Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:9]#[N:10])[CH2:3]1.[CH2:11]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH2:13].C([BH3-])#N.[Na+]>>[CH2:15]([N:14]([CH2:11][CH:12]=[CH2:13])[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:9]#[N:10])[CH2:3]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: N#CC1CCCCC(=O)C1
Reactant: C=CCNCCCCCCC
Agent: [BH3-]C#N
Agent: [Na+]
Product: C=CCN(CCCCCCC)C1CCCCC(C#N)C1

Procedure:
In a manner similar to Preparation 8, react 3-oxocycloheptanecarbonitrile with N-(2-propenyl)heptanamine and sodium cyanoborohydride to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>[Cu]Br.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[CH:5]2
Reactant: Ic1ccccc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Cu+2]
Agent: [Cu]Br
Agent: CC(=O)[O-]
Product: Brc1ccc2c(ccn2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 18 %

Procedure:
Copper(I) bromide (0.073 g, 0.509 mmol) was added to a solution of 5-bromo indole (1 g, 10.2 mmol) in iodo benzene (13.5 g, 66.2 mmol) followed by potassium carbonate (2.7 g, 19.54 mmol), and the mixture was stirred at 100° C. for 10 min. NaOH (150 mg, 3.75 mmol) and copper(II) acetate (0.01 g, 0.055 mmol) was added at 140° C., and the mixture was stirred for 9 h. Insoluble solids were filtered off, filtrate was concentrated and partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography using 8% ethyl acetate in pet ether to afford title compound (0.5 g, 36%) as an oil. 1H NMR (300 MHz, CDCl3): δ 7.80 (m, 1H), 7.60-7.45 (m, 4H), 7.42-7.38 (m, 2H), 7.35-7.25 (m, 2H), 6.62 (d, J=3.3 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][C:21]([OH:25])([C:23]#[CH:24])[CH3:22]>>[F:19][C:3]1[C:2]([C:24]#[C:23][C:21]([OH:25])([CH3:22])[CH3:20])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(C)O
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Yield: 83 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a brown solid (140 mg, 83%).
Reaction SMILES: [CH3:1][C:2]1([O:8][C:9](=[O:12])[NH:10]N)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC(O)=O.N([O-])=O.[Na+].N[C@@H:22]([C:26]([OH:28])=[O:27])[C@H:23]([CH3:25])[OH:24].C([O-])([O-])=O.[Na+].[Na+].Cl>O.CCOC(C)=O.O1CCOCC1>[OH:24][C@H:23]([CH3:25])[C@H:22]([NH:10][C:9]([O:8][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:12])[C:26]([OH:28])=[O:27]
Reactant: CC1(OC(=O)NN)CCCCC1
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H](NC(=O)OC1(C)CCCCC1)C(=O)O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 67 %

Procedure:
In a round bottomed flask equipped with a magnetic stirrer, (1-methylcyclohexyl)-N-aminocarbamate (0.497 g, 2.89 mmol), H2O (4 mL) and CH3COOH (0.33 mL, 5.78 mmol) were added sequentially. The mixture was cooled to 0° C. and NaNO2 (0.239 g, 3.47 mmol) dissolved in H2O (1 mL) was added dropwise. The cloudy mixture was stirred for 40 min at rt, then dioxane (10 mL) was added followed by a D-threonine salt solution [prepared from D-threonine (0.516 g, 4.33 mmol) dissolved in H2O (4 mL) and Na2CO3 (1.25 g, 11.56 mmol)]. The mixture was heated overnight at 45° C., then cooled to rt. AcOEt (50 mL) and H2O (50 mL) were added and, while maintaining a vigorous stirring, the pH was adjusted to 2 with 2M HCl solution. The two phases were separated and the aqueous phase washed again with of AcOEt (15 mL) for 10 min. The combined organic portions were dried over Na2SO4 and concentrated to give a light yellow oil (0.503 g, 67%) which was used in the next step without further purification. MS (ESI) m/z: 282.3 [M−Na]+; (ESI) m/z: 258.1 [M−H]−. 1H NMR (DMSO-d6): δ 1.09 (d, J=6.3 Hz, 3H), 1.10-1.65 (m, 8H), 1.40 (s, 3H), 2.04 (m, 2H), 3.89 (dd, J=9.3, 3.2 Hz, 1H), 4.06 (m, 1H), 6.31 (d, J=9.3, 1H), 12.08 (bs, 1H).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:13][C:14]3[C:19]([N:20]=2)=[CH:18][C:17]([C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=3)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CO.ClCCl.[OH-].[Na+]>O>[C:1]([NH:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:13][C:14]3[C:19]([N:20]=2)=[CH:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(NC(C)=O)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NC1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask was placed methyl 3-(4-acetamidopiperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (100 mg, 0.25 mmol, 1.00 equiv), methanol (15 mL), dichloromethane (7 mL). To this was added a solution of sodium hydroxide (1.5 g, 37.50 mmol, 151.50 equiv) in water (7 mL). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum and diluted with 10 ml of H2O. The pH of the aqueous solution was adjusted to 3 with hydrochloric acid. The resulting solids were collected by filtration. This resulted in 95 mg (94%) of 3-(4-acetamidopiperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a light yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N1C=CC=CC=1.[CH2:25]([CH:32]1[CH2:37][CH2:36][N:35]([CH:38]([CH3:48])[C:39]([C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=2)=[O:40])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)C>[CH2:25]([CH:32]1[CH2:33][CH2:34][N:35]([CH:38]([CH3:48])[C:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:43][CH:42]=2)=[O:40])[CH2:36][CH2:37]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C(=O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCC(=O)Oc1ccc(C(=O)C(C)N2CCC(Cc3ccccc3)CC2)cc1
Reaction time: 5 h

Procedure:
6.5 g of palmitoyl chloride are added to 40 ml of pyridine containing 7 g of 2-(4-benzylpiperidino)-4'-hydroxypropiophenone and the mixture is stirred for 5 hours. It is diluted with 100 ml of diethyl ether and left to stand overnight. The precipitate is then collected by filtration, washed and dried. 11 g of a product which melts at 185°-192° C. with decomposition are thus isolated.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][N:5]=[C:4]([NH2:14])[CH:3]=1.C1C(=O)N([Br:22])C(=O)C1>C(#N)C>[Br:22][C:3]1[C:4]([NH2:14])=[N:5][CH:6]=[C:7]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1cc(-c2cnc(N)cc2F)cn1
Solvent: CC#N
Product: Cn1cc(-c2cnc(N)c(Br)c2F)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 14.2 %

Procedure:
To a solution of 4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (150 mg, 0.780 mmol) in acetonitrile (7. 805 mL) was added NBS (142 mg, 0.796 mmol) in three portions at 0° C. The reaction mixture was stirred at 0° C. for 20 min. LCMS showed the reaction complete. After quenched with sat Na2SO3 and NaHCO3, stirred for 30 min. The reaction mixture was extracted with EtOAc 3 times. Filtered out solid. The solid was not the desired product. The EtOAc layers were washed by sat NaHCO3, water and brine. Dried and concentrated. The crude material was purified with flash chromatography eluting with 0-100% EtOAc (containing 10% MeOH/heptane to provide 30 mg of desired product. LCMS (m/z): 273.1 (MH+), 0.46 min.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]4[NH2:27])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[N+](C1C=CC([CH:39]2[S:43]/[C:42](=[N:44]\[C:45](=O)[O-:46])/[N:41]([C:48]3[CH:53]=[C:52]([CH3:54])[CH:51]=[CH:50][C:49]=3[CH:55]([CH3:57])[CH3:56])[C:40]2=[O:58])=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:55]([C:49]1[CH:50]=[CH:51][C:52]([CH3:54])=[CH:53][C:48]=1[N:41]1[C:40](=[O:58])[CH2:39][S:43]/[C:42]/1=[N:44]\[C:45]([NH:27][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:28])[F:29])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[O:46])([CH3:57])[CH3:56]
Reactant: NC1CCCCC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1ccc(C(C)C)c(N2C(=O)C(c3ccc([N+](=O)[O-])cc3)S/C2=N\C(=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NC2CCCCC2c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 5.9 %

Procedure:
To 2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclohexanamine (CB56) (0.200 g, 0.497 mmol) and (Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50) (0.205 g, 0.497 mmol) were dissolved in acetonitrile (10 mL) in a vial. Cesium carbonate (0.162 g, 0.497 mmol) was added, and the reaction was stirred at room temperature for 25 hours. The solution was adsorbed onto silica. Purification by reverse-phase flash column chromatography using 0-100% acetonitrile/water as eluent afforded the title compound as a red oil (0.020 g, 6%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]C)=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(OC1C=NC(C2C=CC(CCCCCCCCCCCC)=CC=2)=NC=1)CCCCCCC.C(OC1C=NC(C2C=CC(CCCCCCCCCCC)=CC=2)=NC=1)CCCCCCC>>[CH2:1]([O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=2)=[N:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1cnc(-c2ccc(CCCCCC)cc2)nc1
Agent: CCCCCCCCCCCCc1ccc(-c2ncc(OCCCCCCCC)cn2)cc1
Agent: CCCCCCCCCCCc1ccc(-c2ncc(OCCCCCCCC)cn2)cc1
Product: CCCCCCCCOc1cnc(-c2ccc(CCCCC)cc2)nc1

Procedure:
5-octyloxy-2-(4-hexylphenyl)pyrimidine ##STR10## 5-octyloxy-2-(4-heptylphenyl)pyrimidine ##STR11## 5-octyloxy-2-(4-octylphenyl)pyrimidine ##STR12## 5-octyloxy-2-(4-nonylphenyl)pyrimidine ##STR13## 5-octyloxy-2-(4-decylphenyl)pyrimidine ##STR14## 5-octyloxy-2-(4-undecylphenyl)pyrimidine 5-octyloxy-2-(4-dodecylphenyl)pyrimidine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][C:11]3=[N:13][N:14]=[C:15]([S:16][CH3:17])[N:10]3[CH:9]=[CH:8][C:7]=2[CH:18]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][C:11]3=[N:13][N:14]=[C:15]([S:16]([CH3:17])=[O:27])[N:10]3[CH:9]=[CH:8][C:7]=2[CH:18]=1
Reactant: COc1ccc2c(c1)C=Cn1c(nnc1SC)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COc1ccc2c(c1)C=Cn1c(nnc1S(C)=O)C2

Procedure:
By a procedure similar to that described in Example 17, 8-methoxy-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine was reacted with m-chloroperbenzoic acid to obtain 8-methoxy-3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from chloroform-methanol), m.p. 241°-242° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]([F:32])([F:31])[C:24]1([CH2:29][OH:30])[CH2:28][CH2:27][NH:26][CH2:25]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][CH2:28][C:24]([CH2:29][OH:30])([C:23]([F:31])([F:32])[F:22])[CH2:25]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: OCC1(C(F)(F)F)CCNC1
Agent: Cl
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC(CO)(C(F)(F)F)C1
Yield: 35.9 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 20 mg, 70.4 μmol) was reacted with (3-(trifluoromethyl)pyrrolidin-3-yl)methanol hydrochloride (CAN 1260812-78-9, 17.4 mg, 84.4 μmol) to obtain the title compound (11 mg, 36%) as colorless liquid, MS (EI): m/e=436.4 [MH+].
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[N+]([O-])([O-])=O.[Na+].[Cl:35][C:36]1[CH:37]=[C:38]([SH:43])[CH:39]=[CH:40][C:41]=1[Cl:42]>S(=O)(=O)(O)O.O.[OH-].[Na+]>[CH2:23]([N:20]1[CH2:19][CH2:18][N:17]([C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]3[CH:4]=[CH:3][C:2]([S:43][C:38]4[CH:39]=[CH:40][C:41]([Cl:42])=[C:36]([Cl:35])[CH:37]=4)=[CH:7][N:6]=3)=[CH:10][CH:11]=2)=[O:16])[CH2:22][CH2:21]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccc(Oc2ccc(C(=O)N3CCN(Cc4ccccc4)CC3)cc2)nc1
Reactant: Sc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(c1ccc(Oc2ccc(Sc3ccc(Cl)c(Cl)c3)cn2)cc1)N1CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of [4-(5-aminopyridin-2-yloxy)phenyl](4-benzylpiperazin-1-yl)methanone (0.73 g, 1.88 mmol) in concentrated sulfuric acid (0.38 mL)-water (1.1 mL) were added dropwise a solution of sodium nitrate (0.13 g, 1.88 mmol) in water (0.6 mL) under ice cooling. The reaction mixture was stirred for 10 minutes. This reaction mixture was added to a solution of 3,4-dichlorobenzenethiol (0.24 mL, 1.88 mmol) in 2 N aqueous sodium hydroxide (2 mL) under cooling with ice. Water was added to the resulting reaction solution, and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (dichloromethane:methanol=80:1), to thereby yield 0.1 g of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH:24]([CH3:26])[CH3:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH:24]([CH3:26])[CH3:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 103.4 %

Procedure:
tert-Butyl (3R)-6-cyclohexyl-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 46) (250 mg, 0.69 mmol) was treated with trifluoroacetic acid (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 45 minutes. The solvent was removed under reduced pressure and the residue azeotroped from toluene then dichloromethane to afford the title compound as a white solid (220 mg).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:39]([C:35]3[S:34][CH:38]=[CH:37][CH:36]=3)=[O:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)c1cccs1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccs4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.620 g, 4.07 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione hydrochloride (0.600 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 2-thiophene-carbonyl chloride (0.3 g, 2.03 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: EtOAc 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-thienylcarboxamide (0.35 g, 47%) as a white solid: mp 192-194° C.; 1H NMR (DMSO-d6) δ d 11.16 (s, 1H), 9.18 (t, J=5.8 Hz, 1H), 7.88-7.72 (m 5H), 7.20-7.17 (dd, J=3.9 and 4.7 Hz, 1H), 5.22-5.15 (dd, J=5.5 and 12.7 Hz, 1H), 4.94 (d, J=5.8 Hz, 2H), 2.98-2.85 (m, 1H), 2.66-2.50 (m, 2H), 2.11-2.06 (m, 1H); 13C NMR (DMSO-d6) δ d 172.72, 169.80, 167.51, 166.93, 161.52, 139.26, 139.14, 134.83, 133.14, 131.53, 131.11, 128.51, 127.96, 127.12, 121.93, 48.89, 38.09, 30.93, 21.99; Anal. Calcd. For C19H15N3O5S: C, 57.42; H, 3.80; N, 10.57; S, 8.07. Found: C, 57.80; H, 3.93; N, 10.22; S, 7.99.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[N+:22]#[C-:23])/[C:11](/[N+:20]#[C-:21])=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CN(C=O)C>[CH2:30]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[C:11]([N+:20]#[C-:21])[C:10]([N+:22]#[C-:23])=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:14][CH:15]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: [C-]#[N+]C(=C\c1ccc(O)cc1)/C(=C/c1ccc(OC)cc1)[N+]#[C-]
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: [C-]#[N+]C(=Cc1ccc(OC)cc1)C(=Cc1ccc(OCCCCCC)cc1)[N+]#[C-]
Yield: 94 %

Procedure:
13 mg of xanthocillin X monomethyl ether was dissolved in 2 ml of DMF and 40 mg of potassium carbonate was added thereto. Further, 50 μl of n-hexyl bromide was added thereto and the mixture thus formed was extracted with 30 ml portions of ethyl acetate thrice. The extracts were combined, successively washed with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The sodium sulfate was filtered off and the solvent was distilled from the filtrate. Thus 15 mg of 1-(4'-n-hexyloxyphenyl)-4-(4'-methoxyphenyl)-2,3-diisocyano-1,3-butadiene was obtained in the form of a brown solid. Yield: 94%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([S:16]([CH:19]=[CH2:20])(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:26][CH:25]1[C:37]([NH2:39])=[O:38])=[O:23].[CH2:40]([NH:42][CH2:43][CH3:44])[CH3:41]>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([S:16]([CH2:19][CH2:20][N:42]([CH2:43][CH3:44])[CH2:40][CH3:41])(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:26][CH:25]1[C:37]([NH2:39])=[O:38])=[O:23]
Reactant: CCNCC
Reactant: C=CS(=O)(=O)N1CCC(Oc2ccc(CC(=O)N3CCN(c4ccccc4C)CC3C(N)=O)c(OC)c2)CC1
Solvent: CO
Product: CCN(CC)CCS(=O)(=O)N1CCC(Oc2ccc(CC(=O)N3CCN(c4ccccc4C)CC3C(N)=O)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(2-Methoxy-4-(1-ethenylsulfonyl-4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl)piperazine-2-carboxamide (52 mg, 0.093 mmol) was dissolved in methanol (5 ml), treated with diethylamine (0.013 ml, 9.2 mg, 0.12 mmol), and stirred at ambient temperature under nitrogen for 18 hours. An additional 0.01 ml of diethylamine was added and the mixture stirred another 24 hours at ambient temperature. The reaction was concentrated in vacuo and the residue was chromatographed on silica gel eluted with 3% followed by 5%, then 7% methanol in methylene chloride. The combined product fractions were evaporated to dryness in vacuo to give 1-(2-methoxy-4-(1-(2-(N,N-diethylamino)-ethylsulfonyl)-4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl)piperazine-2-carboxamide: mp 70°-140° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:22]2[CH2:23][C:24]([CH3:31])([CH3:30])[O:25][C:26]([CH3:29])([CH3:28])[CH2:27]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(=O)O)cc2)CC(C)(C)O1
Temperature: 75 °C
Yield: 95.1 %

Procedure:
Ethyl (2E)-3-{4-[(4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}prop-2-enoate (54) (0.1095 g, 0.260 mmole) was dissolved in ethanol (5 mL). Potassium hydroxide (0.260 mL of a 3 M aqueous solution, 0.780 mmole) was added and the mixture was heated to 75° C. for 2.5 h. The solution was cooled to RT and concentrated. Water (25 mL) was added and the mixture was extracted with ether (10 mL). The organics were thrown out and the aqueous layer was treated with 1 N aqueous HCl to pH=3. The resulting mixture was extracted with methylene chloride (3×10 mL). The organics were dried (Na2SO4) and concentrated to provide 0.097 g (95%) of compound 55 as a pale yellow solid. 1H NMR (DMSO-d6): δ 12.33 (s, 1H), 9.34 (s, 1H), 7.59 (d, J=8.2 Hz, 2H), 7.52 (d, J=15.9 Hz, 1H), 7.15 (d, J=8.2 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.4 Hz, 2H), 6.44 (d, J=15.9 Hz, 1H), 2.14 (s, 2H), 2.11 (s, 2H), 1.11 (s, 6H), 1.10 (s, 6H). LRMS (ESI): m/z 391 (M−H)−.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([CH2:34][C:33]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:32]=2[F:31])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)ccc1Cl
Reactant: Fc1ccc(CBr)c(F)c1
Product: C=CCOc1cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Cl

Procedure:
The product from Example 91D and 2,4-difluorobenzyl bromide were processed as described in Example 6B to provide the title compound. MS (ESI+) m/z 573 (M+H)+.