Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[F:24])([CH3:4])([CH3:3])[CH3:2].O1CCCC1>CO.[C].[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[F:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1F
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)cn2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A suspension of tert-butyl{2-fluoro-5-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate (3.49 g, 10 mmol) and 10% palladium-carbon (1.0 g) in methanol (20 mL)-tetrahydrofuran (20 mL) was vigorously stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure, and the residue was triturated with diethyl ether to give the title compound (3.00 g, 94%) as a white amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[CH2:12]([O:14][C:15]([C:17]1[N:18]=[C:19](Br)[S:20][CH:21]=1)=[O:16])[CH3:13].[Cl-].[Na+]>O.C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15]([C:17]1[N:18]=[C:19]([O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[S:20][CH:21]=1)=[O:16])[CH3:13]
Reactant: Oc1cccc(Cl)c1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1csc(Oc2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
13.72 g (106.72 mmol) 3-chlorophenol were added to a mixture of 19.21 g (106.72 mmol) sodium methylate-solution (30% in methanol) and 200 ml toluene and the mixture stirred 15 minutes at room temperature. The solution was evaporated to dryness, the residue suspended in 100 ml of toluene and evaporated to dryness again. The residue was dissolved in 100 ml dimethylsulphoxide and 24 g (101.65 mmol) of ethyl-2-bromothiazole-4-carboxylate [prepared as in Example 1b] were added in one portion. The solution was stirred for 24 hours at 80° C., cooled to room temperature and poured into 1200 ml water. 200 ml of saturated sodium chloride solution were added and the mixture extracted three times with 300 ml toluene. The organic layers were combined and washed with 200 ml 0.1 m NaOH and 200 ml of diluted sodium chloride solution, dried over Na2SO4 and evaporated to dryness to give 27.72 g (96%) of pale brown oily ethyl-2-(3-chlorophenoxy)thiazole-4-carboxylate. NMR (CDCl3):1.35(t,3H,CH3); 4.4(q,2H,CH2); 7.3(m,4H,Arom.) 7.7(s,1H,arom.).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH2:12][C:13](=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17]C=1)[CH3:2].[CH3:22][O:23][CH:24](OC)[O:25]C.O.O.O.[N+]([O-])([O-])=O.[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Tl+]>CCOCC.CO>[CH3:22][O:23][C:24](=[O:25])[CH:12]([CH2:13][C:14]1[CH:15]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:8]1[C:7]2[C:11](=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][CH:6]=2)[NH:10][CH:9]=1
Reactant: COC(OC)OC
Reactant: CCc1cccc2c(CC(=O)Cc3ccccc3)c[nH]c12
Agent: O=[N+]([O-])[O-]
Agent: [Tl+3]
Agent: [Tl+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CCc1cccc2c(C(Cc3ccccc3)C(=O)OC)c[nH]c12

Procedure:
According to the procedure of E. C. Taylor et al, J. Amer. Chem. Soc., 98, 3037 (1976), a solution of 1-(7-ethyl-1H-indol-3-yl)-3-phenylpropanone (2.77 g, 10 mmol) in a 1:1 mixture of methanol and trimethylorthoformate (25 mL) was added to thallium (III) nitrate trihydrate (4.88 g, 11 mmol), and the mixture was heated under reflux until precipitation of thallium (I) nitrate was complete (about 3 hours). The dark brown mixture was diluted with 25 mL of ether, and the thallium (I) nitrate was removed by filtration. The filtrate was washed successively with 1×50 mL portions of water, 5% aqueous sodium bicarbonate, and water and was then dried over anhydrous MgSO4. Concentration of the filtrate and flash chromatography of the crude product (20% ethyl acetate/hexane, silica gel) have the ester as a red-brown oil (0.98 g, 31.9%).
Reaction SMILES: [NH2:1][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:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.C[O:30][CH:31]1[CH:35]=[CH:34][CH:33](OC)O1.Cl>C(#N)C.CCOC(C)=O>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([N:1]3[CH2:33][CH:34]=[CH:35][C:31]3=[O:30])[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][CH3:22])=[O:20])([CH3:25])([CH3:27])[CH3:26]
Reactant: COC1C=CC(OC)O1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N)sc2c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CC=CC3=O)sc2c1-c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
To a solution of (S)-methyl 2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (40 mg, 0.1 mmol) in acetonitrile (1 mL) was added 2,5-dimethoxy-2,5-dihydrofuran (26 μL, 0.2 mmol), followed by hydrochloric acid (0.2 N, 0.8 mL, 0.16 mmol). The mixture was stirred for 24 hours, and was diluted with EtOAc and quenched with saturated sodium bicarbonate solution. The organic layer was separated, and was washed with water and brine, dried with sodium sulfate and filtered. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)benzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C25H25ClN2O4S: 485.1 (M+H+); Found: 485.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:32]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:1][C:2]1[N:6]([S:37]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])[C:5]([CH3:7])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CCOC(=O)c1cc(Br)[nH]c1C
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)n(S(=O)(=O)c2cccnc2)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
Ethyl 5-bromo-2-methyl-1H-pyrrole-3-carboxylate (2.26 g) was dissolved in tetrahydrofuran (100 mL), sodium hydride (60% in oil, 1.16 g) was added and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (5.90 mL) was added and the mixture was further stirred at the same temperature for 15 min. 3-Pyridinesulfonyl chloride hydrochloride (3.13 g) was added and the reaction mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as a yellow oil (yield 2.31 g, 64%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 86.9 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (2.21 g, 0.01 mol) in pyridine (10 mL), methanesulfonyl chloride (0.77 mL, 0.01 mol) was added dropwise at 0-5° C. with stirring. The reaction mixture was stirred overnight at room temperature, and then diluted with water. The resulting solid was filtered and dried to afford N-[3-(quinoxalin-2-yl)phenyl]methanesulfonamide (2.6 g, 87% yield). LCMS calculated for C15H13N3O2S (M+H): 300.07. found 300. 1H-NMR (DMSO-d6, 250 Mhz) δH: 10.01 (1H, br. s), 9.50 (1H, s), 8.20-8.00 (4H, m), 7.95-7.70 (2H, m), 7.60-7.52 (1H, m), 7.48-7.40 (1H, m), 3.04 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH:31]3[CH2:35][O:34]C(C)(C)[O:32]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18].Cl.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH:31]([OH:32])[CH2:35][OH:34])[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18]
Reactant: Cc1ccc(-c2cn(CC3COC(C)(C)O3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cn(CC(O)CO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of compound 105 (535 mg, 1.16 mmol) in THF (6.0 mL) was added aqueous HCl (1M, 6 mL)) and the mixture was stirred for 24 h at RT. The reaction mixture was poured into a mixture of EtOAc/saturated NaHCO3. The aqueous phase was washed with more EtOAc. The collected organic phases were washed with water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 2:98 to 10:90 as the eluent to afford the title compound as yellow foam. 13C NMR (DMSO-d6) δ 194.9, 158.7 (dd), 155.7 (dd), 149.3, 145.0, 139.8, 135.7, 133.7, 133.7, 131.6, 128.4, 127.1, 126.6, 126.5 (dd), 124.9, 124.2 (dd), 122.3, 114.8, 112.0 (dd), 111.8, 105.0 (dd), 70.3, 63.2, 53.0, 19.4
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:35]2[CH:40]=[CH:39][C:38](I)=[CH:37][CH:36]=2)=[CH:19]/[CH2:20][O:21][C:22]2[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:24]([CH3:34])[CH:23]=2)=[CH:14][CH:13]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.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.[Cu]I>[Cl:11][C:12]1[CH:13]=[CH:14][C:15](/[C:18](/[C:35]2[CH:36]=[CH:37][C:38]([C:10]#[C:9][CH2:8][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:39][CH:40]=2)=[CH:19]/[CH2:20][O:21][C:22]2[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:24]([CH3:34])[CH:23]=2)=[CH:16][CH:17]=1
Reactant: C#CCN1CCN(C)CC1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCN(C)CC3)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under nitrogen atmosphere, 1-methyl-4-propargylpiperazine (380 mg, 2.75 mmol) was added to a degassed solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)-allyloxy]-2-methylphenoxy]acetate (450 mg, 0.82 mmol; prepared as described in example 7) in a mixture of tetrahydrofuran (10 mL) and triethylamine (8 mL) The solution was cooled, tetrakis(triphenylphosphine)palladium (85 mg, 0.073 mmol) and copper(I) iodide (22 mg, 0.115 mmol) were added. The reaction mixture was stirred at ambient temperature for 48 h, diluted with benzene (100 mL) and washed with water (2×50 mL). The organic solution was dried with anhydrous potassium carbonate and subsequently evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethanol 1:0-1:2) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(4-methylpiperazin-1-yl)propynyl]phenyl]-allyloxy]-2-methyl-phenoxy]acetate.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C@H:17]3[CH2:26][CH2:25][C@@:19]4([NH:23][C:22](=[O:24])[O:21][CH2:20]4)[CH2:18]3)[CH:13]=2)[CH:8]=1)(=O)=O.CN1C(=O)CCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:46]([Mg]Br)[CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].CCOCC>C1COCC1>[CH2:46]([C:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C@H:17]3[CH2:26][CH2:25][C@@:19]4([NH:23][C:22](=[O:24])[O:21][CH2:20]4)[CH2:18]3)[CH:11]=[CH:10][C:9]=2[CH:8]=1)[CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]
Reactant: CCCCCC[Mg]Br
Reactant: O=C1N[C@@]2(CC[C@H](c3ccc4c(c3)CCC(OS(=O)(=O)C(F)(F)F)=C4)C2)CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCCCCCC1=Cc2ccc([C@H]3CC[C@]4(COC(=O)N4)C3)cc2CC1
Reaction time: 0.25 h

Procedure:
To a mixture of 6-((5R,7S)-2-oxo-3-oxa-1-azaspiro[4.4]nonan-7-yl)-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (Int. 6, 1 g, 2.396 mmol) and NMP (2.306 mL, 23.96 mmol) in THF (20 mL) at −40° C. was added a solution of lithium bis(trimethylsilyl)amide in THF (2.396 mL, 2.396 mmol). The reaction mixture was stirred for 15 minutes, and then ferric acetylacetonate (0.042 g, 0.120 mmol) and hexylmagnesium bromide in ether (2.396 mL, 4.79 mmol) were added. The reaction mixture was stirred for 30 minutes and quenched with water. The reaction mixture was diluted with ethyl acetate and washed with 1M HCl. The organic layer was dried with MgSO4, filtered and concentrated. The crude material was purified on a silica gel cartridge (40 g) using an EtOAc/hexane gradient (0-100% EtOAc over 12 CV) to afford 662 mg of (5R,7S)-7-(6-hexyl-7,8-dihydronaphthalen-2-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one as a white solid. HPLC retention time=1.28 min (Condition G); LC/MS M+1=354: 1H NMR (400 MHz, chloroform-d) δ 7.03-6.88 (m, 3H), 6.21 (s, 1H), 5.16 (br. s., 1H), 4.44-4.15 (m, 2H), 3.13-2.96 (m, 1H), 2.80 (t, J=8.0 Hz, 2H), 2.47-2.08 (m, 6H), 2.05-1.93 (m, 2H), 1.90-1.73 (m, 1H), 1.68-1.43 (m, 4H), 1.41-1.22 (m, 5H), 1.01-0.83 (m, 3H).
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][N:17]([CH3:22])[N:18]=[CH:19][CH:20]=O.[O-]CC.[Na+].[Na]>C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:16][N:17]([CH3:22])[N:18]=[CH:19][CH:20]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: CN(C)N=CC=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)N=CC=C(C(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
To a mixture of 19.6 g (0.1 mole) desoxybenzoin and 10 g (0.1 mole) of glyoxal mono(dimethylhydrazone) in 100 ml ethanol was added dropwise a solution of sodium ethoxide prepared by dissolving 2.3 g (0.1 mole) sodium metal in 100 ml ethanol. The mixture was heated at reflux for one-half hour. TLC (90/10, toluene/ethyl acetate) showed a small amount of starting desoxybenzoin, so 2.0 g (0.02 mole) of additional glyoxal mono(dimethylhydrazone) was added. Heating was continued another two hours. TLC at this time showed no starting material, and two clean close yellow product spots (isomers). The mixture was poured into 1 l ice water then extracted with methylene chloride. The organic extracts were dried and concentrated on a rotary evaporator to give 28.7 g (100%) of yellow oil. The NMR showed the presence of two major N(CH3)2 containing materials (product isomers). The crude oil crystallized from isopropanol to give one pure isomer of product, 13.4 g (48%), pale yellow crystals, m.p. 131° -2°.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C@@H:3]([C:15]([OH:17])=O)[NH:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[C@H:20]12[CH2:26][C@H:23]([NH:24][CH2:25]1)[CH2:22][N:21]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.O>[CH3:18][C:2]([CH3:1])([CH3:19])[C@@H:3]([C:15]([N:24]1[CH2:25][C@@H:20]2[CH2:26][C@H:23]1[CH2:22][N:21]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:17])[NH:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.9 %

Procedure:
A mixture of 3-methyl-N-{[(phenylmethyl)oxy]carbonyl}-L-valine (1.55 g, 5.84 mmol), 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.1 g, 5.56 mmol), EDC (1.28 g, 111 mmol), HOBt (150 mg, 1.11 mmol), NMM (1.69 g, 16.7 mmol) in CH2Cl2 (20 mL) was stirred at room temperature for 18 h. The reaction was diluted with water and CH2Cl2. The two layers were separated; the organic dried over anhydrous Na2SO4 and concentrated to give the title compound (2.5 g) as a pale yellow solid. LCMS (m/z): 446.2 (M+H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[N:5]=1)#[N:2].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O.O>[C:9]1([N:8]2[C:7]3[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]=[C:4]2[CH2:3][C:1]2[NH:21][N:20]=[N:19][N:2]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1nc2ccccc2n1-c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-n2c(Cc3nnn[nH]3)nc3ccccc32)cc1
Temperature: 100 °C
Yield: 72.2 %

Procedure:
A mixture of 2-cyanomethyl-1-phenyl-1H-benzimidazole (6.2 g), sodium azide (5.18 g) and ammonium chloride (4.27 g) in N,N-dimethylformamide (62 ml) was heated at 100° C. for 4 hours. The reaction mixture was poured into water (620 ml) and the aqueous mixture was adjusted to pH 9 with 1 N sodium hydroxide. After being washed with ethyl acetate, the aqueous layer was further adjusted to pH 4 with acetic acid and extracted twice with ethyl acetate. The combined extract was washed with water and saturated sodium chloride in turn and dried over magnesium sulfate. The solvent was removed under reduced pressure to give a residue, which was recrystallized from a mixture of methanol and diisopropyl ether to give 5-(1-phenyl-1H-benzimidazol-2-yl)methyl-1H-tetrazole (5.3 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][C:9]=2[N:10]=1.S(Cl)([Cl:19])=O>>[Cl:19][CH2:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:10][C:9]=2[CH:11]=1
Reactant: OCc1ccc2oc(-c3cccs3)nc2c1
Reactant: O=S(Cl)Cl
Product: ClCc1ccc2oc(-c3cccs3)nc2c1
Reaction time: 3 h
Yield: 85 %

Procedure:
To 2-(2-thienyl)-5-benzoxazolylmethanol (600 mg) was added thionyl chloride (3 ml) at 0° C., stirred for 3 hours. The reaction mixture was concentrated, which was neutalized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure to give crystals of 5-chloromethyl-2-(2-thienyl) benzoxazole (550 mg, 85%). The recrystalization from ethyl acetate-hexane gave colorless needles, mp 152-153° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].C(=O)(O)[O-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>O.C(O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCCCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCNc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 97 %

Procedure:
5 g (38.11 mmol) of 6-aminocaproic acid are dissolved in 50 ml of water in the presence of 1.5 g (1 eq) of sodium hydroxide and 4.2 g (1.3 eq) of sodium bicarbonate in a 250 ml three-necked flask equipped with a reflux condenser and a thermometer. A solution of 4.9 ml (1.2 eq) of 4-fluoronitrobenzene in 50 ml of ethanol is run into the mixture, which mixture is subsequently brought to reflux (85°-90° C.) for 48 hours. The mixture is cooled and then extracted 3 times with dichloromethane. The aqueous phase is acidified to pH˜3 with 5N hydrochloric acid. A yellow precipitate is formed; the mixture is left overnight in a refrigerator. The precipitate is pulled dry and washed with water and with acetone. After drying, 9.3 g of a yellow product are obtained, i.e. a final yield of 97%.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]([S:13]([CH2:16][C:17]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[CH3:29])[N:20]=[C:19]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[N:18]=1)(=[O:15])=[O:14])[CH3:12].C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:11]([S:13]([CH2:16][C:17]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[CH3:29])[N:20]=[C:19]([C:30]2[CH:31]=[CH:32][C:33]([NH:34][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:35][CH:36]=2)[N:18]=1)(=[O:14])=[O:15])[CH3:12]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCS(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108 %

Procedure:
Phenyl chloroformate (0.207 mL, 1.65 mmol) was added dropwise to 4-[4-(ethylsulfonylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (620 mg, 1.65 mmol) and sodium bicarbonate (208 mg, 2.47 mmol) in dioxane (15 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and the residue partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was dried (MgSO4), filtered and evaporated to give the desired material as a white solid (885 mg).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH:27](C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45].O.CCCCCC.CC(C)=O>N1C=CC=CC=1>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:34]([CH3:35])[C@H:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
To a solution of methyl pheophorbide-a (100 mg, 0.17 mmol) in pyridine (25 mL) was added distilled water (48 μL, 2.7 mmol, 16 equiv.) and the mixture was refluxed under argon with stirring. The reaction was monitored by HPLC (hexane-acetone, 90:10-mobile phase, LiChrospherCN-column, detection at 425 and 410 nm). The HPLC of the reaction aliquots after 2 h and 20 min showed 87% completion (by peak area). After 2 h and 40 min of reflux, more distilled water (32 L, 1.8 mmol, 11 equiv.) was added and reflux continued. An HPLC of reaction aliquot at 5 h and 40 min showed 99.5% completion (by peak area). The solution was cooled to room temperature and solvent removed under reduced pressure. The residue was crystallized from methylene chloride-methanol to give methyl pyropheophorbide-a (50 mg, 56%).