Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[C@@H:12]([CH2:22][O:23]CC2C=CC=CC=2)[O:11][C@H:10]1[N:31]1[CH:39]=[N:38][C:37]2[C:32]1=[N:33][C:34]([F:41])=[N:35][C:36]=2[NH2:40])C1C=CC=CC=1>[Pd](Cl)Cl>[C@@H:10]1([N:31]2[CH:39]=[N:38][C:37]3[C:32]2=[N:33][C:34]([F:41])=[N:35][C:36]=3[NH2:40])[O:11][C@H:12]([CH2:22][OH:23])[C@@H:13]([OH:14])[C@@H:9]1[OH:8]
Reactant: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: Cl[Pd]Cl
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reaction time: 1 h
Yield: 66 %

Procedure:
Compound (VI) (3.6 mmole) and palladium chloride (1.4 g, 7.9 mmole) were used as in Example 1. The pressure was about 35 psig. The reaction was complete in about 1 hour and gave a 66% yield of product (VII). The amount of catalyst was 70% by weight or 2.2 moles per mole of (VI). The yield was not optimal and there was a risk of defluorination of (VI). Too much catalyst was necessary.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:29])[N:17]([C@@H:19]([CH2:27]O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:18])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)C(C)C)C.C(O)(=O)C.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C([BH3-])#N.[Na+]>ClCCl>[C:11]([O:15][C:16](=[O:29])[N:17]([C@H:19]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:27][NH:50][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH3:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CO)Cc1ccccc1
Reactant: NCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C(=O)OC(C)(C)C)[C@@H](CNCc1ccccc1)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 53.1 %

Procedure:
A solution of oxalyl chloride (3.16 ml, 36.17 mmol) in dichloromethane (50 ml) was coooled to −78° C. A solution of dimethylsulfoxide (3.42 ml, 48.22 mmol) in dichloromethane (50 ml) was added dropwise. The reaction mixture was stirred for 5 min at −78° C. A solution of N-((1R)-1-(hydroxymethyl)-2-phenylethyl)-N-methylcarbamic acid tert-butylester (6.40 g, 24.11 mmol) in dichloromethane (100 ml) was added dropwise over a period of 10 min. The solution was stirred for 25 min at −78° C. Ethyldiisopropylamine (16.68 ml, 96.44 mmol) was added dropwise at −78° C. The solution was warmed to −35° C., and immediately cooled to −78° C. Glacial acetic acid (6.07 ml, 106.08 mmol) was added. The reaction mixture was warmed to room temperature and diluted with dichloromethane (150 ml). It was washed with saturated sodium chloride solution (2×200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was dissolved in methanol (200 ml). Benzylamine (2.6 ml, 24.1 mmol) was added. Glacial acetic acid (6.0 ml, 106 mmol) and 3 Å mol sieves (32 g) were added. Sodium cyanoborohydride (1.00 g, 15.9 mmol) was added as a solid. The reaction mixture was stirred for 1 h, before another portion of sodium cyanoborohydride (0.97 g, 15.4 mmol) was added. The mixture was first stirred for 16 h at room temperature and successively left 3 days without stirring. The mol sieves was filtered off through a plug of celite. The celite was washed with methanol (200 ml). The solvent was removed in vacuo. The residue was dissolved in 1 N sodium hydroxide solution/diethyl ether (250 ml/250 ml). The phases were separated. The aqueous phase was extracted with diethyl ether (2×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (230 g), using dichloromethane/methanol/25% aqueous ammonia (first 100:10:1, then 50:10:1) as eluent, to give 4.54 g of N-((1R)-1-benzyl-2-(benzylamino)ethyl)-N-methylcarbamic acid tert-butylester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:14]([O-])=O)[C:12]=1[OH:13])[C:7]([OH:9])=[O:8])([O-])=O>C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([NH2:14])[C:12]=1[OH:13])[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cc(C(=O)O)cc(N)c1O
Reaction time: 4 h
Yield: 69.9 %

Procedure:
3,5-Dinitro-4-hydroxybenzoic acid (Aldrich) (4.56 g, 20 mmole) was dissolved in glacial acetic acid (25ml) and 10% Pd/C (15 mg) was added. The mixture was hydrogenated under hydrogen gas at 60 psi at 60° C. for 4 hours. It was then filtered through a celit pad and evaporated to dryness. The residue was crystallized from water to give 3,5-diamino-4-hydroxybenzoic acid (2.35g, 70%), m.p. 205° C. (lit ref., Simandi et al., Hungarian Patent 53602-A2-901128 (1990), m.p. 205° C.).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11](OCC)=[O:12].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.ClCCl>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]=[O:12]
Reactant: CCOC(=O)c1oc2ccccc2c1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1c(C=O)oc2ccccc12
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution (40 mL) of ethyl 3-methyl-1-benzofuran-2-carboxylate (2.00 g) in tetrahydrofuran was added dropwise 1.5M diisobutylaluminum hydride toluene solution (19.6 mL) at 0° C., and the mixture was stirred for 2 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a white solid. To a solution (40 mL) of the obtained solid in dichloromethane was added Dess-Martin periodinane (4.96 g) at 0° C., and the mixture was stirred at room temperature overnight. Saturated sodium sulfite aqueous solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9, volume ratio) to give the title object compound (753 mg, 48%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:18]=[C:19]([N:23]3[CH:27]=[C:26]([C:28]#[N:29])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][CH:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1C[O:48]CC1>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:18]=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:29])=[O:48])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][CH:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3)ncc2c1
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3)ncc2c1
Reaction time: 1 h
Yield: 68 %

Procedure:
1-(3-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)-3-(4-(morpholine-4-carbonyl)phenylamino)-1H-pyrazole-4-carbonitrile (30 mg, 0.050 mmol) was dissolved in 4 mL of THF and 0.5 mL of water. Then dihydrogen tris(dimethylphosphinito)hydroplatinate (2.3 mg, 0.0052 mmol) was added and the mixture was stirred under fluxing. After 1 hr, TLC indicated complete consumption of the starting material. LC/MS indicated clean desired product formed. The mixture was evaporated and the residue was dissolved in dichloromethane and dried over sodium sulfate, filtered through micron filter and evaporated. The residue was purified through flash column chromatography using methanol in methylene chloride (0% to 5% methanol in 10 minutes, 12 g silica gel) to give 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-phenyl]-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazole-4-carboxylic acid amide as a white solid (21 mg, 68% yield). LC/MS clacd for C33H32FN7O4 (m/e) 609.25, obsd 608.0 (M−H, ES−); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (s, 9H), 3.51 (br. s., 4H), 3.59 (br. s., 4H), 7.39 (d, J=8.3 Hz, 3H), 7.56 (d, J=7.8 Hz, 1H), 7.65-7.73 (m, 3H), 7.75-7.86 (m, 3H), 7.89 (s, 1H), 7.98 (br. s., 1H), 8.60 (d, J=2.0 Hz, 1H), 9.04 (s, 1H), 9.42 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([CH3:25])[N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=1)[CH3:9])=[O:6].C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=[CH:34][N:35]=1)CCC.CN(C)C=O>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][C:23]1[CH:22]=[C:4]([CH:3]=[C:2]([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)[N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=1)[CH3:9])=[O:6]
Reactant: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(-c2nccs2)n1
Temperature: 120 °C
Reaction time: 6 h
Yield: 10.7 %

Procedure:
A mixture of 2-bromo-6-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)isonicotinamide (25 mg, 0.060 mmol, Step-1, single enantiomer), 2-tributylstannylthiazole (27 mg, 0.072 mmol), bis(triphenylphosphine)palladium(II) dichloride (8.4 mg, 0.012 mmol) and N,N-dimethylformamide (1 mL) is stirred at 120° C. under nitrogen atmosphere for 6 hours. After cooling to room temperature, the mixture is diluted with ethyl acetate (20 mL) and washed with water (20 mL). The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.) and then by preparative LC-MS to give 2.7 mg (11% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].CO.[Si](C=[N+]=[N-])(C)(C)[CH3:17]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([O:13][CH3:17])=[O:12]
Reactant: COc1ccc(CC(=O)O)c(F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(OC)cc1F
Reaction time: 0.25 h

Procedure:
To a solution of (2-fluoro-4-methoxyphenyl)acetic acid (500 mg, 2.72 mmol) in toluene (20 mL) was added MeOH (3 mL) and TMS diazomethane (2.04 mL of a 2M solution in hexanes, 4.08 mmol). After 15 min, the reaction was quenched by the addition of HOAc (250 μL). The reaction was diluted with EtOAc (100 mL) and washed with saturated NaHCO3 (2×25 mL) and brine (25 mL). The organic layer was dried (Na2SO4), filtered and concentrated. Purification of the residue by flash chromatography (0 to 25% EtOAc/hexanes) afforded methyl (2-fluoro-4-methoxyphenyl)acetate. 1H NMR (500 MHz, CDCl3): δ 7.15 (t, J=8.6 Hz, 1H), 6.62-6.68 (m, 2H), 3.78 (s, 3H), 3.70 (s, 3H), 3.60 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7](Cl)=[O:8])[CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[N:23][C:24]=3[NH2:26])[N:19]([C@H:27]3[CH2:32][CH2:31][C@@H:30]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH2:29][CH2:28]3)[N:18]=2)=[CH:13][C:12]=1[O:40][CH3:41]>N1C=CC=CC=1>[NH2:26][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:19]([C@H:27]3[CH2:32][CH2:31][C@@H:30]([N:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)[CH2:29][CH2:28]3)[N:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:7]([C:4]4[CH:3]=[C:2]([CH3:1])[O:6][N:5]=4)=[O:8])=[C:12]([O:40][CH3:41])[CH:13]=3)[C:25]=12
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc(C)on1
Reaction time: 5 h

Procedure:
5-Methyl-3-isoxazolecarbonyl chloride (20 mg, 0.137 mmol) was added to a solution of cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.067 mmol) in pyridine (0.5 mL). After 5 hours, the solvent was evaporated and the residue was purified by preparative HPLC (Hypersil BSD C18, 5 um, 100×21 mm, 0%-100% acetonitrile/0.05M ammonium acetate over 10 min, 25.0 mL/min). The resulting products were further purified by partitioning between dichloromethane (4 ml) and 1.0 N sodium hydroxide (2 ml) and passing through an Empore™ high performance extraction disk cartridge (C 18-SD octadecyl) to give cis-N3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-5-methyl-3-isoxazolecarboxamide (14 mg, 38%). 1H NMR (DMSO-d6) δ 1.81 (m, 2H), 2.14 (m, 2H), 2.35 (m, 2H), 2.53 (s, 3H), 2.76 (m, 3H), 3.37 (bm, 8H), 3.99 (s, 3H), 4.93 (m, 1H), 6.74 (s, 1H), 7.36 (m, 2H), 8.26 (m, 1H), 9.48 (s, 1H); LCMS (Finigan-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.0 mL/min.): MH+ =546.4, Rt=1.82 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[N:20]=[C:19]([C:21]3[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:22]=3[O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[CH:18]=[CH:17][CH:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2]>C(O)(=O)C.O>[F:48][C:44]1[C:22]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:29][CH:30]=2)=[C:21]([C:19]2[N:20]=[C:15]([N:9]3[C:10]([C:11]([F:13])([F:14])[F:12])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]3)[CH:16]=[CH:17][CH:18]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCNCC4)cc3)n2)c1C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of the title compound from Example 5 Step B (800 mg, 1.20 mmol) in acetic acid (4 mL) and water (1 mL) was stirred at 90° C. for 14 h. The reaction mixture was allowed to cool to ambient temperature and evaporated in vacuo. The product was used in the subsequent step without further purification: LCMS m/z 568.8 [M+H]+.
Reaction SMILES: C1(C)C=CC(S([C:10]2[C:21]3=[C:22]4[N:17]([CH2:18][CH2:19][CH2:20]3)[CH:16]=[C:15]([C:23]([OH:25])=[O:24])[C:14](=[O:26])[C:13]4=[CH:12][CH:11]=2)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CS(C)=O.Cl>O>[N:28]1([C:10]2[C:21]3=[C:22]4[N:17]([CH2:18][CH2:19][CH2:20]3)[CH:16]=[C:15]([C:23]([OH:25])=[O:24])[C:14](=[O:26])[C:13]4=[CH:12][CH:11]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1
Reactant: C1CNCCN1
Reactant: Cc1ccc(S(=O)(=O)c2ccc3c(=O)c(C(=O)O)cn4c3c2CCC4)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cn2c3c(c(N4CCNCC4)ccc3c1=O)CCC2
Yield: 17.3 %

Procedure:
19.1 g of 8-(p-toluenesulfonyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 ml of anhydrous dimethyl sulfoxide and the mixture was heated in an autoclave under flow of nitrogen at 10 atm. at a temperature of 150° to 160° C. for 18 hours while stirring. After completion of the reaction, the solvent and excess piperazine were removed under reduced pressure and a mixture of methanol and ethanol was added to the residue. The preicpitates formed were separated by filtration and washed with diethyl ether. The crystals thus-obtained were suspended in a mixture of 200 ml of water and 40 ml of a 10% aqueous hydrochloric acid solution and insoluble materials were removed by filtration. The filtrate was rendered neutral with saturated aqueous solution of sodium bicarbonate and purified through column chromatography using Amberlite LH-20 (a trade name for a product of Tokyo Organic Chemical Industries Ltd.) (eluent: water, ethanol). Recrystallization of the eluate from dimethylformamide gave 2.7 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 267° to 268° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[CH:7]=[CH:6]2.C(N(CC)CC)C.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.O>C1COCC1>[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH:7]=[CH:6]3)=[O:36])=[CH:33][CH:32]=1
Reactant: COc1ccccc1CNc1ccc2cc(CN)ccc2n1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1CNc1ccc2cc(CNC(=O)c3ccc(F)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
To a cooled (ice bath) and stirred solution of (6-aminomethyl-quinolin-2-yl)-(2-methoxy-benzyl)-amine (200 mg, 0.68 mmol) and triethyl amine (75 mg, 0.76 mmol) in THF (4 ml) was added 4-fluorobenzoyl chloride (119 mg, 0.75 mmol) and the mixture was allowed to stir at room temperature for 16 h. The reaction mixture was poured into water (15 ml) and extracted with diethyl acetate (2×20 ml). The combined organic layers were washed with brine (1×20 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/hexane) to yield the title compound as white foam (250 mg, 88%).
Reaction SMILES: O1CCCC1.C([O:8][C:9](=[O:36])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20](=[O:35])[C:21]([S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH:32]([CH3:34])[CH3:33])=[C:22]([OH:24])[CH:23]=2)=[CH:14][CH:13]=1)C.[OH-].[Na+].Cl>O>[OH:24][C:22]1[CH:23]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:9]([OH:36])=[O:8])=[CH:17][CH:16]=2)[O:19][C:20](=[O:35])[C:21]=1[S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]([CH3:33])[CH3:34]
Reactant: CCOC(=O)COc1ccc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(OCC(=O)O)cc2)oc1=O
Reaction time: 1.5 h

Procedure:
To a tetrahydrofuran (10 ml) solution of 4-[4-Hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-6H-pyran-2-yl]phenoxy acetic acid ethyl ester (0.319 g. 0.75 mmol) was added 1N sodium hydroxide (1.80 mL, 1.81 mmol). The reaction was stirred for 1.5 h, and then water (10 ml) was added followed by acidification with conc. hydrochloric acid to pH 2. The aqueous layer was then extracted 2× with ethyl acetate (100 ml). the combined organic extracts were then washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by column chromatography (silica gel-230 to 400 mesh) using 94/5/1 methylene chloride/methanol/acetic acid as the eluent. m.p. 217° C.; (dec.); 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.42 (m, 1H), 4.79 (s, 2H), 6.75 (s, 1H), 6.90 (d, 1H), 7.06 (m, 4H), 7.26 (d, 1H), 7.79 (d, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]1([C:30](Cl)=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)=[O:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1cccc2ccccc12
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1cccc2ccccc12

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 1-naphthoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-1-naphthamide as an off white powder, m.p. 174.5° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ8.52 (t, J=5.6 Hz, 1H), 8.49 (s, 1H), 8.24 (m, 3H), 8.10 (d, J=8.1 Hz, 1H), 7.97 (m, 2H), 7.80 (d, J=8.2 Hz, 1H), 7.65 (t, J=7.3 Hz, 1H), 7.57-7.41 (m, 5H), 4.75 (t, J=6.9 Hz, 2H), 2.03-1.98 (m, 2H), 1.69-1.64 (m, 2H); MS (EI) m/e 409.1903 (409.1903 calcd for C25H23N5O).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:35])[CH2:19][C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=1)[CH3:16]>>[CH2:15]([O:17][C:18](=[O:35])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[NH2:14])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1)[CH3:16]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3N)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[OH-].[K+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([N:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][C:20]2=[O:35])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@H:16]1[CH2:18][O:17]1>C1COCC1.CCOC(C)=O>[CH2:1]([S:3][CH2:18][C@@H:16]([OH:17])[CH2:15][O:14][C:13]1[CH:12]=[CH:11][C:10]([N:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][CH:26]=3)=[CH:21][C:20]2=[O:35])=[CH:9][C:8]=1[O:7][CH3:6])[CH3:2]
Reactant: CCS
Reactant: COc1cc(-n2ccc(-c3ccc(C(F)(F)F)cc3)cc2=O)ccc1OC[C@H]1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCSC[C@@H](O)COc1ccc(-n2ccc(-c3ccc(C(F)(F)F)cc3)cc2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Ethanethiol (47.6 mg, 0.76 mmol) and 25% aq. potassium hydroxide (172 mg, 0.77 mmol) were added to a solution of (R)-1-(3-methoxy-4-(oxiran-2-ylmethoxy)phenyl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (32 mg, 0.08 mmol) Part A in THF (1.5 mL). The mixture was stirred overnight at RT. Diluted with EtOAc, washed with sat. NaHCO3, dried (Na2SO4), and concentrated. The residue was purified using ISCO flash chromatography (silica gel/hexanes/ethyl acetate 100:0 to 0:100 gradient) to afford the desired product (S)-1-(4-(3-(ethylthio)-2-hydroxypropoxy)-3-methoxyphenyl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one 15B (28 mg, 0.06 mmol, 76% yield) as a light yellow solid. LC/MS 480 (M+H)+, tR 0.97 min (method 5).