Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[NH:12][C:11](=[O:16])[C:10]=1[CH2:17][NH:18][C:19]([C:21]1[CH:29]=[C:28]([C:30]2[CH:31]=[CH:32][C:33]([N:36]3[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][C@H:37]3[CH3:49])=[N:34][CH:35]=2)[CH:27]=[C:26]2[C:22]=1[C:23]([CH3:53])=[CH:24][N:25]2[CH:50]([CH3:52])[CH3:51])=[O:20]>C(Cl)Cl>[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[NH:12][C:11](=[O:16])[C:10]=1[CH2:17][NH:18][C:19]([C:21]1[C:22]2[C:23]([CH3:53])=[CH:24][N:25]([CH:50]([CH3:52])[CH3:51])[C:26]=2[CH:27]=[C:28]([C:30]2[CH:35]=[N:34][C:33]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][C@H:37]3[CH3:49])=[CH:32][CH:31]=2)[CH:29]=1)=[O:20]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)C[C@H]4C)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCNC[C@H]4C)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
Added trifluoroacetic acid (1 ml, 12.98 mmol) to a solution of (R)-tert-butyl 4-(5-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1-isopropyl-3-methyl-1H-indol-6-yl)pyridin-2-yl)-3-methylpiperazine-1-carboxylate (57 mg, 0.091 mmol) in DCM (3 mL) and let stir at RT for 1 hour. Concentrated on rotovap. Partitioned between DCM and sat′d Na2CO3, separated and washed DCM phase with water, brine, dried (MgSO4), filtered and rotovapped off DCM. Obtained 25 mg of the title compound as a tan solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (d, 2H), 1.46-1.59 (m, 6H), 2.21 (s, 3H), 2.27 (s, 3H), 2.44 (s, 3H), 2.83 (dd, J=12.13, 3.54 Hz, 1H), 2.96-3.29 (m, 4H), 3.90 (br. s., 1H), 4.47-4.76 (m, 5H), 6.00 (s, 1H), 6.51 (d, J=8.59 Hz, 1H), 7.05 (s, 1H), 7.45 (s, 1H), 7.68 (dd, J=8.72, 2.40 Hz, 1H), 8.43 (d, J=2.27 Hz, 1H), 10.11-12.70 (m, 1H). LCMS: [M+H]+ 527.5.
Reaction SMILES: C(O)CC=C.C=CC=C.C([O-])(=O)C=CC=C.[C:17](SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)(=[O:22])[CH2:18][C:19]([OH:21])=[O:20].[C:71]([S:74][CH2:75][CH2:76][NH:77][C:78](=[O:121])[CH2:79][CH2:80][NH:81][C:82](=[O:120])[C@H:83]([OH:119])[C:84]([CH3:118])([CH3:117])[CH2:85][O:86][P:87]([OH:116])(=[O:115])[O:88][P:89]([OH:114])(=[O:113])[O:90][CH2:91][C@H:92]1[O:96][C@@H:95]([N:97]2[C:106]3[N:105]=[CH:104][N:103]=[C:101]([NH2:102])[C:100]=3[N:99]=[CH:98]2)[C@H:94]([OH:107])[C@@H:93]1[O:108][P:109]([OH:112])([OH:111])=[O:110])(=[O:73])[CH3:72]>>[O:22]=[C:17]([CH2:18][C:19]([OH:21])=[O:20])[CH2:72][C:71]([S:74][CH2:75][CH2:76][NH:77][C:78](=[O:121])[CH2:79][CH2:80][NH:81][C:82](=[O:120])[C@H:83]([OH:119])[C:84]([CH3:117])([CH3:118])[CH2:85][O:86][P:87]([OH:116])(=[O:115])[O:88][P:89]([OH:114])(=[O:113])[O:90][CH2:91][C@H:92]1[O:96][C@@H:95]([N:97]2[C:106]3[N:105]=[CH:104][N:103]=[C:101]([NH2:102])[C:100]=3[N:99]=[CH:98]2)[C@H:94]([OH:107])[C@@H:93]1[O:108][P:109]([OH:112])([OH:111])=[O:110])=[O:73]
Reactant: CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CC(=O)O
Agent: C=CC=C
Agent: C=CC=CC(=O)[O-]
Agent: C=CCCO
Product: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CC(=O)CC(=O)O

Procedure:
Pathways to 3-butene-1-ol, butadiene and 2,4-pentadienoate from malonyl-CoA and acetyl-CoA are shown in FIG. 21. In these pathways, malonyl-CoA and acetyl-CoA are joined by a thiolase to form 3-oxoglutaryl-CoA. This intermediate can then be converted to 3,5-dihydroxypentanoate by several alternate routes (Steps B/C/D, Steps B/G, Steps H/I/J, Steps H/L/D, K/J). Once formed, 3,5-dihydroxypentanoate can be decarboxylated by a 3-hydroxyacid decarboxylase to form 3-butene-1-ol (Step M). Subsequent dehydration by a 3-butene-1-ol dehydrogenase or a chemical catalyst yields butadiene (Step O). Alternately, 3,5-dihydroxypentanoate can be dehydrated to 5-hydroxypent-2-enoate as shown in Step E. This intermediate can then be decarboxylated to 3-butene-1-ol (Step N) or further dehydrated to 2,4-pentadienoate (Step F).
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[C:20]([C:8]4[C:9]=2[C:4]([CH:5]=[CH:6][CH:7]=4)=[CH:3][CH:2]=1)=[N:19][C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]=3.O[S:22]([OH:25])(=[O:24])=[O:23].[O:26]=[S:27](=[O:29])=[O:28]>O>[CH:1]1[C:10]2[C:11]3[C:20]([C:8]4[C:9]=2[C:4]([CH:5]=[C:6]([S:22]([OH:25])(=[O:24])=[O:23])[CH:7]=4)=[CH:3][C:2]=1[S:27]([OH:29])(=[O:28])=[O:26])=[N:19][C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]=3
Reactant: O=S(=O)=O
Reactant: O=S(=O)(O)O
Reactant: c1cc2c3c(cccc3c1)-c1nc3ccccc3nc1-2
Solvent: O
Product: O=S(=O)(O)c1cc2c3c(cc(S(=O)(=O)O)cc3c1)-c1nc3ccccc3nc1-2

Procedure:
Acenaphtho[1,2-b]quinoxaline (10 g) was charged into 10% oleum (49 ml), stirredfor 30 minutes and heated at 180–190° C. for 30 hours. The reaction mixture was then diluted with water (95 ml), and the formed precipitate was filtered and washed with acetic acid (˜30 ml). The filtered cake was dried on air at 120° C. to yield 8.2 g of acenaphtho[1,2-b]quinoxaline-2,5-disulfonic acid. 1H NMR (Bruker AMX-400, DMSO-d6, δ, ppm): 7.82 (q, 2H, 3 Hz); 8.18 (q, 2H, 3 Hz); 8.24–8.36 (broad s, 2H); 8.62 (s, 4H). Elemental analysis calculated for C18H10N2O6S2: C, 52.17; H, 2.43; N, 6.76; found: C, 52.02; H, 2.35; N, 6.56.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[N:6][CH:7]=1.C1C=CC2N(O)N=[N:17][C:15]=2C=1.C(Cl)CCl.Cl.CN.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Br:1][C:2]1[C:3]([C:8]([NH:17][CH3:15])=[O:10])=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1ncncc1Br
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ncncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.5 %

Procedure:
To a mixture of 5-bromopyrimidine-4-carboxylic acid (0.3 g, 1.478 mmol) in DMF (3 mL) were added HOBt (0.260 g, 1.921 mmol), EDC (0.397 g, 2.069 mmol), methanamine HCl (0.200 g, 2.96 mmol), followed by N-ethyl-N-isopropylpropan-2-amine (0.772 mL, 4.43 mmol). The reaction mixture was stirred for 18 hours at room temperature. The crude residue was purified by preparative HPLC (Waters SunFire C18, 5 μm, 30 mm ID×75 mm column) eluting with 5% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) to give the title compound as a light brown solid (0.11 g, 35%). ESI-MS m/z [M+H]+ calc'd for C6H7BrN3O, 216.0. found 216.0.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[OH:13][C@H:14]([CH2:20][CH2:21][CH3:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:23]([C@H:15]([C@H:14]([OH:13])[CH2:20][CH2:21][CH3:22])[C:16]([O:18][CH3:19])=[O:17])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCC[C@@H](O)CC(=O)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC[C@@H](O)[C@@H](Cc1ccccc1)C(=O)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
Diisopropylamine (8.61 mL, 65.7 mmol) is dissolved in 40 mL of anhydrous THF and chilled to 0° C. n-Butyllithium (30.1 mL of a 2.0M solution in hexanes, 60.2 mmol) is added dropwise over 10 min and the resulting pale yellow solution cooled to −78° C. A 15-mL THF solution of methyl (3R)-3-hydroxyhexanoate (4.00 g, 27.4 mmol) is added over 10 min and stirred for 30 min. Benzyl bromide (3.60 mL, 30.1 mmol) is dissolved in 12 mL of a 1:1 THF/HMPA solution and added at −78° C. dropwise. The resulting solution is allowed to warm slowly to 0° C. over 3 h. Aqueous 5% citric acid solution (250 mL) is added and the organics are extracted with two 250-mL portions of ether. The combined organics are washed with saturated aqueous sodium chloride. Drying over sodium sulfate and concentration is followed by which is chromatography on silica gel (elution with 25% EtOAc-hexanes) giving methyl (2R,3R)-2-benzyl-3-hydroxyhexanoate as an oil (3.03 g, 64% yield).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]3[C:19]4[C:18]([C:4]=2[CH:3]=1)=[CH:17][CH:16]=[CH:15][C:14]=4[C:13]([CH3:21])([CH3:20])[C:12]1[C:7]3=[CH:8][CH:9]=[N:10][CH:11]=1.C([Li])CCC.[B:29](OC)([O:32]C)[O:30]C>C1COCC1.C1CCCCC1>[CH3:20][C:13]1([CH3:21])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[N:6]2[C:19]3[C:18]([C:4]4[CH:3]=[C:2]([B:29]([OH:32])[OH:30])[CH:23]=[CH:22][C:5]=42)=[CH:17][CH:16]=[CH:15][C:14]1=3
Reactant: CC1(C)c2cnccc2-n2c3ccc(Br)cc3c3cccc1c32
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC1(C)c2cnccc2-n2c3ccc(B(O)O)cc3c3cccc1c32
Temperature: 25 °C

Procedure:
94 g (259 mmol) of 3-bromo-8,8-dimethyl-8H-10,12b-diazabenzo[a]aceanthrylene are dissolved in 1500 ml of dry THF, 135 ml (337 mmol) of a 2.5 M solution of n-butyllithium in cyclohexane are added dropwise at −70° C., after 1 h 37 ml of trimethyl borate (336 mmol) are added dropwise, the mixture is warmed to room temperature over the course of 1 h, the solvent is removed, and the residue, which is uniform according to 1H-NMR, is employed in the subsequent reaction without further purification. Yield: 59 g (181 mmol), 70% of theory, purity according to 1H-NMR about 96%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.OO.C(=O)([O-])[O-:22].[Na+].[Na+].[OH2:27]>C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:11]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:22])=[O:27]
Reactant: O
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(Sc2c[nH]c3ccc(Br)cc23)cc1
Agent: OO
Agent: [Na+]
Solvent: O=CO
Product: O=S(=O)(c1ccc(F)cc1)c1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 5-Bromo-3-(4-fluoro-phenylsulfanyl)-1H-indole (1.34 g, 4.16 mmol) from Step 1 was suspended in formic acid (20 mL). To this was added 30% hydrogen peroxide (0.94 g, 8.3 mmole). The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with 80 mL water and extracted with 100 mL ethyl acetate. The organic phase was washed with 1.5M sodium carbonate (20 mL, 30 mmol), dried (magnesium sulfate), and concentrated under reduced pressure. The residue was recrystallized from ether/hexane to provide 5-Bromo-3-(4-fluoro-benzenesulfonyl)-1H-indole (1.4 g, 4.0 mmol), m.p. 163–164°.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:13])[C@H:6]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[NH2:7].C(N([CH2:19][CH3:20])CC)C.[CH2:21]([O:28][CH2:29][C:30](Cl)=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C>[CH3:3][O:4][C:5](=[O:13])[CH:6]([NH:7][C:30](=[O:31])[CH2:29][O:28][CH2:21][C:20]1[CH:19]=[CH:24][CH:23]=[CH:22][CH:27]=1)[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:30](=[O:31])[CH2:29][O:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COC(=O)[C@@H](N)CCCCN
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C(CCCCNC(=O)COCc1ccccc1)NC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
To a mixture of L-lysine methyl ester dihydrochloride (50 grams, 214.4 mmol), triethylamine (131 grams, 1.294 moles) in ethyl acetate (750 mL) at room temperature was added benzyloxy acetyl chloride (120 grams, 650.4 mmol) drop wise. The mixture was further stirred at room temperature for 2 hours. The solids were filtered off. The organic phase was washed with 5% sodium bicarbonate (2×100 mL), water (2×100 mL), dried over sodium sulphate and distilled. The crude 2 was purified by column chromatography on silica gel using Benzene: Ethyl acetate (9:1) to get pure 2 (30 grams, 31.8%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10]([CH:12]=O)=O>C(O)(C)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:12][CH:10]=[N:9]2
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=CC=O
Solvent: CC(C)O
Product: Cc1ccc2nccnc2c1
Temperature: 80 °C
Yield: 93 %

Procedure:
To a solution of 4-methylbenzene-1,2-diamine (50.0 g, 0.41 mol) in isopropanol (300 mL) was added a solution of glyoxal (40% in water, 65.3 g, 0.45 mol) at room temperature. The reaction mixture was heated at 80° C. for 2 Hours and evaporated under vacuum to give 6-methylquinoxaline (55 g, 93%), which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 8.77 (dd, J=1.5, 7.2 Hz, 2H), 7.99 (d, J=8.7 Hz, 1H), 7.87 (s, 1H), 7.60 (dd, J=1.5, 8.4 Hz, 1H), 2.59 (s, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16]([CH3:19])([CH3:18])[CH2:15][CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:13]=2[CH:26]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>ClCCl>[C:1]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16]([CH3:19])([CH3:18])[CH2:15][CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=3[O-:35])[C:13]=2[CH:26]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccccc3)ccc2O1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C(=O)c3ccccc3)ccc2O1
Yield: 20.3 %

Procedure:
94 mg of 6-benzoyl-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran and 52 mg of m-chloroperbenzoic acid were stirred in 15 ml of dichloromethane at room temperature until thin-layer chromatography indicated that the reaction was complete. The mixture was washed in succession with sodium bisulphite solution and sodium bicarbonate solution, then dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 10% (v/v) methanol/ethyl acetate for the elution. After trituration with diethyl ether there were obtained 20 mg of 2-(6-benzoyl-3,4-dihydro-2,2-dimethyl-2H-1-benzo-pyran-4-yl)pyridine N-oxide of melting point 134°-136° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:8]C)(=O)[C@H:4]([CH3:6])[OH:5].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[OH:5][C@@H:4]([CH3:6])[C:3]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:8]
Reactant: C1COCCN1
Reactant: COC(=O)[C@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@H](O)C(=O)N1CCOCC1

Procedure:
Under a nitrogen atmosphere, 60% sodium hydride (1.92 g, 0.048 mol) was added slowly portionwise to a mixture of methyl L-lactate (50.0 g, 0.48 mol) and morpholine (46 mL, 0.528 mol) with stirring in an ice-bath, and the resulting mixture was stirred at 50° C. for 3 hours. Toluene was added thereto and evaporated under reduced pressure. This procedure was repeated further twice to give B-1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[CH:2]=1.[CH3:17][C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:17][C:18]1[N:19]=[C:20]([NH:23][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:9]=2)[S:21][CH:22]=1
Reactant: Cc1csc(N)n1
Reactant: O=C(O)c1cccc(Oc2cccnc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1csc(NC(=O)c2cccc(Oc3cccnc3)c2)n1
Yield: 24.4 %

Procedure:
Compound 2 (0.1 g, 0.5 mmol, 1 eq), 4-methylthiazol-2-amine (111 mg, 0.972 mmol, 2.10 eq), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (371 g, 0.972 mmol, 2.10 eq), and DIEA (170 μL, 0.972 mmol, 2.10 eq) were dissolved in CH2Cl2 (5 mL) and DMF (1 mL) and stirred rt for 48 h. The reaction was diluted with CH2Cl2 and washed with water (1×). The organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 38 mg (26%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=2.1 Hz, 1H), 8.49 (d, J=4.6 Hz, 1H), 7.94-7.90 (m, 1H), 7.76 (t, J=2.0 Hz, 1H), 7.69 (ddd, J=8.5, 2.7, 1.1 Hz, 1H), 7.62-7.57 (m, 2H), 7.38 (dd, J=8.0, 2.1 Hz, 1H), 6.81 (s, 1H), 2.29 (s, 3H); [M+1]+: 312.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][C:6]([C:8]2[NH:25][C:11]3=[N:12][CH:13]=[CH:14][C:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[O:23][CH3:24])=[C:10]3[CH:9]=2)=[CH:5][CH2:4][NH:3]1.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(N(CC)CC)C>CN(C)C=O>[F:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:25][C:8]([C:6]4[CH2:7][C:2]([CH3:26])([CH3:1])[N:3]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:4][CH:5]=4)=[CH:9][C:10]=23)[CH:21]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCNC(C)(C)C3)cc12
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(CC(=O)OC(C)(C)C)C(C)(C)C3)cc12

Procedure:
A mixture of Example 272B (0.388 g, 0.915 mmol), tert-butyl bromoacetate (0.264 g, 1.35 mmol) and triethylamine (0.7 mL, 5.02 mmol) in N,N-dimethylformamide (2 mL) was heated at 70° C. for 8 hours and was concentrated. The residue was partitioned between ethyl acetate and water and the organic layer was dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel eluting with 50% ethyl acetate in hexanes gave the title compound. MS (ESI) m/e 466.4 (M+1)1.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.CN(C=O)C.Br[CH2:25][CH2:26][CH2:27][Cl:28]>[Cl-].[Na+].O>[Cl:28][CH2:27][CH2:26][CH2:25][N:6]1[C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: ClCCCBr
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1S2
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Temperature: 65 °C

Procedure:
A solution of 2-(trifluoromethyl)-10H-phenothiazine (2.04 g, 7.6 mmol) and DMF (16 mL) was mixed with CS2CO3 (7.5 g, 22.9 mmol) and 1-bromo-3-chloropropane (1.1 mL, 11.5 mmol) The reaction mixture was heated at 65° C. for 12 h. Once no starting material was observed by analytical LCMS, EtOAC (250 mL) and brine (250 mL) were added. The organic layer was separated, and the aqueous layer was washed with EtOAC (3×100 mL). The combined organic extracts were washed with brine (2×100 mL), dried over MgSO4, and concentrated to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[H-].[Na+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].O>CN(C=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:5]=1[C:10](=[O:11])[N:9]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]2=[O:8])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NC(=O)c2c1cccc2[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 3-nitrophthalimide (1 g, 5.20 mmol) in dry DMF (35 ml), cooled in an ice bath, NaH (60% w/w dispersion in mineral oil, 0.250 g, 6.25 mmol) was added, followed after 15 minutes by t-butyl bromoacetate (0.845 ml, 5.73 mmol). After stirring for 1 hour at room temperature, the mixture was poured into water and the resulting precipitate was washed with water and with a little amount of Et2O; after drying, tert-butyl 2-(4-nitro-1,3-dioxoisoindolin-2-yl)acetate was obtained (1.44 g, 4.70 mmol, 90% yield, MS/ESI+ 328.9 [MNa]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10]Br)[CH:6]=[CH:7][CH:8]=1.[Mg].[CH3:13][C:14]1([CH3:31])[CH2:18][O:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[C:20]=2OC)=[N:15]1.O>O1CCCC1>[CH3:28][O:27][C:21]1[C:20]([CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:19]([C:16]2[O:17][CH2:18][C:14]([CH3:13])([CH3:31])[N:15]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1cccc(CCBr)c1
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(OC)c1OC
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CCc2c(C3=NC(C)(C)CO3)ccc(OC)c2OC)c1
Reaction time: 16 h

Procedure:
A solution of 2-(3-methoxyphenyl)ethylbromide (12.2 g) in dry tetrahydrofuran (20 ml) was added dropwise to a suspension of magnesium (1.46 g) in dry tetrahydrofuran (20 ml), under an atmosphere of nitrogen, at a rate sufficient to maintain a state of reflux. After 1 hour the cooled solution was added to a stirred solution of 4,5-dihydro-4,4-dimethyl-2-(2,3,4-trimethoxyphenyl) oxazole (7.95 g) in dry tetrahydrofuran (50 ml) under an atmosphere of nitrogen. The mixture was stirred at 20° for 16 hours. Water (400 ml) was added and the aqueous phase thoroughly extracted with ethyl acetate (2×250 ml). The organic phase was dried over magnesium sulphate, filtered and the solvent removed in vacuo to yield a yellow oil which was purified by flash column chromatography on silica gel, using 10% ethyl acetate/90% petroleum ether as eluent, and by Kugelruhr distillation (air bath temperature 200°/1 mm Hg) 9.7 g of the title compound were obtained ms m/e 369.
Reaction SMILES: C[S:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][F:13])=[CH:6][CH:5]=1)=O.ClC1C=CC=C(C(OO)=O)C=1.N1C(C)=CC=CC=1C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(#N)C>[SH:2][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][F:13])=[CH:8][CH:9]=1
Reactant: CS(=O)c1ccc(OCCF)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: FCCOc1ccc(S)cc1
Yield: 9.5 %

Procedure:
In a manner similar to Sugihara et al. (Synthesis, p 881 (1978)), the reaction of 8.7 grams (0.043 mole) of 2-fluoroethyl 4-methylsulfinylphenyl ether (Compound 80, prepared by the method of Example 4 using one equivalent of 3-chloroperbenzoic acid), 10.0 ml (0.086 mole) of 2,6-lutidine and 12.2 ml (0.086 mole) of trifluoroacetic anhydride in 160 ml of dry acetonitrile yielded 0.7 gram of 2-fluoroethyl 4-mercaptophenyl ether as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]([OH:20])=[CH:10][C:9]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C.O.CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]([O:20][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:10][C:9]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCCBr
Reactant: COCCOCOc1c(-c2ccccc2)cc(O)cc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1cc(-c2ccccc2)c(OCOCCOC)c(-c2ccccc2)c1
Temperature: 60 °C
Reaction time: 96 h
Yield: 92.3 %

Procedure:
To a stirred solution of 2′-methoxyethoxymethoxy-[1,1′;3′,1″]terphenyl-5′-ol (0.240 g, 0.685 mmol) in DMF (10 mL) at room temperature was added K2CO3 (0.123 g, 0.890 mmol) followed by dropwise addition of 1-bromobutane (0.147 mL, 1.37 mmol). The reaction mixture was then heated to 60° C. After 4 days at this temperature, the resulting solution was diluted with H2O (10 mL) and excess EtOAc (100 mL). The organic layer was washed with 1 N HCl (10 mL), sat. aq. NaHCO3 (10 mL), and brine (10 mL) and then dried (MgSO4). After concentration, the residue was purified by preparatory plate chromatography (20% EtOAc/petroleum ether) to afford the product (0.257 g, 92%) as a solid; 1H NMR (CDCl3) δ 0.97 (t, J=8.1 Hz, 3H), 1.46-1.57 (m, 2H), 1.72-1.82 (m, 2H), 2.80 (t, J=5.6 Hz, 2H), 2.95 (t, J=5.6 Hz, 2H), 3.17 (s, 3H), 3.99 (t, J=6.9 Hz, 2H), 4.37 (s, 2H), 6.87 (s,;2H), 7.28-7.46 (m, 6H), 7.58 (d, J=7.5 Hz, 4H); mass spectrum [(+) ESI], m/z 429 (M+Na)+.