Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[S:22][C:21]([C:23]([O:25]CC)=[O:24])=[CH:20][CH:19]=2)=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-].[K+].Cl>CO>[CH3:1][C:2]1[C:3]([C:16]([C:18]2[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=2)=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1ccc(C(=O)c2cc3c(cc2C)C(C)(C)CCC3(C)C)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(cc1C(=O)c1ccc(C(=O)O)s1)C(C)(C)CCC2(C)C
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
To a suspension of the ester 37 (50 mg, 0.13 mmol) in 75% aqueous methanol (3 mL) was added one pellet of potassium hydroxide (0.1 g). The reaction mixture was stirred at 70° C. for 1.5 h during which time the material dissolved. The solution was cooled to room temperature, acidified with 1N aqueous hydrochloric acid, and then extracted with 80% ethyl acetate/hexane. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to afford a white solid (46 mg). Recrystallization from methanol afforded the desired acid 38 as a white crystalline solid (42 mg, 1%): m.p. 214°-215° C. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:11]2[CH:10]=[C:9]([C:12]([O:14]C)=[O:13])[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.O.[OH-].[Li+].O>CO>[F:16][C:2]([F:1])([F:17])[C:3]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc2c(C(F)(F)F)cccc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c(C(F)(F)F)cccc2s1
Temperature: 75 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
A mixture of 290 mg of methyl 4-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 60 mg of lithium hydroxide monohydrate, 2 ml of water and 6 ml of methanol was stirred at 75° C. for 1 hour. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. To the residue was added water, and then washed with tert-butyl methyl ether 3 times. To the aqueous layer was added concentrated hydrochloric acid, and then extracted with chloroform 3 times. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 240 mg of 4-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid (the present compound 3).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:18]2[N:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)=[CH:20][CH:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[NH2:29][C:30]1[CH:35]=[C:34]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[CH:33]=[CH:32][C:31]=1[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:18]2[N:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([NH:29][C:30]3[CH:35]=[C:34]([C:36]4[S:37][CH:38]=[CH:39][CH:40]=4)[CH:33]=[CH:32][C:31]=3[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:28])=[CH:20][CH:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(-c2ccc(/C=C/C(=O)O)cn2)cc1OC
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccc(/C=C/C(=O)Nc3cc(-c4cccs4)ccc3NC(=O)OC(C)(C)C)cn2)cc1OC
Yield: 100.4 %

Procedure:
A solution of acid 40 (0.10 g, 0.25 mmol), amine 4 (72.7 mg, 0.25 mmol) and BOP reagent (0.133 g, 3.0 mmol) in pyridine (2 mL) was stirred 18 h at room temperature. The reaction mixture was concentrated and the residue was purified by flash chromatography (eluent: 1:1 hexane:AcOEt) to give title compound 41 (0.14 g, 61% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8](=O)[NH:9][C:10]3[C:15]([C:16]=2[CH3:17])=[C:14]([OH:18])[CH:13]=[C:12]([CH3:19])[CH:11]=3)=[CH:4][CH:3]=1.O.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:8]1[C:7]([CH2:6][C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:16]([CH3:17])[C:15]2[C:14]([OH:18])=[CH:13][C:12]([CH3:19])=[CH:11][C:10]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c2c(C)c(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1
Solvent: O
Product: Cc1cc(O)c2c(C)c(Cc3ccc(Cl)cc3)c(Cl)nc2c1

Procedure:
A solution of 3-(4-chlorobenzyl)-5-hydroxy-4,7-dimethyl-1H-quinolin-2-one (1.8 g) in phosphorus oxychloride (9.0 mL) was heated at 180° C. in a microwave reactor for 15 minutes. The solution was poured onto a mixture of ice and water and the resulting precipitate collected by filtration, washed with water and then dried to afford title compound, 2.3 g.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:30]4[C:25](=[C:26]5[CH:34]=[CH:33][C:32]([C:35]6[NH:39][C:38]([C@@H:40]7[CH2:44][CH2:43][CH2:42][N:41]7[C:45]([O:47][CH2:48][C:49]7[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=7)=[O:46])=[N:37][CH:36]=6)=[CH:31][C:27]5=[CH:28][CH:29]=4)[O:24][CH2:23][C:22]=3[CH:55]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.[CH3:57][O:58][C:59]([NH:61][C@@H:62]([CH:66]([CH3:68])[CH3:67])[C:63]([OH:65])=O)=[O:60].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(#N)C.CO.[OH-].[Na+].C(OCC)(=O)C.C(O)C>[CH3:57][O:58][C:59]([NH:61][C@@H:62]([CH:66]([CH3:68])[CH3:67])[C:63]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:30]4[C:25](=[C:26]5[CH:34]=[CH:33][C:32]([C:35]6[NH:39][C:38]([C@@H:40]7[CH2:44][CH2:43][CH2:42][N:41]7[C:45]([O:47][CH2:48][C:49]7[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=7)=[O:46])=[N:37][CH:36]=6)=[CH:31][C:27]5=[CH:28][CH:29]=4)[O:24][CH2:23][C:22]=3[CH:55]=2)=[CH:16][N:17]=1)=[O:65])=[O:60]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc([C@@H]5CCCN5C(=O)OCc5ccccc5)[nH]4)ccc23)[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CO
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc([C@@H]5CCCN5C(=O)OCc5ccccc5)[nH]4)ccc23)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
A solution of (S)-benzyl 2-(5-(8-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.2 g, 1.6 mmol), concentrated HCl (1.5 mL) and ethanol (10 mL) was heated to 60° C. for one hour. The reaction was concentrated and redissolved in a minimal amount of methanol. An equal volume of dichloromethane was added and the solution was again concentrated. Dichloromethane was added to the resulting residue and concentrated off three more times, until the crude material was a yellow powder. A portion of the crude amine (0.3 g, ˜0.40 mmol) was dissolved in dimethylformamide (4.7 mL). To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (125 mg, 0.7 mmol), HATU (270 mg, 0.7 mmol) and diisopropylethylamine (0.82 mL, 4.7 mmol). The reaction was stirred at room temperature for one hour, and then diluted with acetonitrile (2 mL) and methanol (2 mL). To this solution was added ten drops of 5M aqueous NaOH solution and stirring was continued for 30 minutes. The reaction was diluted with ethyl acetate and the organic layer was washed with water and brine. The combined aqueous washings were extracted three times with ethyl acetate, and the combined organic layers were dried (MgSO4) and concentrated. The crude material was purified by flash column chromatography to yield (S)-benzyl 2-(5-(8-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (260 mg, ˜80%). LCMS-ESI+: calculated for C46H47N7O6: 793.91; observed [M+1]+: 794.70.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[H-].[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:21][C:22](=[O:23])[NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2cnccc2c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 6-aminoisoquinoline in DMF at −40° C. was added NaH and solution was warmed to 0° C. for 30 minutes. Then benzylchloroformate was added and the reaction stirred at 0° C. for 2 hours. The solution was quenched with AcOH, poured into NaHCO3(sat) and extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Flash chromatography (SiO2 90% EtOAc/Hex) gave benzylisoquinolin-6-ylcarbamate. (E87).
Reaction SMILES: NC[C@@H]1C[C@H](O)C1.CS([O:12][C@H:13]1[CH2:16][C@@H:15]([CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH2:14]1)(=O)=O.[Cl:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[C:32]([F:40])[C:33]=1[CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O.O>[Cl:27][C:28]1[CH:29]=[C:30]([CH:31]=[C:32]([F:40])[C:33]=1[CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[O:12][C@H:13]1[CH2:16][C@H:15]([CH2:17][N:18]([CH3:19])[C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14]1
Reactant: Oc1cc(F)c(CN2CCCC2)c(Cl)c1
Reactant: CN(C[C@H]1C[C@@H](OS(C)(=O)=O)C1)C(=O)OC(C)(C)C
Agent: NC[C@H]1C[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C[C@H]1C[C@H](Oc2cc(F)c(CN3CCCC3)c(Cl)c2)C1)C(=O)OC(C)(C)C
Temperature: 92.5 °C

Procedure:
A mixture of intermediate 6, cis-3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}cyclobutyl methanesulfonate (1.5 g, 5.2 mmol), intermediate 18, 3-chloro-5-fluoro-4-(pyrrolidin-1-ylmethyl)phenol (2.38 g, 10.4 mmol) and Cs2CO3 (3.38 g, 10.4 mmol) in DMSO (20 mL) was heated at 90-95° C. for 4 h under vigorous stirring in a flow of argon, then cooled. Water (40 ml) and EtOAc (40 ml) were added, and the layers were separated. The water layer was extracted with ether (20 ml), the combined organic layers were washed with 1N NaOH (3×25 mL), brine, dried with Na2SO4, and evaporated to give the title compound (1.8 g, 82%) as a yellow oil. LC/MS data: 427.6, 429.6, 430.5 (M+H) (calculated for C22H32CFIN2O3 426.96). 1H NMR-data (DMSO-d6): 6.76 (br. s, 1H, Ar—H); 6.71 (dd, 1H, J1=2.2 Hz, J2=11.5 Hz, Ar—H); 4.79-4.92 (m, 1H); 3.65 (s, 2H); 3.32 (d, 2H, J=8.0 Hz); 2.78 (s, 3H, NCH3); 2.38-2.62 (m, 5H+DMSO); 2.20-2.28 (m, 2H); 2.05-2.17 (m, 2H); 1.58-1.73 (m, 4H); 1.41 (s, 9H, Boc).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][O:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24](OC)=[O:25])[CH:6]=[CH:7][CH:8]=1.COCCO[AlH2-]OCCOC.[Na+].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][O:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[CH2:24][OH:25])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccccc1OCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccccc1OCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
In a flask placed under an argon flow, 0.16 g (0.352 mmol) of methyl 2-((3-((3-(trifluoromethyl)-phenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)benzoate were dissolved in 4 ml of tetrahydrofurane with magnetic stirring, the mixture was cooled to 0° C. and then 0.148 ml (0.492 mmol) of RED-Al were added. The mixture was stirred at 0° C. for 15 min before being diluted with 15 ml of ethyl acetate and poured into 20 ml of water. With intense stirring, 1 ml of a NaOH aqueous solution (32% by mass) was slowly added. After separation, the organic phase was washed with 2×10 ml of water. The aqueous phases were extracted with 2×5 ml of ethyl acetate. The combined organic phases were washed with 20 ml of a saturated NaCl aqueous solution and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by trituration in 10 ml of diisopropyl ether. The solid was isolated by filtration and dried in vacuo. 0.091 g (yield=58%) of (2-((3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl) methoxy)phenyl)methanol were obtained as a pale brown solid. LC-MS: m/z=425 (M+2H+); UV purity at 254 nm=94%. 1H NMR (300 MHz, DMSO) δ 8.77 (d, J=6.8 Hz, 1H), 8.05 (s, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.73 (dt, J=14.3, 7.8 Hz, 3H), 7.55-7.43 (m, 1H), 7.38 (d, J=7.4 Hz, 1H), 7.20 (d, J=3.6 Hz, 3H), 7.03-6.86 (m, 1H), 5.39 (s, 2H), 4.98 (t, J=5.7 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[CH:14]=[N:13]2)[CH:9]=[C:8]([Cl:20])[C:7]=1[CH:21]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:22](Cl)=[O:23].Cl>C1C=CC=CC=1>[Cl:20][C:8]1[CH:9]=[C:10]([N:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[CH:14]=[N:13]2)[CH:11]=[C:6]([Cl:5])[C:7]=1[CH:21]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:22](=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(c1ccccc1)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 10 °C
Reaction time: 20 h
Yield: 13 %

Procedure:
A mixture of 4.7 parts of aluminium trichloride and 67.5 parts of benzene was stirred in an ice bath till a temperature of ±10° C. A solution of 4.9 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetylchloride in 22.5 parts of benzene was added dropwise during a period of 15 minutes at this low temperature (exothermic reaction). Upon complete addition, stirring was continued for 20 hours at room temperature. The reaction mixture was poured into 500 parts of ice water and the whole was acidified with concentrated hydrochloric acid. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified three times by column chromatography over silica gel using first a mixture of trichloromethane and methanol (97:3 by volume) and then a mixture of trichloromethane and methanol (99:1 by volume) and finally a mixture of trichloromethane and ethyl acetate (92.5:7.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was crystallized from 8 parts of ethanol. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 0.7 parts (13.0%) of 2-[3,5-dichloro-4-[1-(4-chlorophenyl)-2-oxo-2-phenylethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione; mp. 143.0° C. (intermediate 41).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.F[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[N:19]=[CH:18][CH:17]=[N:16]2.C(=O)([O-])[O-].[K+].[K+].CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>O>[CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[N+:23]([O-:25])=[O:24])[N:19]=[CH:18][CH:17]=[N:16]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Sc1cccc2cnccc12
Reactant: O=[N+]([O-])c1cc2nccnc2cc1F
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cc2nccnc2cc1Sc1cccc2cnccc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A mixture of 5-isoquinolinethiol 220 mg (1.4 mmol), 6-fluoro-7-nitroquinoxaline 260 mg (1.4 mmol), potassium carbonate 380 mg (2.7 mmol) and DMF 3 ml was stirred for 2 hours at 100° C. The reaction solution was poured into water, the precipitates were collected and washed with water, and 6-(5-isoquinolylthio)-7-nitroquinoxaline 410 mg (90.4%) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[CH3:36]N>O>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][N:22]([CH3:36])[C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CN
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN(C)C(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 130 °C
Yield: 85 %

Procedure:
A mixture of 3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 7 of Example 1, 627 mg, 9.0 mmol), a solution of methylamine (40% in methanol, 6 mL) and water (6 mL) was placed in a sealed tube and heated overnight at 130° C. The reaction mixture was partitioned between dichloromethane (50 mL) and water (50 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined organic extracts were washed with brine (50 mL) and dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (5:1) to afford 523 mg (85%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.41 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 6.90 (1H, s), 4.73 (1H, br.s), 2.93 (4H, s), 2.82 (2H, q, J=7.5 Hz), 2.65 (3H, s), 2.51 (3H, s), 2.49 (3H, s), 1.28 (3H, t, J=7.5 Hz).
Reaction SMILES: [OH:1][C@H:2]([CH2:17][N:18]1[CH2:22][C@@H:21]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[N:31]=3)[N:26]=[CH:25][CH:24]=2)[O:20][C:19]1=[O:35])[CH2:3][NH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[S:10][CH2:11][C:12](=[O:16])[NH:13][C:14]=2[N:15]=1.CC1(C)O[C@H](CN)CO1>>[OH:1][C@@H:2]([CH2:17][N:18]1[CH2:22][C@@H:21]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[N:31]=3)[N:26]=[CH:25][CH:24]=2)[O:20][C:19]1=[O:35])[CH2:3][NH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[S:10][CH2:11][C:12](=[O:16])[NH:13][C:14]=2[N:15]=1
Reactant: COc1ccc2nccc([C@@H]3CN(C[C@@H](O)CNCc4ccc5c(n4)NC(=O)CS5)C(=O)O3)c2n1
Agent: CC1(C)OC[C@@H](CN)O1
Product: COc1ccc2nccc([C@@H]3CN(C[C@H](O)CNCc4ccc5c(n4)NC(=O)CS5)C(=O)O3)c2n1

Procedure:
The title compound was prepared using the same procedure as 6-({(S)-2-Hydroxy-3-[(R)-5-(6-methoxy-[1,5]naphthyridin-4-yl)-2-oxo-oxazolidin-3-yl]-propylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one (GSK-207235A) except substituting C-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methylamine for C-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methylamine. 1H NMR (400 MHz, CDCl3): 0.880 (d, J=4.5 Hz, 1H); 8.25 (d, J=9.1 Hz, 1H); 7.71 (d, J=4.6, 1H); 7.56 (d, J=7.9 Hz, 1H); 7.16 (d, J=9.1, 1H); 6.88 (d, J=7.9 Hz, 1H); 6.33 (dd, J=8.9, 7.6 Hz, 1H); 4.53 (t, J=9.4, 1H); 4.04 (s, 3H); 3.87 (m, 1H); 3.75-3.82 (overlapping signals, 2H); 3.65 (dd, J=9.2, 7.2 Hz, 1H); 3.46 (s, 2H); 3.41 (dd, J=14.4, 4.1 Hz, 1H); 3.33 (dd, J=14.5, 6.7 Hz, 1H); 2.77 (dd, J=12.2, 3.4 Hz, 1H); 2.62 (dd, J=12.4, 8.3 Hz, 1H). MS (ES) m/e 497 (M+H)+.
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[C:13]2[CH2:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:34].[CH3:35]C(O)=O>>[CH3:2][O:3][C:4]1[C:5]([O:34][CH3:35])=[CH:6][CH:7]=[C:8]2[C:13]=1[CH2:12][CH2:11][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:9]2[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:22][CH:21]=1
Reactant: CC(=O)O
Reactant: COc1c(O)ccc2c1CCC(c1ccccc1)C2c1ccc(OCCN2CCCC2)cc1
Agent: Br
Product: COc1ccc2c(c1OC)CCC(c1ccccc1)C2c1ccc(OCCN2CCCC2)cc1

Procedure:
Using a procedure analogous to Example 5, from 2.3 g (0.005 mole) of 1-{2-[4-(5,6-dimethoxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenoxy]-ethyl}-pyrrolidine, 80 ml of HOAc and 80 ml of 48% aqueous HBr, was obtained 650 mg of a mixture of 2-methoxy-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ehtoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-1-ol and 1-methoxy-6-phenyl-5-[4-(2-pyrroldin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[F-].[CH2:13]([N+](CCCC)(CCCC)CCCC)CCC.CI>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:13])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of 2,6-dichloropurine (1.10 g, 5.82 mmol) in anhydrous THF (5.0 mL) was added tetra-n-butylammonium fluoride (0.58 mL, 10.58 mmol, 1.8 eq; 1M in THF). Methyl iodide (0.40 mL, 6.42 mmol, 1.1 eq) was added, and the reaction mixture was stirred at RT under N2 for 30 minutes. The reaction mixture was then diluted with ethyl acetate (250 mL). The organic layer was washed with aqueous saturated sodium thiosulfate solution, water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 5 to 100% ethyl acetate in hexane) to give 2,6-dichloro-9-methyl-9H-purine (a-2) as a white solid (780 mg, 66%) followed by gradient 0 to 30% methanol in ethyl acetate to give 2,6-dichloro-7-methyl-7H-purine (a-3) as a white solid (346 mg, 29.3%). 1H NMR of 2,6-dichloro-9-methyl-9H-purine (DMSO-d6, 400 MHz) δ ppm 8.75 (s, 1H), 3.83 (s, 3H). 1H NMR of 2,6-dichloro-7-methyl-7H-purine (DMSO-d6, 400 MHz) δ ppm 8.80 (s, 1H), 4.09 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([C:22]3[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH2:30][C:31]([O:33]CC)=[O:32])=[CH:24][C:23]=3[O:36][CH3:37])[CH:15]=[CH:16][C:17]=2[F:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O>CN(C=O)C.[OH-].[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([C:22]3[C:23]([O:36][CH3:37])=[CH:24][C:25]([CH2:30][C:31]([OH:33])=[O:32])=[CH:26][C:27]=3[O:28][CH3:29])[CH:15]=[CH:16][C:17]=2[F:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cc(OC)c(-c2ccc(F)c3c2CN(C(=O)OCc2ccccc2)CC3)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)O)cc(OC)c1-c1ccc(F)c2c1CN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8-(4-ethoxycarbonylmethyl-2,6-dimethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (9.5 mg, 0.02 mmol, 1 eq.) in DMF (0.1 mL), 2M aq. NaOH soln. (68 μL) was added. The solution was stirred at r.t. for 18 hours. Formic acid was added (0.1 mL). The resulting acidic solution was purified by prep. HPLC (column: Waters XBridge, 19×30 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired acid as a white solid.