Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH2:5].C([O-])([O-])=O.[Na+].[Na+].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH:5][C:25]([O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Yield: 100.9 %

Procedure:
To a stirring solution of L-leucine methyl ester (2.0 g, 11.0 mmol) in 1,4-dioxane (20 mL) was added aqueous Na2CO3 solution (12.1 mL, 2M in H2O) followed by benzylchloroformate (1.96 g, 11.5 mmol). The mixture stirred at room temperature for 4h then partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried (MgSO4), filtered and concentrated to yield the title compound as a colorless oil (3.1 g, 100%). 1HNMR (400 MHz, CDCl3) δ 7.34 (m, 5H), 5.27 (d, 1H), 5.12 (s, 2H), 4.41 (s, 2H), 3.75 (s, 3H), 1.65 (m, 3H), 0.96 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.FC(F)(F)C([O-])=O.[C:32]([C:35]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:40][CH2:39][NH2+:38][CH2:37][CH2:36]1)(=[O:34])[NH2:33].C(N(CC)CC)C>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([N:38]1[CH2:37][CH2:36][C:35]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)([C:32]([NH2:33])=[O:34])[CH2:40][CH2:39]1)[N:10]=[CH:9][N:8]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: NC(=O)C1(c2ccccc2)CC[NH2+]CC1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=O)C1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 55 °C
Yield: 62.3 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (23.1 mg, 0.062 mmol, 1 eq.) in 2 mL of ethanol was added 4-carbamoyl-4-phenylpiperidin-1-ium trifluoroacetate (25 mg, 0.123 mmol, 2 eq.) and triethylamine (0.03 mL, 0.19 mmol, 3 eq.). The reaction was heated to 55° C. for 3 d. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 21 mg (63%) of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidine-4-carboxamide. 1H NMR (300 MHz, METHANOL-d4) δ ppm 2.02-2.21 (m, 2 H) 2.62 (d, J=13.37 Hz, 2 H) 3.82 (br. s., 2H) 4.98 (d, J=15.54 Hz, 2H) 7.07-7.67 (m, 13 H) 8.02-8.29 (m, 1 H), [M+H]+ 543.6.
Reaction SMILES: [Na].S(N[N:13]=[CH:14][C:15]1C=CC=C[C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)(C1C=CC(C)=CC=1)(=O)=O.[C:28]([O:32][C:33](=[O:37])NC=C)([CH3:31])([CH3:30])[CH3:29].O1CCOCC1.C(OC)(C)(C)C>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[C:28]([O:32][C:33](=[O:37])[NH:13][C@@H:14]1[CH2:15][C@@H:16]1[C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)NN=Cc2ccccc2-c2ccc(F)cc2)cc1
Reactant: C=CNC(=O)OC(C)(C)C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 215.4 %

Procedure:
4-Fluorophenyl benzaldehyde-tosylhydrazone sodium salt (786 mg, 2.5 mmol), N-vinyl-carbamic acid tert-butyl ester (1.432 g, 10 mmol) and benzyltriethylammonium chloride (57 mg, 0.25 mmol) were covered with dioxane (11 ml) under argon. Rh2(OAc)4 (11 mg, 0.025 mmol) was added and the suspension stirred at room temperature for 15 minutes. The slurry became thick and difficult to stir so a further 4 ml of dioxane was added. The mixture was stirred at 75° C. for 2 hours, then shaken between tBuOMe and water. The organic phase was washed with water and NaCl (satd), dried over MgSO4 and evaporated to yield a brown viscous oil (1.353 g), which was chromatographed on silica to yield 2-(4-fluoro-phenyl)-cyclopropyl-carbamic acid tert-butyl ester 369 mg (59%, m.p. 117-118° C.) cis and 125 mg (20% m.p. 102-105° C.) trans.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@@H:13]([CH2:15][O:16][C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19](O)=[O:20])[C@H:12]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Cl:33][C:28]1[CH:27]=[C:26]([C@@H:12]2[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][C@H:13]2[CH2:15][O:16][C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19](=[O:20])[NH:38][S:35]([CH3:34])(=[O:37])=[O:36])[CH:31]=[CH:30][C:29]=1[Cl:32]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COc2ccccc2C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COc2ccccc2C(=O)NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
To a solution of 2-{[(6S,7R)-4-(tert-butoxycarbonyl)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methoxy}benzoic acid (100 mg) in DMF (1 ml) were added methanesulfonamide (38.3 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (62.5 mg) and N,N-dimethyl-4-aminopyridine (49.2 mg) at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (40 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([I:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CCO>[CH2:11]([N:4]([CH2:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:3]=1)[C:3]1[CH:5]=[C:6]([CH3:10])[C:7]([I:9])=[CH:8][C:2]=1[CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(I)c(C)cc1N
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1I
Temperature: 50 °C
Reaction time: 12 h
Yield: 167.7 %

Procedure:
A mixture of 2,5-dimethyl-4-iodoaniline (6.44 g, 26.1 mmol), benzyl bromide (11.50 g, 67.24 mmol) and potassium carbonate (8.20 g, 59.3 mmol) in EtOH (100 mL) was stirred at 50° C. for 12 h. The reaction mixture was then concentrated under reduced pressure. The residue (a purple solid) was mixed with DCM and this mixture was filtered using vacuum. The filtrate was purified by silica gel flash chromatography (0-5% MeOH in DCM) to give the title compound (9.35 g, 83% yield) as an oil.
Reaction SMILES: Cl.[NH2:2]O.C([O-])(=O)C.[Na+].[O:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.[N:16]1[O:17][N:18]=[C:19]2[CH:24]=[C:23]([C:25](Cl)=[O:26])[CH:22]=[CH:21][C:20]=12>C(O)C.ClCCl>[O:9]1[CH2:14][CH2:13][CH:12]([NH:2][C:25]([C:23]2[CH:22]=[CH:21][C:20]3=[N:16][O:17][N:18]=[C:19]3[CH:24]=2)=[O:26])[CH2:11][CH2:10]1
Reactant: NO
Reactant: O=C(Cl)c1ccc2nonc2c1
Reactant: O=C1CCOCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: O=C(NC1CCOCC1)c1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
A mixture of hydroxylamine hydrochloride (5.56 g), sodium acetate (6.56 g) and tetrahydro-4H-pyran-4-one (4 g, 40 mmol) in ethanol (100 ml) was refluxed over night. The solids were filtered off and the solvent evaporated. The remaining material was suspended in 100 ml of dry THF and decanted. LiAlH4 (6.07 g) was slowly added and the mixture was refluxed for 1 hour. The cooled mixture was quenched with 10% sodium hydroxide solution, celite was added, and the solids were filtered off. The solvent was evaporated and the residue re-dissolved in dichloromethane (10 ml) and triethylamine (1 ml). This mixture was slowly added to a solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (365 mg, 2.0 mmol) in dichloromethane (10 ml) and stirred at room temperature for 0.5 h. The mixture was washed with 1N HCl (100 ml) and NaHCO3 (100 ml) solution and the aqueous re-extracted with dichloromethane (100 ml). The combined organics were dried over magnesium sulfate, and concentrated under vacuum to give a white solid (410 mg). Mp=204-205° C., 1H NMR (300 MHz, CDCl3) δ 8.20-8.18 (m, 1H), 7.92 (dd, 1H, J=9.3 and 1.2 Hz); 7.82 (dd, 1H, J=9.3 and 1.2 Hz); 6.25-6.10 (m, NH, 1H); 4.33-4.17 (m, 1H), 4.07-4.00 (m, 2H), 3.59-3.51 (m, 2H), 2.07-2.03 (m, 2H) and 1.69-1.58 ppm (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[H-].[Na+].[C:17](=O)([O:20]C)[O:18][CH3:19]>C1C=CC=CC=1>[CH3:19][O:18][C:17]([CH:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH3:1])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]1=[O:8])=[O:20]
Reactant: COC(=O)OC
Reactant: CC1(c2ccccc2)CCCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)C1CCCC(C)(c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-2-phenylcyclohexanone (4.7 g, 25 mmol) from Preparation 3 above, and sodium hydride (1.1 g of 60% dispersion in mineral oil, 28 mmol) in 15 mL of dimethyl carbonate and 75 mL of benzene, was heated under reflux for 4 h. The mixture was cooled to room temperature and poured into dilute ice-cold aqueous HCl. The organic layer was washed with brine, dried (sodium sulfate) and evaporated to afford 6.36 g of 3-methyl-2-oxo-3-phenyl-cyclohexanecarboxylic acid methyl ester as an oil.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[OH-].[Na+]>O1CCCC1.O.CO>[Cl:25][C:21]1[CH:20]=[C:19]([CH:12]([CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[CH:5][N:6]=2)=[O:26])[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2cccc(Cl)c2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)C(CC2CCCC2)c2cccc(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 44.9 %

Procedure:
A solution of 6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester (146.9 mg, 0.38 mmol) in tetrahydrofuran/water/methanol (10 mL, 3:1:1) at 25° C. was treated with a 2N aqueous sodium hydroxide solution (0.4 mL, 0.80 mmol). The reaction mixture was stirred at 25° C. for 4 d. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with diethyl ether (1×50 mL). The aqueous layer was acidified to pH=1 by the dropwise addition of a 3N aqueous hydrochloric acid solution. This solution was extracted with a solution of methylene chloride/methanol (3:1, 3×75 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was triturated with diethyl ether/hexanes (2:1) to afford 6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid (63.6 mg, 44.4%) as a white solid: mp 251–255° C.; EI-HRMS m/e calcd for C20H21ClN2O3 (M+) 372.1240, found 372.1250.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.[CH2:10]([O:12][C:13]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[C:14]#[CH:15])[CH3:11]>[Cu]I.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.C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:15]#[C:14][C:13]([O:16][CH2:17][CH3:18])([O:12][CH2:10][CH3:11])[O:19][CH2:20][CH3:21]
Reactant: Clc1ccc(Br)c(I)c1
Reactant: C#CC(OCC)(OCC)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: CCOC(C#Cc1cc(Cl)ccc1Br)(OCC)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
A mixture of 1-bromo-4-chloro-2-iodobenzene (10 g, 32 mmol) in 100 mL degassed ACN and TEA (29 g, 284 mmol), was treated with 3,3,3-triethoxyprop-1-yne (6.0 g, 35 mmol), copper(I) iodide (0.60 g, 3.2 mmol), and dichlorobis(triphenylphosphine)palladium(II) (1.1 g, 1.6 mmol). The mixture was stirred at room temperature for 2 hours at room temperature (the mixture turned dark green after 5 minutes). TLC showed that all starting material was converted, and a new spot was produced. The mixture was concentrated in vacuo. The residue was diluted with 100 mL ether, washed with H2O (2×20 mL), 5% ammonia water (2×20 mL), brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography pretreated with TEA and eluted with 0-15% EtOAc/hexane to give 7.6 g of the product as a pale yellow oil. The oil solidified after it was stored in the refrigerator.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:9])=[CH:4][CH:3]=1.[F:18][C:19]([F:26])([F:25])[CH2:20][S:21](Cl)(=[O:23])=[O:22]>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[S:21]([CH2:20][C:19]([F:26])([F:25])[F:18])(=[O:23])=[O:22])[CH3:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: CC(NCc1cccnc1)c1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(c1ccc(Br)cc1)N(Cc1cccnc1)S(=O)(=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of N-(1-(4-bromophenyl)ethyl)pyrid-3-ylmethylamine (630 mg, 2.16 mmol) and 4-(dimethylamino)pyridine (263 mg, 2.16 mmol) in 18 ml of dichloromethane was treated with 2,2,2-trifluoroethylsulfonyl chloride (420 mg, 2.3 mmol) with stirring for 15 minutes at room temperature. The solution was concentrated to approximately 2 ml and directly purified by radial chromatography on a 1 micron silica plate, eluting with 3% methanol/dichloromethane. The fractions were concentrated to afford the title compound. 1H NMR: 8.52 (bs,1H), 8.42 (bs,1H), (d,1H,J=8 Hz), 7.45 (d,2H,J=8 Hz), 7.22 (d,2H,J=8 Hz), 5.25 (q,1H,J=8 Hz), 4.38 (q,2H,ABX), 3.6 (q,2H,J=12 Hz), 1.68 (d,3H,J=8 Hz). MS calcd. 437.3; MS (M+1),(M+2), 438.0,439.0.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([NH2:9])=[O:8])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)C[C@@H](N)C(N)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Reaction time: 24 h

Procedure:
The above polymer-bound D-Leu-NH2 (20 g) was treated with CH2Cl2 (150 mL), pyridine (100 mL) and 4-chlorophenylsulfonyl chloride (20.0 g, 94.8 mmol). The mixture was shaken for 24 h, drained, washed with DMF (4×200 mL), CH2Cl2 (4×200 mL) and concentrated to give polymer-bound (R)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid amide as a yellow resin (22 g). The completion of the reaction and the loading of the resin (0.57 mmol/g) were determined by the treatment of 50 mg of the resin with 10% (v/v) TFA/CH2Cl2 (2 mL) to give 8.7 mg of (R)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid amide.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].O.[OH-].[Li+]>O1CCOCC1.O>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([NH:5][CH2:4][C:3]([OH:38])=[O:2])=[O:37]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a suspension of 0.148 g (0.27 mmol) {2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-acetic acid methyl ester (Example 29) in 1.5 mL dioxane and 1.5 mL water was added 0.014 g (0.33 mmol) lithium hydroxide monohydrate. After 2 hours stirring at room temperature the organic solvent was evaporated. The pH of the resulting yellow solution was adjusted to 1 with 1M aqueous hydrochloric acid and the solution was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to give 0.091 g (63%) of the title compound as a yellow foam. MS (ESI): m/z=541.104 [M+H]+.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH3:40])[C:35](=[O:41])[CH2:34]2.COCC(O)C>>[CH3:20][O:19][C:16]1[N:15]=[CH:14][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[N:36]([CH3:40])[C:35](=[O:41])[CH2:34]5)=[N:5]3)=[CH:10][CH:11]=2)=[CH:18][CH:17]=1
Reactant: CN1C(=O)Cc2cc(N)ccc21
Reactant: COc1ccc(-c2ccc3cnc(S(C)=O)nn23)cn1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc3cnc(Nc4ccc5c(c4)CC(=O)N5C)nn23)cn1
Yield: 8.3 %

Procedure:
2-Methanesulfinyl-7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004335 mol), N,N-Diisopropylethylamine (0.249 mL, 0.00143 mol) and 5-Amino-1-methyl-1,3-dihydro-indol-2-one (0.141 g, 0.000867 mol) were dissolved in 1-Methoxy-2-propanol (0.498 mL, 0.00510 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 13.85 mg of 5-[7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-1-methyl-1,3-dihydro-indol-2-one as a lyophilized powder. (M+H)=387.1. 1H NMR (400 MHz, DMSO, d6) δ 9.40 (s, 1H), 8.96 (s, 2H), 8.47 (d, 1H, J=8.73 Hz), 7.82 (s, 1H), 7.51 (d, 1H, J=8.40 Hz), 7.16 (d, 1H, J=4.37 Hz), 7.04 (d, 1H, J=8.65 Hz), 6.91 (m, 2H), 3.95 (s, 3H), 3.59 (s, 2H), 3.12 (s, 3H).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19](Br)[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.CN([CH:31]=[O:32])C>>[CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:31]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:32])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cncn1C1CCCc2ccc(Br)cc21
Reactant: C1CCNC1
Reactant: CN(C)C=O
Product: CC(C)OC(=O)c1cncn1C1CCCc2ccc(C(=O)N3CCCC3)cc21
Temperature: 100 °C

Procedure:
3-[7-(Pyrrolidine-1-carbonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3H-imidazole-4-carboxylic acid isopropyl ester and 3-[7-(dimethylcarbamoyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3H-imidazole-4-carboxylic acid isopropyl ester can be obtained from the reaction mixture resulting from this procedure. A pressure tube fitted with a septum is charged with 3-(7-bromo-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester, which can be prepared as described in Example 5, (0.304 g, 0.836 mmol), pyrrolidine (0.298 g, 4.184 mmol), (bis-triphenylphosphine)palladium dichloride (0.029 g, 0.418 mmol), and DMF (4 mL). Carbon monoxide is bubbled through the solution for 15 min, and then the septum is replaced with a screw cap and the mixture is heated to 100° C. overnight. The reaction is cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered, and concentrated. The resulting residue is purified by silica gel chromatography (dichloromethane-methanol mixtures) to give 3-[7-(pyrrolidine-1-carbonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 382.2 (M+H)+; 1H NMR (400 MHz, MeOD) δ ppm 1.37 (d, J=6.3 Hz, 3 H), 1.39 (d, J=6.3 Hz, 3 H), 1.85-2.01 (m, 6 H), 2.28-2.33 (m, 2 H), 2.90-2.98 (m, 1 H), 3.09 (dt, J=17.4, 6.3 Hz, 1 H), 3.27-3.33 (m, 1 H), 3.38-3.42 (m, 1 H), 3.56 (t, J=6.9 Hz, 2 H), 5.21 (sept, J=6.3 Hz, 1 H), 6.37 (t, J=5.9 Hz, 1 H), 7.05 (br. s, 1 H), 7.36 (d, J=7.8 Hz, 1 H), 7.45 (dd, J=7.8, 1.5 Hz, 1 H), 7.56 (s, 1 H), 7.76 (s, 1 H); and
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N+:9]2[O-])=[N:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=[O:20])=CC=1.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[NH:9]2)=[N:4][CH:3]=1
Reactant: [O-][n+]1cccc2ncc(F)cc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1ccc2ncc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
To a solution of 60 mg of 7-fluoro-1,5-naphthyridine 1-oxide in 1.6 mL of chloroform, 84 mg of p-toluenesulfonyl chloride, 171 mg of potassium carbonate and 0.5 mL of water were added, and the mixture was stirred at room temperature overnight. The solid was filtered off, and purified by silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and an eluent of chloroform:methanol=10:1 to obtain 14 mg of 7-fluoro-1,5-naphthyridin-2(1H)-one as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:21][N:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH2:8][C@@H:4]2[CH2:3]1.[C:22]1([CH2:28][S:29](Cl)(=[O:31])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(CC)CC>ClCCl>[O:20]=[C:6]1[N:5]2[CH2:21][C@H:2]([NH:1][S:29]([CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:31])=[O:30])[CH2:3][C@H:4]2[CH2:8][N:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=1
Reactant: N[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](NS(=O)(=O)Cc3ccccc3)CN12
Reaction time: 12 h
Yield: 66.5 %

Procedure:
(6R,7aS)-6-Amino-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 1, step h) (100 mg, 0.33 mmol), phenylmethanesulfonyl chloride (125 mg, 0.66 mmol) and Et3N (0.1 g, 0.99 mmol) were added to dichloromethane (3 mL), and the mixture was stirred for 12 hours. The mixture was directly purified by prep-TLC (DCM/MeOH=30:1) to yield 100 mg (67%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.58-7.55 (m, 2H), 7.43-7.40 (m, 5H), 7.20-7.17 (m, 2H), 4.40-4.37 (m, 1H), 4.29 (s, 2H), 4.05-3.97 (m, 4H), 3.68-3.62 (m, 1H), 2.85-2.81 (m, 1H), 2.11-2.07 (m, 1H), 1.78-1.72 (m, 1H); LC-MS: 456.1 [M+1]+.