Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]2C(=O)C3=C(C#N)[CH:13]=[C:14]([N:17]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:18]4[CH:23]=[CH:22][N:21]=[CH:20][N:19]=4)[C:15](=[O:16])[N:10]3[C:9]32[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.[C@H:54](O)([C:60]([O-:62])=O)[C@@H:55](O)[C:56]([O-:58])=O.[Na+].[K+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:56](=[O:58])[C:55]3=[C:54]([CH:60]=[O:62])[CH:13]=[C:14]([N:17]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[C:18]4[CH:23]=[CH:22][N:21]=[CH:20][N:19]=4)[C:15](=[O:16])[N:10]3[C:9]32[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:42][CH:43]=1
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reactant: COc1ccc(CN(c2ccncn2)c2cc(C#N)c3n(c2=O)C2(CCCCC2)N(Cc2ccc(OC)cc2)C3=O)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(CN(c2ccncn2)c2cc(C=O)c3n(c2=O)C2(CCCCC2)N(Cc2ccc(OC)cc2)C3=O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-8′-carbonitrile (3, 1 g, 1.73 mmol) in dichloromethane (20 mL) at 0° C. is added diisobutylaluminum hydride (1 M in dichloromethane, 3.46 mL, 3.46 mmol) dropwise. The reaction is stirred at 0° C. for 2 h. The resulting mixture is poured into saturated aqueous Rochelle's salt solution. The biphasic mixture is stirred overnight and filtered. The filtrate is extracted with dichloromethane. The organic is dried over magnesium sulfate, filtered and concentrated. The crude is purified via column chromatography to afford 2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-8′-carbaldehyde (4).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([N+:20]([O-])=O)[CH:3]=1.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:20][C:4]1[CH:3]=[C:2]([Cl:1])[CH:19]=[CH:18][C:5]=1[N:6]([CH3:17])[S:7]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2N)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.4 %

Procedure:
A mixture of 4′-chloro-N-methyl-2′-nitro-p-toluenesulfonanilide (7.11 g (20.9 mmol)), stannous chloride (14.7 g (62.6 mmol)) and ethanol (100.0 ml) was stirred at room temperature for 45 minutes, and at 50° C. for 16 hours. After being allowed to cool to room temperature, the reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate and the insolubles were removed by filtration. The filtrate was extracted with ethyl acetate and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with acetone-chloroform-hexane (1:3:5) as eluent to give 5.22 g (81%) of the title compound as white crystals.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:11]([N+:33]([O-:35])=[O:34])=[C:12]2[C:17](=[C:18]([O:21][CH3:22])[C:19]=1[F:20])[N:16]([C@@H:23]1[CH2:25][C@@H:24]1[F:26])[CH:15]=[C:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:13]2=[O:32].O>CN(C)C=O>[F:20][C:19]1[C:18]([O:21][CH3:22])=[C:17]2[C:12]([C:13](=[O:32])[C:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:15][N:16]2[C@@H:23]2[CH2:25][C@@H:24]2[F:26])=[C:11]([N+:33]([O-:35])=[O:34])[CH:10]=1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(OC)c(F)c(N)c([N+](=O)[O-])c2c1=O
Agent: CC(C)CCON=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(OC)c(F)cc([N+](=O)[O-])c2c1=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 44.6 %

Procedure:
Isoamyl nitrite (3.81 g, 32.5 mmol) was added to dimethylformamide (60 ml), and while stirring at 70° C., a solution, wherein ethyl 6-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (8.90 g, 23.2 mmol) was dissolved in dimethylformamide (120 ml), was added dropwise thereto over a period of 3 hours. After completion of dripping, the reaction solution was stirred at 70° C. for 1 hour, allowed to cool, and then poured into water (500 ml). After extraction with ethyl acetate (300 ml×3), the organic layers combined were washed with 1 mol/l hydrochloric acid (300 ml) and saturated saline solution (200 ml×2) in that order, and then dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and the crude crystals obtained were recrystallized in ethanol and then dried under a reduced pressure. 3.81 g (45%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: C=O.Cl.[O:4]=[C:5]([N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[CH2:23][CH2:22]1)[CH2:6][NH:7][C:8]([C:10]1[N:11]=[N:12][N:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:14]=1)=[O:9].[C:38](O)(=O)C.N>O.[Zn]>[O:4]=[C:5]([N:21]1[CH2:22][CH2:23][CH:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=2)[CH2:25][CH2:26]1)[CH2:6][NH:7][C:8]([C:10]1[N:11]=[N:12][N:13]([CH:15]2[CH2:16][CH2:17][N:18]([CH3:38])[CH2:19][CH2:20]2)[CH:14]=1)=[O:9]
Reactant: CC(=O)O
Reactant: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cn(C2CCNCC2)nn1
Agent: C=O
Agent: Cl
Agent: N
Solvent: O
Product: CN1CCC(n2cc(C(=O)NCC(=O)N3CCC(Oc4cccc(C(F)(F)F)c4)CC3)nn2)CC1
Reaction time: 0.08 h
Yield: 46.3 %

Procedure:
37% Aqueous formaldehyde (29.22 mg, 0.97 mmol) solution was added to a stirred solution of 1-piperidin-4-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide hydrochloride (252 mg, 0.48 mmol) in a mixture of acetic acid (240 mg, 4.0 mmol) and H2O (2 mL) and stirring was continued at ambient temperature for 5 minutes. Zinc dust was added to the reaction mixture (94.1 mg, 1.44 mmol) and stirring was continued at ambient temperature for 1 hr. The reaction mixture was cooled, basified with aqueous ammonia solution and extracted with DCM. The organic layer was collected and dried over sodium sulfate and concentrated under reduced pressure to afford 110 mg (45.6% Yield) of 1-(1-methyl-piperidin-4-yl)-1H-[1,2,3]triazole-4-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 495.2. 1H NMR (300 MHz, DMSO-d6): δ 8.7 (s, 1H), 8.3 (t, 1H), 7.5 (t, 1H), 7.3 (t, 3H), 4.8 (m, 1H), 4.5 (m, 1H), 4.2 (d, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.4 (m, 2H), 2.9 (m, 2H), 2.2 (s, 3H), 2.1 (m, 6H), 1.95 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:5][C:6](=O)[C:7]=1[CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10].P(Cl)(Cl)([Cl:25])=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:25][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([CH3:1])[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)[nH]c1=O
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Yield: 73 %

Procedure:
To a suspension of methyl 2-(4-methyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)pentanoate (0.900 g; 3 mmol) in dry toluene (6 mL) under a nitrogen atmosphere were carefully added phosphorus oxychloride (3 mL), dimethylaniline (0.3 mL) and the reaction mixture was heated to reflux for 3 h. The volatiles were removed under reduced pressure, the residue was cooled down in an ice-bath and quenched by adding crushed-ice and a saturated solution of sodium hydrogencarbonate until neutralization. The product was extracted with ethyl acetate, the combined organics were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.701 g (73%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.FC(F)(F)C(O)=O.[BH4-].[Na+].[OH-].[Na+]>>[Cl:8][C:3]1[C:2]([NH:1][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: Nc1cccnc1Cl
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCC(Nc2cccnc2Cl)CC1
Temperature: 26 °C
Reaction time: 0.08 h

Procedure:
To a 2 L three-neck Morton-type flask equipped with a mechanical agitator and temperature probe was charged 3-amino-2-chloropyridine and ethyl 4-oxo-1-piperidinecarboxylate followed by IPAC. The mixture became homogeneous after 5 min agitation (16° C.). Trifluoroacetic acid was charged to the mixture over 30 s, causing an increase in temperature to 26° C. (no cooling used). After 15 min age, a caplet of NaBH4 (0.95 g, 0.025 mol) was added. The temperature was observed to increase to 28° C. over a 30 min period and the caplet dissolved completely within this time. This method of NaBH4 addition was repeated, allowing each caplet to dissolve before adding the next, until a total of eight caplets had been added over 7 h. At this time, LC analysis indicated >95% conversion of the 3-amino-2-chloropyridine. A solution of 10 wt % aqueous NaOH was added to the mixture at 30-40° C. (no cooling) over 10 min. When the pH of the mixture was 12-14, the phases were allowed to separate. The separated aqueous phase was 450 mL and LC assay indicated this contained 0.5 g, <1.0% of product. The organic phase washed with brine then the separated organic phase was assayed. The separated brine wash was 275 mL and LC assay indicated this contained negligible product. The organic phase was 690 mL and LC assay indicated this contained 87.5 g, 97% AY of reductively alkylated product and 2.1 g, 5% of starting amine. The yellow organic phase was concentrated (45° C. bath temperature) to approximately one-third original volume. Fresh IPAC was added and this process was repeated until the water content was 110 μg/mL by KF titration. The solution was concentrated to a volume of 170 mL then THF (230 mL) was added. This solution was used directly for the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CO>[CH3:17][C:16]([CH3:19])([CH3:18])[C:15]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a solution of 2-aminopyridine (50.0 g, 531 mmol) in methylene chloride (500 mL) were added triethylamine (81.4 mL, 584 mmol) and pivaloyl chloride (71.9 mL, 584 mmol) at 0° C., which was stirred for 4 hours and 30 minutes at room temperature. The reaction solution was partitioned into water and methylene chloride. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. To a solution of the resulting residue in methanol (300 mL) was added potassium carbonate (73.4 g, 531 mmol) at 0° C., which was stirred for 90 minutes at room temperature. The reaction solution was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. Heptane (300 mL) was added to the residue, and the precipitated solids were filtered to obtain the title compound (80.2 g, 85%). The filtrate was then concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (12.2 g, 13%).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:10]2[C:5]3[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[O:29][CH3:28])=[CH:3][C:4]=3[C:12](=[O:13])[N:11]2[C@H:14]2[CH2:15][CH2:16][C@H:17]([OH:20])[CH2:18][CH2:19]2)=[CH:22][CH:23]=1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N([C@H]1CC[C@H](O)CC1)C2=O
Reactant: COc1ccccc1B(O)O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N([C@H]1CC[C@H](O)CC1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-6-(4-chloro-phenyl)-5-(trans-4-hydroxy-cyclohexyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate F) and 2-methoxyphenylboronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR: 6.99 min (HPLC 2); ESI-MS: tR=1.18 min, [M+H]+ 479/481 (LC-MS 1); TLC: Rf=0.10 (EtOAc).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.O1CCOCC1.C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1)CCC>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.C(OCC)(=O)C>[N:30]1[CH:31]=[CH:32][N:33]=[CH:34][C:29]=1[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2ccc(-c3cnccn3)cc2cn1)C1CC1
Yield: 54.8 %

Procedure:
To a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide 1 (42.8 mg, 0.147 mmol) and 1,4-Dioxane (1.5 mL, 19 mmol) was added 2-(tributylstannyl)pyrazine (51.0 uL, 0.162 mmol) and tetrakis(triphenylphosphine)palladium(0) (14.0 mg, 0.0121 mmol). The reaction mixture was subjected to microwave irradiation at 130° C. for 30 minutes. The reaction mixture is poured into ethyl acetate and washed with dilute NH4OH. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 23.4 mg (55%) of N-(7-(pyrazin-2-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT=4.106, M+H=291.0, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.42 (s, 1H), 9.27 (s, 1H), 8.87 (s, 1H), 8.78 (s, 1H), 8.66 (s, 1H), 8.51 (s, 1H), 8.45 (d, J=8.6 Hz, 1H), 8.01 (d, J=8.7 Hz, 1H), 2.10 (s, 1H), 0.94-0.74 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1)#[N:2].[C:43](O)(C(F)(F)F)=[O:44]>C(Cl)Cl>[S:28]1[CH:29]=[CH:30][N:31]=[C:27]1[NH:26][S:23]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[C:13]([C:4]1[CH:5]=[CH:6][C:7]([C:9]([F:11])([F:12])[F:10])=[CH:8][C:3]=1[C:1](=[NH:2])[O:44][CH3:43])=[N:14][CH:15]=[CH:16]2)(=[O:25])=[O:24]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4C#N)nccc3c2)c(OC)c1
Solvent: ClCCl
Product: COC(=N)c1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
1-(2-cyano-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.011 g, 0.018 mmol) was dissolved in 1 mL of DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated, dissolved in methanol, and passed through an SCX ion exchange column (pre-wetted with methanol). The column was flushed several times with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The product-containing filtrate was concentrated to afford an orange solid. The material was purified via silica gel column chromatography (12 g silica gel column, gradient elution 0 to 10% MeOH:DCM) to afford methyl 2-(6-(N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)-5-(trifluoromethyl)benzimidate (0.008 g, 0.016 mmol, 9.10% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.90 (br. s., 1H), 8.78 (br. s., 1H), 8.66 (d, J=5.6 Hz, 1H), 8.58 (s, 1H), 8.14 (d, J=5.0 Hz, 1H), 8.06 (br. s., 1H), 7.99 (d, J=7.5 Hz, 1H), 7.89-7.83 (m, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.28 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 3.02 (s, 3H). m/z (ESI) 493.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]([CH3:11])([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([OH:6])=[O:5])#[N:2].S(Cl)(Cl)=O.[CH2:16]([C:26]1[CH:27]=[N:28][C:29]([C:32]2[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=2)=[N:30][CH:31]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C1N2CCN(CC2)C1.[H-].[Na+].Cl>C1C=CC=CC=1.C(Cl)Cl>[C:1]([C:3]([CH3:11])([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([O:6][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[N:28]=[CH:27][C:26]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:31][N:30]=2)=[CH:37][CH:36]=1)=[O:5])#[N:2]
Reactant: CCCCC(C)(C#N)C(=O)O
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: C1CN2CCN1CC2
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCc1cnc(-c2ccc(OC(=O)C(C)(C#N)CCCC)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.3 %

Procedure:
155 mg (1 mM) of (-)-2-cyano-2-methylhexanoic acid ([α]D -6.15 degrees (c1, methanol)) and 2 ml of thionyl chloride were placed in a dried flask and heat-refluxed in a nitrogen atmosphere, followed by distilling-off of excessive thionyl chloride under reduced pressure. To the resultant acid chloride was added a solution of 312 ml (1 mM) of 4-(5-n-decyl-2-pyrimidyl)phenol and 240 mg (2 mM) of triethylenediamine in 2.5 ml of dry benzene, followed by 2 hours of reaction at 50° C. Further, a solution of 80 mg (2 mM) of sodium hydride in dry benzene was added thereto, followed by 2 hours of reactions. After the reaction, the mixture was cooled to room temperature, followed by addition of 1N-hydrochloric acid and distilled water and extraction with ether. The resultant ether layer was dried on sodium sulfate, followed by distilling-off of the solvent and purification by thin layer chromatography (developer solvent: methylene chloride) to obtain 59 mg of p-(5-n-decyl-2-pyrimidyl)phenyl 2-cyano-2-methylbexanoate. Yield: 11.3% [α]D -3.5 degrees (c1, methylene chloride) m.p.=38°-43° C.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([I:14])=[N:10][NH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15]C([O-])(C)C.[K+].IC>C1COCC1>[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([I:14])=[N:10][N:11]2[CH3:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(I)n[nH]c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2ccc(C(C)(C)C)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 6-tert-butyl-3-iodo-1H-indazole (820 mg, 2.73 mmol) in THF (8 ml) at 0° C. was added KOt-Bu (429 mg, 3.82 mmol). The reaction mixture was stirred at 0° C. for 30 min then added iodomethane (0.24 ml, 3.82 mmol). Stirred at 0° C. for 30 min then warmed to room temperature and stirred for 1.5 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 10% to 50% EtOAc/heptane to afford 592 mg (69%) of 6-tert-butyl-3-iodo-1-methyl-1H-indazole as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.37-7.43 (m, 1H), 7.31 (d, J=9.8 Hz, 2H), 4.10 (s, 3H), 1.41 (s, 9H). The minor 6-tert-butyl-3-iodo-2-methyl-1H-indazole regioisomer was also observed but not isolated.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].Br[C:15]1[CH:20]=[C:19]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[CH:24]=[C:23]([CH2:35][OH:36])[C:22]=2[CH2:37][OH:38])[CH:18]=[CH:17][N:16]=1.N>CN(C)C=O.[Cu]I.C(OCC)(=O)C>[O:1]=[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:15]1[CH:20]=[C:19]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[CH:24]=[C:23]([CH2:35][OH:36])[C:22]=2[CH2:37][OH:38])[CH:18]=[CH:17][N:16]=1
Reactant: Oc1cnc2ccccc2n1
Reactant: COc1cc2cc(CO)c(CO)c(-c3ccnc(Br)c3)c2cc1OC
Agent: [Cu]I
Agent: N
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4c(=O)cnc5ccccc54)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.2 %

Procedure:
A solution of 2-hydroxyquinoxaline (2.92 g) in dimethylformamide (20 ml) is cooled with ice under nitrogen atmosphere, and thereto is added 60% sodium hydride (0.78 g). The mixture is stirred at room temperature for 15 minutes, and thereto is added copper (I) iodide (4.19 g). The mixture is stirred at 120° C. for 15 minutes, and cooled to room temperature. To the mixture is added 1-(2-bromo-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (2.02 g), and the mixture is stirred at 120° C. for five hours. After the reaction is complete, to the mixture are added ethyl acetate and aqueous ammonia, and the ethyl acetate layer is collected. The ethyl acetate layer is filtered, washed, dried, and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=20:1) to give 1-[2-(2-oxo-1,2-dihydroquinoxalin-1-yl)-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (450 mg), which is listed in Table 2.
Reaction SMILES: [CH3:1][N:2]([C:13]([NH:15][CH3:16])=[S:14])[NH:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.C(=O)(O)[O-].[Na+]>>[CH3:1][N:2]1[C:13](=[S:14])[N:15]([CH3:16])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)=[N:3]1
Reactant: CNC(=S)N(C)NC(=O)c1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1nc(-c2cccc(F)c2)n(C)c1=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Dimethyl-l-(3-fluorobenzoyl)thiosemicarbazide (11.1 g, 46.0 mmol) and 1 molar aqueous sodium bicarbonate (460 mL, 0.460 mol) were stirred and heated to reflux. After being refluxed for 5 h, the reaction was allowed to cool to room temperature. After stirring overnight, the reaction was placed in the freezer for several hours. The precipitate was then collected by filtration. Crystallization from isopropanol afforded the desired product as colorless, matted needles, mp 126°-128° C.
Reaction SMILES: [CH:1]12[CH:9]([CH2:10][C:11]([O:13]CC)=[O:12])[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2>CO.[OH-].[Na+]>[CH:5]12[CH:9]([CH2:10][C:11]([OH:13])=[O:12])[CH:1]([CH2:2][CH2:3][CH2:4]1)[CH2:8][CH2:7][CH2:6]2
Reactant: CCOC(=O)CC1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC1C2CCCC1CCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of Example 56B (8.5 g 40.4 mmol) in methanol (100 mL), aqueous NaOH (50%, 25 mL) was added. The reaction was stirred at room temperature for 24 hours. Methanol was evaporated and the mixture was extracted with ether and then acidified with 6N HCl to pH 2. The mixture was extracted with ether (2×50 mL), the organic layer was dried with magnesium sulfate, filtered, and concentrated to afford the title compound.