Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH:22]=[C:21]([O:26][CH2:27][C:28]([O:30]C)=[O:29])[CH:20]=[CH:19]4)=[CH:14][N:15]=2)=[CH:3]1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH:22]=[C:21]([O:26][CH2:27][C:28]([OH:30])=[O:29])[CH:20]=[CH:19]4)=[CH:14][N:15]=2)=[CH:3]1
Reactant: COC(=O)COc1ccc2cc(-c3cnc(-c4cn(C)c5ccccc45)o3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ncc(-c3ccc4cc(OCC(=O)O)ccc4c3)o2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
A mixture of methyl ({6-[2-(1-methyl-1H-indol-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetate (254 mg, 0.925 mmol), prepared in the previous step, and 1N NaOH (925 μL, 0.925 mmol) in 30 mL of THF, 30 mL of methanol and 10 mL of H2O was stirred at room temperature for 16 h (overnight). The reaction was acidified by the addition of 1.0 mL of 1N HCl and then concentrated under reduced pressure to remove the THF and methanol. The yellow solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (218 mg, 89%) as a yellow solid, mp 269-272° C. Elemental Analysis for C24H18N2O4 Calc'd: C, 72.35; H, 4.55; N, 7.03. Found: C, 71.97; H, 4.78; N, 6.73.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6]1([CH3:14])[O:10][CH:9]([CH:11]2[O:13][CH2:12]2)[CH2:8][O:7]1.[Cl-].[Na+]>O.O1CCOCC1>[N:1]([CH2:12][CH:11]([CH:9]1[CH2:8][O:7][C:6]([CH3:14])([CH3:5])[O:10]1)[OH:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)OCC(C2CO2)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OCC(C(O)CN=[N+]=[N-])O1
Temperature: 60 °C

Procedure:
4.23 g of sodium azide is dissolved in a mixture of 50 ml of water and 100 ml of dioxane. The solution is heated to 60° C., 8.65 g of 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethylene oxide in 10 ml of dioxane is added dropwise thereto, and the mixture is heated for 2 hours to 80° C. After cooling, the aqueous phase is saturated with sodium chloride. The organic phase is separated, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is distilled with a water-jet aspirator. 2-Azido-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol passes over at 130°-132° C./13 mm as a colorless oil. Yield: 9.1 g (81% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH:21]=[O:22].[BH4-].[Na+].CC(C)=O>C(O)C.C1COCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][OH:22]
Reactant: CSc1ccc(/C=C2/C(C)=C(C=O)c3cc(F)ccc32)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(/C=C2/C(C)=C(CO)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the aldehyde from Step 2 (1.0 g, 3.2 mmol) in ethanol (50 mL) and THF (20 mL) there was added cerous chloride (0.79 g, 3.2 mmol) and sodium borohydride (0.13 g, 3.5 mmol). The mixture was stirred at room temperature for 30 minutes, there was added acetone (3 mL) and after 5 minutes the mixture was diluted with brine (100 mL) and extracted with ether (100 mL). The crude material was purified by column chromatography on silica gel, eluting with a 1:5 mixture of ethyl acetate-hexane to afford the title compound as a thick yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:15])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:16][O:17]C(Cl)Cl.Cl>ClCCl.C(OCC)(=O)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH3:15])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:7][C:8]=1[CH:16]=[O:17]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(C2(C)CCOCC2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C2(C)CCOCC2)cc1C=O
Reaction time: 0.33 h
Yield: 122.3 %

Procedure:
A solution of 4-(4-methoxyphenyl)-4-methyltetrahydro-2H-pyran (0.518 g, 2.51 mmol) in dichloromethane (12.0 mL) was cooled to −15° C., and titanium tetrachloride (1.22 mL, 11.0 mmol) was added dropwise thereto. After stirring the mixture for 20 minutes, dichloromethyl methyl ether (0.336 mL, 3.77 mmol) was added dropwise thereto. After stirring the mixture for 1 hour, 1 mol/L hydrochloric acid was added to stop the reaction. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and then with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was then evaporated under reduced pressure to obtain 0.719 g of the crude product containing the captioned compound.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1([OH:23])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br.Br[CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)=[O:37]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:9][C:10]1([OH:23])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]1)[CH2:35][C:36](=[O:37])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CNCc2ccccc2)CC1
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O)(CN(CC(=O)c2ccccn2)Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 92 %

Procedure:
To tert-butyl 4-[(benzylamino)methyl]-4-hydroxy-piperidine-1-carboxylate (3.0 g, 9.36 mmol) in DMF (19 mL) at 0° C. was added diisopropyl ethylamine (3.4 mL, 19.66 mmol) followed by the addition of 2-bromo-1-(2-pyridyl)ethanone hydrobromide salt (2.6 g, 9.36 mmol) and reaction mixture was stirred for 2 hours warming from 0° C. to 10° C. The reaction mixture was diluted with ethyl acetate and washed with sat. NaHCO3 solution and then brine. The organics were separated, dried over Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified using silica gel column chromatography using MeOH/DCM (1-15%) as eluent to give tert-butyl 4-[[benzyl-[2-oxo-2-(2-pyridyl)ethyl]amino]methyl]-4-hydroxy-piperidine-1-carboxylate (3.8, 92%). ESI-MS m/z calc. 439.2. Found 440.0 (M+1)+; Retention time: 1.12 minutes (3 min run).
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[F:48][C:49]([F:59])([F:58])[C:50]1[N:55]=[CH:54][C:53]([CH2:56][NH2:57])=[CH:52][CH:51]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:57][CH2:56][C:53]4[CH:54]=[N:55][C:50]([C:49]([F:59])([F:48])[F:58])=[CH:51][CH:52]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1ccc(C(F)(F)F)nc1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(C(F)(F)F)nc1
Yield: 63 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (6-(trifluoromethyl)pyridin-3-yl)methanamine, the title compound was obtained as a colorless solid in 63% yield: 1H NMR (300 MHz, CDCl3) δ 8.70 (s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.30-7.23 (m, 2H), 7.08-6.99 (m, 2H), 6.20 (t, J=5.8 Hz, 1H), 6.09 (s, 1H), 4.65 (d, J=5.8 Hz, 2H), 4.43 (s, 2H), 3.85-3.77 (m, 2H), 3.49-3.40 (m, 2H), 2.49 (s, 3H); MS (ES+) m/z 493.2 (M+1).
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([C:27]3[C:28]([CH3:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[OH:26])[CH:23]=2)[N:18]=[C:17]([O:35][CH3:36])[C:16]=1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=1>C1COCC1>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:7]3[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=3)([C:27]3[C:28]([CH3:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[OH:26])[CH:23]=2)[N:18]=[C:17]([O:35][CH3:36])[C:16]=1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]([F:46])([F:45])[F:47])=[CH:42][CH:43]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1ncc(Br)n1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.82 mL, 2.05 mmol) was added dropwise by syringe to a solution of 5-bromo-1,2-dimethyl-1H-imidazole (361.1 mg, 2.063 mmol) in dry THF (20 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone (0.500 g, 1.03 mmol, Intermediate 12: step f) in dry THF (5 mL) was added dropwise. The reaction was stirred for 1.5 hours, then was removed from the cold bath and allowed to warm to room temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-3% MeOH-DCM) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=2.2 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.53-7.48 (m, 2H), 7.42-7.36 (m, 3H), 7.11 (d, J=8.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 5.99 (s, 1H), 4.33 (s, 2H), 4.06 (s, 3H), 3.36 (s, 3H), 2.52 (s, 3H), 2.40 (s, 3H), 2.31 (s, 3H); MS m/e 581.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:12][O:13][C:14](=[O:35])[CH2:15][CH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[N:30][C:31](Cl)=[N:32][CH:33]=3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:12][O:13][C:14](=[O:35])[CH2:15][CH:16]1[CH2:17][CH2:18][CH:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[N:32][C:31]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][CH:5]=4)=[N:30][CH:29]=3)=[CH:26][CH:27]=2)[CH2:20][CH2:21]1
Reactant: COC(=O)CC1CCC(c2ccc(-c3cnc(Cl)nc3)cc2)CC1
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: COC(=O)CC1CCC(c2ccc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Temperature: 150 °C

Procedure:
To a glass vial add 6-trifluoromethyl-pyridin-3-ylamine (35 mg, 0.217 mmol), {4-[4-(2-chloro-pyrimidin-5-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (50 mg, 0.145 mmol), Pd(OAc)2(5 mg, 5% mol), X-Phos (7 mg, 10% mol), and Cs2CO3 (118 mg, 0.363 mmol). Flush with N2. Add tBuOH (0.25 mL), toluene (0.75 mL), and seal the tube. The reaction mixture is heated to 150° C. for 30 min by microwave irradiation. The reaction is diluted with EtOAc and filtered. The filtrate is concentrated and chromatographed on silica gel (25-50% EtOAc/Hexanes) to afford (4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester as 90% pure. (4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester (45 mg, 0.096 mmol) is taken up in DMF (1.5 mL) and 4 M LiOH (0.5 mL) and stirred at room temperature for 16 h. The reaction is heated to 50° C. for 12 h and then heated to 70° C. for 8 h. The reaction is diluted with 1 N HCl (2 mL) and H2O (2 mL). The precipitate is collected by filtration and purified by HPLC (Xterra C8 30×100 mm, 22-50% ACN/H2O+ 5 mM NH4OH) to afford (4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-acetic acid as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.18 (m, 2 H) 1.43-1.56 (m, J=12.95, 12.66, 12.66, 3.16 Hz, 2H) 1.68-1.87 (m, 6 H) 2.08 (d, J=6.57 Hz, 2 H) 7.35 (d, J=8.34 Hz, 2 H) 7.65 (d, J=8.34 Hz, 2 H) 7.85 (d, J=8.59 Hz, 1 H) 8.55 (dd, J=8.59, 2.02 Hz, 1 H) 8.91 (s, 2 H) 9.06 (d, J=2.27 Hz, 1 H) 10.42 (s, 1 H); (M+H)+ 457.0.
Reaction SMILES: F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+].[O:25]1CCO[CH:26]1[C:30]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:31]=1[CH2:32][CH2:33][C:34](=[O:48])[N:35]2[CH2:40][CH2:41][CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.Br[C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[C:53]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:54]=[CH:55][C:50]([N:45]2[CH2:44][CH2:43][CH:42]([CH2:41][CH2:40][N:35]3[C:36]4[CH:37]=[CH:38][CH:39]=[C:30]([CH:26]=[O:25])[C:31]=4[CH2:32][CH2:33][C:34]3=[O:48])[CH2:47][CH2:46]2)=[CH:51][CH:52]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: O=C1CCc2c(C3OCCO3)cccc2N1CCC1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1cccc2c1CCC(=O)N2CCC1CCN(c2ccc(-c3ccccc3)cc2)CC1
Temperature: 100 °C
Reaction time: 7.5 h
Yield: 32 %

Procedure:
Palladium acetate (34 mg, 0.15 mmol), tri-tert-butylphosphine tetrafluoroborate (66 mg, 0.23 mmol) and sodium tert-butoxide (218 mg, 2.27 mmol) were added to a toluene solution (10 ml) of 5-(1,3-dioxolan-2-yl)-1-(2-piperidin-4-ylethyl)-3,4-dihydro-1H-quinolin-2-one (500 mg, 1.52 mmol) and 4-bromobiphenyl (424 mg, 1.82 mmol), followed by stirring in an argon atmosphere at 100° C. for 7.5 hours. After cooling to room temperature, water was added to the reaction mixture, and extraction with ethyl acetate was performed. The extract was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=2:1). The purified product was concentrated under reduced pressure, and the residue was dissolved in acetone (10 ml). p-Toluenesulfonic acid monohydrate (104 mg) and water (2 ml) were added, followed by heating under reflux for 15 minutes. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was rendered basic by adding an aqueous solution of potassium carbonate, and washed for 10 minutes in an ultrasonic washing machine. The produced insoluble matter was collected by filtration, washed with water and dried to thereby obtain 213 mg (yield: 32.1%) of 1-[2-(1-biphenyl-4-ylpiperidin-4-yl)ethyl]-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:3]([C:5]1[C:10]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])COC)=[CH:9][C:8]([Cl:29])=[CH:7][N:6]=1)=[O:4].Cl>O.O1CCOCC1>[CH3:1][N:2]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:3]([C:5]1[C:10]([NH:11][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=2)(=[O:17])=[O:16])=[CH:9][C:8]([Cl:29])=[CH:7][N:6]=1)=[O:4]
Reactant: COCN(c1cc(Cl)cnc1C(=O)N(C)c1ccc(F)cc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccc(F)cc1

Procedure:
5-Chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid N-methyl-N-(4-fluorophenyl)amide (141 mg, 0.258 mmol) was magnetically stirred in water (1.0 mL) and 4N HCl in dioxane (2.5 mL) and heated at 85° C. (oil bath) for 7 h. LCMS indicated complete reaction; the reaction was concentrated and the residue was neutralized (pH 7) with aqueous sodium bicarbonate and extracted with EtOAc (3×80 mL). The extracts were dried (MgSO4), filtered, and chromatographed on silica gel using ethyl acetate-hexane gradient (0:100 to 50:50) to provide 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid N-methyl-N-(4-fluorophenyl)amide. MS m/z 522.1 (M+H).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])(=O)=O.[O:29]=[C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[N-:31]1.[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:26]1([NH:25][C:23]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=3)[C:7]=2[CH2:6][N:31]2[C:32](=[O:39])[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:30]2=[O:29])=[O:24])[CH2:27][CH2:28]1
Reactant: O=C1[N-]C(=O)c2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)methyl methanesulfonate (1.02 g, 2.5 mmol) obtained in Example 126a) and potassium 1,3-dioxo-1,3-dihydroisoindol-2-ide (463 mg, 2.5 mmol, 1.0 eq.) were dissolved in DMF (10 ml), and the mixture was stirred at 50° C. for 30 min. The reaction mixture was diluted with ethyl acetate (20 ml), and the precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (1.0 g, 87.7%).
Reaction SMILES: Cl.[NH2:2][O:3][CH:4]([CH3:8])[C:5]([OH:7])=[O:6].[CH:9]1[C:18]2[N:19]3[C:23]([C:24](=O)[C:16]4[C:17]=2[C:12]([CH:13]=[CH:14][N:15]=4)=[CH:11][CH:10]=1)=[CH:22][CH:21]=[CH:20]3>O.C(O)C.N1C=CC=CC=1>[C:5]([CH:4]([O:3][N:2]=[C:24]1[C:16]2[C:17]3[C:12]([CH:13]=[CH:14][N:15]=2)=[CH:11][CH:10]=[CH:9][C:18]=3[N:19]2[C:23]1=[CH:22][CH:21]=[CH:20]2)[CH3:8])([OH:7])=[O:6]
Reactant: CC(ON)C(=O)O
Reactant: O=c1c2nccc3cccc(c32)n2cccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: CC(ON=c1c2nccc3cccc(c32)n2cccc12)C(=O)O
Yield: 76.4 %

Procedure:
A solution of 2-aminooxypropionic acid hydrochloride (15.0 g.) in water (37.5 cc.) is added to a stirred boiling solution of 7H-indolizino[5,6,7-ij]isoquinolin- 7-one (15.0 g.) in ethanol (375 cc.) and pyridine (8.14 g.). Boiling is maintained for 2 hours 30 minutes. After cooling, the orange crystals are filtered off, washed with 90% ethanol, then with absolute ethanol and finally with diethyl ether. After drying, 7-(1-carboxyethoxyimino)-7H-indolizino[5,6,7-ij]isoquinoline (16.0 g.), melting at 225° C. with decomposition, is obtained.
Reaction SMILES: C([O:4][C@@H:5]([CH3:27])[C:6]([NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[C:19]([C:10]1[NH:11][C:12]2[C:17]([C:9]=1[NH:8][C:6](=[O:7])[C@@H:5]([OH:4])[CH3:27])=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)O[C@@H](C)C(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[C@H](O)C(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Yield: 81.7 %

Procedure:
A solution of (S)-(−)-3-(2-acetoxypropionylamino)-2-benzoyl-6-chloroindole (Example 58, 580 mg, 1.5 mmol) and potassium carbonate (2.0 g, 14 mmol) in ethanol (30 ml) and water (10 ml) was stirred for 2 h. The mixture was concentrated and extracted with ethyl acetate (50 ml×2). The organic extracts were dried (MgSO4) and concentrated to give a yellow amorphous solid. Recrystallization from ethyl acetate/hexane gave 420 mg (81%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([NH:25][C@@H:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)=[N:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[CH:12][C:5]=2[N:4]=[CH:3]1.[O:31]([C:33]#[N:34])[K].Cl>CO>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([NH:25][C@@H:26]3[CH2:30][CH2:29][N:28]([C:33]([NH2:34])=[O:31])[CH2:27]3)=[N:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[CH:12][C:5]=2[N:4]=[CH:3]1
Reactant: N#CO[K]
Reactant: Cn1cnc2cc(-c3ccc(N4CCOCC4)cc3)nc(N[C@@H]3CCNC3)c2c1=O
Agent: Cl
Solvent: CO
Product: Cn1cnc2cc(-c3ccc(N4CCOCC4)cc3)nc(N[C@@H]3CCN(C(N)=O)C3)c2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-methyl-7-(4-morpholinophenyl)-5-(pyrrolidin-3-ylamino)pyrido[4,3-d]pyrimidin-4(3H)-one (8.0 mg, 0.0197 mmol) in methanol (0.2 mL) were added KOCN (2.9 mg, 0.0354 mmol) and 1N aqueous HCl solution (19.7 μL, 0.0197 mmol). The reaction mixture was stirred at room temperature overnight, evaporated under vacuo, and purified by preparatory LC/MS to provide the title compound; HPLC-MS calculated for C23H27N7O3 (M+H+) 450.2, found 450.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[C:29](O)(=[O:32])[CH:30]=[CH2:31]>>[O:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:12]3[N:11]=[C:10]([S:9][C:5]4[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=4)[CH2:2][NH:1][C:29](=[O:32])[CH:30]=[CH2:31])[CH:15]=[CH:14][N:13]=3)=[CH:22][CH:21]=2)[CH2:28][CH2:27]1
Reactant: NCc1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Reactant: C=CC(=O)O
Product: C=CC(=O)NCc1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Yield: 31.3 %

Procedure:
In a procedure analogous to Example 15, reaction of 4-(3-(aminomethyl)phenylthio)-N-(4-morpholinophenyl)pyrimidin-2-amine (60 mg, 0.15 mmol) and acrylic acid (16 mg, 0.23 mmol) furnished the product (21 mg, 31%).
Reaction SMILES: NC1C=CC(C=CC(OCC)=O)=CC=1.S(Cl)(C)(=O)=O.[S:20]([NH:24][C:25]1[CH:37]=[CH:36][C:28]([CH:29]=[CH:30][C:31]([O:33]CC)=[O:32])=[CH:27][CH:26]=1)([CH3:23])(=[O:22])=[O:21].S(N(C1C=CC(C=CC(OCC)=O)=CC=1)S(C)(=O)=O)(C)(=O)=O.[OH-].[Na+].Cl>C(Cl)Cl.C(O)C.O.C(N(CC)CC)C>[S:20]([NH:24][C:25]1[CH:37]=[CH:36][C:28]([CH:29]=[CH:30][C:31]([OH:33])=[O:32])=[CH:27][CH:26]=1)([CH3:23])(=[O:21])=[O:22]
Reactant: CCOC(=O)C=Cc1ccc(NS(C)(=O)=O)cc1
Agent: CCOC(=O)C=Cc1ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc1
Agent: CCOC(=O)C=Cc1ccc(N)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 4-aminocinnamate (150 mg) and triethylamine (94 mg) in methylene chloride (3 ml) was added mesyl chloride (0.08 ml) under ice-cooling under nitrogen atmosphere, and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into water, and extracted with methylene chloride twice. The combined organic layer was washed with water, dried over magnesium sulfate and concentrated to give a residue including ethyl 4-mesylaminocinnamate and ethyl 4-(N,N-dimesylamino)cinnamate. The residue was dissolved in ethanol, and 1N aqueous sodium hydroxide solution (1.5 ml) was added thereto at 40° C. The mixture was stirred at ambient temperature for 2 days, and 1N hydrochloric acid (1.5 ml) was added thereto. The mixture was concentrated in vacuo, and the residue was partitioned between 10% methanol-methylene chloride and water. The organic layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (methylene chloride-methanol, 10:1, V/V) to give 4-mesylaminocinnamic acid (49.3 mg).