Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:30])[CH2:10][CH2:11][CH2:12][C:13](=[O:29])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26])=[CH:17][CH:16]=1.[C:31]([O:35][C:36](=[O:49])[CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][NH2:48])([CH3:34])([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:31]([O:35][C:36](=[O:49])[CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][NH:48][C:9](=[O:30])[CH2:10][CH2:11][CH2:12][C:13](=[O:29])[NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26])=[CH:19][CH:20]=1)([CH3:32])([CH3:34])[CH3:33]
Reactant: CC(=O)CC(=O)CCc1ccc(NC(=O)CCCC(=O)ON2C(=O)CCC2=O)cc1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)CC(=O)CCc1ccc(NC(=O)CCCC(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)cc1

Procedure:
A solution of 4-[4-(3,5-dioxo-hexyl)-phenylcarbamoyl]-butyric acid 2,5-dioxo-pyrrolidin-1-yl ester (1.5 g, 3.6 mmol), 3-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-propionic acid tert-butyl ester (1.0 g, 3.6 mmol) and DIEA (1.3 L, 7.2 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The solvent was removed in vacuo and the residual oil purified using column chromatography EtOAc/MeOH (95:5) to give the title compound as a transparent oil, (M+1)=579.
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.C(OCC)(=O)C>CN(C=O)C>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:6]2[C:2]([CH3:1])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:3](=[O:20])[N:4]([C:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)=[O:9])[C:5]2=[O:7])=[CH:32][CH:31]=1
Reactant: CC1(c2ccccc2)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine -2,4-dione (43 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 4-fluorobenzyl bromide (24 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 38 mg of white crystals.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[C:24]([CH:25]=4)=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C(O)(=[O:28])C>O>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[C:17]1[C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:28])[CH:7]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: CC(=O)O
Reactant: Fc1cc(-c2ccc3c(-c4cc5ccccc5[nH]4)n[nH]c3c2)ccn1
Solvent: O
Product: O=c1cc(-c2ccc3c(-c4cc5ccccc5[nH]4)n[nH]c3c2)cc[nH]1

Procedure:
A solution of the fluoropyridine (3-3, 38 mg, 0.116 mmol) in 80% acetic acid in water (13 mL) was heated at 110° C. for 10 h. The reaction mixture was concentrated in vacuo, partitioned between ethyl acetate and 0.5N-NaOH. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. Trituation of the crude solid with ethyl acetate afforded the desired intermediate (3-4); 1H NMR (500 MHz, DMSO-d6) δ 13.5 (s, 1H), 11.7 (bs, 1H), 11.6 (s, 1H), 8.28 (d, 1H, J=8.6 Hz), 7.85 (s, 1H), 7.60 (d, 1H, J=7.8 Hz), 7.55 (dd, 1H, J=8.5, 1.5 Hz), 7.50 (d, 1H, J=6.8 Hz), 7.45 (d, 1H, J=8.1 Hz), 7.16 (d, 1H, J=1.9 Hz), 7.12 (dt, 1H, J=8.1, 0.98 Hz), 7.02 (t, 1H, J=1.9 Hz), 6.69 (d, 1H, J=1.9 Hz), 6.62 (dd, 1H, J=6.8, 1.7 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.[Br:25][C:26]1[C:27]([I:35])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].CCN(CC)CC>O.C1(C)C=CC=CC=1>[Br:25][C:26]1[C:27]([I:35])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([N:22]([C:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH:10]=1)[CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:30]
Reactant: COc1ccc(CN)cc1
Reactant: O=C(Cl)c1cccc(Br)c1I
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CN(C(=O)c2cccc(Br)c2I)C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
A mixture of tert-butyl-4-oxopiperidine-1-carboxylate (19 g, 0.0.096 mol), 4-methoxybenzylamine (13 g, 0.096 mol) and toluene was stirred at 100° C. for 3 h and then concentrated to give a residue. Toluene (300 mL), 3-bromo-2-iodo-benzoyl chloride (25 g, 0.077 mol), and Et3N (24.5 g, 0.23 mol) were added to the residue and the mixture was stirred at 80° C. overnight. The mixture was cooled, and poured into water and extracted with EtOAc. The organic layer was dried and concentrated to give the crude product which was purified by column chromatography to afford tert-butyl 4-(3-bromo-2-iodo-N-(4-methoxybenzyl)benzamido)-5,6-dihydropyridine-1(2H)-carboxylate (30 g, 63%). 1H NMR: (400 MHz, MeOD): δ=1.38 (s, 9H), 1.43 (m, 2H), 1.48 (m, 4H), 1.63 (m, 2H), 3.18 (m, 2H), 3.60 (m, 2H), 3.80 (s, 3H), 4.55 (d, 1H), 5.49 (m, 1H), 6.88 (m, 3H), 7.02 (m, 2H), 7.16 (m, 1H), 7.32 (m, 3H), 7.55 (m, 1H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[O:19])[C@H:11]3[CH2:18][CH2:17][CH2:16][C@H:12]3[NH:13][C:14]=2[CH:15]=1.C(N(C(C)C)CC)(C)C.[CH2:29]([OH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+].Cl>C1COCC1>[F:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[O:19])[C@H:11]3[CH2:18][CH2:17][CH2:16][C@H:12]3[N:13]([C:1]([O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:2])[C:14]=2[CH:15]=1
Reactant: O=C1c2ccc(F)cc2N[C@@H]2CCC[C@H]12
Reactant: OCc1ccccc1
Reactant: O=C(Cl)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1c2ccc(F)cc2N(C(=O)OCc2ccccc2)[C@@H]2CCC[C@H]12
Temperature: 23 °C
Reaction time: 2 h

Procedure:
Phosgene (20% in toluene, 1.0 g, 2.2 mmol, 1.5 equiv) was added to a solution of cis-6-fluoro-1,2,3,3a,4,9a-hexahydro-9H-cyclopenta[b]quinolin-9-one 6B (300 mg, 1.5 mmol, 1 equiv) and diisopropyl ethylamine (380 uL, 2.2 mmol, 1.5 equiv) in THF (14.6 mL). After stirring at 23° C. for two hours the solution was treated with benzyl alcohol (450 μL, 4.4 mmol, 3 equiv) and sodium hydride (60% in mineral oil, 230 mg, 5.9 mmol, 4 equiv). After stirring at 23° C. for 12 hours the reaction was neutralized to pH=7 with 1N HCl. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The filtrate was purified by flash-column chromatography (hexanes, grading to 50% ethyl acetate-hexanes) to afford 6C. [M+H]+: 340.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13]C)[N:7]=1)[CH3:2].C(#N)C.[I-].[K+].C[Si](C)(C)Cl>O>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[NH:7][C:8](=[O:13])[CH:9]=[C:10]([Cl:12])[N:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1nc(Cl)cc(OC)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)Cc1nc(Cl)cc(=O)[nH]1
Temperature: 100 °C
Yield: 81 %

Procedure:
33 g of (4-chloro-6-methoxypyrimidin-2-yl)acetic acid ethyl ester (example 8b, step 2b) and 750 ml of acetonitrile are placed in a 1000 ml autoclave and then 71.2 g of potassium iodide and 55.85 ml of trimethylchlorosilane are added; an orangey-colored heterogeneous solution is obtained, which is stirred while heating under an argon pressure of 10 bar at 100° C. for 2 hours. The reaction medium is drawn off, then insoluble material is filtered off, washing is carried out with 3 times approximately 100 ml of EtOAc, and the filtrate is concentrated until a pasty residue is obtained, which is taken up in 500 ml of water. After stirring, extraction is carried out with 3 times approximately 350 ml of ethyl acetate, the combined organic extracts are washed with 500 ml of saturated NaCl solution, drying is carried out over MgSO4, filtration is carried out through a VF filter, and the resulting product is concentrated under vacuum. The compound obtained is purified by chromatography on silica gel (40-63 μm), elution being carried out with a mixture of EtOAc/n-heptane (2/8 v/v). The fractions containing the expected compound are combined and evaporated. A solid is isolated, which is triturated from diisopropyl ether, filtered through sintered glass and dried. (4-Chloro-6-oxo-1,6-dihydropyrimidin-2-yl)acetic acid ethyl ester is isolated in the form of a beige solid: 25.2 g; yield 81%.
Reaction SMILES: [Mg].[C:2]([O:6][CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9]I)([CH3:5])([CH3:4])[CH3:3].[C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[C:28](=[O:32])[CH2:29][CH2:30][CH:31]=1)([O:18][CH2:19][CH3:20])=[O:17].[Cl-].[NH4+]>C(OCC)C.O>[C:2]([O:6][CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][C@@H:31]1[C@@H:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:28](=[O:32])[CH2:29][CH2:30]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CCCCCC(CCI)OC(C)(C)C
Reactant: CCOC(=O)CCCCCCC1=CCCC1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OC(C)(C)C
Yield: 85 %

Procedure:
To a Grignard solution, prepared from 5.05 g. of magnesium and 65.8 g. of 3-(tert-butoxy)-1-iodooctane in 150 ml. of diethyl ether under nitrogen atmosphere, is added 4.0 g. of copper iodide-tri-n-butylphosphine complex followed by dropwise addition of 49 g. of 2-(6-carbethoxyhexyl)cyclopent-2-en-1-one [Hardegger et al., Helv. Chim. Acta 50, 2501 (1967)] and the resulting mixture is stirred for 18 hours. Saturated ammonium chloride (110 ml.) is added followed by 100 ml. of water and 100 ml. of diethyl ether. Unreacted magnesium is removed by filtration. The ethereal layer is washed successively with aqueous sodium thiosulfate solution, ammonium chloride solution, and water, dried over magnesium sulfate and taken to dryness to give an oil. Distillation at 0.05 mm. (bath 100°-185° C.) gives 45.4 g. of material containing unreacted starting material and 30 g. (85% yield based on non-recovered starting material; see below) of residue which contains the desired product. This material is chromatographed on silica gel. The product is eluted with diethyl ether to give 25.2 g. (71% based on recovered starting material) of a syrup; this material has no significant ultra-violet absorption; λmaxKBr 5.74, 7.20, 7.35, 8.35 μ; nmr 2H quartetδ 4.09 (OCH2 of ester), 1H broad singlet 3.57 (carbinolic proton), 5H overlapping multiplets 2.0-2.4 (protons next to C=O), 3H triplet 1.22 (CH3 of ethyl), 9H singlet 1.17 (CH3 's to t-butyl) and 3H triplet 0.9 (terminal methyl); mass spectrum: m/e 424.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6](/[CH:10]=[N:11]/[S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH:7]=[CH:8][CH:9]=1.[CH3:20][Mg]Br>C1COCC1>[F:19][C:2]([F:1])([F:18])[O:3][C:4]1[CH:5]=[C:6]([C@H:10]([NH:11][S@:12]([C:14]([CH3:16])([CH3:15])[CH3:17])=[O:13])[CH3:20])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)[S@](=O)/N=C/c1cccc(OC(F)(F)F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: C[C@@H](N[S@@](=O)C(C)(C)C)c1cccc(OC(F)(F)F)c1
Temperature: -76 °C
Yield: 50.2 %

Procedure:
In a round-bottomed flask, (S)-2-methyl-propane-2-sulfinic acid 1-(3-trifluoromethoxyphenyl)-meth-(E)-ylideneamide (424 mg, 1.45 mmol) was dissolved in THF (2.9 ml). The light yellow solution was cooled to −76° C. and methylmagnesium bromide (3.0 M in diethyl ether, 0.86 ml, 2.58 mmol) was added dropwise. The reaction mixture was allowed to warm slowly to room temperature overnight then quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient: 0-10% EtOAc) to give 225 mg (50%) of (S)-2-methyl-propane-2-sulfinic acid [(R)-1-(3-trifluoromethoxy-phenyl)-ethyl]-amide as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.33-7.41 (m, 1H), 7.24-7.28 (m, 1H), 7.22 (s, 1H), 7.13 (dd, J=8.1, 1.0 Hz, 1H), 4.62 (q, J=6.7 Hz, 1H), 1.55 (d, J=6.6 Hz, 3H), 1.22 (s, 9H). Also isolated 161 mg (36%) of (S)-2-methyl-propane-2-sulfinic acid [(S)-1-(3-trifluoromethoxy-phenyl)ethyl]-amide as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.35-7.43 (m, 1H), 7.28-7.33 (m, 1H), 7.21 (s, 1H), 7.11-7.18 (m, 1H), 4.58 (qd, J=6.4, 2.9 Hz, 1H), 1.53 (d, J=6.6 Hz, 3H), 1.25 (s, 9H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].O>CN(C)C=O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Ic1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
3-Iodo-1H-pyrrolo[2,3-b]pyridine 67 (2.00 g, 8.20 mmol) was dissolved in N,N-dimethylformamide (50 mL). Sodium hydride (60% dispersion in mineral oil, 390 mg, 9.8 mmol) was added. After 20 minutes, triisopropylsilyl chloride (1.74 mL, 8.20 mmol) was added dropwise. After 1.5 hours, the reaction was poured into water and extracted with ethyl acetate, washed with saturated sodium bicarbonate and brine. The organic portions were dried over anhydrous sodium sulfate and concentrated. Purification by silica gel chromatography, 0-25% gradient ethyl acetate/hexane gave compound 68 as a white solid (3.224 g, 98.2%). 1H-NMR was consistent with the desired compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH2:15][OH:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])C.O.[Li+].[OH-]>C1COCC1>[OH:16][CH2:15][C:12]1[CH:13]=[CH:14][C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[S:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)c1cc2ccc(CO)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2ccc(CO)cc2s1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
6-Hydroxymethyl-benzo[b]thiophene-2-carboxylic acid ethyl ester (2.4 g, 9.6 mmol, 1 eq) was dissolved in THF (10 mL, 4 vol) and water added (10 mL) along with LiOH (0.69 g, 28.8 mmol). The reaction mixture was stirred at 50° C. for 3 h and then concentrated to dryness and taken onto the next stage without purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)(=O)C>COCCCOCCCO>[N:16]1([C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: COCCCOCCCO
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc2c(N3CCNCC3)ccnc2c1
Yield: 42.7 %

Procedure:
4-Chloro-7-(trifluoromethyl)quinoline (2.3 g, 10 mmol) was dissolved in dipropyleneglycolmonomethyl ether (10 ml) together with piperazine (6.8 g, 0.1 mol) and glacial acetic acid (0.3 ml) and heated at reflux for 2 days. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica, gradient from ethylacetate to methanol containing 1% ammonia) to yield a yellow crystalline solid (1.2 g, 43%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4](Cl)[N:3]=1.[CH3:13][O-:14].[Na+].O.Cl>CO>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4]([O:14][CH3:13])[N:3]=1
Reactant: C[O-]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(Cl)c(C(=O)O)cc1F
Yield: 65 %

Procedure:
A solution of 2,6-dichloro-5-fluoro-3-pyridinecarboxylic acid (51.12 g, 243 mmol) in methanol (400 ml) was treated with sodium methoxide in methanol (25% w/v, 100 ml, 535 mmol) and the mixture heated to reflux for 4 hours. The cooled mixture was treated with water (400 ml) and acidified to pH2 with aqueous hydrochloric acid (2M) then concentrated to ca 400 ml. Filtration, washing with water and drying in vacuo over P2O5 for 18 h afforded the product as a white solid (32.65 g, 65%).
Reaction SMILES: [CH3:1][C:2]([OH:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[CH:4].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][C:2]([OH:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[C:4][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CC(C)(O)CC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(C)(O)CC(C)C)c21

Procedure:
Using Method C above, 3,5-dimethyl-1-hexyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2 supra) (146 mg, 0.4 mmol) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3,5-dimethyl-3-hydroxy-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 87 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].ClCCCl.CCN=C=NCCCN(C)C.Cl.Cl.[F:44][C:45]([F:53])([F:52])[CH2:46][NH:47][C:48]([NH:50][NH2:51])=[O:49]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([NH:51][NH:50][C:48]([NH:47][CH2:46][C:45]([F:53])([F:52])[F:44])=[O:49])=[O:5]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: NNC(=O)NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)NNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.9 %

Procedure:
To a solution containing (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (120 mg, 0.246 mmol), 1,2-dichloroethane (DCE) (5 mL) was added sequentially EDC.HCl (70.6 mg, 0.368 mmol), N-(2,2,2-trifluoroethyl)hydrazinecarboxamide hydrochloride (52.3 mg, 0.270 mmol) and DMAP (63.0 mg, 0.516 mmol). The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2, washed with 0.1N HCl then with aqueous NaHCO3, dried (MgSO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography afford the title compound as a glassy oil (40 mg, 26%): 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.65 (s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.51 (d, J=6.4 Hz, 1H), 7.40 (s, 3H), 6.54 (d, J=15.8 Hz, 1H), 6.42 (dd, J=16.0, 7.7 Hz, 1H), 5.95 (s, 1H), 4.10 (s, 1H), 3.91 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −68.56, −73.02; ESIMS m/z 627.9 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=1.C[N:20](C=O)C>O>[CH3:18][C:16]1[C:17](=[N:20][NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)[C:13]([NH2:12])=[N:14][N:15]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(N)n[nH]1
Reactant: CN(C)C=O
Solvent: O
Product: CC1=NN=C(N)C1=NNc1ccc(C(F)(F)F)cc1

Procedure:
5-methyl-4-[(4-trifluoromethylphenyl)hydrazono]-4H-pyrazol-3-ylamine was prepared from 4-trifluoromethylaniline (0.36 g, 2.2 mmol) and 3-amino-5-methylpyrazole (0.3 g, 3.1 mmol) according to procedure described above except that the substituted aniline was initially dissolved in a mixture of water (3.6 mL) and DMF (2.0 mL) prior to being acidified. The crude material was purified by column chromatography (CHCl3:MeOH=10:1) to yield 0.041 g (7%) of the compound as an orange solid. MS (m/z, ES+): 270.2 (M+1, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([O:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[C:17]([CH2:21][NH2:22])[NH:18]2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CCN(C(C)C)C(C)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([O:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[C:17]([CH2:21][NH:22][S:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:41])=[O:40])[NH:18]2)=[CH:14][CH:13]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:23])[CH3:10]
Reactant: CCOC(=O)C(Oc1ccc2cc(CN)[nH]c2c1)C(=O)OCC
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(Oc1ccc2cc(CNS(=O)(=O)c3ccccc3)[nH]c2c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2-Aminomethyl-1H-indol-6-yloxy)-malonic acid diethyl ester (80 mg, 0.2 5 mmol) is dissolved in DCM (2 ml). DIEA (87 □l, 0.50 mmol) is added. To the solution, benzenesulfonyl chloride (44 mg, 0.25 mmol) is added. The reaction is stirred at room temperature for two hours. The reaction mixture is concentrated and the residue is purified by chromatography (30% ethyl acetate in hexanes) to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([N:15]1[CH2:19][CH2:18][CH2:17]C1)[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].C(N)(=[O:23])C=C>O>[C:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]3[CH2:17][CH2:18][C:19](=[O:23])[NH:15][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(c1)CCC(N1CCCC1)=C2
Reactant: C=CC(N)=O
Solvent: O
Product: CC(C)(C)c1ccc2c(c1)CCC1=C2CCC(=O)N1
Temperature: 89 °C
Reaction time: 8 h

Procedure:
To 6-t-butyl-2-pyrrolidinyl-3,4-dihydronaphthalene (7.25 g; 28.37 mmol) was added 3.0 equiv. of acrylamide (6.05 g; 85.11 mmol). The reaction mixture was stirred at 89° C. overnight. The temperature was then increased to 130° C. and held there for 20 minutes. Water (100 ml) was cautiously added and the reaction mixture was cooled to room temperature. The resulting solid was triturated with water and collected on a filter to afford a brown solid. The solid was recrystallized twice from dimethyl formamide (DMF)/H2O to afford the subtitle compound. Melting point 265°-268° C. decomp.