Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=CC)=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:29]=[O+][O-].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:26]=[O:29])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC=Cc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Reaction time: 8 h

Procedure:
{(2R)-7-Nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (10.5 g, 25.9 mmole) dissolved in 400 mL of methylene chloride was treated with excess ozone at −78° C. Diisopropylethylamine (11.5 mL, 66.0 mmole) was then added dropwise over 30 minutes and the mixture allowed to come to room temperature and stir overnight under a nitrogen atmosphere. The mixture was then diluted to 600 mL with methylene chloride, washed three times with 100 mL portions of 2N HCl (aq), twice with 200 mL portions of saturated aqueous sodium bicarbonate and with 200 mL of saturated brine. The solution was dried over magnesium sulfate, filtered and concentrated in vacuum to a crude brown oil, which was column chromatographed on silica gel with 10% hexane/methylene chloride to give 7.52 g of the (R)-enantiomer of the title compound as a yellow solid. 1H-NMR (CDCl3): doublet 7.8 δ(2 H); doublet 7.62 δ(1 H); doublet 7.4 δ(2 H); doublet 7.0 δ(1 H); multiplet 4.4-4.6 δ(2 H); multiplet 4.2 δ(3 H); singlet 2.4 δ(3 H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[Mg].Br[CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>O1CCCC1.[Cl-].[Zn+2].[Cl-].CCOCC>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:4]=1)[CH3:20])[CH3:19]
Reactant: CCOC(=O)C(C)Br
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)c1cccc(C(F)(F)F)c1
Temperature: 55 °C

Procedure:
3-Trifluoromethylbromobenzene 50 (0.2 mol) was dissolved in dry tetrahydrofuran (100 mL). A small amount of magnesium metal was added and the mixture was warmed until reaction commenced. Additional magnesium (0.2 mol) was added. The mixture was maintained at reflux until the magnesium was consumed. A solution of anhydrous zinc chloride (0.2 mol) in tetrahydrofuran (50 mL) was added. The mixture was maintained at 55° C. for 2 hours, and then ethyl 2-bromopropionate (0.2 mol) was added. The mixture was maintained at 55° C. and the progress of the reaction was monitored by TLC. When the reaction was complete, the mixture was cooled and added to water and ether. The organic layer was dried and concentrated, and the residue was chromatographed to afford 2-(3-trifluoromethyl-phenyl)-propionic acid ethyl ester 51.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CS(C)=[O:14].[OH-].[Na+]>O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([OH:14])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: CS(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)cc1O
Temperature: 60 °C
Reaction time: 22 h

Procedure:
192 g of 2,4-dichloronitrobenzene, 220 g of DMSO and 0.5 ml of the emulsifier specified in Example 1 are introduced into the reaction vessel. 160 g of 50% NaOH are added at 60° C. within 1 hour and the reaction mixture is stirred for 22 hours at 60° C. Subsequently 150 ml of water are added, the mixture is stirred until the temperature has cooled to 20° C. and the red sodium salt of 5-chloro-2-nitrophenol is suction-filtered and washed three times with 50 ml portions of water. The moist salt is added to 122 g of 30% HCl yielding 5-chloro-2-nitrophenol as an oil which is separated and dried in vacuo. The yield is 151.5 g of 5-chloro-2-nitrophenol (87% of the theory), m.p. 36.5° C. having a degree of purity of 100% according to gas chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18](OC)[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH3:44][C:45]1[N:46]=[C:47]([CH:50]([NH2:52])[CH3:51])[S:48][CH:49]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:36]([NH:52][CH:50]([C:47]2[S:48][CH:49]=[C:45]([CH3:44])[N:46]=2)[CH3:51])=[O:42])=[CH:21][CH:22]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Reactant: Cc1csc(C(C)N)n1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4nc(C)cs4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4-methyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (32 mg, yield 68%).
Reaction SMILES: [H-].[Na+].C1COCC1.[O:8]=[C:9]1[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][S:13][CH2:12][CH2:11][NH:10]1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28]Br>O.CCOC(C)=O>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28][N:10]1[C:9](=[O:8])[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:14][S:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1CSCCNC1=O
Reactant: Fc1ccc(CBr)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CSCCN(Cc2ccc(F)c(F)c2)C1=O
Yield: 61 %

Procedure:
81 mg of sodium hydride as a 60% suspension in oil (2.03 mmol) are introduced at room temperature into a 50 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 20 ml of THF and 500 mg of 26 (2.03 mmol). The medium is stirred for 1 hour and 420 mg (2.03 mmol) of 3,4-difluorobenzyl bromide are then added. The medium is stirred overnight, 20 ml of EtOAc and 20 ml of water are added to the reaction medium and, after separation of the phases by settling, the organic phase is washed once with 20 ml of water. The organic phase is dried, filtered and then evaporated to dryness. 1.5 g of crude product are recovered, which product is chromatographed on silica (eluent: 80/20 heptane/EtOAc). 460 mg of product 30 are recovered (yield=61%).
Reaction SMILES: I.[F:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](SC)=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[C:13]([CH3:14])=[N:12][CH:11]=[N:10]1.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[C:26](O)=O.[NH2:36][NH2:37]>>[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:26]1[NH:37][N:36]=[C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[C:13]([CH3:14])=[N:12][CH:11]=[N:10]3)=[C:3]([F:2])[CH:4]=2)[N:17]=1)[C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1
Reactant: O=C(O)C(CCCCCl)c1ccc(F)cc1
Reactant: CSC(=N)Nc1ccc(-n2ncnc2C)c(F)c1
Reactant: NN
Agent: I
Product: Cc1ncnn1-c1ccc(Nc2n[nH]c(C(CCCCCl)c3ccc(F)cc3)n2)cc1F
Yield: 18 %

Procedure:
Methyl 3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (0.739 g, 2.79 mmol, from preparation C) and 6-chloro-2-(4-fluorophenyl)hexanoic acid (0.750 g, 3.07 mmol, from preparation AE) were coupled and then reacted with hydrazine (0.350 mL, 11.2 mmol) using a procedure analogous to Step A of Example 13. The crude products were purified using silica gel chromatography (0-95% ethyl acetate/chloroform) to afford 5-(5-chloro-1-(4-fluorophenyl)pentyl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (230 mg, 0.502 mmol, 18% yield) as a viscous oil. LC-MS (M+H)+ 458.2.
Reaction SMILES: C1(C([O:14][C:15](=[O:36])[C:16]([OH:35])=[CH:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[N:22]([C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:21]=2)=[O:19])C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH3:33][N:31]([CH3:32])[C:30]([N:22]1[C:23]2[C:28](=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:20]([C:18](=[O:19])[CH:17]=[C:16]([OH:35])[C:15]([OH:36])=[O:14])=[CH:21]1)=[O:34]
Reactant: CN(C)C(=O)n1cc(C(=O)C=C(O)C(=O)OC(c2ccccc2)c2ccccc2)c2cc(Cl)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)n1cc(C(=O)C=C(O)C(=O)O)c2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 356 mg (0.7 mmol) of the ester derivative obtained in above (1) in dichloromethane (3.6 ml) was added under ice-cooling, 0.5 ml of trifluoroacetic acid. The mixture was stirred for 30 minutes under ice-cooling. The reaction solution was concentrated under reduced pressure. The residues was dissolved in ethyl acetate. The ethyl acetate was washed successively with water and brine, and then dried. The obtained residue was crystallized from ether and recrystailizedl from 95% ethanol to give 0.16 g of the titled compound. Yield: 67%.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.CS([Cl:27])(=O)=O>C(Cl)Cl.CN(C=O)C>[Cl:27][CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([S:2][CH3:1])[S:4][C:5]=2[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CSc1nc2ccc(CO)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1nc2ccc(CCl)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a solution of (2-(methylthio)benzo[d]thiazol-6-yl)methanol (4.1 g, 19.4 mmol) from Step 2 of this Example and DIEA (3.26 g, 25.3 mmol) in CH2Cl2 (200 mL) was added methanesulfonyl chloride (2.88 g, 25.3 mmol) slowly at 0° C. The mixture was then treated with 2 drops of DMF and stirred at rt overnight. The mixture was quenched with 300 mL of saturated aq NaHCO3. The separated aqueous layer was extracted with CH2Cl2 (2×250 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole as a light brown solid (4.4 g, 99%). 1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J=1.5 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.53 (dd, J=1.6, 8.4 Hz, 1H), 4.89 (s, 2H), 2.80 (s, 3H). LCMS (ESI) m/z 231 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=O)[CH:5]=[CH:6][CH:7]=1.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:17][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccccc1
Reactant: O=CCc1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1cccc(-c2c[nH]c3ccccc23)c1

Procedure:
A solution of 2-(3-chlorophenyl)-acetaldehyde (5.80 g, 37.5 mmol) and phenylhydrazine (6.22 g, 57.5 mmol) in glacial acetic acid (150 mL) was saturated with nitrogen by bubbling N2 through the solution. The solution was then refluxed for about 2.5 hours. Solvent was removed in vacuo and the residue obtained was dissolved in DCM and washed with 1N HCl aqueous solution (2 times), saturated NaHCO3 aqueous solution (2 times) and brine (2 times), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluting with EtOAc/hexane 1:6. The title compound was obtained as a reddish oil. Yield: 5.30 g, 62%. Rf=0.26 (silica, EtOAc/hexane 1:4).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH3:26])[CH3:25])[N:16]=[CH:17][C:10]=2[N:9]([CH3:35])[C:8]1=[O:36])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:36])[N:9]([CH3:35])[C:10]=3[CH:17]=[N:16][C:15]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH:24]([CH3:26])[CH3:25])=[CH:33][CH:32]=1
Reactant: CC(C)c1ccccc1-c1ncc2c(c1Cc1ccc(Cl)cc1)c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccccc1-c1ncc2c(c1Cc1ccc(Cl)cc1)c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-(2-isopropylphenyl)-1-methyl-2,4-dioxo-1,2-dihydro pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (7 mg, 0.0138 mmol) in THF (0.5 mL) and water (0.5 mL) was added LiOH.H2O (1.2 mg, 0.0277 mmol). The reaction was stirred at RT for 30 min then diluted with EA (5 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:2) to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-6-(2-isopropylphenyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (2.4 mg, 36.4% yield) as a white solid. 1H NMR (CDCl3) δ: 8.79 (s, 1H), 7.38 (d, J=3.8 Hz, 2H), 7.20-7.12 (m, 1H), 7.10 (t, J=8.4 Hz, 2H), 6.97 (d, J=7.5 Hz, 1H), 6.71 (d, J=8.4 Hz, 2H), 5.34 (s, 1H), 4.79 (d, J=14.9 Hz, 1H), 4.19 (t, J=6.1 Hz, 2H), 3.76 (s, 3H), 3.48 (d, J=6.1 Hz, 2H), 2.77 (s, 1H), 2.01 (d, J=5.9 Hz, 1H), 1.92-1.80 (m, 2H), 1.10 (d, J=6.8 Hz, 3H), 1.02 (d, J=6.9 Hz, 3H). LCMS: MH+ 478 and TR=4.088 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[I:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[CH3:19])[NH2:15]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:12]([I:11])[CH:13]=1)=[O:7]
Reactant: Cc1ccc(N)cc1I
Reactant: O=C(O)c1ccnc(Cl)c1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1I
Yield: 89.7 %

Procedure:
2-Chloroisonicotinic acid (3.3 g) HATU (8.75 g) DIPEA (10.9 ml) and 3-iodo-4-methylaniline (5.00 g) in DMF (50 ml) were heated under nitrogen for 16 h. The reaction was cooled, the solvent was removed under vacuum and the residue was dissolved in dichloromethane (150 ml). The solution was washed with water (3×100 ml) and brine (100 ml) dried (magnesium sulphate) and the solvent was removed under vacuum. The residue was purified by column chromatography on silica eluting with ethyl acetate/cyclohexane (40:60) to give the title compound as a white solid (7.00 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:20]N(C)C(=O)C>>[C:3]([O:7][C:8]([N:10]([CH3:20])[C@@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@@H](C(=O)O)CC1

Procedure:
Sodium hydride (0.22 g) is added to a solution of cis-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (0.49 g) in N,N-dimethylacetamide (5 mL) chilled in an ice bath.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[O:18][CH2:17][O:16][C:5]=2[CH:6]=[C:7]([CH2:9][C@H:10]2[CH2:15][O:14][C:12](=[O:13])[CH2:11]2)[CH:8]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH:24]=O.[H-].[Na+].CO.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]2[O:18][CH2:17][O:16][C:5]=2[CH:6]=[C:7]([CH2:9][C@H:10]2[CH2:15][O:14][C:12](=[O:13])/[C:11]/2=[CH:24]/[C:23]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:21]([O:20][CH3:19])[CH:22]=2)[CH:8]=1
Reactant: COc1cc(C[C@H]2COC(=O)C2)cc2c1OCO2
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2/C(=O)OC[C@@H]2Cc2cc(OC)c3c(c2)OCO3)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.2 %

Procedure:
A solution of (R)-3-[1-(5-methoxy-3,4-methylenedioxyphenyl)methyl]butanolide (21.0 g, 0.084 mol) and 3,4,5-trimethoxybenzaldehyde (26.0 g, 0.133 mol) in toluene (350 ml) was cooled to 0° C. under an argon stream, followed by the addition of sodium hydride (60%, 9.1 g, 0.228 mol) and methanol (0.33 ml, 0.0082 mol). After stirred at 0° C. for 15 minutes and then at room temperature for 18 hours, the reaction mixture was ice cooled and then acidified with 2N-HCl. After the addition of ethyl acetate (100 ml), the organic layer was separated. The water layer was extracted with ethyl acetate (50 ml×2). The extracts were combined with the previously-obtained organic layer. The organic layer was washed successively with water, saturated NaHCO3 and saturated NaCl, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off. The residue thus obtained (52.9 g) was purified by column chromatography (silica gel: "MERCK #9385", 500 g, eluent: 1:2 mixed solvent of ethyl acetate and hexane), whereby 16.62 g of the title compound were obtained as colorless oil (yield: 46%). [α]27D : -53.7° (C=1.04, CHCl3)
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][N:31]1[C:35]2[CH:36]=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][C:34]=2[N:33]=[N:32]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:38]3[CH:37]=[CH:36][C:35]4[N:31]([CH3:30])[N:32]=[N:33][C:34]=4[CH:39]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cn1nnc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
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: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)nnn4C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a vial flushed with argon was added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.202 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole (62 mg, 0.24 mmol), Pd(PPh3)4 (23 mg, 20 μmol), and K2CO3 (83 mg, 0.6 mmol). De-gassed dioxane (2 mL) and water (0.5 mL) were then added, and the reaction was heated to 100° C. for 1 h. After cooling to 23° C., the reaction was filtered over a plug of Celite, concentrated, and purified by column chromatography (gradient 0 to 35% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.31 (dd, J=8.7, 1.4 Hz, 1H), 7.90 (s, 1H), 7.66-7.44 (m, 5H), 5.17 (s, 1H), 4.33 (s, 3H), 4.26-4.16 (m, 2H), 2.61 (s, 3H), 1.30-1.22 (m, 3H), 0.98 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH2:15](I)[CH2:16][CH3:17].C(I)C>>[CH2:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])[N:9]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCI
Reactant: Cc1cccc(-n2c(C)ccc2C)n1
Solvent: CCI
Product: CCCCc1cccc(-n2c(C)ccc2C)n1
Yield: 64.4 %

Procedure:
The product from Example 2a 1.0 g, 5.37 mmol) was reacted with propyl iodide 0.55 mL, 5.64 mmol) in place of ethyl iodide following the procedure from Example 2b to give the title compound (790 mg, 64%).
Reaction SMILES: I[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[N+:13]([C:16]1[N:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([O-:15])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[N+:13]([C:16]1[N:21]=[CH:20][C:19]([O:22][CH:2]2[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(O)cn1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc([N+](=O)[O-])nc2)C1
Temperature: 125 °C
Yield: 58.8 %

Procedure:
A mixture of 206a (2.24 g, 7.9 mmol), 6-nitropyridin-3-ol (1.0 g, 7.2 mmol), and Cs2CO3 (2.6 g, 7.9 mmol) in DMF (8 mL) was heated at 125° C. in a sealed tube overnight. The solid was filtered and washed with ethyl acetate (2×20 mL). The combined filtrate was evaporated in vacuo and the residue was purified on reverse-phase Combiflash to afford 206b (1.25 g, 59%). MS-ESI: [M+H]+ 296.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9](Cl)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[Cl:12])=[O:5])[CH3:2].CO.O.[CH2:21]([NH:23][NH2:24])[CH3:22]>C(N(CC)CC)C>[Cl:12][C:11]1[C:10]([N+:13]([O-:15])=[O:14])=[C:9]([NH:24][NH:23][CH2:21][CH3:22])[N:8]=[C:7]([CH3:17])[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCNN
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CCNNc1nc(C)c(C(=O)OCC)c(Cl)c1[N+](=O)[O-]

Procedure:
27.9 g. of 4,6-Dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.2 mol.) are dissolved in about 100 ml. of methanol and 20 ml. of water. 15 g. of triethylamine are added and at 25°-30° 4.5 g. ethyl hydrazine are dropped in with stirring. After the addition is complete, stirring is continued for 1 additional hour. On cooling, 4-chloro-6-(1-ethyl)hydrazino-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester precipitates, yield 19.7 g. (65%) m.p. 117°-120°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[O:5][C:6]=1[CH3:7].[C:10](=O)([O-])[O-].[Na+].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[S:27]([O-:30])([O-])=[O:28].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([S:27]([CH3:10])(=[O:30])=[O:28])[O:5][C:6]=1[CH3:7]
Reactant: O=C([O-])[O-]
Reactant: O=S([O-])[O-]
Reactant: CSc1nc(C)c(C)o1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nc(S(C)(=O)=O)oc1C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
4,5-Dimethyl-2-methylthiooxazole (4.21 g, 0.029 m) in dry chloroform (15 ml) was cooled to 0° C. and anhydrous sodium carbonate (8.0 g, 0.0755 m) added. 88.5% 3-Chloroperbenzoic acid (11.5 g, 0.059 m) in dry chloroform was then added over 45 minutes, and the mixture stirred for a further 45 minutes at 0° C. Solid sodium sulphite (5 g) was then added and the mixture allowed to warm to room temperature. The mixture was then filtered and the filtrate evaporated, the residue being chromatographed on silica using diethyl ether. The resulting solid was recrystallised from ethyl acetate/hexane as the title product, m.p. 42° C.