Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].S(O[CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)(C1C=CC(C)=CC=1)(=O)=O>CC(N(C)C)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:32][CH2:31]2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 90 °C
Yield: 54.2 %

Procedure:
Cesium carbonate (16.29 g, 50 mmoles, 2 equivalents) was added to a stirred solution of 4-amino-3-nitrophenol (3.85 g, 25 mmoles, 1 equivalent) and tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate (10.16 g, 27.5 mmoles, 1.1 equivalent) in anhydrous DMA (25 mls). The stirred reaction mixture was then heated to 90° C. (thermostatically controlled heating mantle) for 22 hours. The reaction mixture was then allowed to cool to room temperature and was filtered through a plug of Celite. The reaction flask and the Celite were then washed with ethyl acetate (250 ml). The organic solution was then transferred to a separatory funnel and extracted with additional ethyl acetate (3×200 ml). The combined ethyl acetate solution was then washed with water (2×100 ml), saturated sodium chloride (2×100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a crude product. This material was triturated with diethylether to give a solid which was filtered off and washed with ether to give 4.76 g of tert-butyl 4-((4-amino-3-nitrophenoxy)methyl)piperidine-1-carboxylate as a yellow solid (yield=54%). 1H-NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 7.89 (d, 1H), 7.74 (d, 1H), 3.82 (d, 2H), 3.65 (m, 2H), 2.40 (s, 3H), 1.76 (m, 1H), 1.54 (m, 2H), 1.38 (s, 9H), 0.98 (m, 2H). MS (EI): 352 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:20])[C:17](F)=[CH:18][C:13]=2[NH:12][C:11](=[S:21])[CH2:10][N:9]=1.[H-].[Na+].[CH3:24][O:25][CH2:26][CH2:27][OH:28]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:20])[C:17]([O:28][CH2:27][CH2:26][O:25][CH3:24])=[CH:18][C:13]=2[NH:12][C:11](=[S:21])[CH2:10][N:9]=1
Reactant: COCCO
Reactant: Fc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=S)N2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COCCOc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=S)N2
Temperature: 120 °C

Procedure:
A mixture of 1.0 g (0.0031 mole) of 5-(2-chlorophenyl)-1,3-dihydro-7,8-difluoro-2H-1,4-benzodiazepin-2-thione (IImm), 0.372 g of sodium hydride and 20 mL of 2-methoxyethanol was heated in a microwave vessel at 120° C. for 30 minutes, cooled and then diluted with ethyl acetate. The mixture was washed successively with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ethyl acetate to give 0.74 g of 5-(2-chlorophenyl)-1,3-dihydro-7-fluoro-8-methoxyethoxy-2H-1,4-benzodiazepin-2-thione (IIf) as a white solid, which was then used to prepare 5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-methoxyethoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVf) in accordance with Example 58 without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][S:5][CH2:4]1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl.CO>[NH2:1][CH2:2][C:3]1([N:8]([CH3:10])[CH3:9])[CH2:4][S:5](=[O:19])[CH2:6][CH2:7]1
Reactant: CN(C)C1(CN)CCSC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CN(C)C1(CN)CCS(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-(aminomethyl)-N,N-dimethyltetrahydrothiophen-3-amine (160 mg, 0.998 mmol) in DCM: MeOH (4:1, 10 mL) was added MCPBA (246 mg, 1.098 mmol) at 0° C. The reaction was slowly warmed to room temperature and stirred overnight. The crude was purified by cation exchange resin to give the title compound without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C@H:7]([N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][CH2:9]I)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]1[C:41]([CH3:43])([CH3:42])[C:40](=[O:44])[NH:39][C:38]1=[O:45].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[C:1]([O:5][C:6](=[O:35])[C@H:7]([N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][CH2:9][N:39]1[C:40](=[O:44])[C:41]([CH3:43])([CH3:42])[N:37]([CH3:36])[C:38]1=[O:45])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H](CCI)N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CN1C(=O)NC(=O)C1(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(CC[C@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)S(=O)(=O)c2ccc(-c3ccc(Cl)cc3)cc2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
To a solution of the title F compound, (2R)-[t-butyloxycarbonyl(4′-chlorobiphenyl-4-sulfonyl)amino]-4-iodobutyric acid t-butyl ester (0.6 g, 0.94 mmol) in 10 mL DMF is added 3,4,4-trimethyl-2,5-dioxoimidazolidine and potassium carbonate (0.65 g, 4.72 mmol) followed by 2 mg of 18-crown-6. The reaction mixture is stirred at room RT for 3 h, then partitioned between water and EtOAc. The organic solution is washed with brine, dried over anhydrous Na2SO4 and concentrated. Chomatography on silica gel (eluant; 1/19—EtOAc/hexane) affords the title compound as a white foam (0.25 g, 41%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:17]=[C:18]([NH:25][C:26]2[N:31]=[C:30]([CH3:32])[C:29]([C:33]([OH:35])=[O:34])=[CH:28][CH:27]=2)[C:19]([C:22](=[O:24])[NH2:23])=[N:20][CH:21]=1)=O)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>ClCCl>[OH:42][C:36]([C:38]([F:41])([F:40])[F:39])=[O:37].[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:17]=[C:18]([NH:25][C:26]2[N:31]=[C:30]([CH3:32])[C:29]([C:33]([OH:35])=[O:34])=[CH:28][CH:27]=2)[C:19]([C:22](=[O:24])[NH2:23])=[N:20][CH:21]=1
Reactant: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C(N)=O)ccc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)cnc2C(N)=O)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-{[5-({(1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)-2-carbamoylpyridin-3-yl]amino}-2-methylpyridine-3-carboxylic acid (49 mg, 0.10 mmol) in dichloromethane (1 mL) was added TFA (0.12 mL, 1.5 mmol), and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 6-[(5-{[(1R,2S)-2-aminocyclohexyl]amino}-2-carbamoylpyridin-3-yl)amino]-2-methylpyridine-3-carboxylic acid TFA salt. MS ESI calc'd. for C19H25N6O3 [M+H]+ 385. found 385. 1H NMR (500 MHz, DMSO-d6) δ 12.73 (s, 1H), 12.22 (s, 1H), 8.67 (s, 1H), 8.05 (d, J=8.6 Hz, 1H), 8.01 (s, 1H), 7.85 (s, 3H), 7.76 (s, 1H), 7.48 (s, 1H), 6.73 (d, J=8.6 Hz, 1H), 6.45 (d, J=7.8 Hz, 1H), 3.93-3.77 (m, 1H), 3.64-3.49 (m, 1H), 2.72 (s, 3H), 1.94-1.79 (m, 2H), 1.79-1.70 (m, 1H), 1.71-1.50 (m, 3H), 1.51-1.36 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: CC(C)COC(=O)Cl
Product: CC(C)COC(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using isobutyl chloroformate (72 μL, 0.55 mmol) to provide isobutyl [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]carbamate (0.046 g).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]([CH2:20][CH3:21])[C:8]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=1[CH:10]=O.[Cl-].[OH:32][NH3+:33].C([O-])(=O)C.[Na+].O>C(O)C.[Cl-].[Na+].O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]([CH2:20][CH3:21])[C:8]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=1[CH:10]=[N:33][OH:32]
Reactant: [NH3+]O
Reactant: CCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1C=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1C=NO
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
2-[(3,5-Bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyl-benzaldehyde (275 mg) is dissolved in ethanol (2.5 ml) and thereto are added hydroxylammonium chloride (86 mg) and sodium acetate (102 mg), and the mixture is stirred at 60° C. under nitrogen atmosphere for 1 hour and a half. To the reaction solution are added a saturated brine and water, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=24:1→83:17) to give 2-[(3,5-bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyl-benzaldehydeoxime (244 mg). MS (m/z): 459 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH:17](Br)([CH3:19])[CH3:18]>CN(C)C=O.CC(C)=O>[CH:17]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:19])[CH3:18]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC(C)Oc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A solution of 2-nitrophenol (10 g, 71.9 mmol) and potassium carbonate (21.85 g, 158.1 mmol) in N,N-dimethylformamide:acetone (1:2, 150 mL) was heated under reflux and isopropyl bromide (14.8 mL, 158 mmol) was added dropwise (in 30 minutes) during reflux and stirred overnight. The reaction was cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% ethyl acetate:hexanes) to provide the title compound as a golden yellow oil (11.5 g, 88%). 1H NMR (300 MHz, CDCl3) δ 1.4 (d, 6H, J=6 Hz), 4.7 (septet, 1H, J=6 Hz), 6.98 (m, 1H), 7.09 (d, 1H, J=9 Hz), 7.45 (m, 1H), 7.78 (dd, 1H, 3 Hz); MS (DCI/NH3) m/e 182 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH3:16][NH2:17].[Cl-].[NH4+].Cl>>[OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([NH:17][CH3:16])=[O:5]
Reactant: CN
Reactant: C=CCc1c(O)ccc(C(=O)OC)c1O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: C=CCc1c(O)ccc(C(=O)NC)c1O
Yield: 75 %

Procedure:
The compound of Example 5 (3.5 g) and excess methyl amine (40% aqueous solution) were stirred overnight at 50° C. in the presence of a few crystals of ammonium chloride. The reaction mixture was cooled and neutralized with 10% hydrochloric acid then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The crude crystals were dissolved in chloroform and then hexane was added until the product precipitated out of solution. The precipitate was filtered and dried to give the product (2.5 g, 75% yield).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[CH3:3].[Li]CCCC.[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[O:19]=[C:15]([N:5]1[C@@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:8][O:7][C:6]1=[O:9])[CH2:16][CH2:17][CH3:18]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: CCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: 0 °C
Yield: 104.6 %

Procedure:
A mechanically stirred, cooled (-78° C.) solution of the oxazolidinone of Step 5 (32.3 g, 250 mmol) in anhydrous THF (830 mL) was metalated with 163 mL (1.6M in hexane, 261 mmol) of n-BuLi and treated with freshly distilled butanoyl chloride (28.1 mL, 271 mmol). The reaction mixture was warmed to 0° C. and stirred for 0.5 h. Excess acid chloride was hydrolyzed by the addition of 1M aqueous K2CO3 (165 mL) followed by stirring the resultant two-phase mixture for 1 h at r.t. Volatiles were removed in vacuo and the product was extracted into CH2Cl2 (3×). The combined organic extracts were successively washed with H2O and brine, dried over MgSO4 and concentrated to give the title compound as a pale yellow oil (52.1 g, quantative). A portion of this crude product was purified by flash chromatography on silica with EtOAc:hexane 1:4 to give a colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:16]([C:17](=[S:20])[NH:18][NH2:19])[N:15]=[C:14]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[S:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36]>ClCCl>[C:35]([NH:19][NH:18][C:17]([N:16]1[N:15]=[C:14]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[S:13][C:12]1([CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[S:20])(=[O:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NN
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NNC(=S)N1N=C(c2cc(F)ccc2F)SC1(CCCNC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-tert-butoxycarbonylaminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothiohydrazide (0.016 g, 0.032 mmol) in dichloromethane (1 mL) was added acetic anhydride (0.032 g, 0.32 mmol). After stirring for 1 hour at room temperature, the reaction mixture was concentrated under reduced pressure and chromatographed (10:1 hexanes/ethyl acetate) to provide the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:15][CH2:16][C:17](Br)=[O:18]>C1(C)C=CC=CC=1>[Br:15][CH2:16][C:17]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(CBr)Nc1ccc(Cl)cc1

Procedure:
To a solution of 5 g 4-Chloro-phenylamine and 1.5 ml pyridine in 30 ml toluene, 8 g bromo-acetyl bromide dissolved in 10 ml toluene was added dropwise under ice cooling. After 2 h the precipitate was isolated by filtration and recrystallized from toluene to yield a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[N+:11]([O-])([O-:13])=[O:12].[K+].O.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: NC(=O)c1ccc(N)nc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC(=O)c1cnc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 23 %

Procedure:
To a solution of 6-aminonicotinamide (524 mg, 3.82 mmol) in TFA (10 mL) was added KNO3 (524 mg, 5.18 mmol) at room temperature with stirring. The resulting solution was stirred at 80° C. for 18 h, cooled to room temperature, then cooled water (100 mL) was added (no precipitate was formed). The resulting acidic aqueous solution was basified to pH 9 with 40% aq NaOH. The precipitate was filtered, washed with cooled water (2×5 mL), and dried to give 160 mg (23%) of 65 as a yellow powder, mp 289°-90° C. 1H NMR (DMSO-d6), 7.430 (s, 1H), 8.078 (s, 1H), 8.285 (bs, 2H, easily exchanged with D20), 8.840 (s, 2H).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]=1)C.[OH-].[K+].Cl>C(O)C.O>[N:16]1([CH2:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:22])=[O:3])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)CCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCOc1cccc(CN2CCCCC2)c1
Yield: 88.6 %

Procedure:
A solution of ethyl-4-[3-(1-piperidinylmethyl)phenoxy]butanoate (6.1 g) and potassium hydroxide (6.0 g) in ethanol (50 ml) and water (50 ml) was heated under reflux during 0.5 h. The cool solution was neutralised to pH 7 with 5N hydrochloric acid, and evaporated to dryness under reduced pressure. The residue was dissolved in ethanol (100 ml), filtered and the filtrate was evaporated to leave a residue which was crystallised from a mixture of methanol and ether to give the title compound as a white crystalline solid (4.91 g) m.p. 73.5°; tlc System B, Rf 0.3.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1[CH:27]=[C:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:25]=[CH:24][C:19]=1[O:20][CH2:21][CH2:22][NH2:23]>C1(C)C=CC=CC=1>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:23][CH2:22][CH2:21][O:20][C:19]2[CH:24]=[CH:25][C:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:27][C:18]=2[CH3:17])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: CCCCCc1ccc(OCCN)c(C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(OCCNc2ncnc(Cl)c2C)c(C)c1
Reaction time: 5 h

Procedure:
To a solution of 3.2 g (0.02 mol) of 4,6-dichloro-5-methylpyrimidine in 50 ml of toluene were added 2.0 g (0.02 mol) of triethylamine and 4.4 g (0.02 mol) of 2-(2-methyl-4-n-pentylphenoxy)ethylamine. The mixture was then refluxed with stirring for 5 hours.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]1[C:12]([NH2:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[CH3:22])[CH:10]=[CH:9][N:8]=1)[CH3:5].[C:23](OC)(=[O:27])[C:24]([CH3:26])=O>>[CH3:1][O:2][CH2:3][CH:4]([N:6]1[C:23](=[O:27])[C:24]([CH3:26])=[N:13][C:12]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:10][CH:9]=[N:8][C:7]1=2)[CH3:5]
Reactant: COCC(C)Nc1nccc(-c2ccc(OC)cc2C)c1N
Reactant: COC(=O)C(C)=O
Product: COCC(C)n1c(=O)c(C)nc2c(-c3ccc(OC)cc3C)ccnc21

Procedure:
N2-(2-Methoxy-1-methyl-ethyl)-4-(4-methoxy-2-methyl-phenyl)-pyridine-2,3-diamine (0.066 g, 0.22 mmol) and methyl pyruvate (79 μL, 0.88 mmol) were treated substantially as in Part E of Example 67a to give 4-(2-methoxy-1-methyl-ethyl)-8-(4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 73a): 1H NMR (300 MHz, CDCl3): δ 8.49–8.47 (d, 1H, J=4.8 Hz), 7.16–7.12 (m, 2H), 6.86–6.82 (m, 2H), 4.41–4.36 (m, 1H), 3.87 (s, 3H), 3.84–3.80 (m, 2H), 3.34 (s, 3H), 2.48 (s, 3H), 2.12 (s, 3H), 1.62–1.60 (d, 3H, J=6.9 Hz). MS (AP) 354.2 [(M+H)+, 100].
Reaction SMILES: [C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=2)[N:8]([CH2:18][O:19][CH3:20])[C:7]([CH3:21])=[N:6][C:5]=1[CH3:22])([OH:3])=O.Cl.CN(C)CCCN=C=NCC.[CH3:35][O:36][C:37]([C:39]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][NH2:48])[CH2:41][CH2:40]1)=[O:38]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:17][C:12]1[CH:11]=[C:10]([CH:9]2[N:8]([CH2:18][O:19][CH3:20])[C:7]([CH3:21])=[N:6][C:5]([CH3:22])=[C:4]2[C:1]([NH:48][CH2:47][CH2:46][CH2:45][N:42]2[CH2:41][CH2:40][C:39]([C:37]([O:36][CH3:35])=[O:38])([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:44][CH2:43]2)=[O:3])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: COC(=O)C1(c2ccccc2)CCN(CCCN)CC1
Reactant: COCN1C(C)=NC(C)=C(C(=O)O)C1c1ccc(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCN1C(C)=NC(C)=C(C(=O)NCCCN2CCC(C(=O)OC)(c3ccccc3)CC2)C1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A mixture of 5-carboxy-6-(3,4-difluoro-phenyl)-1,6-dihydro-1-methoxymethyl-2,4-dimethylpyrimidine (0.13 g, 0.42 mmol.), 4-dimethylaminopyridine (0.1 g, 0.84 mmol.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.16 g, 0.82 mmol.) and CH2Cl2 (5 mL) was stirred at room temperature for 0.5 hr. After the addition of 3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propylamine (0.17 g, 0.62 mmol.), the mixture was refluxed overnight. To the mixture was added another 25 mL of CH2Cl2 and washed with saturated NH4Cl solution. After removal of the solvent, the residue was flash chramotographed over silica gel (eluent: 80:20 v/v ethyl acetate- methanol) to give the title compound in 32% yield (0.075 g) as a pale yellow solid: mp 53-57° C. Anal. Calcd. for C31H38F2N4O4.0.25CHCl3: C, 62.71; H, 6.44; N, 9.36. Found: C, 62.62; H, 6.79; N, 9.19.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][NH:8][CH:7]2[CH2:10][CH2:11][N:12]([C:13](=[O:35])[CH:14]([NH:21][C:22](=[O:34])[CH:23]([N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:26])[CH3:24])[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:6]12)=[O:4].CCN(C(C)C)C(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([S:46]([CH3:45])(=[O:48])=[O:47])[CH:7]2[CH2:10][CH2:11][N:12]([C:13](=[O:35])[CH:14]([NH:21][C:22](=[O:34])[CH:23]([N:25]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH3:26])[CH3:24])[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:6]12)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CNC2CCN(C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C3CCCCC3)C21
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CN(S(C)(=O)=O)C2CCN(C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C3CCCCC3)C12
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of 19 (0.31 g, 0.63 mmol) in DCM (10 mL) was cooled to 0° C. and treated with DIPEA (0.2 mL, 1.2 mmol) and DMAP (5 mg, 0.04 mmol). Methanesulfonyl chloride (0.08 mL, 1 mmol) was added. After 2 h, the solution was diluted with DCM, washed successively with 1M HCl, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 20 as an orange-colored oil (362 mg) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:4][N:3]=1.Cl.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][NH2:29].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[N:28]([C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[F:20])[N:29]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(C=Cc1ccnc(Br)c1)C(F)(F)C(F)(F)F
Reactant: NNc1ccc(F)cc1F
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccnc(Br)c2)c(F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
1-(2-Bromo-pyridin-4-yl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (2.9 g, 8.9 mmol) prepared in Step 3, 2,4-difluorophenylhydrazine hydrochloride (2.4 g, 8.9 mmol), and piperidine (1.8 mL, 17.8 mmol) were added to ethanol (88.8 mL). The reaction mixture was stirred at 90° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with distilled water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 1.8 g of the titled compound as a yellow liquid.