Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:3]=1[O:4][CH2:5][C:6](=O)[CH3:7].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][NH2:33])=[N:26][CH:27]=1.[Cl-].[NH+]1C=CC=CC=1.Cl>N1C=CC=CC=1>[F:34][C:21]([F:20])([F:35])[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][N:33]=[C:6]([CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:12][C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:10][C:9]=2[Cl:19])[CH3:7])=[N:26][CH:27]=1
Reactant: NOCCCOc1ccc(C(F)(F)F)cn1
Reactant: CC(=O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: CC(COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A mixture of 0.34 g of (2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)-phenoxy)acetone, 0.24 g of O-(3-(5-trifluoromethyl-2-pyridyloxy)propyl)-hydroxylamine, 0.14 g of pyridinium chloride, and 10 ml of pyridine was stirred at room temperature for 2 hours. The reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.40 g (yield, 71%) of (2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-acetone O-(3-(5-trifluoromethyl-2-pyridyloxy)propyl)oxime, nD23.0 1.5310.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([NH:12][C:13]2[CH:22]=[C:21]3[NH:23][N:24]=[C:19]4[C:20]3=[C:15]([CH2:16][CH2:17][NH:18]4)[N:14]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([N:18]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([NH:12][C:10]([NH:9][C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])=[O:11])[CH:22]=[C:21]3[NH:23][N:24]=[C:19]1[C:20]=23)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: C[C@@H](NC(=O)Nc1cc2[nH]nc3c2c(n1)CCN3)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2nc(NC(=O)N[C@H](C)c3ccccc3)cc3[nH]nc1c23
Reaction time: 1 h

Procedure:
(R)-1-(1-phenylethyl)-3-(1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)urea (Example 136; 13 mg, 0.040 mmol) and triethylamine (50 mg, 0.494 mmol) were taken in DCM (0.15 mL) and added acetyl chloride (20 mg, 0.255 mmol) and stirred for 1 hour. The reaction mixture was diluted with DCM, washed with aqueous sodium bicarbonate, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-15% MeOH-DCM) gave (R)-1-(3 acetyl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C19H20N6O2 [M+H]+ 365. found 365. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.13-9.05 (m, 1H), 8.05-7.86 (m, 1H), 7.39-7.28 (m, 6H), 7.27-7.18 (m, 1H), 3.06-2.96 (m, 2H), 1.38 (t, J=9.1, 3H), 1.25-1.18 (m, 2H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:11]#[N:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH2:2].[O:13]([C:20]1[CH:21]=C([CH:25]=[CH:26][CH:27]=1)CO)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:1]([CH:3]1[CH2:5][C:4]1([C:11]#[N:12])[C:6]([O:8][CH2:9][C:10]1[CH:25]=[CH:26][CH:27]=[C:20]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:21]=1)=[O:7])=[CH2:2]
Reactant: C=CC1CC1(C#N)C(=O)OCC
Reactant: OCc1cccc(Oc2ccccc2)c1
Product: C=CC1CC1(C#N)C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
Utilizing the product prepared in Example I, a transalcoholysis was carried out with 3-phenoxybenzyl alcohol to obtain (3-phenoxy)benzyl 2-vinyl-1-cyanocyclopropane-1-carboxylate. A three-fold molar excess of the ethyl 2-vinyl-1-cyanocyclopropane-1-carboxylate was employed for the reaction. About 0.7 wt. percent calcium acetate, based on the total reactant charge, was used as the catalyst and a small amount of hydroquinone added as an oxidation and polymerization inhibitor. The reaction mixture was heated with agitation to 150° C. and about 4 wt. percent dibutyltin oxide charged. After 5 hours additional heating the reaction was terminated and the resulting product, containing about 35% of the desired (3-phenoxy)benzyl 2-vinyl-1-cyanocyclopropane-1-carboxylate, dissolved in ethyl ether, filtered to remove insoluble catalyst residue, washed with 5% aqueous sodium hydroxide and saturated sodium chloride solutions. After evaporation of the ethyl ether, the product was dissolved in toluene and separated from the unreacted starting materials using a Waters Preparatory Liquid Chromatograph 500A equipped with a gel permeation column and operated at a flow rate of 0.1 l/min. After two passes, 92+% pure (3-phenoxy)benzyl 2-vinyl-1-cyanocyclopropane-1-carboxylate was obtained and the structure of the product confirmed by mass spectroscopy and nuclear magnetic resonance spectroscopy.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[CH2:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21])[CH3:12].[OH-].[Na+]>O>[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:13]([CH2:11][CH3:12])[CH:8]=[O:10])(=[O:22])[CH3:21]
Reactant: CCNc1ccccc1C(C)=O
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCN(C=O)c1ccccc1C(C)=O
Reaction time: 4 h

Procedure:
A mixture of acetic anhydride (23 ml) and formic acid (15.5 ml) was stirred at 50° for 4 hours and then cooled to 0° in an ice/salt bath. 2'-(Ethylamino)-acetophenone (20.5 g) was added in small portions over 15 minutes and the mixture allowed to stand at room temperature for 1 hour. The mixture was cooled to 0° and water (100 ml) followed by aqueous sodium hydroxide (specific gravity 1.5, 10 ml) was added dropwise whilst maintaining the temperature below 10°. The resultant mixture was extracted with dichloromethane (4×100 ml) and the combined extracts were dried over magnesium sulphate to give a solution of 2'-acetyl-N-ethylformanilide.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:7]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.Cl.N1CCC(C2NN=C(C3C=CC(Cl)=CC=3)C=2C2C=CN=CC=2)C[CH2:26]1>>[CH3:26][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:7]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: Fc1ccc(-c2n[nH]c([C@H]3CCCN3)c2-c2ccncc2)cc1
Agent: Cl
Product: CN1CCC[C@@H]1c1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1

Procedure:
By following the method of Example C-75 and substituting (R)-5-(2-pyrolidinyl)-4-(4-pyridyl)-3-(4-fluorophenyl)pyrazole Example C-125) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 323 (base peak).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=4)[NH2:25])=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([NH:25][C:41]([CH:38]5[CH2:40][CH2:39]5)=[O:42])[CH:26]=[CH:27][CH:28]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1)C1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 103.6 %

Procedure:
A mixture of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)aniline (10 mg, 0.025 mmol), diisopropylethylamine (13 mg, 0.10 mmol), and dichloromethane (2 mL) was treated with cyclopropanecarbonyl chloride (30 mg, 0.028 mmol) and stirred at room temperature for 6 hours. The solvent was removed in vacuo and the remaining residue was dissolved in ethyl acetate (25 mL), washed with aqueous sodium bicarbonate solution (2×20 mL), and the organic fraction was separated and concentrated. The product was purified by column chromatography over silica gel using 1% methanol and 0.01% ammonia in 1:1 ethyl acetate/hexanes to give 12 mg (quantitative yield) of N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)phenyl]cyclopropanecarboxamide as a yellow gum. MS [M+H] 464.0,
Reaction SMILES: [CH:1]([C:5]1[C:10]([OH:11])=[C:9]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH:8]=[C:7]([CH2:16]OC)[CH:6]=1)([CH2:3][CH3:4])[CH3:2].[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[OH:27].S(=O)(=O)(O)O.C1(C)C(O)=CC=CC=1>C(Cl)Cl>[OH:11][C:10]1[C:9]([CH:12]([CH3:13])[CH2:14][CH3:15])=[CH:8][C:7]([CH2:16][C:24]2[CH:23]=[C:22]([CH3:26])[C:21]([OH:27])=[C:20]([CH3:19])[CH:25]=2)=[CH:6][C:5]=1[CH:1]([CH3:2])[CH2:3][CH3:4]
Reactant: Cc1cccc(C)c1O
Reactant: CCC(C)c1cc(COC)cc(C(C)CC)c1O
Agent: Cc1ccccc1O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCC(C)c1cc(Cc2cc(C)c(O)c(C)c2)cc(C(C)CC)c1O
Yield: 90 %

Procedure:
The procedure of Example 2 was followed using 50.45 grams (0.202 mol) of 2,6-di-sec-butyl-α-methoxy-p-cresol in 30 mL methylene chloride and 39.0 grams (0.320 mol) 2,6-dimethylphenol with 42 grams 78% sulfuric acid. The reaction was carried out at about 8° C. with mechanical stirring. The 2,6-di-sec-butylephenol used to prepare the cresol according to the procedure of Example 3 was of only 85.7 percent purity. Accordingly, the yield of the cresol was only 67% (86.9 area % by gas chromatography). The product of the invention: [4-[[4-hydroxy-3,5-bis(1-methylpropyl)phenyl]methyl]-2,6-dimethylphenol, was obtained as a viscous oil (liquid) at room temperature in 90 percent yield (61.77 grams) (84.4 area percent by gas chromatography). The compound has a pour point of 22° C. (as measured by ASTM test D-97).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([Cl:13])[N:8]=1.[NH3:17]>>[F:1][C:2]([F:16])([F:15])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([Cl:13])[N:8]=1
Reactant: N
Reactant: FC(F)(F)CNC(=S)Nc1cncc(Cl)n1
Product: NC(=NCC(F)(F)F)Nc1cncc(Cl)n1
Temperature: 25 °C

Procedure:
To a solution of 2-[3-(2,2,2-trifluoroethyl)-thioureido]-6-chloropyrazine (0.7 g.) in alcoholic ammonia (35 ml.) was added red mercuric oxide (0.65 g.) with stirring at room temperature. After stirring overnight, the black mixture was filtered and the black solid washed with alcohol. The resulting yellow filtrate was evaporated to give a yellow solid (0.7 g.). Recrystallisation from hot toluene diluted with petroleum ether (b.p. 60°-80°) yielded colourless needles (0.5 g.) of 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-chloropyrazine m.p. 139°-140°.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[C:9]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[O:10])([O-:5])=[O:4].Br[CH2:20][CH2:21][CH2:22][CH3:23].C(OCC)(=O)C>CN(C)C=O>[CH2:20]([N:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9](=[O:10])[C:8]1[CH:16]=[CH:17][CH:18]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCBr
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCn1cccc1C(=O)c1cccc([N+](=O)[O-])c1
Yield: 95.8 %

Procedure:
4 G (160 mmol) of 50% sodium hydride were suspended, under nitrogen atmosphere, in 250 ml of anhydrous dimethylformamide. A solution of 15 g (69 mmol) of 2-(3-nitrobenzoyl)pyrrole, prepared, for example, as described in Preparation 3A, in 50 ml of anhydrous dimethylformamide was added thereto, in a dropwise fashion and under stirring, maintaining the temperature at 20°-25° C. The resulting mixture was stirred for 2 additional hours and then a solution of 18 ml (170 mmol) of 1-bromobutane in 50 ml of dry dimethylformamide was added. The reaction mixture was stirred at room temperature for 18 hours further and then poured into 2000 ml of ethyl acetate. The organic extract was washed with water (5×500 ml), dried and evaporated in vacuo. The residue was purified by column chromatography on 1 Kg of silica gel, using hexane-acetone (90:10) as eluant, thus obtaining 18 g (95%) of 1-butyl-2 -(3'-nitrobenzoyl)pyrrole, the title compound, as an oil.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([Cl:19])=[O:8])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Reaction time: 10 h

Procedure:
Dissolve 10 g (42 mmole) of 2-acetylthiomethyl-3-phenyl propionic acid and 10 g (84 mmole) of thionyl chloride in 50 ml of toluene. Stir for 10 hrs. under nitrogen and concentrate in vacuo. Dissolve the residue in 50 ml of toluene and again concentrate in vacuo. Repeat this step five times to obtain the product as a light brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:9]=[N:10][N:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH3:26][S:27]([O:15][CH2:14][C:13]([N:11]1[CH:12]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:18])[CH:9]=[N:10]1)([CH3:17])[CH3:16])(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)Nc1cnn(C(C)(C)CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cnn(C(C)(C)COS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)carbamate (3.4 g) obtained in Step A of Example 114 were added successively triethylamine (2.4 mL) and methanesulfonyl chloride (1.2 mL) in an ice bath, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the crude title compound (2.2 g).
Reaction SMILES: CCC1C2N=C(C=C3C(C=C)=C(C)C(=CC4[C@@H](C)[C@H](CCC(O)=O)C(=C(CC(O)=O)C5NC(C=2)=C(C)C=5C(O)=O)N=4)N3)C=1C.[CH3:45][CH2:46][C:47]1[C:51]2=[CH:52][C:53]3[N-:57][C:56]4[C:58]([C@@H:100]([C:103]([O:105][CH3:106])=[O:104])[C:101](=[O:102])[C:55]=4[C:54]=3[CH3:107])=[C:59]3[N:63]=[C:62]([CH:64]=[C:65]4[N-:70][C:68](=[CH:69][C:49](=[N:50]2)[C:48]=1[CH3:108])[C:67]([CH:71]=[CH2:72])=[C:66]4[CH3:73])[C@@H:61]([CH3:74])[C@@H:60]3[CH2:75][CH2:76][C:77]([O:79][CH2:80]/[CH:81]=[C:82](/[CH2:84][CH2:85][CH2:86][C@@H:87]([CH2:89][CH2:90][CH2:91][C@@H:92]([CH2:94][CH2:95][CH2:96][CH:97]([CH3:99])[CH3:98])[CH3:93])[CH3:88])\[CH3:83])=[O:78].[Mg+2]>>[CH3:45][CH2:46][C:47]1[C:48]([CH3:108])=[C:49]2[NH:50][C:51]=1[CH:52]=[C:53]1[N:57]=[C:56]3[C:55]([C:101]([C@H:100]([C:103]([O:105][CH3:106])=[O:104])[C:58]3=[C:59]3[N:63]=[C:62]([CH:64]=[C:65]4[NH:70][C:68](=[CH:69]2)[C:67]([CH:71]=[CH2:72])=[C:66]4[CH3:73])[C@@H:61]([CH3:74])[C@@H:60]3[CH2:75][CH2:76][C:77]([O:79][CH2:80]/[CH:81]=[C:82](/[CH2:84][CH2:85][CH2:86][C@@H:87]([CH2:89][CH2:90][CH2:91][C@@H:92]([CH2:94][CH2:95][CH2:96][CH:97]([CH3:98])[CH3:99])[CH3:93])[CH3:88])\[CH3:83])=[O:78])=[O:102])=[C:54]1[CH3:107]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[n-]c(cc6nc(cc1[n-]2)C(C)=C6CC)c(C)c5C(=O)[C@@H]4C(=O)OC)[C@@H](CCC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@@H]3C
Agent: C=Cc1c(C)c2cc3nc(c(CC(=O)O)c4[nH]c(cc5nc(cc1[nH]2)C(C)=C5CC)c(C)c4C(=O)O)[C@@H](CCC(=O)O)[C@@H]3C
Agent: [Mg+2]
Product: C=Cc1c(C)c2cc3nc(c4c5nc(cc6[nH]c(cc1[nH]2)c(C)c6CC)C(C)=C5C(=O)[C@@H]4C(=O)OC)[C@@H](CCC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@@H]3C

Procedure:
According to a preferred embodiment, the chlorin e6-protocol A comprises the steps of (a) treating chlorophyll-a obtained by the above method with the acid to eliminate Mg2+ from chlorophyll-a, thereby obtaining the precipitate of pheophytin a; (b-1) adding the acetone solvent to the precipitate of pheophytin a to obtain a solution of pheophytin a, followed by elimination of the acetone solvent; (b-2) adding ethanol to the residual pheophytin a to obtain the pheophytin a solution; and (b-3) treating the pheophytin a solution with the base to obtain chlorin e6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[N:21]=[C:22]([CH3:25])[S:23][CH:24]=3)[N:13]=[C:12]2[CH3:26])[CH:5]=1.[Cl:28]N1C(=O)CCC1=O>C(O)(C)C.ClC(Cl)C(O)=O>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:28])=[C:14]([O:18][CH2:19][C:20]3[N:21]=[C:22]([CH3:25])[S:23][CH:24]=3)[N:13]=[C:12]2[CH3:26])[CH:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)cc2=O)c1
Agent: O=C(O)C(Cl)Cl
Solvent: CC(C)O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Cl)c2=O)c1
Temperature: 60 °C
Yield: 96 %

Procedure:
To a solution of 4-methyl-3-[2-methyl-4-(2-methyl-thiazol-4-ylmethoxy)-6-oxo-6H-pyrimidin-1-yl]-benzoic acid methyl ester from Step A, of Example 11 (120 mg, 0.31 mmol) in isopropanol (1.5 mL) was added N-chlorosuccinimide (46 mg, 0.34 mmol) and 2 drops of dichloroacetic acid. The solution was heated at 60° C. for three hours. The solution was allowed to cool and concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the chlorinated product as colorless oil (125 mg, 96%). MS (M+H): 420
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[C:12](OC(=O)C)(=[O:14])[CH3:13].O>N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][C:12](=[O:14])[CH3:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(N)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(NC(C)=O)cc(OC)c1

Procedure:
A solution of 15.3 g of 3,5-dimethoxyaniline and 57.5 ml of acetic anhydride in 40 ml of anhydrous pyridine is heated at reflux for 1 hour. The reaction mixture is then cooled and poured into 350 ml of water. The precipitate formed is suspended in 20% aqueous Na2CO3 solution and is then filtered off using a Buchner funnel, washed with water and dried under a phosphoric vacuum. A precipitate of 14.5 g of the expected product is obtained in the form of a white amorphous solid.
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[CH:7]=[C:6]([Br:19])[C:5]=1[OH:20])[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>O>[Br:19][C:6]1[C:5]2[O:20][CH:2]([C:36]([OH:37])=[O:39])[CH2:1][C:4]=2[C:17]2[O:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:18])[C:8]=2[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)c(Br)cc2c(=O)c3ccccc3oc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C1Cc2c(c(Br)cc3c(=O)c4ccccc4oc23)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.8 %

Procedure:
A mixture of 4-allyl-2-bromo-3-hydroxy-9-oxo-9H-xanthene (3.0 g), m-chloroperbenzoic acid (10 g) and chloroform (250 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (20 g) and water (400 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent distilled off. The residue was dissolved in acetone (300 ml) and, to the stirred solution, a mixture of chromium trioxide (5 g), water (25 ml) and concentrated sulfuric acid (8 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.5 g of 4-bromo-1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 283°-286° C. This compound showed a mass spectrum having a molecular ion peak at m/e 360.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[C:6](Cl)[CH:5]=[C:4]([CH3:14])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:22][SH:23]>C(#N)C.O.Cl>[Cl:1][C:2]1[C:7]2[C:8]([OH:10])=[C:22]([C:21]([O:25][CH2:26][CH3:27])=[O:24])[S:23][C:6]=2[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1sc2cc(C)nc(Cl)c2c1O
Reaction time: 15 h
Yield: 93.9 %

Procedure:
To a suspension of ethyl 2,4-dichloro-6-methylpyridine-3-carboxylate (10.0 g, 42.7 mmol) in acetonitrile (45 mL) were added potassium carbonate (8.85 g, 64.1 mmol) and ethyl thioglycolate (4.68 mL, 42.7 mmol), and the mixture was stirred for 15 hr under refluxing conditions. The reaction mixture was diluted with water (150 mL), 6N hydrochloric acid (15 mL) was added and the mixture was stirred for 30 min. The precipitated solid was collected by filtration, washed with water and ethanol-diisopropyl ether (1/1), and dried under reduced pressure to give the title compound (10.9 g, 94%) as a white powder.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].[CH3:7][PH:8](=[O:10])[CH3:9].C[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:7][P:8]([CH3:9])([CH:2]([OH:3])[C:1]([O:5][CH3:6])=[O:4])=[O:10]
Reactant: COC(=O)C=O
Reactant: C[PH](C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)C(O)P(C)(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 17.6 g (0.2 mol) of methyl glyoxylate in 30 ml of dioxane is added dropwise to a solution of 15.6 g (0.2 mol) of dimethylphosphine oxide in 50 ml of dioxane. A spatula-tip of sodium methylate is added, the mixture is stirred at 25° C. for 24 hours and the evaporated residue is freed from adhering dioxane under a high vacuum and taken up in ethyl acetate to give, after trituration, 16.4 g (49.4%) of colorless product of melting point 84°-86°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:15]([N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][C:28]#[N:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCCl>[CH2:15]([N:22]1[C:26]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:25][CH:24]=[C:23]1[CH2:27][C:28]#[N:29])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#CCc1cccn1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: N#CCc1ccc(C(=O)c2ccc(Cl)cc2)n1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 8.43 ml. (0.0663 mole) of p-chlorobenzoyl chloride and 8.8 g. (0.0663 mole) of aluminum chloride in 100 ml. of 1,2-dichloroethane is added to a solution of 13.0 g. (0.0663 mole) of 1-benzylpyrrole-2-acetonitrile in 50 ml. of 1,2-dichloroethane at 5° C. over a 5 minute period. The mixture is stirred for 15 minutes, and then heated quickly to reflux for 3 minutes. The reaction mixture is poured into ice-hydrochloric acid and then filtered. The aqueous layer is separated and washed with chloroform. The combined organic solutions are washed successively with N,N-dimethylaminopropylamine solution, dilute hydrochloric acid, and brine and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the oily residue dissolved in benzene-methylcyclohexane and seeded with crystals of 1-benzyl-4-(p-chlorobenzoyl)-pyrrole-2-acetonitrile. After crystallization of the latter substance is complete, the mother liquor is filtered and evaporated and the residue crystallized from methanol. The crystals thus obtained are recrystallized from methanol to give 1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile as a yellow solid, m.p. 104-106° C.