Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[F:32][CH:33]([F:50])[C:34]1[CH:35]=[CH:36][C:37]([F:49])=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:39]=1>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][CH:33]([F:50])[C:34]1[CH:35]=[CH:36][C:37]([F:49])=[C:38]([C:16]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=2[C:6]2[C:2]([CH3:25])([CH3:1])[CH2:3][CH2:4][CH:5]=2)[CH:39]=1
Reactant: CC1(C)OB(c2cc(C(F)F)ccc2F)OC1(C)C
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2=CCCC2(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(C(F)F)ccc2F)c(C2=CCCC2(C)C)c1
Temperature: 90 °C
Reaction time: 19 h
Yield: 89.7 %

Procedure:
To a stirred solution of 66.6I (1.1209 g, 2.962 mmol) in dry DMF (10 mL) at 23° C. was added potassium carbonate (1.2262 g, 8.872 mmol) and then tetrakis(triphenylphosphine)palladium (0.3408 g, 0.2949 mmol). The mixture was purged with argon and placed under vacuum and the purging and vacuum process repeated three times. Before heating, 66.50A (1.6019 g, 5.888 mmol) was added via syringe and then the mixture was heated to 90° C. After 19 hours, LC-MS showed that the reaction was complete. The mixture was cooled to room temperature and then diluted with water. After extracting three times with EtOAc, the mixture was concentrated in vacuo and then purified on silica gel (0%-10% EtOAc/hexane) to afford 66.50B as a clear oil (994.4 mg, 90% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.00 (1H, dd, J=8.0, 1.8 Hz), 7.94 (1H, d, J=1.6 Hz), 7.50 (3H, m), 7.16 (1H, t, J=9.0 Hz), 6.63 (1H, t), 5.53 (1H, s), 3.96 (3H, s), 2.25 (2H, td, J=7.0, 2.3 Hz), 1.65 (2H, t, J=7.0 Hz), 0.85 (6H, s).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[CH:13][C:12]([NH:18][C:19](=[O:40])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][C:28](=[O:39])[C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=4)[CH:21]=3)=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH3:38][O:37][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[O:35][CH3:36])[C:28]([NH:27][CH2:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:19](=[O:40])[NH:18][C:12]2[CH:13]=[N:14][C:15]3[CH2:16][CH2:17][NH:8][CH2:9][C:10]=3[CH:11]=2)[CH:21]=1)=[O:39]
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3cnc4c(c3)CN(C(=O)OC(C)(C)C)CC4)c2)cc1OC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3cnc4c(c3)CNCC4)c2)cc1OC
Reaction time: 8 h
Yield: 102.5 %

Procedure:
Dissolved 3-{3-[(3,4-dimethoxy-benzoylamino)-methyl]-benzoylamino}-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid tert-butyl ester (120 mg, 0.22 mmol) in 3 mL CH2Cl2 and added HCl in dioxane (1.00 mL/4.0 mmol). The mixture was stirred overnight resulting in a heterogenous mixture. Concentrated the mixture to dryness to give 100.7 mg of the desired product. MS, electrospray 447.4 (M+H).
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=[O:11].[Ce].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>CO.[N+]([O-])(O)=O.[Pt]>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]=[O:11])=[CH:17][CH:18]=1
Reactant: COc1ccc(C)cc1
Reactant: O=[N+]([O-])[O-]
Agent: [Pt]
Agent: [Ce+3]
Agent: [Ce]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: COc1ccc(C=O)cc1
Yield: 96 %

Procedure:
A 18.2 g quantity of cerium(III) nitrate is dissolved in 100 ml of methanol containing 10 ml of 65% by weight of nitric acid, and the solution is placed into an anode chamber. A methanol solution containing 10 ml of 65% by weight of nitric acid is placed into a cathode chamber. The cerium salt is electrolyzed with a constant current of 60 mA using platinum electrodes to pass electricity across the electrodes in a quantity of 1.2 F/mole. A 1.22 g of quantity of p-methyl anisole is oxidized with the solution withdrawn from the anode chamber after the electrolysis. The same procedure as in Example 1 is thereafter repeated to obtain 1.306 g of anisaldehyde. Yield: 96.0%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:24][N:25]1[C:29]([Sn](CCCC)(CCCC)CCCC)=[CH:28][C:27]([C:43]([F:46])([F:45])[F:44])=[N:26]1>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:29]2[N:25]([CH3:24])[N:26]=[C:27]([C:43]([F:46])([F:45])[F:44])[CH:28]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(F)(F)F)nn1C
Reactant: COC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Product: COC(=O)c1nc(-c2cc(C(F)(F)F)nn2C)c2cc(Oc3ccccc3)ccc2c1O

Procedure:
4-Hydroxy-1-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester was prepared from 1-bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester using 1-methyl-5-tributylstannanyl-3-trifluoromethyl-1H-pyrazole under conditions analogous to Example 132(a). MS ESI(−) m/e: 442.0128 (M−1.)
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][CH2:16][NH2:17])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[O-:21][C:22]#[N:23].[K+]>O.Cl>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][CH2:16][NH:17][C:22]([NH2:23])=[O:21])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C1CCc2cccc(CCN)c2C1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(CCNC(N)=O)c2C1
Reaction time: 1 h

Procedure:
1.1 g (4 mmol) of 2-dipropylamino-8-(2-aminoethyl)-1,2,3,4-tetrahydronaphthalene were dissolved in 8 ml of water and 8 ml of 1N hydrochloric acid, and heated to +60° C. A solution of 3.24 g (40 mmol) of potassium cyanate and 15 ml of water was added dropwise at this temperature. The mixture was stirred for 1 h at +60° C. The mixture was then cooled and filtered under suction. The product was recrystallized from petroleum ether/diisopropyl ether with activated charcoal.
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].[NH4+].[Ce].[C:7]([O:10][C:11]1[CH:28]=[CH:27][C:26]2[C@@H:25]3[C@H:16]([C@H:17]4[C@@:21]([CH2:23][CH2:24]3)([CH3:22])[C@@H:20]([O:29][C:30](=[O:32])[CH3:31])[CH2:19][CH2:18]4)[C@H:15]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][S:42]([CH2:45][CH2:46][CH2:47][C:48]([F:54])([F:53])[C:49]([F:52])([F:51])[F:50])(=[O:44])=[O:43])[CH2:14][C:13]=2[CH:12]=1)(=[O:9])[CH3:8].C(O)(=[O:57])C>>[C:7]([O:10][C:11]1[CH:28]=[CH:27][C:26]2[C@:25]3([OH:57])[C@H:16]([C@H:17]4[C@@:21]([CH2:23][C@@H:24]3[O:2][N+:1]([O-:4])=[O:3])([CH3:22])[C@@H:20]([O:29][C:30](=[O:32])[CH3:31])[CH2:19][CH2:18]4)[C@@H:15]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][S:42]([CH2:45][CH2:46][CH2:47][C:48]([F:54])([F:53])[C:49]([F:50])([F:51])[F:52])(=[O:43])=[O:44])[CH2:14][C:13]=2[CH:12]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1ccc2c(c1)C[C@@H](CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Reactant: CC(=O)O
Reactant: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Product: CC(=O)Oc1ccc2c(c1)C[C@H](CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)[C@H]1[C@@H]3CC[C@H](OC(C)=O)[C@@]3(C)C[C@H](O[N+](=O)[O-])[C@]21O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
18.6 g of cerium ammonium nitrate is added to a solution of 3.0 g of 3,17β-diacetyloxy-7α-(9-[4,4,5,5,5-pentafluoropentanesulfonyl]-nonyl)-estra-1,3,5(10)-triene in 50 ml of aqueous acetic acid (90%), and it is stirred for 4 hours at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10](Br)=[C:11]([S:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)(=[O:16])=[O:15])[CH:12]=2)[CH:7]=[CH:6]1.C(N(CC)CC)C>[Pd].[C]>[CH3:1][O:2][C:3](=[O:34])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)(=[O:15])=[O:16])[CH:12]=2)[CH:7]=[CH:6]1
Reactant: COC(=O)Cn1ccc2cc(Br)c(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)cc21
Agent: [Pd]
Solvent: CCN(CC)CC
Product: COC(=O)Cn1ccc2ccc(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)cc21
Yield: 83.1 %

Procedure:
{5-Bromo-6-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-acetic acid methyl ester (135 mg, 0.24 mmol), triethylamine (40 μL, 0.29 mmol) and 10% Pd/carbon (cat) were stirred under an atmosphere of hydrogen until all the starting material was gone. The reaction was then filtered through celite, concentrated and purified by flash column chromatography (60% hexanes in ethyl acetate) to afford {6-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-acetic acid methyl ester (96 mg, 83%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, 1H) 7.75 (d, 1H), 7.51 (dd, 1H), 7.44 (dd, 2H), 7.31 (d, 1H), 6.84 (d, 2H), 6.67 (d, 1H), 4.11 (dd, 2H), 3.78 (s, 3H), 3.33 (m, 4H), 3.16 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[N:9][CH:8]=[CH:7][CH:6]=2.[C:21](OC)(OC)(OC)[CH2:22][CH2:23][CH3:24].Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:22]([C:21]1[N:12]([CH2:13][C:14]2([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:23][CH3:24]
Reactant: CCCC(OC)(OC)OC
Reactant: Nc1cnc2cccnc2c1NCC1(O)CCCCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCc1nc2cnc3cccnc3c2n1CC1(O)CCCCC1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A solution of 1-{[(3-amino[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol (prepared as described in Part B, 15.1 mmol), trimethyl orthobutyrate (2.63 mL, 16.6 mmol), and pyridine hydrochloride (0.650 g, 5.64 mmol) in toluene (100 mL) was heated at reflux overnight. The solution was allowed to cool to rt, then was concentrated under reduced pressure. The residue was partitioned between chloroform (200 mL) and saturated aqueous sodium bicarbonate (75 mL). The aqueous layer was extracted with chloroform (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting solid was triturated with ethyl acetate and isolated by filtration. The filtrate was concentrated and the solid was again triturated with ethyl acetate; this procedure was repeated two more times. The white solids were combined and dried under vacuum to yield 1-[(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclohexanol (3.40 g, 70% over two steps).
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[O:28][CH:27]=[N:26][C:25]=2[C:29](O)=[O:30])[CH:21]=[CH:22][CH:23]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:29]([C:25]3[N:26]=[CH:27][O:28][C:24]=3[C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)=[O:30])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Reactant: O=C(O)c1ncoc1-c1cccc(Cl)c1
Product: CC(F)(F)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(Cl)c3)n2)n1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N+:12]#[C-:13])[CH2:9][CH2:10][CH3:11].[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>Cl(O)(=O)(=O)=O>[CH2:8]([NH:12][C:13]1[N:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:2]2=[N:1][C:14]=1[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH3:17])[CH2:9][CH2:10][CH3:11]
Reactant: Nc1ncccn1
Reactant: Cc1ccccc1C=O
Reactant: [C-]#[N+]CCCC
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCCCNc1c(-c2ccccc2C)nc2ncccn12

Procedure:
Compound (14) was prepared in accordance with the general instructions from 1.0 ml 2-aminopyrimidine solution (0.1 M, MC), 0.575 ml n-butylisonitrile solution (0.2 M, MC), 0.500 ml 2-methylbenzaldehyde solution (0.3 M, MC), and 10 μl perchloric acid (w=20%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12](=[O:29])[NH:13][C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:23](=[O:26])[CH2:24]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:10])([CH3:9])[CH3:8].O>CN(C)C=O>[C:7]([O:11][C:12]([N:13]1[CH2:24][C:23](=[O:26])[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][C:14]1([CH3:28])[CH3:27])=[O:29])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(CN(C(=O)CBr)c1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2)CC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
11.19 g of cesium carbonate (34.4 mmol) was added to a solution of 4.41 g of {2-[(2-bromoacetyl)phenylamino]-1,1-dimethylethyl}carbamic acid t-butyl ester obtained in the above reaction (11.5 mmol) in N,N-dimethylformamide (58 ml) under ice-cooling, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=10/1-5/1-2/1) to obtain 1.83 g of 2,2-dimethyl-5-oxo-4-phenylpiperazine-1-carboxylic acid t-butyl ester (yield: 53%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=3[CH:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[Cl:24]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>O.C1COCC1>[Cl:24][C:16]1[C:17]2[N:9]([CH2:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[N:10]=[CH:11][C:12]=2[C:13]([NH2:18])=[CH:14][CH:15]=1
Reactant: Cc1cccc(Cn2ncc3c(N)cccc32)n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(Cn2ncc3c(N)ccc(Cl)c32)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.5 %

Procedure:
A solution of 1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (0.390 g, 1.64 mmol) and THF (8.0 mL) was cooled to −78° C. under N2. H2SO4 (0.0436 mL, 0.818 mmol) was added and the resulting brown suspension was stirred for 5 minutes. N-chlorosuccinimide (0.219 g, 1.64 mmol) was added in one portion and the reaction was stirred at −78° C. for 1 hour. Sodium carbonate (0.173 g, 1.64 mmol) was added and the mixture was warmed to ambient temperature. The mixture was diluted with water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (5 to 30% EtOH/hexanes). The desired product was found in the lower band from the column but it was contaminated with succinimide, so the product was dissolved in 0.5N HCl and extracted with CHCl3. The aqueous phase was basified with NaHCO3 and extracted with EtOAc. The EtOAc was washed with brine, dried over Na2SO4, filtered and concentrated providing the title compound as a pale orange solid (0.150 g, 33%).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=O.[C:11]([NH:34][CH2:35][CH2:36][NH:37]C(=O)/C=C/C(OC)=O)(=[O:33])[CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH3:32]>>[C:11]([NH:34][CH2:35][CH2:36][NH:37][C:4](=[O:6])/[CH:3]=[CH:2]/[C:1]([O:8][CH2:9][CH3:10])=[O:7])(=[O:33])[CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH3:32]
Reactant: CCOC(=O)/C=C/C(=O)[O-]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)/C=C/C(=O)OC
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)/C=C/C(=O)OCC

Procedure:
Mono ethyl fumarate (commercially available) was subjected to the same reaction conditions outlined earlier in the preparation of (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate. The desired product, namely (E)-ethyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate, was obtained after purification by silica gel chromatography. MS (EI) calcd for C30H40N2O4: 496.33. found 497 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[O:14][CH2:15][C:16]([OH:18])=[O:17].CC(C)([O-])C.[K+].CC(N(C)C)=O>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(O)COc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)COc1ccccc1Oc1ccc([N+](=O)[O-])cc1

Procedure:
4-(fluoro)nitrobenzene was reacted with 2-(2-hydroxyphenoxy)acetic acid in the presence of potassium t-butoxide/DMA at 150° C. for 2 hrs to give 2-[(2-(4-nitrophenoxy)phenoxy]acetic acid. The product was purified by chromatography.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[C:3]=1[C:11]1[C:12](=[O:33])[NH:13][C:14](=[O:32])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)[CH:17]=1.[BH4-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[C:3]=1[C:11]1[C:12](=[O:33])[NH:13][C:14](=[O:32])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([C@H:25]2[CH2:26][CH2:27][C@@H:28]([OH:31])[CH2:29][CH2:30]2)[CH:17]=1.[F:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[C:3]=1[C:11]1[C:12](=[O:33])[NH:13][C:14](=[O:32])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([C@H:25]2[CH2:26][CH2:27][C@H:28]([OH:31])[CH2:29][CH2:30]2)[CH:17]=1
Reactant: O=C1CCC(n2cc(C3=C(c4c(F)ccc5ccoc45)C(=O)NC3=O)c3ccccc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2c(F)ccc3ccoc23)=C1c1cn([C@H]2CC[C@@H](O)CC2)c2ccccc12
Product: O=C1NC(=O)C(c2c(F)ccc3ccoc23)=C1c1cn([C@H]2CC[C@H](O)CC2)c2ccccc12
Temperature: 0 °C

Procedure:
Cool a solution of 3-(6-fluorobenzofur-7-yl)-4-[1-(4-oxocyclohexyl)-1H-indol-3-yl]pyrrole-2,5-dione (395 mg, 0.89 mmol) in tetrahydrofuran (20 ml) in an ice bath. Add sodium borohydride (10 mg, 0.27 mmol) in one portion and stir for 5 minutes. Add another portion of sodium borohydride (10 mg, 0.27 mmol) and stir for 10 minutes in the ice bath. Quench the reaction is with water, then dilute with ethyl acetate, wash with water, 1N HCl, brine, dry over magnesium sulfate, filter, concentrate to a red foam. Purification by flash chromatography separates cis and trans isomers to give cis 3-(6-fluorobenzofur-7-yl)-4-[1-(4-hydroxycyclohexyl)-1H-indol-3-yl]pyrrole-2,5-dione and trans 3-(6-fluorobenzofur-7-yl)-4-[1-(4-hydroxycyclohexyl)-1H-indol-3-yl]pyrrole-2,5-dione as red solids. ES(M++H): 445.1.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:18]#[C:19][C:20]4[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=4)[CH:14]=[CH:15][C:16]=3[OH:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[C:1]12([C:11]3[CH:12]=[C:13]([C:18]#[C:19][C:20]4[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OCCCCCCBr
Reactant: COC(=O)c1ccc(C#Cc2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(C#Cc2ccc(OCCCCCCO)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
2 g (5.1 mmol) of methyl 4-[3-(1-adamantyl)-4-hydroxyphenylethynyl]benzoate, 1.1 ml (8.3 mmol) of 6-bromo-1-hexanol, 1.2 g (8.8 mmol) of potassium carbonate, 20 mg of potassium iodide and 100 ml of 2-butanone were introduced into a round-bottomed flask. The reaction mixture was heated at reflux for twelve hours and was evaporated to dryness, the residue was taken up in water and ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([S:14](N3C=CC=C3)(=[O:16])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+].P(Cl)(Cl)([Cl:26])=O.P(Cl)(Cl)(Cl)(Cl)Cl>CO>[Cl:26][S:14]([C:12]1[S:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)(=[O:16])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Temperature: 50 °C

Procedure:
A solution of N-[5-(4-ethylphenyl)thiophene-2-sulfonyl]pyrrole (100 mg, 0.32 mmol) and 6 N sodium hydroxide (1 mL) in methanol (1.5 ml) was refluxed for approximately 6 h. Evaporation of solvents and drying in vacuo resulted in an oil. Phosphorus oxychloride (258 ml, 2.52 mmol) and phosphorus pentachloride (131 mg, 0.63 mmol) were added to the oil and the resulting brown suspension was heated at 50° C. for 3 h. The resulting clear brown solution was carefully added to about 20 mL of crushed ice and then extracted with ethyl acetate (3×25 mL). The combined organic layers was washed with brine (2×5 mL), dried (MgSO4) and evaporated to leave an oily residue. Flash chromatography over silica gel using 2% ethyl acetate/hexanes yielded (53 mg, 59%) of the pure ulfonyl chloride as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[CH:10]1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[CH3:29][C:30]([O:35][CH2:36][C:37]#[CH:38])([CH3:34])[C:31]([OH:33])=[O:32].C(N)(C)(C)C>O.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>[CH3:10][O:32][C:31](=[O:33])[C:30]([O:35][CH2:36][C:37]#[C:38][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:34])[CH3:29]
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: Nc1ccc(Cl)cc1I
Reactant: C#CCOC(C)(C)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(C)(C)N
Product: COC(=O)C(C)(C)OCC#Cc1cc(Cl)ccc1N

Procedure:
A mixture of 2 g (7.89 mM) of 4-chloro-2-iodoaniline, 75 mg (0.395 mM) of cuprous iodide, 277 mg (0.39 mM) of bis(triphenylphosphine)dichloropalladium, 221 mg (0.79 mM) of tri-(cyclohexyl)phosphine, 3.08 g (19.7 mM) of the methyl ester of 2-methyl-2-(2-propynyloxy)-propanoic acid and 15 ml of tert-butylamine is prepared. The reaction mixture is refluxed gently for 16 hours and then cooled, hydrolyzed in 60 ml of water and extracted with 3×40 ml of dichloromethane. The combined organic phases are washed with water and then dried over magnesium sulfate and concentrated under reduced pressure. The residual oil is purified by chromatography on silica gel using a dichloromethane/ethyl acetate mixture (98/2; v/v) as the eluent to give 1.84 g of the expected product in the form of an orange oil (yield=83%).