Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([NH:10][C:11]([C:13]([O:15]CC)=[O:14])=[O:12])[S:6][C:7]=1[CH2:8][CH3:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>C(O)(=O)C>[CH2:1]([C:3]1[N:4]=[C:5]([NH:10][C:11]([C:13]([OH:15])=[O:14])=[O:12])[S:6][C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1nc(CC)c(CC)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCc1nc(NC(=O)C(=O)O)sc1CC
Reaction time: 0.08 h

Procedure:
Ethyl 4,5-diethylthiazol-2-ylcarbamoylcarboxylate (897 mg., 3.5 mmoles), 1 N potassium carbonate (3.5 ml., 3.5 equivalents) and 27 ml. of water were combined and heated on a steam bath for 10 minutes. Clear solution was noted after 5 minutes. The reaction mixture was cooled and made acidic with acetic acid. Crude product (625 mg.) was recovered by filtration. Recrystallization from approximately 33 ml. of absolute ethanol gave purified 4,5-diethylthiazol-2-ylcarbamoylcarboxylic acid [470 mg.; m.p. 206° C. (dec.)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[N:6][CH:7]=1.[Br-].[Na+].CC1(C)N([O])C(C)(C)CCC1.ClN1C(=[O:32])N(Cl)C(=O)N(Cl)C1=O.C(=O)(O)[O-].[Na+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:32])=[O:11])=[N:6][CH:7]=1
Reactant: OCCCc1ccc(Br)cn1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CC(C)=O
Product: O=C(O)CCc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(5-bromopyridin-2-yl)propan-1-ol (2.07 g, 9.60 mmol, J. Org. Chem. 1988, 53, 386), sodium bromide (195 mg, 1.90 mmol), TEMPO (30 mg, 0.20 mmol), and trichloroisocyanuric acid (4.46 g, 19.2 mmol), acetone (90 mL) and 15% sodium bicarbonate (30 mL) was stirred at 0° C. for 15 minutes and rt for 4 h. The reaction was quenched with isopropanol (6 mL), and the resulting mixture was filtered through Celite. The filtrate was concentrated, and the resulting residue was partitioned between water (100 mL) and ethyl acetate (125 mL) with the pH of the aqueous layer adjusted to 7 with 1N HCl. The organic layer was separated and the aqueous layer extracted with ethyl acetate (3×125 mL). The extracts were concentrated and the residue was purified by flash column chromatography on silica gel eluting with 0-20% CH3OH in CH2Cl2 to give 3-(5-bromopyridin-2-yl)propionic acid. Step B: A solution of 3-(5-bromopyridin-2-yl)propionic acid (1.28 g, 5.56 mmol), intermediate 9 (887 mg, 6.12 mmol), EDC (1.61 g, 8.35 mmol), HOBt (1.13 g, 8.35 mmol) and diisopropylethylamine (4.1 mL, 23.4 mmol) in DMF (30 mL) was stirred at rt for 4 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×75 mL). The extracts were washed with 5% lithium chloride (2×75 mL), dried over sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography (silica gel, eluting with 0% to 5% methanol in methylene chloride) to give 3-(5-bromopyridin-2-yl)-N-(2-hydroxy-4,4-dimethylhexyl)propionamide.
Reaction SMILES: [CH3:1][C:2]1[S:26][C:5]2=[N:6][C:7]([CH3:25])=[C:8]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([O:20]C)=[O:19])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:4]2[C:3]=1[CH3:27].[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[S:26][C:5]2=[N:6][C:7]([CH3:25])=[C:8]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([OH:20])=[O:19])[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:4]2[C:3]=1[CH3:27]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc(C)c(C)c2c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc2sc(C)c(C)c2c1-c1ccc(C)cc1
Yield: 51.9 %

Procedure:
To a solution of methyl 2-(2,3,6-trimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.074 g; 0.194 mmol) in methanol (4 mL) and ethanol (2 mL) was added a 5% sodium hydroxide solution (2 mL; 2.50 mmol). The reaction mixture was heated under reflux for 2 h. 5% sodium hydroxide solution (2 mL; 2.500 mmol) was added again and reflux was maintained for 2 h. 5% Sodium hydroxide solution (1 mL; 1.250 mmol) was added. After 3 h at reflux, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.037 g (52%) of the title compound as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1>CO.[Pd]>[OH:1][C:2]1[CH2:7][CH:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1
Reactant: Cc1cc(O)cc(=O)o1
Agent: [Pd]
Solvent: CO
Product: CC1CC(O)=CC(=O)O1
Reaction time: 7 h
Yield: 72.2 %

Procedure:
To a solution of 20.0 g (0.16 mole) of 4-hydroxy-6-methyl-2-pyrone in 250 ml of methanol was added 1.0 g of 5% palladium on carbon as the hydrogenation catalyst. Hydrogenation was carried out at room temperature under a pressure of 20 kg/cm2 for 7 hours. The catalyst was removed by filtration and the solvent was removed by evaporation under a reduced pressure. The precipitated crystal was recovered by filtration and recrystallized from ethanol to obtain 14.8 g (yield: 73%) of 4-hydroxy-5,6-dihydro-6-methyl-2-pyrone in the form of a crystal, m.p. 103°-104° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([O:12][CH3:13])=[O:11]>CN(C=O)C.[Ag]=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CBr
Reactant: Oc1ccccn1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.4 %

Procedure:
To a solution of 2-hydroxypyridine(5 g) in DMF(150 ml) was added silver oxide (I) (24 g) and methyl bromoacetate(20 g) and stirred at room temperature for 2 hours. After the catalyst was filtered off through celite, the filtrate was evaporated. The residue was dissolved in ethyl acetate and the solution was washed with brine, dried(MgSO4) and evaporated to dryness. The residue was purified by column chromatography on silica gel (chloroform: methanol=100:1) to obtain methyl 2-(2-pyridyloxy)acetate(1.0 g). According to the same manner as described above, the title compound was synthesized (0.1 g). m.p. 110° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8](Br)[CH2:9][CH2:10][Cl:11])=[O:7])=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[I-].[K+]>C1C=CC=CC=1>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:9][CH2:10][Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)C(Br)CCCl
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(c1ccc(F)cc1)C(CCCl)N1CCOCC1

Procedure:
15 g. of 1-p-fluorobenzoyl-1-bromo-3-chloropropane, 9.4 g. of morpholine and a catalytic quantity of potassium iodide in 100 cc anhydrous benzene are stirred at room temperature for 36 hrs. The resulting solid is filtered and the filtrate extracted with dilute HCl. The aqueous phase is separated, made alkaline, under cold conditions, with dilute soda solution, and extracted with diethyl ether. The extract is dried and evaporated to give 1-p-fluorobenzoyl-1-morpholino-3-chloropropane.
Reaction SMILES: [C:1]([C:13]1[CH:14]=[C:15](/[CH:19]=[CH:20]/[C:21](OCC)=[O:22])[CH:16]=[CH:17][CH:18]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+]>C(OCC)(=O)C>[C:1]([C:13]1[CH:14]=[C:15]([CH2:19]/[CH:20]=[CH:21]/[OH:22])[CH:16]=[CH:17][CH:18]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC#Cc1cccc(/C=C/C(=O)OCC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC#Cc1cccc(C/C=C/O)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81.5 %

Procedure:
To a solution of ethyl trans-3-[3-(1-dodecynyl)phenyl]-2-propenoate (10.0 g) and dry tetrahydrofuran (100 ml) at -78° C. was added diisobutylaluminum hydride (1.5M in toluene) (49 ml) slowly. The reaction mixture was stirred for 20 mins at -78° C., and 25% sodium hydroxide solution (3 ml) was added. The mixture was slowly warmed to room temperature and an additional 25% sodium hydroxide solution (3 ml) was added. The mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was flash chromatographed over silica gel (eluted with ethyl acetate/hexane/1:3). The appropriate fractions were collected and evaporated to afford 7.14 g (81%) of product.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[CH2:66][CH2:65][NH:64][C:63]2=[O:67])[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[CH:18][C@:19]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=4)=[O:50])[C@H:46]([CH:62]4[CH2:66][CH2:65][NH:64][C:63]4=[O:67])[CH2:45]3)([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: O=C1NCCC1[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C[C@@](C)(S[C@H]3C[C@@H](C4CCNC4=O)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H]12
Yield: 75.6 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (180 mg, 0.30 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon- 3-yl)pyrrolidine (110 mg, 0.30 mmol) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (161 mg, yield: 74.9%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=O)=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:24][NH2:25]>>[F:1][C:2]1[CH:9]=[C:8]2[C:7]([C:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)=[N:24][NH:25]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NN
Reactant: N#Cc1cc(C(=O)c2ccc3ccccc3c2)c(F)cc1F
Solvent: O
Product: N#Cc1cc2c(-c3ccc4ccccc4c3)n[nH]c2cc1F

Procedure:
A total of 2.1 g of 2,4-difluoro-5-(naphthalene-2-carbonyl)-benzonitrile was allowed to react with hydrazine monohydrate by the procedure of Production Example II-10-c and thereby yielded 1.6 g of the title compound as a colorless powder. 1H-NMR (400 MHz, DMSO-d6) δ 7.53-7.61 (2H, m), 7.72 (1H, d, J=9.6 Hz), 7.93-7.98 (1H, m), 8.03 (1H, d, J=8.5 Hz), 8.14-8.19 (1H, m), 8.18 (1H, d, J=8.5 Hz), 8.65 (1H, s), 9.03 (1H, d, J=6.0 Hz), 13.83-13.97 (1H, bs).
Reaction SMILES: C([O:4][C:5]1[CH:33]=[CH:32][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:12]([CH2:19][N:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=[O:22])[C:11]2=[O:31])=[CH:7][CH:6]=1)C=C.N1CCOCC1.O>ClCCl.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>[CH2:24]([O:23][N:20]([CH2:19][CH:12]1[CH:13]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:14][N:10]([CH2:9][C:8]2[CH:32]=[CH:33][C:5]([OH:4])=[CH:6][CH:7]=2)[C:11]1=[O:31])[CH:21]=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=CCOc1ccc(CN2CC(CCCC)C(CN(C=O)OCc3ccccc3)C2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: ClCCl
Solvent: O
Product: CCCCC1CN(Cc2ccc(O)cc2)C(=O)C1CN(C=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a solution of (+/−)-(3RS,4SR)-N-[1-(4-allyloxybenzyl)-4-butyl-2-oxopyrrolidin-3-yl-methyl]-N-benzyloxyformamide (2.6 g, 5.77 mmol) in dichloromethane (60 mL) under argon was added morpholine (6 mL), water (1.2 mL) and then tetrakis(triphenylphosphine)palladium (0.33 g, 0.28 mmol). The reaction mixture was stirred at rt for 1 h, filtered through a Celite pad and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate/hexanes 4:1) to afford (+/−)-(3RS,4SR)-N-benzyloxy-N-[4-butyl-1-(4-hydroxybenzyl)-2-oxopyrrolidin-3-yl-methyl]formamide as a white solid (2.1 g, 88%). MS(ES) m/e 411 [M+H]+.
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:22][CH3:23])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([Cl:21])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CN(C=O)C>[C:2]1([S:8]([C:11]2[C:12]([S:22][CH3:23])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([Cl:21])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Product: CSc1nn2c(N)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
10 ml of a 50% solution of NH3 in MeOH were added to a solution of 0.35 g (0.935 mmol) of 3-benzenesulphonyl-5,7-dichloro-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 10 ml of DMF and stirred at RT for 12 hrs. The DMF was evaporated in a high vacuum and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (silica gel, CH2Cl2/AcOEt 15:1) and crystallization from EtOH yielded 0.28 g (84%) of 3-benzenesulphonyl-5-chloro-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])(=[O:11])=[O:10])=[CH:5][N:4]=1)=[CH2:2].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[CH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])(=[O:10])=[O:11])=[CH:5][N:4]=1
Reactant: C=Cc1ccc(S(=O)(=O)c2ccccc2F)cn1
Reactant: OB(O)c1ccc(F)cc1F
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1=CCCC=CCC1
Product: O=S(=O)(c1ccc(CCc2ccc(F)cc2F)nc1)c1ccccc1F
Temperature: 150 °C
Yield: 13.9 %

Procedure:
2-Vinyl-5-[(2-fluorophenyl)sulfonyl]pyridine (Example 6 Step 1; 50 mg, 0.19 mmol), 2,4-difluorophenylboronic acid (75 mg, 0.475 mmol), chloro(1,5-cyclooctadiene)rhodium(I) dimer (2 mg, 0.004 mmol) and sodium carbonate (40 mg, 0.377 mmol) were taken up in water (1 mL) and heated in a microwave reactor at 150° C. for 10 minutes. The dark suspension was diluted with water and extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried over MgSO4 and concentrated while loading onto silica. Eluting through a plug of silica using 20% ethyl acetate/isohexane followed by mass-triggered preparative HPLC gave the title compound as a pale yellow solid (10 mg, 14%). δH (500 MHz, d6DMSO): 8.99 (1H, s), 8.21 (1H, dd, J=1.8, 8.3 Hz), 8.06 (1H, td, J=1.6, 7.6 Hz), 7.84–7.78 (1H, m), 7.52–7.48 (2H, m), 7.43 (1H, t, J=9.5 Hz), 7.28 (1H, q, J=8.0 Hz), 7.11 (1H, td, J=2.4, 9.9 Hz), 6.94 (1H, td, J=2.1, 8.5 Hz), 3.12–3.10 (2H, m), 3.01–2.98 (2H, m); m/z (ES+) 378 [MH+].
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][O:27]CC4C=CC=CC=4)=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[ClH:35]>CO.[Pd]>[ClH:35].[ClH:35].[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][OH:27])=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(CCOCc4ccccc4)cc3)cc3ccccc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCN(c2nc(-c3ccc(CCO)cc3)cc3ccccc23)CC1

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-[4-(2-benzyloxyethyl)phenyl]isoquinoline (0.46 g) was converted into a hydrochloride in a conventional manner. The resulting hydrochloride was then dissolved in methanol (50 ml), followed by the addition of 10% palladium/carbon catalyst (0.10 g), and the catalytic reduction was conducted at atmospheric pressure overnight. The catalyst was filtered off, while the solvent was evaporated. Water was added thereto, followed by the addition of a 1N aqueous solution of sodium hydroxide to adjust to pH 8, and then the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.24 g of the free compound of the title compound as a pale brown viscous oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([CH2:22][CH3:23])[N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([Li])[CH2:25]CC.CCCCCC.C(I)C>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([CH2:22][CH3:23])[N:12]=[C:11]1[CH2:24][CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ncn(COCc2ccccc2)c1Sc1ccccc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: CCc1nc(CC)n(COCc2ccccc2)c1Sc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
In a mixture of 5 ml of dry tetrahydrofuran and 2.5 ml of dry hexamethylphosphoric triamide is dissolved 150 mg of 1-benzyloxymethyl-4-ethyl-5-phenylthioimidazole (I-4) (0.46 mmol) obtained in Example 4, and the resulting solution is chilled at -78° C. To the solution is added dropwise 1.64M n-butyl lithium solution in 0.49 ml of hexane (0.8 mmol). Five minutes later, 110 mg of ethyl iodide (0.8 mmol) is added to the mixture, which mixture is allowed to stand for 10 minutes, when it is poured onto ice water and extracted with ethyl ether. The extract is washed with water, dried over sodium sulfate and filtered. The filtrate is chromatographed on a column of silica gel, eluting with ethyl acetate/n-hexane (1:2) to give 50 mg of the product (I-19) as an oil. Yield, 31%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=3)[N:12]([CH3:23])[C:11](=[O:24])[C:10]=12)=[O:5])[CH3:2].[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:25])[N:9]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=3)[N:12]([CH3:23])[C:11](=[O:24])[C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1c(=O)n(C)c1cc(C(F)(F)F)ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)n2c1c(=O)n(C)c1cc(C(F)(F)F)ccc12
Yield: 39.5 %

Procedure:
To a solution of 5-methyl-4-oxo-7-trifluoromethyl-4,5-dihydroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (3.9 g) in carbon tetrachloride (250 ml) was added N-bromosuccinimide (20 g). The mixture was stirred vigorously and was refluxed for 18 hours. After removal of solvent under water aspirator vacuum the residue was chromatographed via a short silica gel dry column (chloroform as eluant). The product was isolated out as an off-white solid (1.9 g, 39% yield). Recrystallized from acetonitrile, m.p. 205°-207° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[Cl-].[Al+3].[Cl-].[Cl-].[Br:17]Br.Cl>ClCCCl.O>[Br:17][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:12])=[N:8]2
Reactant: BrBr
Reactant: Cc1ccc2cc(F)ccc2n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: Cc1ccc2c(Br)c(F)ccc2n1
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
A solution of 12.1 kg (75 mole) of 6-fluoro-2-methylquinoline in 33 liters of 1,2-dichloroethane was chilled to 5° C., and 15.0 kg (113 mole) of aluminum chloride was added thereto in portions over 15 minutes. The mixture was purged with nitrogen and then heated to 75° C. A solution of 13.2 kg (82.6 mole) of bromine in 2 liters of 1,2-dichloroethane was added over a period of 5.5 hours. The reaction was maintained at 75° C. during the addition and for an additional 15 minutes after the addition was completed. The reaction was stirred at 70° C. for 23 hours and was then cooled to 10° C. and slowly added to a mixture of 8 kg of 30% hydrochloric acid, 41 liters of water and 31.75 kg of ice. The mixture warmed to 50° C. during the addition. The mixture was heated in reflux and the 1,2-dichloroethane was removed by azeotropic distillation. The remaining aqueous solution was cooled to 60° C. and 12 kg of 10% hydrochloric acid was added. The solution was treated with Celite® (available from Johns-Manville Corp.) and filtered. The filtrate was cooled to 25° C. and 18 kg of 30% hydrochloric acid and 10.22 kg of zinc chloride were added. The resulting slurry was chilled to 5° C. and allowed to stir for several days. The solid was collected and then reslurried with 10 gallons of water. The slurry was chilled to 5° C. and 22 kg of chilled ammonium hydroxide was added. The resulting slurry (pH 10-11) was diluted with 25 gallons of water and the solid was collected, rinsed with water and dried in vacuo at 60° C. to give crude 5-bromo-6-fluoro-2-methylquinoline (84.5% pure by gas chromatography analysis). The material was recrystallized from hexane to give 99.2% pure 5-bromo-6-fluoro-2-methylquinoline.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[C:4]([F:12])[CH:3]=1.[OH-].[NH4+:14]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:14])=[O:10])=[C:4]([F:12])[CH:3]=1
Reactant: [NH4+]
Reactant: O=C(Cl)Cc1ccc(Br)cc1F
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)Cc1ccc(Br)cc1F
Temperature: 0 °C
Yield: 64.1 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (0.1 g, 0.429 mmol) in sulfurous dichloride (5 mL, 0.429 mmol) was added DMF (3.32 μL, 0.043 mmol). The resulting mixture was stirred at 60° C. After 2 h, TLC analysis (PE/EA=1/1) showed the starting material had disappeared. The solvent was removed in vacuo to give 2-(4-bromo-2-fluorophenyl)acetyl chloride (110 mg, 0.416 mmol, 97% yield). A solution of 2-(4-bromo-2-fluorophenyl)acetyl chloride (110 mg, 0.437 mmol) in THF (5 mL) was added to ammonium hydroxide (10 mL, 257 mmol). The resulting mixture was stirred at 0° C. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in EA (50 mL) and washed with H2O (10 mL) and brine (10 mL). The organic layer was dried and concentrated to give a white solid of 2-(4-bromo-2-fluorophenyl)acetamide (100 mg, 0.280 mmol, 63.9% yield), which was used into the next step without further purification: 1H NMR (400 MHz, CD3OD) δ 7.32-7.30 (m, 2H), 7.24 (t, J=8.2 Hz, 1H), 3.54 (s, 2H); ES-LCMS m/z 232.0 (M+H).