Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[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].[OH-].[Na+].Cl[CH2:30][CH:31]([OH:34])[CH2:32][OH:33]>CN(C)P(N(C)C)(N(C)C)=O.O.CCOCC>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:30][CH:31]([OH:34])[CH2:32][OH:33])=[O:23])=[CH:25][CH:26]=1)[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]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: OCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Temperature: 140 °C

Procedure:
A solution of 7.35 g of 4-(n-hexadecylamino)benzoic acid in 50 ml of hexamethylphosphoramide is treated with 4.80 g of 25% aqueous sodium hydroxide followed by 11.0 g of 3-chloro-1,2-propanediol and then is heated at 140° C for 6 hours. The mixture is diluted with water and ether and filtered to yield a white solid. Recrystallization from acetonitrile and then from carbon tetrachloride affords analytically pure 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate, mp 112°-113° C.
Reaction SMILES: [NH:1]1[CH:5]([C:6](O)=O)[CH2:4][CH2:3][C:2]1=[O:9].[CH3:10][C:11]1[CH:16]=C[CH:14]=[CH:13][C:12]=1[O:17][CH3:18].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O>C(Cl)Cl.O>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][C:6]([CH:5]2[NH:1][C:2](=[O:9])[CH2:3][CH2:4]2)=[CH:10][C:11]=1[CH3:16]
Reactant: O=C1CCC(C(=O)O)N1
Reactant: COc1ccccc1C
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C2CCC(=O)N2)cc1C
Temperature: 100 °C
Yield: 55.9 %

Procedure:
2-Pyrrolidone-5-carboxylic acid (2.0 g, 15.5 mmol) and 2-methylanisole (2.1 mL, 17.0 mmol) were added to a mixture of 1.0 g (3.52 mmol) of phosphorous pentoxide and 6.7 mL methanesulfonic acid. The mixture was heated at 100° C. for 2 hr, cooled down to rt, and poured into a mixture of H2O and CH2Cl2. The aqueous layer was separated, and extracted with CH2Cl2 (3×20 mL). Organic layers were combined, washed with sat'd NaHCO3, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+M cartridge using 4:1 v/v EtOAc/hexanes as the eluant afforded 1.78 g (56%) of the title compound: 1H NMR δ 1.88-1.97 (m, 1H), 2.21 (s, 3H), 2.35-2.54 (m, 3H), 3.81 (s, 3H), 4.66 (t, J=7.1, 1H), 6.53 (br. s, 1H), 6.79 (d, J=8.6, 1H), 7.05-7.09 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.8 %

Procedure:
To a solution of tert-butyl 3-bromopropylcarbamate (0.5 g, 2 mmol) and 3,4-dichlorophenol (0.38, 2.3 mmol) in DMF (10.5 mL) was added Cs2CO3 (1.02 g, 3.10 mmol). The reaction mixture was stirred at rt for 72 h. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with saturated aqueous NaCl and water (1:1), dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by silica gel chromatography to provide Intermediate 3A (543 mg, 56% yield). HPLC/MS (Method B) RT=3.85 min, [M+H]+ 320.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH2:12][CH3:13])[CH3:2].[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[C:17]=1[CH2:25][CH3:26])[CH3:15]>C(OCC)(=O)C>[CH2:12]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[NH2:9])[CH3:13].[CH2:25]([C:17]1[C:16]([CH2:14][CH3:15])=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:22])[CH3:26]
Reactant: CCc1ccc([N+](=O)[O-])cc1CC
Reactant: CCc1cccc([N+](=O)[O-])c1CC
Solvent: CCOC(C)=O
Product: CCc1ccc(N)cc1CC
Product: CCc1cccc(N)c1CC
Temperature: 25 °C
Reaction time: 10 h
Yield: 19 %
Yield: 71 %

Procedure:
A mixture of 1,2-diethyl-4-nitrobenzene (16) and 1,2-diethyl-3-nitrobenzene (17) (1.4 g, 7.82 mmol) was dissolved in ethyl acetate (20 mL). To this solution was added 10% Pd--C (350 mg, 20%; Aldrich). The mixture was agitated at room temperature under a pressure of 35 psi (H2) for 10 h. The catalyst was removed through a column of Celite (5 g) and washed with ethyl acetate (3×15 mL). The filtrates were combined and evaporated in vacuo to give a residue, which was separated by preparative TLC (Hexanes:EtOAc=8:2), giving 3,4-diethylaniline (19) (0.822 g, 71%) as a pale yellow oil (Rf =0.7) and 2,3-diethylaniline (20) (0.219 g, 19%) as a brown oil (Rf =0.6). 1H NMR (CDCl3, 300 MHz): δ(19): 1.184 (t, 6H, J=7 Hz), 2.573 (q, 4H, J=7 Hz), 3.456 (br, s, 2H) 6.513 (m, 2H), 6.970 (d, 1H, J=7.8 Hz). (20): 1.215 (t, 6H, J=7 Hz), 2.617 (q, 4H, J=7 Hz), 6.570 (d, 1H, J=7.5 Hz), 6.650 (d, 1H, J=7.5 Hz), 6.973 (m, 1H).
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9]([C:23]#[N:24])=[C:10]([CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+].O>CN(C)C=O.CCOC(C)=O>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][C:10]1[N:11]=[C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[S:8][C:9]=1[C:23]1[NH:27][N:26]=[N:25][N:24]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1sc(N2CCOCC2)nc1Cc1ccc2ccccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc2cc(Cc3nc(N4CCOCC4)sc3-c3nnn[nH]3)ccc2c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 43.7 %

Procedure:
To a solution of 2-(morpholin-4-yl)-4-(2-naphthylmethyl)-1,3-thiazole-5-carbonitrile (213 mg, 0.635 mmol) in N,N-dimethylformamide (3.00 mL) was added sodium azide (61.9 mg, 0.952 mmol) and ammonium chloride (102 mg, 1.90 mmol). The mixture was heated to 100° C. and stirred for 24 hrs. The resulting mixture was cooled to rt and distributed between water and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layer was washed with 10% LiCl(aq) solution (×2), dried, and concentrated. Purification on HPLC (reverse phase, AA) provided 4-[4-(2-naphthylmethyl)-5-(1H-tetrazol-5-yl)-1,3-thiazol-2-yl]morpholine as a yellow solid (105 mg, 43.7% yield). LCMS: (AA) ES+ 379; 1H NMR (400 MHz, MeOD) δ 7.79-7.61 (m, 4H), 7.43-7.31 (m, 3H), 4.57-4.45 (s, 2H), 3.82-3.68 (t, J=4.9 Hz, 4H), 3.53-3.43 (t, J=4.9 Hz, 4H).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]4[CH2:45][CH2:44][CH:43]([O:46][C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)[CH2:42][CH2:41]4)[C:38]([CH3:53])=[C:37]([OH:54])[C:36]3=[O:55])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]4[CH2:41][CH2:42][CH:43]([O:46][C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)[CH2:44][CH2:45]4)[C:38]([CH3:53])=[C:37]([O:54][CH3:3])[C:36]3=[O:55])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1C1CCC(Oc2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CO
Solvent: CCOCC
Product: COC1=C(C)C(C2CCC(Oc3ccccc3)CC2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (9 eq), ethylene glycol/Et2O (1/3 v/v, 40 ml), 1-(1H-Benzo[d]imidazol-6-yl)-3-hydroxy-4-methyl-5-(4-phenoxycyclohexyl)-1H-pyrrol-2(5H)-one (0.900 g, 2.23 mmol, 1 eq) and MeOH (10 ml) and was purified by preparative HPLC; yield: 0.051 g (12.2%); MS m/z: 418.2 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 12.52 (b, 1H), 8.26-8.25 (d, 1H), 7.67-7.53 (m, 2H), 7.27-7.15 (m, 3H), 4.80-4.72 (m, 1H), 4.50 (s, 0.5H), 4.20 (m, 1H), 3.86 (s, 3H), 2.03-1.90 (m, 4H), 1.69-1.65 (m, 2H), 1.46-1.39 (m, 2H), 1.21-0.99 (m, 2H); HPLC (METHOD [A]): rt 13.30 min (97.08%)
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.CI.[Mg].[C:14](=[O:16])=[O:15].Cl>CCOCC.C1(C)C=CC=CC=1>[S:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]([C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: Brc1csc2ccccc12
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Solvent: Cc1ccccc1
Product: O=C(O)c1csc2ccccc12
Temperature: 25 °C
Yield: 44 %

Procedure:
A solution of 3-bromobenzothiophene (0.40 mole, (D15)) and methyl iodide (25 ml, 0.40 mole) in dry ether (400 ml) was added to a stirred mixture of magnesium turnings (24 g, 1.0 mole) and dry ether (100 ml) under nitrogen, at such a rate as to maintain a steady reflux. After the addition was complete, the reaction mixture was heated under reflux for 30 minutes and then allowed to cool to room temperature. The solution was diluted with dry toluene (500 ml) and stirred vigorously as dry carbon dioxide was bubbled through over 3 hours. The thick precipitate which formed was dissolved by the addition of dilute hydrochloric acid and the organic layer was then separated. The aqueous solution was extracted with ethyl acetate (2×300 ml) and all the organic solutions were then combined and extracted with 10% sodium carbonate solution (4×300 ml). The aqueous extracts were combined, washed with ether (2×200 ml) and then acidified with dilute hydrochloric acid. The precipitate was filtered off, washed with water and then dried under vacuum to give the title compound as a white solid (31.2 g, 44%) m.p. 171°-173°.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[C:15]([Cl:21])[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[Cl:19][C:17]1[CH:18]=[C:13]([NH2:12])[CH:14]=[C:15]([Cl:21])[C:16]=1[O:20][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: Clc1nc2c(Cl)cccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1cc(Cl)c(Oc2nc3c(Cl)cccc3s2)c(Cl)c1
Temperature: 145 °C
Yield: 33.3 %

Procedure:
To solution of 2,4-dichlorobenzothiazole (255, 2.23 g, 11 mmol) and 4-amino-2,6-dichlorophenol (Aldrich, 1.78 g, 10 mmol) in 10 mL of DMSO was add K2CO3 (Aldrich, 4.14 g, 30 mmol). The mixture was heated at 145° C. for 4 h. After cooled to room temperature, the reaction mixture was diluted with EtOAc (300 mL) and filtered through a pad of silica gel and activated carbon followed by washing with EtOAc (500 mL). The filtrate was concentrated and the residue was purified by chromatography (20%-30% EtOAc/Hexanes) to give 1.15 g (33%) of product.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC>C1(C)C=CC=CC=1>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:6]2[C:7]3[C:3](=[C:2]([CH:21]=[CH2:22])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cccc32)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 76.7 %

Procedure:
4-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indole (600 mg, 1.71 mmol; Intermediate 3), tributyl(vinyl)stannane (0.550 mL, 1.88 mmol) and Pd(PPh3)2OAc2 (32 mg, 0.043 mmol) were mixed in dry toluene (8 mL) and stirred 24 h at 110° C. using a STEM block, then rt. for 40 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (20% DCM in hexane-50% DCM in hexane). This afforded the title compound 390 mg, 77% as a colorless sticky oil. MS (ESI+) for C17H15NO2S m/z 298 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:22])[C:11](=[O:21])[N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][CH:6]=1)(=O)C.[N+:23]([O-])([O-:25])=[O:24].[K+]>S(=O)(=O)(O)O>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:22])[C:11](=[O:21])[N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24]
Reactant: CC(=O)Nc1ccc2[nH]c(=O)c(=O)n(C3CCCCC3)c2c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Nc1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c(=O)n2C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
20.6 g (68 mmol) of 7-acetamido-1-cyclohexyl-2,3(1H,4H)-quinoxalinedione were dissolved in 250 ml of concentrated sulfuric acid. Then, at 0°-5° C., 7.2 g (71 mmol) of potassium nitrate were added a little at a time. The mixture was then stirred at 0° C. for 30 min and at room temperature for 2 h and subsequently poured into 1.5 1 of ice-water and then heated on a water bath for 4 h. The resulting precipitate was filtered off with suction. The filtrate was adjusted to pH 6 with a little ammonia solution and was extracted with methylene chloride. The organic phase was dried and concentrated under reduced pressure. This residue and the first precipitate were combined to yield 13.4 g (64%) of the product. Melting point>260° C.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1.Cl.Cl.O.O1CCCC1>CO>[S:16]1[C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:2]=[O:1])=[CH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]1=2
Reactant: c1ccc(C2OCCO2)c(-c2cc3ccccc3s2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=Cc1ccccc1-c1cc2ccccc2s1

Procedure:
For example, the 2-(2-[1,3]dioxolan-2-yl-phenyl) benzo[b]thiophene (3) product is treated with a suitable acid, such as a hydrochloric acid, preferably an aqueous acid, such as a hydrochloric acid/water mixture. The reaction is carried out in a suitable organic solvent such as tetrahydrofuran or methanol. The reaction is heated to reflux for a period of time ranging from about 20 minutes to about 6 hours. The reaction is then quenched with a weak base such as, for example, sodium bicarbonate. The solvent is removed and the resulting mixture may be extracted, concentrated and purified according to techniques well known in the art, to provide benzo[b]thiophen-2-yl-benzaldehyde (4).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:13]C1C=CC(C[C@@H](C(O)=O)N)=CC=1.N[C@H](C(O)=O)CC[Se]C>>[F:13][NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: C[Se]CC[C@H](N)C(=O)O
Product: O=C(O)[C@H](Cc1ccccc1)NF
Reaction time: 21 h

Procedure:
Replacement of phenylalanine residues in a protein with p-fluoro-L-phenylalanine (F-Phe) can be implemented for the structural analysis of the protein by19F NMR8, 9. However, as with selenomethionine substitution, F-Phe substitution is cytotoxic. We followed the expression of the CspA in a manner analogous to that demonstrated for selenomethionine EnvZB. CspA was expressed with pColdI(SP4)cspA for 21 hr with and without the addition of F-Phe (FIG. 4A). The addition of F-Phe did not adversely affect CspA production in the SPP system. We then affinity purified the 86-residue CspA product and used mass spectroscopy to determine the extent of F-Phe substitution (FIGS. 4B,C). Although the endogenous Phe biosynthesis was not inhibited in the present SPP system, substantial incorporation of F-Phe (approximately 60 to 70% of total Phe residues) was observed, indicating that toxic F-Phe can be efficiently incorporated into a protein without affecting its yield.
Reaction SMILES: BrC1C=C[C:12]2[C:11]3[C:6](=CC(Br)=[CH:9][CH:10]=3)[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Br:29])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Br:22])[C:4]=2C=1.[C:30]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36](C(C)(C)C)[C:35]=1O)([CH3:33])(C)C.[CH2:45](C([Sn])=C(CCCC)CCCC)[CH2:46]CC.[F-].[K+]>CCOCC.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.C1(C)C=CC=CC=1>[Br:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:5]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Br:29])[C:35]2[CH:36]=[C:37]([CH:45]=[CH2:46])[CH:38]=[CH:39][C:34]=2[C:30]2[C:4]1=[CH:12][C:11]([CH:10]=[CH2:9])=[CH:6][CH:33]=2
Reactant: BrCCCCCCC1(CCCCCCBr)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)C(CCCCCCBr)(CCCCCCBr)c1cc(C=C)ccc1-2
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A flask with a stirring bar was charged with a mixture of compound 1 (1.000 g, 1.54 mmol), PdCl2(PPh3)2 (0.0588 g, 0.065 mmol), a few crystals of 2,6-ditert-butylphenol, and toluene (15.0 mL). The mixture was heated to 100° C. under nitrogen, and tributylvinyltin (1.125 g, 3.534 mmol) was added dropwise. The mixture was further heated for 23 hours. It was subsequently diluted with 60 mL of ether and treated with KF solution (˜10%). The mixture was stirred for 20 hours and followed by filtration to remove the insoluble solid. The organic layer was washed with water and dried over anhydrous MgSO4. After removal of the solvent, the residue was purified by column chromatography with n-hexane as eluent to afford 0.650 g of compound 2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>O1CCCC1>[Cl:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])[CH:7]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2Cl)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2Cl)ccn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Amino-4-(2-chloro-4-nitrophenoxy)pyridine (574 mg) was dissolved in tetrahydrofuran (10 ml) under a nitrogen atmosphere, and then triethylamine (0.602 ml) and phenyl chloroformate (0.542 ml) were added dropwise thereto while cooling in an ice bath, followed by stirring at room temperature for 10 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to provide a crude product of 4-(2-chloro-4-nitrophenoxy)-2-(phenoxycarbonylamino)pyridine (1.272 g). The crude product (637.3 mg) was dissolved in tetrahydrofuran (6.5 ml), and then pyrrolidine (1.06 ml) was added at room temperature, followed by stirring for 1 hr and evaporating the solvents under a reduced pressure. The resultant residue was dissolved in ethanol (20 ml)-water (5 ml), and then electrolytic iron powder (500 mg) and ammonium chloride (1 g) were added thereto, followed by heating under reflux for 1 hr. The reaction mixture was cooled down to room temperature, and filtered through celite to remove an insoluble portion, which was washed with ethyl acetate-tetrahydrofuran (1:1) and water. The organic layer of the filtrate was separated, washed with water and brine in this order, dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent; ethyl acetate) to provide the titled compound (227 mg) as pale yellow powder.
Reaction SMILES: [NH2:1][C:2]12[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[CH2:11]([O:14][CH2:15][CH2:16]Cl)[CH2:12][Cl:13]>>[ClH:13].[CH3:9][C:8]1([CH3:10])[C:2]2([N:1]3[CH2:16][CH2:15][O:14][CH2:11][CH2:12]3)[CH2:7][CH2:6][CH:5]1[CH2:4][CH2:3]2
Reactant: ClCCOCCCl
Reactant: CC1(C)C2CCC1(N)CC2
Product: CC1(C)C2CCC1(N1CCOCC1)CC2
Product: Cl

Procedure:
A stirred mixture of 1-amino-7,7-dimethylnorbornane (0.7 gm) potassium carbonate (0.77 gm) and 2,2'-dichlorodiethyl ether (3 ml) was heated at 130° for 2 hrs. The reaction mixture was then cooled and partitioned between ether and 2 N hydrochloric acid solution. The aqueous layer was separated basified and extracted into ether. The organic layer was dried, and evaporated. The residue (0.8 gm) after purification by chromatography was dissolved in dry ether and treated with hydrogen chloride to give the title compound (0.33 gm) m.p. 243° to 246°.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].CO.C[O-].[Na+].Cl[CH:13]=[CH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:19]=1>C(OCC)C>[OH:30][CH:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][CH2:16][CH:15]=[CH:14][CH2:13][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC(O)c1cccc(OCCC=CCl)c1
Reactant: O=C(O)CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCCCCC(O)c1cccc(OCC=CCSCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9.15 ml. (0.105 mole) 3-mercaptopropionic acid are dissolved in 70 ml. methanol and stirred with 315 ml. 1M sodium methylate solution for 10 minutes at ambient temperature under an atmosphere of nitrogen. Subsequently, 19.79 g. (0.07 mole) 1-chloro-4-[3-(1-hydroxyhexyl)-phenoxy]-but-1-ene in 70 ml. methanol are added dropwise thereto in the course of 15 minutes. The reaction mixture is further stirred for 3 hours at ambient temperature and the solvent is then stripped off. The residue is taken up in diethyl ether and extracted several times with 2M aqueous sodium hydroxide solution. The aqueous solution is acidified with 2M hydrochloric acid and the desired compound is extracted with methylene chloride. After drying and stripping off the solvent, there are obtained 22.5 g. (91% of theory) of the title compound in the form of an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][F:11].CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=[NH:77])(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[F:11][CH2:10][CH2:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:77]
Reactant: FCCOc1ccccc1Br
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Nc1ccccc1OCCF
Temperature: 120 °C
Yield: 99.9 %

Procedure:
To a solution of the product of Example 126, Step 1 (800 mg, 3.65, mmol) in deoxygenated toluene (15 mL) was added NaOtBu (498 mg, 5.2 mmol), BINAP (364 mg, 0.58 mmol) Pd2(dba)3 (217 mg, 0.24 mmol) and benzophenone imine (0.8 mL, 4.7 mmol). The reaction mixture was heated at 120° C. for 3 h. The crude mixture was then washed with DCM and the aqueous layer was made basic with sat. NaHCO3. The aqueous layer was extracted with DCM and the combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography on silica gel (0-5% MeOH in DCM) to afford the title compound (566 mg, 90%). MS (ESI) mass calcd. C8H10FNO, 155.1. m/z found, 156.1 [M+H]+.