 Hz, 1H), 8.07 (s, 1H), 8.72 (br. s., 2H). HRMS (ESI) m/z 398.1487 [(M+H)+ Calcd for C24H20N3O3: 398.1505].