Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1.Cl>CN(C)C=O>[C:1]1([C:7]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=2)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)(c1ccccc1)c1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 146.4 %

Procedure:
14.9 g of diethyl phenylmalonate was dissolved in 50 ml of N,N-dimethylformamide and 2.52 g of sodium hydride (60% oily) was added thereto at room temperature. Next, 5.0 g of 2-chloro-5-nitropyridine was added thereto and the resulting mixture was stirred at 80° C. for 2 hours. After the completion of the reaction, the reaction mixture was poured into ice-water/ethyl acetate and neutralized with dilute hydrochloric acid. After extracting with ethyl acetate, the extract was dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 16.55 g of the title compound as a reddish brown oily substance.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13]([O:15]CC)=O.[NH2:18][NH2:19]>C(O)C>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13]([NH:18][NH2:19])=[O:15]
Reactant: NN
Reactant: CCOC(=O)c1nc(-c2cccnc2)[nH]c1C
Solvent: CCO
Product: Cc1[nH]c(-c2cccnc2)nc1C(=O)NN
Temperature: -10 °C

Procedure:
A solution of 32 g of 5-methyl-2-(3-pyridinyl)-1H-imidazole-4-carboxylic acid, ethyl ester (prepared as described above) in ethanol was heated to boiling. A 79 ml portion of hydrazine was added. This mixture was stirred at reflux for 14 hours and then cooled to -10° C. The mixture was taken to dryness in vacuo and then evaporated to dryness in vacuo twice from 125 ml portions of methyl cellosolve. The residue was shaken with 100 ml of ethanol and the solids collected, washed with 100 ml of ethanol and two 100 ml portions of ether and dried at 60° C. in vacuo, giving 18.7 g of 5-methyl-2-(3-pyridinyl)-1H-imidazole-4-carboxylic acid, hydrazide.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[C:9]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[C:10]=2[O:11][C:12]=1[CH3:13])=[O:5])[CH3:2]>[Pd].O1CCOCC1.C(O)C>[NH2:18][C:14]1[C:10]2[O:11][C:12]([CH3:13])=[C:8]([CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:9]=2[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C=Cc1c(C)oc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)CCc1c(C)oc2c(N)cccc12
Reaction time: 3 h
Yield: 103.4 %

Procedure:
10%-Palladium on carbon (30 mg) was added to a solution of 3-(2-ethoxycarbonylethenyl)-2-methyl-7-nitrobenzo[b]furan (210 mg) in a mixture of dioxane (3 ml) and ethanol (1 ml). The mixture was hydrogenated at 3 atoms for 3 hours and the catalyst was filtered off. The filtrate was concentrated in vacuo to give 7-amino-3-(2-ethoxycarbonylethyl)-2-methylbenzo[b]furan (195 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([CH:19]([CH3:29])[CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:11]=2)=[O:9])[CH:3]=1.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:33]=[C:34]([CH2:38][C:39](O)=[O:40])[CH:35]=[CH:36][CH:37]=1>>[OH:21][CH2:20][CH:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:42])([F:30])[F:43])[CH:33]=3)[CH:7]=[CH:6][N:5]=2)=[O:9])=[CH:11]1)[CH3:29]
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(N)ccn2)c2cnccc21
Product: CC(CO)n1cc(C(=O)c2cc(NC(=O)Cc3cccc(C(F)(F)F)c3)ccn2)c2cnccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Prepared according to method described for Method 1 (Example 19) using (4-aminopyridin-2-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 1, Preparation 30) and 3-trifluoromethylphenylacetic acid. The residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution, the organic layer collected, washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue was dissolved in THF and 10% HCl in dioxane was added. The reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and purified using preparative HPLC to afford the title compound.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:9][CH:8]=1)=[O:6]>CO.C1COCC1>[C:22]([O:21][C:19]([NH:18][CH2:17][CH2:16][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:15]=2)[CH:11]=[CH:12]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)c1ccc2ccn(CCNC(=O)OC(C)(C)C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCn1ccc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 68 h

Procedure:
Sodium hydroxide (1N, 6.0 mL, 6.00 mmol) was added to a solution of 1-(2-tert-Butoxycarbonylamino-ethyl)-1H-indole-6-carboxylic acid methyl ester (0.501 g, 1.57 mmol) in methanol (12 mL) and THF (4.0 mL). The reaction was stirred at room temperature for 68 hr. The reaction was concentrated in vacuo. The aqueous residue was acidified to pH ˜1 with 1N HCl and extracted with ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was carried forward without purification. ESI-MS m/z 327 (M+Na)+.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[C:12]([F:22])[CH:11]=1)#[N:9].[S:23](=O)(=[O:26])([OH:25])[OH:24].C([O-])(=O)C.[K+:32]>C(OCC)(=O)C.C(O)C>[K+:32].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[S:18][C:19]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:20][CH:21]=2)=[C:12]([F:22])[CH:11]=1)#[N:9]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(Sc2cccs2)c(F)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Sc2ccc(S(=O)(=O)[O-])s2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (7.34 g, 0.072 mol) was added to (4-cyano-2-fluorophenylthio)thiophene (8.46 g, 0.036 mol) in 200 ml ethyl acetate at 0° C. A cooled solution of sulfuric acid (3.88 g, 0.0395 mol) and ethyl acetate (10 ml) was added dropwise and allowed to stir at room temperature overnight. After cooling to 0° C. potassium acetate (4.23 g, 0.043 mol) in a minimum amount of ethanol was added slowly. A white solid (11.70 g) was collected after stirring one hour.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][C:3]1=2.Cl>CO.C(Cl)Cl>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[N:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)nc31)CNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.6 %

Procedure:
tert-Butyl 9-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (70 mg, 0.13 mmol) was treated with 1.25 M HCl in MeOH (3.4 mL), and the resulting suspension was stirred at ambient temperature for 18 h. The resulting suspension was diluted with CH2Cl2 (1.8 mL) and stirred at ambient temperature for 4 h. To the suspension 1.25 M HCl in MeOH (2.0 mL) was added, and the resulting suspension was stirred at ambient temperature for 18 h. The resulting solids were collected by filtration, dissolved in CH2Cl2 (30 mL), and washed with saturated NaHCO3 solution (50 mL). The resulting layers were separated, and the organic extraction was dried over Na2SO4 and concentrated under reduced pressure to dryness. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 1 column volumes, increased to 0:100 over 20 column volumes and held for 83 column volumes) provided the title compound (38 mg, 67%) as a yellow powder: 1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J=8.5 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.13 (d, J=7.0 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.22 (dd, J=7.5, 2.0 Hz, 1H), 3.91 (s, 2H), 3.69 (s, 3H), 3.11 (t, J=5.5 Hz, 2H), 2.78 (t, J=5.5 Hz, 2H); ESI MS m/z 427 [M+H]+.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:29])[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[CH:16]=1)C1C=CC=CC=1.C(ONC(=O)CCCOC1C=CC=C(C2C=CC(F)=CC=2)C=1)C1C=CC=CC=1>>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[O:14][CH2:13][CH2:12][CH2:11][C:10]([NH:9][OH:8])=[O:29])=[CH:26][CH:25]=1)#[N:28]
Reactant: N#Cc1ccc(-c2cccc(OCCCC(=O)NOCc3ccccc3)c2)cc1
Agent: O=C(CCCOc1cccc(-c2ccc(F)cc2)c1)NOCc1ccccc1
Product: N#Cc1ccc(-c2cccc(OCCCC(=O)NO)c2)cc1

Procedure:
The desired compound was prepared according to the method of Example 15, step 4, except substituting O-benzyl-4-[3-(4-cyanophenyl)phenoxy]butanohydroxamic acid, prepared as in step 1, for N-benzyloxy-4-[3-(4-fluorophenyl)phenoxy]butyramide. 1H NMR (DMSO-d6) δ 1.97 (m, 2H), 2.15 (t, 2H, J=7.3 Hz), 4.05 (t, 2H, J=6.2 Hz), 7.01 (m, 1H), 7.29 (m, 2H), 7.42 (t, 1H, J=8.1 Hz), 7.91 (m, 4H), 8.72 (s, 1H), 10.42 (s, 1H). MS (FAB(+)) 297 (M+H+, 95), 264 (80), 102 (100); (FAB(-)) 295 (M-H-, 20), 194 (100). Anal. Calcd for C17H16N3O3 : C, 68.91; H, 5.44; N, 9.45. Found: C, 57.96; H, 4.66; N, 7.41.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][N:10]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.Br[CH2:37][C:38]([NH2:40])=[O:39]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)=[N:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cn3)ncc2Cl)n[nH]1
Reactant: NC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CC(N)=O)CC4)cn3)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)-N2-(4-methyl-5-(piperidin-4-yl)pyridin-2-yl)pyrimidine-2,4-diamine (50 mg, 0.12 mmol) and triethylamine (50 uL, 0.36 mmol) in DMF (1.5 mL), was added 2-bromo-acetamide (25 mg, 0.18 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was filtered and the filtrate was purified by RP-HPLC to afford 2-(4-(6-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-4-methylpyridin-3-yl)piperidin-1-yl)acetamide as a white solid; 1H NMR (400 MHz, MeOD-d4) δ 8.30 (s, 1H), 8.21 (s, 1H), 7.28 (s, 1H), 6.19 (s, 1H), 4.0 (s, 2H), 3.80-3.73 (m, 2H), 3.33-3.21 (m, 3H), 2.61 (s, 3H), 2.37 (s, 3H), 2.37-2.32 (m, 2H), 2.20-2.16 (m, 2H); ESMS m/z 456.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([NH:8][C:9]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=2[C:11]#[N:12])[CH:7]=1.[Sn](Cl)[Cl:25]>C(O)C.Cl>[ClH:25].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:21]=[C:11]([NH2:12])[C:10]3[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:9]=3[NH:8][C:6]=2[CH:7]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Product: NC1=Nc2ccc(F)cc2Nc2ccc(C(F)(F)F)cc21
Yield: 87.1 %

Procedure:
Heat a solution of 2-(5-fluoro-2-nitro-phenylamino)-5-trifluoromethyl-benzonitrile (1.62 g, 4.98 mmol) in ethanol (24 ml) to 60° C. Add to this a solution of tin (II) chloride (2.83 g, 14.94 mmol) in 5.0 N hydrochloric acid (24 ml). Heat the resulting mixture to reflux for 20 hours. Cool the reaction to room temperature, add 30 ml of 5.0 N hydrochloric acid and place the mixture in a freezer for 16 hours. The product precipitates from the solution and is collected by filtration. Wash solid with 5.0 N hydrochloric acid to obtain 1.44 g of the title compound (4.34 mmol, 87% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 295(M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1.[Br:20]Br>C(O)(=O)C.Br>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH:10]([Br:20])[C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1
Reactant: CSc1ccc(CC(=O)c2ccc(F)cc2F)cc1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of the ketone intermediate from Step 2 (2.05 g, 7.4 mmol) in acetic acid (30 mL) and 33% HBr in acetic acid (0.5 mL) was treated with a 0.99M solution of bromine in acetic acid (7.6 mL, 7.5 mmol) and stirred at room temperature for 1 hour. The solution was concentrated in vacuo and the residue was taken up in dichloromethane, washed with 1N NaHSO3, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give a brown solid (2.39 g, 90%) that was unstable and used directly in the next step without further purification. 1H NMR (CDCl3) 300 MHz 7.94 (q, J=6.3 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 6.97 (m, 1H), 6.84 (m, 1H), 6.28 (s, 1H), 2.46 (s, 3H); 19F NMR (CDCl3) -100.31 (m), -103.50 (m). Mass spectrum: M+H=358.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]3([CH2:13][CH2:14][S:15][C:6]=2[C:5]([CH3:16])=[CH:4][C:3]=1[C:17]([OH:19])=[O:18])[S:12][CH2:11][CH2:10][S:9]3.C(Cl)(=O)C(Cl)=O.[C:26]1(=O)[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[CH2:27]1.C(N(CC)CC)C.[Cl-].[Na+]>C(Cl)Cl.CN(C)C=O>[CH3:1][C:2]1[C:7]2[C:8]3([CH2:13][CH2:14][S:15][C:6]=2[C:5]([CH3:16])=[CH:4][C:3]=1[C:17]([O:19][C:26]1[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[CH:27]=1)=[O:18])[S:12][CH2:11][CH2:10][S:9]3
Reactant: O=C1CCCC(=O)C1
Reactant: Cc1cc(C(=O)O)c(C)c2c1SCCC21SCCS1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)OC2=CC(=O)CCC2)c(C)c2c1SCCC21SCCS1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a solution of the title compound of Step B (0.77 g, 2.4 mmol) in methylene chloride (25 mL) under a nitrogen atmosphere was added oxalyl chloride (Aldrich, 0.63 mL, 7.2 mmol) and 1 drop of N,N-dimethylformamide. The resulting mixture was refluxed for 1.5 h and was then evaporated to dryness. To the resulting residue was added methylene chloride (25 mL) and the resulting mixture was evaporated to dryness. Another 25 mL of methylene chloride was added to the residue, and the solution was cooled to about 0° C. To this mixture was added 1,3-cyclohexanedione (Aldrich, 0.30 g, 2.6 mmol) followed by addition of triethylamine (1.0 mL, 7.2 mmol). The mixture was stirred overnight while warming to room temperature. To the reaction mixture was added saturated aqueous sodium chloride and the resulting mixture was extracted three times with diethyl ether. The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to dryness. Chromatography of the crude product on silica gel with a mixture of hexanes:ethyl acetate (3:1) yielded the title compound of Step C (0.69 g) as a semi-solid. 1H NMR (CDCl3): δ2.13 (m,2H), 2.26 (s,3H), 2.45 (t,2H), 2.66 (m,2H), 2.76 (m,2H), 2.95 (s,3H), 3.18 (m,2H), 3.50-3.70 (4H), 6.00 (s,1H), 7.50 (s,1H).
Reaction SMILES: [C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]3[C:21]([NH2:26])=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].O>C1COCC1>[C@H:1]1([N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[NH:26][C:27]3=[O:28])[CH2:17][CH2:18]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1NC1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2n1C1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
(R)-Acenaphthen-1-yl-amine•hydrochloride (25 g) was dissolved in water (200 ml) and the mixture was alkalified with potassium carbonate and extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained (R)-acenaphthen-1-yl-amine (21 g, 124 mmol) was dissolved in ethanol (200 ml). Potassium carbonate (2.5 g, 18 mmol) and 1-ethyl-1-methyl-4-oxopiperidinium iodide (40 g) dissolved in water (100 ml) was added and the mixture was heated under reflux for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give (R)-1-(acenaphthen-1-yl)-piperidin-4-one (22 g) as a red-yellow oil. (4) A solution of (R)-1-(acenaphthen-1-yl)-piperidin-4-one (12.6 g, 50 mmol) and 1,2-phenylenediamine (10.8 g, 100 mmol) in THF (100 ml) was cooled to (0° C.), sodium triacetoxy borohydride (30 g) and acetic acid (12 ml) were added thereto, and the mixture was stirred at room temperature for 24 hr. The reaction mixture was poured into water, and potassium carbonate was added for neutralization. The mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give (R)—N-[1-(acenaphthen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (9 g) as yellow crystals. (5) (R)—N-[1-(Acenaphthen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (9 g, 26 mmol) was dissolved in THF (100 ml), and carbonyldiimidazole (5 g, 30 mmol) was added. The mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (8.8 g) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6](OS(C)(=O)=O)[CH2:5][CH2:4][NH:3]1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])=[CH:16][C:15]=1[CH3:28].CCN(C(C)C)C(C)C>C(#N)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH:22]2[CH2:27][CH2:26][N:25]([C@@H:6]3[CH2:5][CH2:4][NH:3][C:2]3=[O:1])[CH2:24][CH2:23]2)=[O:21])=[CH:16][C:15]=1[CH3:28]
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1C
Reactant: CS(=O)(=O)O[C@H]1CCNC1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)C2CCN([C@@H]3CCNC3=O)CC2)cc1C
Temperature: 85 °C
Yield: 67.4 %

Procedure:
In a 1 L round bottom flask was added methanesulfonic acid (S)-2-oxo-pyrrolidin-3-yl ester (prepared according to procedure in Eur. Pat. Appl., 257602, 2 Mar. 1988) (18.75 mmol, 3.36 g) and (4-methoxy-3-methyl-phenyl)-piperidin-4-yl-methanone (18.75 mmol, 4.37 g) in DIEA (75 mmol, 13.1 mL) and acetonitrile (100 mL). The reaction mixture was heated at 85° C. for 4 hours. The reaction was evaporated under a vacuum and silica gel flash column chromatography was performed on the remaining residue eluting with ethyl acetate to 20% MeOH/ethyl acetate to provide the title compound as a white solid (4 g, 67.4% yield). Calculated for C18H24N2O3 MS=316.4036. found MS (ESI) m/e 317.1863 (M+H+); 1H NMR (400 MHz, MeOD) δ ppm 1.69-1.89 (m, 4H) 2.08-2.21 (m, 1H) 2.24-2.30 (m, 1H) 2.44-2.56 (m, 1H) 2.73-2.84 (m, 1H) 2.84-2.92 (m, 1H) 3.08-3.17 (m, 1H) 3.30-3.42 (m, 6H) 3.45-3.54 (m, 1H) 3.90 (s, 3H) 6.95-7.04 (m, 1H) 7.72-7.81 (m, 1H) 7.83-7.90 (m, 1H); analytical RP-HPLC retention time=4.67 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[CH3:10].OS(O)(=O)=O.[N+]([C:19]1[CH:20]=C(S(O)(=O)=O)C=C[CH:24]=1)([O-])=O>OCC(CO)O>[CH3:1][O:2][C:3]1[CH:9]=[C:8]2[C:6](=[CH:5][C:4]=1[CH3:10])[N:7]=[CH:20][CH:19]=[CH:24]2
Reactant: COc1ccc(N)cc1C
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: OCC(O)CO
Product: COc1cc2cccnc2cc1C
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To 4-methoxy-3-methylaniline (6.7 g) was added concentrated H2SO4 (12.4 mL), followed by glycerin (21.1 g), m-nitrobenzenesulfonic acid (6.53 g), H3BO3 (3.4 g) and FeSO4.7H2O (3.2 g). The mixture was stirred at 140° C. for 1 h. The reaction was cooled to 25° C., quenched with ice-water and neutralized with 30% KOH. The mixture was extracted with DCM (2×), and the combined extracts dried with Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (EtOAc) to give 6-methoxy-7-methylquinoline LCMS-ESI+ (m/z): 174.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:35]#[N:36])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:31]([CH3:33])[CH3:32])[C:17]([NH:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[C:22]([CH3:30])[CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:35]#[N:36])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:31]([CH3:33])[CH3:32])[C:17]([NH:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[C:22]([CH3:30])[CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(NC(=O)C(C(C)C)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cn(C(C(=O)Nc2ccc(C(=O)O)c(C)c2)C(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
105 mg (207 μmol) of methyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)-2-methylbenzoate (racemate) were dissolved in 4.0 ml of methanol. 0.83 ml of a 1N sodium hydroxide solution was added and the mixture was heated to reflux for 1 h. The reaction mixture was then concentrated under reduced pressure and the residue was taken up in water and acidified with 1N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, the organic phase was dried over sodium sulphate and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (column: Chromatorex 125 mm×30 mm, 10 μm, mobile phase: 0.1% aqueous ammonium formate solution and acetonitrile, gradient 30% acetonitrile to 70% acetonitrile). The isolated product was finally triturated with water and filtered off with suction. Yield: 15 mg (15% of theory)