Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CCN(c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CC1CCN(c2cc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2N)CC1
Yield: 103.4 %

Procedure:
A solution of 4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.090 g, 0.22 mmol) (as prepared in Example 33, step (d)) in methanol (2 mL) was hydrogenated over 10% Pd/C at 12 psi for 2 h. The solution was filtered and concentrated to give 0.085 g (100%) of the title compound as an oil. Mass spectrum (ESI, m/z): Calcd. for C22H35N3O2, 374.3 (M+H), found 374.1.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[O:12][C:13]3[C:19]([C:20]([O:22]C)=O)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].O.[NH4+:25]>C(O)C>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[O:12][C:13]3[C:19]([C:20]([NH2:25])=[O:22])=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3]
Reactant: COC(=O)c1cccc2nc(-c3cccc(CN(C)C)c3)oc12
Reactant: [NH4+]
Solvent: O
Solvent: CCO
Product: CN(C)Cc1cccc(-c2nc3cccc(C(N)=O)c3o2)c1
Temperature: 30 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
Methyl 2-(3-((dimethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (66 mg, 0.18 mmol) and ammonium water (50.4 mg, 1.44 mmol) were added to ethanol (30 mL) and the mixture was stirred at 30° C. for 1 hr. The resulting mixture was evaporated under reduced pressure and purified with Pre-HPLC to obtain 2-(3-((dimethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide (12 mg, yield 22%). 1H-NMR (400 MHz, DMSO-d6) δ 2.88 (s, 5H), 4.36 (s, 2H), 7.02 (s, 1H), 7.37-7.41 (t, J=8 Hz, 1H), 7.54-7.61 (m, 2H), 7.84-7.86 (d, J=8 Hz, 1H), 7.97-7.99 (d, J=8 Hz, 1H), 8.28-8.29 (d, J=4 Hz, 1H), 8.50 (s, 1H); LC-MS (ESI) m/z 296 [M+1]+.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:11][C:12]1[NH:16][N:15]=[C:14]([CH2:17][OH:18])[N:13]=1>COCCO>[CH3:2][C:1]1[C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:16]2[N:15]=[C:14]([CH2:17][OH:18])[N:13]=[C:12]2[N:11]=1
Reactant: CC(=O)C1CCCCC1=O
Reactant: Nc1nc(CO)n[nH]1
Solvent: COCCO
Product: Cc1nc2nc(CO)nn2c2c1CCCC2
Temperature: 23 °C
Yield: 50.8 %

Procedure:
To a round bottomed flask was loaded 4.2 grams of 2-acetylcyclohexanone, 3.52 grams of (5-Amino-1H-[1,2,4]triazol-3-yl)-methanol and 50 ml 2-methoxyethanol. The mixture was refluxed for 18 hours. Then it was cooled down to 23° C. and concentrated to 5 ml. Then 50 ml ethyl ether was added and the precipitate was filtered and vacuum dried to yielded 3.32 grams of product Yield. 49%. This compound was used directly for the next step. MS: 219.2(M+H). H-NMR(DMSO): δ 5.49(t, 1H, OH, J=6 Hz), 4.61(d, 2H, J=6 Hz), 3.24 (m, 2H), 2.93 (m, 2H), 2.69 (s, 3H), 2.52 (s, 2H), 1.84 (m, 4H).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH:3]([OH:12])[CH2:2]1.O[C:14]1[C:15]([C:31]([F:34])([F:33])[F:32])=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C@:24]1([CH3:30])[CH2:28][O:27][C:26](=[O:29])[NH:25]1)[CH:18]=[CH:17]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:30][C@@:24]1([C:19]2[CH:18]=[CH:17][C:16]3[C:21](=[CH:22][CH:23]=[C:14]([O:12][CH:3]4[CH2:2][CH2:1][C:6]5([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]5)[CH2:5][CH2:4]4)[C:15]=3[C:31]([F:34])([F:32])[F:33])[CH:20]=2)[CH2:28][O:27][C:26](=[O:29])[NH:25]1
Reactant: OC1CCC2(CCCCC2)CC1
Reactant: C[C@@]1(c2ccc3c(C(F)(F)F)c(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@]1(c2ccc3c(C(F)(F)F)c(OC4CCC5(CCCCC5)CC4)ccc3c2)COC(=O)N1
Yield: 69.4 %

Procedure:
The mixture of spiro[5.5]undecan-3-ol (39.3 mg, 0.000234 mol) and (R)-4-(6-hydroxy-5-(trifluoromethyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (60.6 mg, 0.000195 mol), and triphenylphosphine (61.2 mg, 0.000234 mol) in tetrahydrofuran (2 mL, 0.02 mol) was heated to reflux, and diisopropyl azodicarboxylate (0.0460 mL, 0.000234 mol) was added dropwise and was stirred and refluxed for overnight. The mixture was taken up into methylene chloride and subjected to chromatography purification with EtOAc/hexane (10:90 to 80:20) to give (4R)-4-methyl-4-(6-(spiro[5.5]undecan-3-yloxy)-5-(trifluoromethyl)naphthalen-2-yl)oxazolidin-2-one as a white solid (62.5 mg, 70%). LCMS Rf=2.45 min 462.40 ([M+1]+, 70%), 503.43 [M+42], 100%).
Reaction SMILES: O1CCOCC1.C(OC(=O)[NH:13][C:14]([C:26]1[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=1)([CH3:25])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([F:24])[CH:18]=1)=[O:16])(C)(C)C.Cl.O1CCOCC1>O>[NH2:13][C:14]([C:26]1[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=1)([CH3:25])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([F:24])[CH:18]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)NC(C)(C(=O)c1ccc(Cl)c(F)c1)c1ccc(Cl)nc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(N)(C(=O)c1ccc(Cl)c(F)c1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A dioxane (1 ml) solution of the compound (1.23 g, 2.55 mmol) obtained in Step 5 above was added to a 4 N hydrochloric acid/dioxane solution (5 ml) under ice cooling and the resulting mixture was gradually warmed and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and washed with an n-hexane/ethyl acetate mixed solvent and then the aqueous layer was made alkaline by the addition of 15% aqueous sodium hydroxide solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=1:1 (v/v)] to give the title compound (0.75 g, 95%) as a pale yellow solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:15][CH3:16]>C(O)C>[CH3:16][O:15][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[CH2:5][C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1cccc([N+](=O)[O-])c1CBr
Agent: [Na+]
Solvent: CCO
Product: COc1cccc([N+](=O)[O-])c1CC#N
Yield: 61 %

Procedure:
Sodium cyanide (165 mg, 3.36 mmol) was added to a solution of 2-(bromomethyl)-1-methoxy-3-nitro-benzene (680 mg, 2.56 mmol) in ethanol (5 mL) and the mixture was heated at reflux for 16 h. The solvent was removed in vacuo, water (30 mL) was added and the mixture was extracted with dichloromethane (25 mL). The organic phase was washed with water (2×20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using 8% ethyl acetate in petroleum ether to afford 2-(2-methoxy-6-nitro-phenyl)acetonitrile (300 mg, 61%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][OH:7])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCNCCO
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 75 %

Procedure:
Bis(2-hydroxyethyl)amine (5 g) was dissolved in N,N-dimethylformamide (100 ml), added with benzyl bromide (6.52 ml) and potassium carbonate (8.657 g) and stirred at room temperature for 21 hours. The reaction mixture was added with water (200 ml) and extracted twice with dichloromethane (200 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: dichloromethane:methanol=20:1→10:1) to obtain 7.631 g of the title compound. Yield: 75%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:16]=[CH:15][NH:14][N:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH3:19]I>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:16]=[CH:15][N:14]([CH3:19])[N:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CI
Reactant: COC(=O)c1cc(C)ccc1-c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)ccc1-c1ccn(C)n1
Reaction time: 1 h

Procedure:
To a solution of methyl 5-methyl-2-(1H-pyrazol-3-yl)benzoate (0.16 g, 0.744 mmol) in DMF (3 mL) at rt was added NaH (60%, 0.081 g, 2.02 mmol) under argon protection. The mixture was stirred atrt for 1 h, and then MeI (0.07 mL, 1.116 mmol) was added. The resulting mixture was stirred for another 1 h. The solvent was removed in vacuo. The crude was dissolved with EtOAc and washed with satd. NaHCO3, brine, and dried (MgSO4). The solvent was removed and the crude was purified by silica gel chromatography to obtain the faster eluting methyl 5-methyl-2-(1-methyl-1H-pyrazol-5-yl)benzoate as the minor product and the slower eluting methyl 5-methyl-2-(1-methyl-1H-pyrazol-3-yl)benzoate as the title compound and major product. ESI-MS (m/z): 231 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.Cl[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([CH:27]([F:29])[F:28])=[N:25][N:26]=2)[N:23]=1>>[F:29][CH:27]([F:28])[C:24]1[N:22]2[N:23]=[C:18]([N:14]3[CH2:13][CH2:12][N:11]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)([CH3:10])[CH3:9])[CH2:16][CH2:15]3)[CH:19]=[CH:20][C:21]2=[N:26][N:25]=1
Reactant: CC(C)(c1ccc(F)cc1)N1CCNCC1
Reactant: FC(F)c1nnc2ccc(Cl)nn12
Product: CC(C)(c1ccc(F)cc1)N1CCN(c2ccc3nnc(C(F)F)n3n2)CC1
Yield: 62 %

Procedure:
A mixture of 1-[1-(4-fluorophenyl)-1-methyl-ethyl]piperazine (obtained as described in J. Med. Chem. 2007, 50, 3528) and 6-chloro-3-(difluoromethyl)-[1,2,4]-triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 269 to give 3-(difluoromethyl)-6-[4-[1-(4-fluorophenyl)-1-methylethyl]piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine in 62% yield.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[N:14]=[CH:13][N:12]([CH2:15][C:16]([OH:18])=O)[N:11]=2)=[O:8])=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[O:32])=[CH:22][C:21]=1[F:33]>>[F:33][C:21]1[CH:22]=[C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[O:32])[CH:24]=[CH:25][C:20]=1[NH:19][C:16]([CH2:15][N:12]1[CH:13]=[N:14][C:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])=[N:11]1)=[O:18]
Reactant: O=C(O)Cn1cnc(NC(=O)c2ccc(Cl)s2)n1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Product: O=C(Cn1cnc(NC(=O)c2ccc(Cl)s2)n1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
61.4 According to general method B, {3-[(5-chloro-thiophene-2-carbonyl)-amino]-[1,2,4]triazol-1-yl}-acetic acid was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) to give 5-chloro-thiophene-2-carboxylic acid (1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-1H-[1,2,4]triazol-3-yl)-amide. Off-white solid. MS 473.4 ([M+H]+)
Reaction SMILES: Cl.[CH3:2][CH:3]([NH:5][CH2:6][C:7]1([NH2:11])[CH2:10][NH:9][CH2:8]1)[CH3:4].[F:12][C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:15]([CH:19]=[CH:20][C:21]=1[F:22])[C:16](F)=[O:17]>C(=O)(O)[O-].[Na+].O1CCOCC1.O>[F:12][C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:15]([C:16]([N:9]2[CH2:10][C:7]([CH2:6][NH:5][CH:3]([CH3:4])[CH3:2])([NH2:11])[CH2:8]2)=[O:17])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CC(C)NCC1(N)CNC1
Reactant: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)NCC1(N)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.6 %

Procedure:
To a mixture of the 3-{[(1-methylethyl)amino]methyl}azetidin-3-amine hydrochloride (20 mg, 0.079 mmol) in saturated sodium bicarbonate solution (1.0 mL) and dioxane (1.0 mL) was added 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (31 mg, 0.079 mmol), prepared using procedures similar to those described in Reference 1, and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined extract was washed with water then brine solution (5 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by reverse phase HPLC to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylethyl)amino]methyl}azetidin-3-amine (15 mg, 37% yield). 1H NMR (400 MHz, d4-Methanol): 7.46-7.43 (dd, 1H), 7.35-7.33 (dd, 1H), 7.31-7.27 (m, 1H), 7.08-7.01 (dd, 1H), 6.63, 6.58 (td, 1H), 4.09-4.07 (d, 1H), 3.91-3.85 (dd, 2H), 3.76-3.73 (d, 1H). 2.80-2.74 (m, 1H), 2.73 (s, 2H), 1.07-1.05 (d, 6H); MS (EI) for C20H22F3IN4O: 519 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:35])[CH:12]([C:19]2[N:20]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[N:21]=[C:22]3[C:27]=2[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([Cl:36])[CH:5]=1.[OH-].[Li+]>C1COCC1>[Cl:36][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11](=[O:35])[CH:12]([C:19]1[N:20]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[N:21]=[C:22]2[C:27]=1[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:3]([OH:37])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 60.2, [rac]-3-chloro-4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-acetylamino}-benzoic acid methyl ester was treated with aqueous lithium hydroxide solution in THF to give the title compound as off-white solid. MS: m/e=526.0 [M+H+].
Reaction SMILES: [CH3:1][NH2:2].C(O[C:6]([C:8]1[C:9](=[O:34])[C:10]2[CH:15]=[N:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[N:12][C:11]=2[N:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH2:30][CH2:29][CH2:28]3)[CH:24]=1)=[O:7])C>>[CH3:1][NH:2][C:6]([C:8]1[C:9](=[O:34])[C:10]2[CH:15]=[N:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[N:12][C:11]=2[N:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH2:30][CH2:29][CH2:28]3)[CH:24]=1)=[O:7]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCN(C)C)ncc2c1=O
Reactant: CN
Product: CNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCN(C)C)ncc2c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methylamine (1N, 1 mL in methanol) was added to 2-(3-dimethylamino-propylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 6 Step A, 6 mg, 0.015 mmol). The mixture was kept in a sealed tube at 110° C. with stirring for 2 days. The solution, after cooling down to room temperature, was loaded to HPLC for purification (32 mL/min 5-100% MeCN/H2O gradient over 10 min). 2-(3-Dimethylamino-propylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide was obtained as a white solid (4.5 mg, 77%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.70 (br, 1H), 9.26 (s, 1H), 8.75 (s, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.22 (s, 1H), 7.15 (d, J=7.8 Hz, 1H), 6.86 (br, 1H), 2.99 (m, 9H), 2.25-2.10 (m, 10H), 1.62 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C23H28N6O2: 421.23 (M+H). Found. 421.1
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:20]([OH:30])[CH2:21][C@@H:22]([CH3:29])[C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[CH2:38]([C@H:45]([CH2:49][C:50]([N:52]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH3:53])=[O:51])C(O)=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([C@H:45]([CH2:49][C:50]([N:52]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH3:53])=[O:51])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:31][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)[C@@H:20]([OH:30])[CH2:21][C@@H:22]([CH3:29])[C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Reactant: CN(Cc1ccccc1)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Product: CCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N(C)Cc1ccccc1)Cc1ccccc1
Yield: 32.4 %

Procedure:
The procedure described in Example 6(b) was repeated, but using 252 mg (0.468 mmole) of (2R, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-methyl-N-propylhexanamide [prepared as described in Example 18(a)] and 152 mg (0.488 mmole) of 2(R)-benzyl-3-(N-benzyl-N-methylaminocarbonyl)propionic acid, to afford 111 mg of the title compound as a colorless powder, melting at 115°-118° C.
Reaction SMILES: CO.C([C:5]1[N:6]([CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:7]2[C:16]3[CH:15]=[CH:14][C:13](C=CS(C)(=O)=O)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:23])[C:8]=2[N:24]=1)C>[Pd].C(O)C>[O:29]1[CH2:30][CH2:31][CH:26]([CH2:25][N:6]2[C:7]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=[C:9]([NH2:23])[C:8]=3[N:24]=[CH:5]2)[CH2:27][CH2:28]1
Reactant: CCc1nc2c(N)nc3cc(C=CS(C)(=O)=O)ccc3c2n1CC1CCOCC1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Nc1nc2ccccc2c2c1ncn2CC1CCOCC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon (0.2 g), methanol (25 mL), ethanol (25 mL) and 2-ethyl-7-[2-(methylsulfonyl)ethenyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (315 mg, 0.76 mmol). The vessel was evacuated and charged with hydrogen gas (40 psi, 2.8×105 Pa). The reaction was shaken at 50° C. for approximately 18 hours and then cooled to ambient temperature. The reaction mixture was sequentially filtered, concentrated under reduced pressure, and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with CMA:chloroform gradient, 0-10% CMA over 1000 mL followed by 10-25% CMA over 1000 mL). A final recrystallization from acetonitrile provided 125 mg of 2-ethyl-7-[2-(methylsulfonyl)ethyl])-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white crystalline solid, mp 246.5-249.0° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:28][C:29]([NH2:31])=[O:30]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:28][C:29]([NH2:31])=[O:30])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: NC(=O)CBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CC(N)=O)C2=O)CC1
Yield: 6 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-bromoacetamide, to give the desired product as a white solid (6%).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Oc2ccccc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Oc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-phenoxybenzamido)-4-phenylbenzoate (0.049 g) in methanol (1.5 mL) and ethyl acetate (1.5 mL), 10% palladium-carbon (0.025 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture, 10% palladium-carbon (0.050 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and hexane was added to the obtained residue. The solid substance was collected by filtration to obtain 0.017 g of tert-butyl 2-(2-hydroxy-5-phenoxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:18].Cl.[OH:25][NH2:26].Cl>N1C=CC=CC=1>[OH:25][N:26]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:18]
Reactant: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=NO

Procedure:
A stirred solution of (1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid (5.1 g., 0.015 mole) and hydroxyamine hydrochloride (3.2 g., 0.045 mole) in pyridine (60 ml.) is heated at 95°C. on a steam bath for 40 hours then poured into aqueous hydrochloric acid affording (1-hydroxyimino-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 230°C. after recrystallization from ethanol-water.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[N:15]12[CH2:22][CH2:21][CH2:20][C:19]1([CH2:23][NH2:24])[CH2:18][CH2:17][CH2:16]2>>[N:15]12[CH2:22][CH2:21][CH2:20][C:19]1([CH2:23][NH:24][C:2]1[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1)[CH2:18][CH2:17][CH2:16]2
Reactant: O=[N+]([O-])c1ccc(Cl)c2ccccc12
Reactant: NCC12CCCN1CCC2
Product: O=[N+]([O-])c1ccc(NCC23CCCN2CCC3)c2ccccc12
Yield: 50.9 %

Procedure:
1-Chloro-4-nitronaphthalene and (1-azabicyclo[3.3.0]octan-5-yl)methylamine were reacted in the same manner as in Example 1 to obtain the titled compound in a yield of 50.9%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([NH2:7])=[O:6].C1(C)C=CC=CC=1.C(Cl)(=O)[C:22](Cl)=[O:23].Cl>O>[CH3:13][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([N:7]=[C:22]=[O:23])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(OC)c1C(N)=O
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C(=O)N=C=O
Temperature: 60 °C

Procedure:
A 167 g. portion of 2,6-dimethoxybenzamide was slurried in 2 l. of toluene under a nitrogen atmosphere. To this solution was added 145 g. of oxalyl chloride over a one hour period. The solution was heated to 60° C. and maintained at this temperature overnight. HCl was allowed to escape while attempting to prevent water from condensing and going into the reaction mixture. Nitrogen was bubbled subsurface through a gas inlet tube while heating the reaction mixture at reflux (about 110° C.) for 11/2 hours. As stirring continued, the mixture was allowed to come to about 30° C. The solution was filtered through infusorial earth while maintaining a nitrogen atmosphere and the solvent was removed in vacuo. Yield 185 g. (97%). The oil was then stored under nitrogen.