Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCC1C2N=C(C=C3C(C=C)=C(C)C(=CC4[C@@H:32]([CH3:33])[C@H:31]([CH2:34][CH2:35][C:36]([OH:38])=O)C(=C(CC(O)=O)C5NC(C=2)=C(C)C=5C(O)=O)N=4)N3)C=1C.Br.C(O)(=O)C.[CH2:50](O)[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55].CCC1C(C)=C2NC=1C=C1N=C3C(C(C(C(OC)=O)C3=C3N=C(C=C4NC(=C2)C(C=C)=C4C)C(C)C3CCC(OC)=O)=O)=C1C>>[CH2:50]([O:38][CH2:36][CH2:35][CH2:34][CH2:31][CH2:32][CH3:33])[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCO
Reactant: 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: Br
Agent: C=Cc1c(C)c2cc3nc(c4c5nc(cc6[nH]c(cc1[nH]2)c(C)c6CC)C(C)=C5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Solvent: CC(=O)O
Product: CCCCCCOCCCCCC
Yield: 68 %

Procedure:
The chlorin-e6 tetramethyl ester prepared in Example 2 (50 mg) was reacted with HBr/acetic acid and n-hexyl alcohol as described in Example 1 for methyl pheophorbide. The desired product was isolated in 68% yield, and the purity confirmed by TLC and HPLC. The structure was confirmed by NMR and mass spectroscopy; the spectra also showed evidence for aggregation of two chlorin units.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[CH2:25]Cl)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH3:20]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCOc1ccc(CCl)cc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1OCC
Temperature: 70 °C
Reaction time: 3 h
Yield: 122 %

Procedure:
Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (403 mg), 3,4-diethoxybenzyl chloride (802 mg) and potassium carbonate (311 mg) were suspended in DMF (15 ml), and the resulting suspension was stirred at 70° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. After evaporation under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain methyl 7-(3,4-diethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (818 mg) as a yellow amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:25])[N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C@@H:12]([CH3:25])[N:13]([C:16]([C:18]4[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=4)=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CC1c2ccccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: C[C@@H]1c2ccccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1

Procedure:
The enantiomers of 4-[(3-fluoro-6-methylphenanthridin-5(6H)-yl)carbonyl]phenol (720 mg, 2.16 mmol) were separated by automated, on-column solvent change, preparative, normal phase, chiral chromatography on a Chiralpak AD (20 mm×250 mm) column eluting with 35% hexane in ethanol at a flow rate of 15 mL/min with. The fractions containing the first peak were combined and concentrated in vacuo, to provide one peak (99.9%) with a retention time of 3.620 minutes was isolated as a white solid (318 mg, 88% based upon a 1:1 ratio of enantiomers with a theoretical maximum amount of 360 mg). mp 235.7-236.8° C.; [α]D25=−648° (c=0.010 g/mL, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=6.98 Hz, 3 H) 5.68 (q, J=6.73 Hz, 1 H) 6.56 (dd, J=10.48, 2.46 Hz, 1 H) 6.70 (d, J=8.79 Hz, 2 H) 7.06 (td, J=8.60, 2.72 Hz, 1 H) 7.16 (m, 2 H) 7.35 (m, 1 H) 7.42 (m, 2 H) 7.98 (td, J=8.73, 7.11 Hz, 2 H) 10.04 (s, 1H) MS (ESI) m/z 334 ([M+H]+); MS (ESI) m/z 332 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1F)[C:5]([O:7][CH3:8])=[O:6].[CH2:25]([NH2:28])[CH:26]=[CH2:27].CO.O>C1COCC1>[CH2:25]([NH:28][C:11]1[C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])[C:2]=1[F:1])[CH:26]=[CH2:27]
Reactant: C=CCN
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)c(F)c1Nc1ccc(I)cc1F
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCNc1c([N+](=O)[O-])cc(C(=O)OC)c(Nc2ccc(I)cc2F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of methyl 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-nitrobenzoate (3.9 g, 8.62 mmoles) and allylamine (3.5 ml, 43 mmoles) in a mixture of THF (10 ml), MeOH (10 ml) and H2O (2.5 ml) is stirred at room temperature for 30 min. The yellow suspension is filtered and washed with hexane to remove the excess of allylamine. The resulting solid is dried under vacuum to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[NH:7][C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1.[H-].[Na+].[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[CH2:20]Br>CN(C)C=O>[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[CH2:20][N:7]1[C:6]2[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11]
Reactant: Clc1cc(Br)cc(CBr)c1
Reactant: COc1ccc2c(c1)OCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OCC(=O)N2Cc1cc(Cl)cc(Br)c1
Reaction time: 1 h
Yield: 84 %

Procedure:
0.5 grams of 7-methoxy-1,4-benzoxazin-3-one (2.8 mmole) was dissolved in 10 ml of dimethylformamide and cooled in an ice bath. 0.17 grams (3.5 mmole) of sodium hydride (60% wt. inn oil) was added, and after 5 minutes 0.8 grams (2.9 mmole) of 3-bromo-5-chloro-benzylbromide was added all at once. The mixture was stirred at ice bath temperature for 1 hour, and then quenched by addition of 1% hydrochloric acid. The product was extracted with ethyl acetate, that was evaporated under reduced pressure to give an oil which was chromatographed via medium pressure eluting with 10% ethyl acetate in hexanes to yield 0.9 grams of 4-(3-bromo-5-chloro-benzyl)-7-methoxy-4H-benzo[1,4]oxazin-3-one as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([CH2:12][C:13]([NH:15][CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:17][CH2:18][CH3:19])=[O:14])[CH:9]=[CH:8][C:5]=1[CH2:6]Cl)[CH3:2].[H][H]>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([CH2:12][C:13]([NH:15][CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:17][CH2:18][CH3:19])=[O:14])[CH:9]=[CH:8][C:5]=1[CH3:6])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(CCl)c(OCC)c1)c1ccccc1N1CCCCC1
Reactant: [H][H]
Solvent: C1COCCO1
Product: CCCC(NC(=O)Cc1ccc(C)c(OCC)c1)c1ccccc1N1CCCCC1
Reaction time: 3 h

Procedure:
A mixture of 0.54 g (1.2 mmols) of 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzyl chloride (melting point 114°-115° C., prepared from 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl-benzyl alcohol and thionyl chloride in chloroform) and 10 ml of absolute dioxane was hydrogenated for 3 hours at 20° C. and a pressure of 5 bar hydrogen. The reaction mixture was then evaporated in vacuo, and the residue was taken up in a mixture of ethyl acetate and aqueous sodium carbonate. The organic phase was dried, filtered and evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (chloroform/acetone=19/1).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:6]2[NH:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.[H][H]>CO.Cl[Pd]Cl>[N:8]1[C:7]2[CH:11]=[CH:12][NH:13][C:6]=2[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:2]=2[F:1])=[N:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ncnc3cc[nH]c23)c(F)c1
Reactant: [H][H]
Agent: Cl[Pd]Cl
Solvent: CO
Product: Nc1ccc(Oc2ncnc3cc[nH]c23)c(F)c1
Yield: 72.1 %

Procedure:
A solution of 243 (263 mg, 0.966 mmol, scheme 54) in MeOH (10 mL) and PdCl2 (1.8 mg, 0.01 mmol) was stirred in the atmosphere of hydrogen for 60 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Water was added to the residue and the aqueous solution was extracted with DCM. The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure, to afford title compound 247 (170 mg, 72% yield, crude) as a gray solid. MS (m/z): 243.08 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][C:4]=1[OH:12].CC(O)=O.[N:17]([O-])=O.[Na+].[NH4+].[OH-]>CO.O.[Pd]>[CH3:1][N:2]1[C:3]2[C:4]([OH:12])=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]=[N:17]1
Reactant: O=N[O-]
Reactant: CNc1c(O)cccc1[N+](=O)[O-]
Agent: [Pd]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cn1nnc2cccc(O)c21
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
2-Methylamino-3-nitrophenol (2.50 g, 14.9 mmol) in MeOH (200 mL) with HOAc (0.5 mL) was hydrogenated (40 psi, 2 hours) in the presence of 10% Pd on carbon (250 mg). Following removal of the catalyst by filtration the solution was concentrated in vacuo. The residue was resuspended in H2O (30 mL), and 3N HCl (10 mL) was added dropwise while stirring at 0-5° C., immediately followed by 1.1M NaNO2 (15 mL, 16.5 mmol) in H2O dropwise over 20 minutes. After 30 minutes at about 22° C., the mixture was recooled to about 5° C., and the pH adjusted to about 6 with conc. NH4OH. The resulting solution was extracted with EtOAc (3×20 mL). The pooled organic extracts were dried over Na2SO4 and concentrated to yield a dark red-brown solid (2.23 g) which was chromatographed on silica (50→90% EtOAc/hexanes) to afford 1.26 g of pure product as a tan solid (GC/MS m/z 149).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]4[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=4)[C:22]([O:24]CC)=O)=[N:17][N:18]=3)[CH:15]=2)=[CH:6][CH:5]=1.CCO.[CH3:35][NH2:36]>O>[CH3:35][NH:36][C:22](=[O:24])[C:21]1[CH:27]=[CH:28][CH:29]=[C:19]([C:16]2[N:14]3[CH:15]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:31])[F:30])=[CH:5][CH:6]=4)[CH:11]=[CH:12][C:13]3=[N:18][N:17]=2)[CH:20]=1
Reactant: CCOC(=O)c1cccc(-c2nnc3ccc(-c4ccc(OC(F)(F)F)cc4)cn23)c1
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNC(=O)c1cccc(-c2nnc3ccc(-c4ccc(OC(F)(F)F)cc4)cn23)c1

Procedure:
Ethyl 3-(6-(4-(trifluoromethoxy)phenyl)[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzoate, prepared as described above was stirred in 40% CH3NH2 in H2O (2.5 mL) and EtOH (1.5 mL) at 60° C. in a sealed tube overnight. The reaction mixture was concentrated and purified by HPLC followed by further purification with prep-TLC (5% MeOH/CH2Cl2) to afford N-methyl-3-(6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzamide.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].CO/[CH:15]=[CH:16]/[C:17](=O)[CH2:18][CH3:19].N12CCN(CC1)CC2.Cl>COCCOCCO>[CH2:18]([C:17]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:5])[C:3]([C:1]#[N:2])=[CH:15][CH:16]=1)[CH3:19]
Reactant: CCC(=O)/C=C/OC
Reactant: N#CCC(=O)Nc1ccccc1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: COCCOCCO
Product: CCc1ccc(C#N)c(=O)n1-c1ccccc1
Temperature: 120 °C
Yield: 27.3 %

Procedure:
A solution of 2-cyano-N-phenylacetamide (1.08 g, 6.73 mmol), (1E)-1-methoxypent-1-en-3-one (1.0 g, 8.76 mmol) and 1,4-diazabicyclo[2.2.2]octane (755 mg, 6.73 mmol) in 2-(2-methoxyethoxy)ethanol (10 mL) was stirred with heating at 120° C. for 7 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=2/1→4/1) to give the title compound (412 mg, 27%) as a pale-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][C@@H:41]([CH2:45][OH:46])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:29])([F:31])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH:41]([CH2:45][OH:46])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C(CO)C1

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-3-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 3-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>C1COCC1>[CH2:5]([C@H:8]1[CH2:15][CH2:14][C@H:11]([SiH:2]2[CH2:7][CH2:6][CH:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH2:4][CH2:3]2)[CH2:10][CH2:9]1)[CH2:4][CH3:3]
Reactant: N#Cc1ccc(C2CC[SiH](Cl)CC2)cc1
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([SiH]2CCC(c3ccc(C#N)cc3)CC2)CC1

Procedure:
4.7 g (20 mmol) of 4-(4-fluorobutyl) cyclohexyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain Grignard's reagent. This solution was then added to a mixture of 3.0 g (22 mmol) of zinc chloride and 10 ml of TMF to obtain the organic zinc reagent. This reagent was then dripped into a 50 ml THF solution of 4.7 g (20 mmol) of 4-(4-chloro-4-silacyclohexyl) benzonitrile to obtain 4-(4-(trans-4-n-propylcyclohexyl)-4-silacyclohexyl) benzonitrile. This product was a mixture of trans isomers and cis isomers with regard to the silacyclohexane ring. They were separated by means of chromatography to obtain 5.9 g of the trans isomers (yield 83%).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]([NH:12][C:13]2[C:14]([N:19]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]3=[O:26])=[N:15][N:16]([CH3:18])[CH:17]=2)=[O:11])[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:27]1COCC1>C(OCC)(=O)C.O>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][N:19]([C:14]2[C:13]([NH:12][C:10]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([OH:3])([CH3:27])[CH3:2])[N:9]=3)=[O:11])=[CH:17][N:16]([CH3:18])[N:15]=2)[C:20]1=[O:26]
Reactant: C1CCOC1
Reactant: CC(=O)c1cccc(C(=O)Nc2cn(C)nc2N2CCC(C)(C)C2=O)n1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(NC(=O)c2cccc(C(C)(C)O)n2)c(N2CCC(C)(C)C2=O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 6-acetyl-N-(3-(3,3-dimethyl-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide (35 mg) and THF (3.0 mL) was added 3M methylmagnesium bromide diethyl ether solution (0.33 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction solution was diluted with ethyl acetate, and water was added thereto. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was washed with diisopropyl ether, and dried under reduced pressure to give the title compound (14 mg).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[NH:6][C:7](=[O:19])[CH2:8][S:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Cl:24][C:21]1[CH:20]=[C:5]2[C:4]([C:3]([OH:2])=[C:8]([S:9][CH2:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:19])[NH:6]2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)CSCCCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)ccc2c(O)c1SCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 g (5.3 mmol) of 4-chloro-N-(3-phenylpropylthio)acetyl-anthranilic acid methyl ester are placed in 20 ml of tetrahydrofuran at 0°. A 1-molar tetrahydrofuran solution of sodium bis-trimethylsilylamide is added dropwise thereto. The mixture is then stirred for 20 minutes at 0° and for 2 hours at room temperature. The reaction mixture is poured into 200 ml of 2N hydrochloric acid/ice and the resulting white suspension is filtered off. The resulting colourless crystals are made into a suspension in ethanol and stirred for 2 hours. The mixture is filtered, followed by washing with ethanol and diethyl ether. After drying, 7-chloro-4-hydroxy-3-(3-phenylpropylthio)-2(1H)-quinolone is obtained in the form of colourless crystals having a melting point of 184°-186°.
Reaction SMILES: C([O:11][C:12]1[C:17]2[S:18][CH:19]=[CH:20][C:16]=2[S:15](=[O:22])(=[O:21])[N:14]([CH3:23])[C:13]=1[C:24]([NH:26][C:27]1[C:28](=[O:34])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])(=O)C=CC1C=CC=CC=1.[OH-].[Na+]>CO>[OH:11][C:12]1[C:17]2[S:18][CH:19]=[CH:20][C:16]=2[S:15](=[O:22])(=[O:21])[N:14]([CH3:23])[C:13]=1[C:24]([NH:26][C:27]1[C:28](=[O:34])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25]
Reactant: CN1C(C(=O)Nc2cccccc2=O)=C(OC(=O)C=Cc2ccccc2)c2sccc2S1(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(C(=O)Nc2cccccc2=O)=C(O)c2sccc2S1(=O)=O
Yield: 41.5 %

Procedure:
To a suspension of 4-cinnamoyloxy-2-methyl-N-(1-oxo-2,4,6-cycloheptatrien-2-yl)-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide (0.49 g) in methanol (50 ml) was added dropwise 1N aqueous solution of sodium hydroxide (1.5 ml) at ambient temperature. The resultant mixture was stirred at the same temperature for 8 hours. After neutralization with 1N hydrochloric acid, the solvent was removed under reduced pressure. The residue was washed with water and dried up. The crude crystals were recrystallized from N,N-dimethyl-formamide to give 4-hydroxy-2-methyl-N-(1-oxo-2,4,6-cycloheptatrien-2-yl)-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide (0.15 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].COCCOC>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[CH:3][C:2]=1[NH2:1]
Reactant: CC1(C)OB(c2ccc(Cl)c(N)c2)OC1(C)C
Reactant: Cn1cc(Br)cn1
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2ccc(Cl)c(N)c2)cn1
Temperature: 150 °C
Yield: 44.4 %

Procedure:
To a mixture of 3-amino-4-chlorophenylboronic acid pinacol ester (0.110 g, 0.434 mmol), 4-bromo-1-methylpyrazole (0.087 g, 0.54 mmol), 1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) DCM complex (24 mg, 0.029 mmol) was added anhydrous DME (2.5 mL) followed by 1M aqueous sodium carbonate (0.99 mL, 0.99 mmol). The microwave vial was heated at 150° C. for 20 minutes under microwave irradiation. Further catalyst (0.005 g) was added and the vial was heated at 130° C. for 10 minutes under microwave irradiation. The reaction mixture was partitioned between ethyl acetate (55 mL) and a saturated aqueous NaHCO3 solution (15 mL). The organic layer was washed with a saturated aqueous NaHCO3 solution (2×13 mL), dried (Na2SO4) and concentrated in vacuo. This residue was purified using preparative TLC eluting with 30% ethyl acetate in CH2Cl2. The product band was recovered and stirred with 2% MeOH in ethyl acetate/CH2Cl2 (v/v; 1:3) (20 mL). The silica was removed by filtration, washed with ethyl acetate/CH2Cl2 (v/v; 1:3) (2×5 mL) and acetone (3×4 mL) to give the title compound as an off-white solid (0.040 g, 44%). 1H-NMR (500 MHz, DMSO-d6) 3.84 (s, 3H), 5.29 (s, 2H), 6.72 (dd, J=2.1, 8.2 Hz, 1H), 6.94 (d, J=2.1 Hz, 1H), 7.14 (d, J=8.2 Hz, 1H), 7.68 (d, J=0.7 Hz, 1H), 7.98 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13](O)(=O)[CH3:14]>C(OCC)C>[N+:10]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[S:8][C:14]1[CH:13]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1SCl
Reactant: CC(=O)O
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(Cl)ccc1Sc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
To 1.37 g of 3-butenyltributyltin was added 0.89 g. of 4-chloro-2-nitrobenzene sulfenyl chloride dissolved in 20 ml. glacial acetic acid at steam bath temperature. The mixture was then heated on a steam bath for 30 minutes and poured into an ice water bath. The product was taken up in diethyl ether, washed twice with 50 ml. portions of water, twice with 50 ml. portions of saturated sodium bicarbonate and an additional time with 50 ml. of water. The resulting ether layer was separated, dried over magnesium sulfate and filtered. The solvent was removed on a rotary evaporator and the concentrate analyzed by proton nmr. The product proved to be cyclopropylcarbinyl 2-nitro-4-chlorophenyl sulfide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CN
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)CNCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (20 mg), ethyl glycinate (10 mg) and acetic acid (0.1 mL) in DCM (10 mL) was added sodium triacetoxyborohydride (21 mg). The reaction was stirred at 20° C. for 1 h. The reaction mixture was partitioned between DCM (25 mL) and water (25 mL). The organic phase was evaporated to give ethyl N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}glycinate (D89) as a brown oil (20 mg), which was used directly in the next hydrolysis step. MS (ES): C26H29ClN4O4 requires 496; found 497.2 (M+H+).