Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12](=[N:18]O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N=C=NCCCN(C)C)C.C(OCC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH2:18][C:12](=[N:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(N)=NOC(=O)c1ccc(F)cc1
Yield: 88.2 %

Procedure:
To a mixture of 4-fluorobenzoic acid (2.0 g), ethyl 2-amino-2-hydroxyiminoacetate (2.07 g) and 4-dimethylaminopyridine (0.52 g) in methylene chloride (30 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.87 ml) at 0° C. under stirring. After stirring at ambient temperature for 1 hour, diethyl ether (10 ml) was added thereto and the resulting precipitate was filtered off, washed with diethyl ether, and dried in vacuo to give ethyl 2-amino-2-(4-fluorobenzoyloxyimino)acetate (3.2 g).
Reaction SMILES: C([N:5]1[C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[N:12]=2)=[CH:8][C:7]([CH3:34])=[N:6]1)(C)(C)C>C(O)=O.C(Cl)Cl>[CH3:34][C:7]1[CH:8]=[C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[N:12]=2)[NH:5][N:6]=1
Reactant: Cc1cc(Nc2nn(-c3ccc(N4CCCCC4)cc3)c(=O)c3ccccc23)n(C(C)(C)C)n1
Solvent: ClCCl
Solvent: O=CO
Product: Cc1cc(Nc2nn(-c3ccc(N4CCCCC4)cc3)c(=O)c3ccccc23)[nH]n1
Temperature: 95 °C
Yield: 57.6 %

Procedure:
4-(2-tert-Butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-piperidin-1-yl-phenyl)-2H-phthalazin-1-one (0.012 g, 0.026 mmol) was dissolved in formic acid (1 ml) and heated at 95° C. for 4 h. The resulting raw product was dissolved in DCM, after evaporation of formic acid. Extraction with a saturated aqueous NaHCO3 solution, combining of the organic phases, evaporation of the solvent in vacuum and purification by chromatography over silica gel with DCM:MeOH (20:1) yielded the title compound (0.006 g, 57%). 1H-NMR: (400 MHz, D6-DMSO) 11.81 (1H, s), 9.21 (1H, s), 8.48 (1H, d), 8.35 (1H, d), 7.87-7.96 (2H, m), 7.50 (2H, d), 7.01 (2H, d), 6.25 (1H, s), 3.21 (4H, m), 2.19 (3H, s), 1.64 (4H, m), 1.60 (2H, m); MS (ESI+)=401.29 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]1[CH2:13][CH2:12]1)(=[O:10])=[O:9].[NH2:14][C:15]1[C:16]([C:37]#[N:38])=[N:17][C:18]([C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][C:22]=2[F:36])=[CH:19][N:20]=1>>[NH2:14][C:15]1[C:16]([C:37]#[N:38])=[N:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]([CH:11]3[CH2:13][CH2:12]3)(=[O:10])=[O:9])=[CH:23][C:22]=2[F:36])=[CH:19][N:20]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)c(C#N)n3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)C1CC1
Product: N#Cc1nc(-c2ccc(-c3ccccc3S(=O)(=O)C3CC3)cc2F)cnc1N

Procedure:
The title compound was prepared in manner similar to that described in Example 88 using 1-bromo-2-(cyclopropylsulfonyl)benzene and 3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile. MS (ESI): mass calcd. for C20H15FN4O2S, 394.09; m/z found, 395.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.84 (d, J=1.8, 1H), 8.14 (dd, J=8.0, 1.4, 1H), 8.01 (m, 1H), 7.66 (m, 1H), 7.58 (m, 1H), 7.39-7.35 (m, 3H), 5.34 (s, 2H), 2.13-2.05 (m, 1H), 1.13-1.06 (m, 2H), 0.88-0.82 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:4](=[O:27])[C:5]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:14])=[CH:6][C:7]=1[C:8]([O:10]CC)=[O:9].[OH-].[Na+]>C1COCC1.O>[CH3:26][S:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:15][C:13]([C:5]2[C:4](=[O:27])[N:3]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:29]=3)[C:2]([CH3:1])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=2)=[O:14])=[CH:22][CH:21]=1)(=[O:25])=[O:24]
Reactant: CCOC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-methyl-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydropyridine-3-carboxylate (0.70 g, 1.30 mmol) in THF (10 ml) and water (10 ml) was added NaOH (1M, 2 ml, 2 mmol), and the mixture was stirred for 1 h at room temperature, monitoring the progress of the reaction by LC-MS. 20% conversion was observed and another portion of NaOH (1M, 1 ml, 1 mmol) was added, and the reaction was allowed to run for another hour. This process was repeated until complete conversion of the ester was observed (normally 3-4 hours). The outcome of the reaction is two compounds with the same mass, in a 95:5 proportion. The main product is the subtitle compound, and the other is a regioisomer. The reaction mixture was evaporated in order to remove THF, and the residual water solution was acidified and then extracted into EtOAc. The organic phase was collected and dried over Na2SO4. Filtration and evaporation gave a crude product 0.60 g (90%) of a yellowish solid, which was used further without purification. A portion of the product was purified using preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:9][C:8]=2[CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[Cl:39])[C:33](Cl)=[O:34].C(N(CC)C(C)C)(C)C>C(Cl)Cl.O>[C:23]([O:22][C:20]([NH:19][CH2:18][C:8]1[CH:9]=[C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:12][C:7]=1[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:38]([Cl:39])=[C:30]([Cl:29])[CH:31]=2)=[CH:28][CH:27]=1)=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: COC(=O)Cc1ccc(Oc2ccc(N)cc2)c(CNC(=O)OC(C)(C)C)c1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CNC(=O)OC(C)(C)C)c1
Reaction time: 3 h
Yield: 89.7 %

Procedure:
Methyl 2-(4-(4-aminophenoxy)-3-((tert-butoxycarbonyl)aminomethyl)phenyl)acetate (100 mg, 0.259 mmol) was diluted with methylene chloride (3 mL) followed by the addition of 3,4-dichlorobenzoyl chloride (81.3 mg, 0.388 mmol) and N,N-diisopropylethyl amine (0.0451 mL, 0.259 mmol). The reaction was stirred for 3 hours. The reaction mixture was diluted with methylene chloride and water. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 12i eluting with hexanes:ethyl acetate (3:1) to yield 130 mg of methyl 2-(3-((tert-butoxycarbonyl)aminomethyl)-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)acetate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([OH:14])[CH:7]=1)[CH3:2].[Cl:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([CH:24]=1)[CH:22]=[O:23].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:20]2[CH:19]=[CH:18][C:17]([Cl:16])=[CH:24][C:21]=2[CH:22]=[O:23])[CH:7]=1)[CH3:2]
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2C=O)c1
Temperature: 100 °C

Procedure:
(3-Hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester (0.75 g, 4.8 mmol), 5-chloro-2-fluorobenzaldehyde (1.0 g, 4.8 mmol), and potassium carbonate (1.0 g, 7.5 mmol) were combined in 1,4-dioxane (30 mL) and heated to 100° C. for 3 days. After work-up, the crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1F)[C:30]#[N:31].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12])[O:8][C:34]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[F:26]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C#N)cc3F)cc2Cl)C(F)(F)F)cn(C)c1=O

Procedure:
In analogy to Example 156, step 1, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 3,4-difluorobenzonitrile and cesium carbonate to give the title compound as a colorless solid. MS (m/e)=495.2 [M+H+].
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])=[N+:2]=[N-:3].[CH2:15](O)[CH2:16][OH:17].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:15]1[CH2:16][O:17][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[O:8]1
Reactant: OCCO
Reactant: [N-]=[N+]=NCCCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: [N-]=[N+]=NCCCC1(c2ccccc2)OCCO1
Temperature: 25 °C
Yield: 107.6 %

Procedure:
4-Azidobutyrophenone (100.0 mg, 0.53 mmol) was dissolved in toluene (5 ml) at room temperature, and thereto were added ethylene glycol (0.06 ml, 1.06 mmol) and p-toluene sulfonic acid mono hydrate (10.1 mg, 0.05 mmol) in sequential order at the same temperature, and thereafter, the mixture was refluxed using a Dean Stark tube for 24 hours. The reaction solution was cooled to room temperature and added to water thereafter, followed by the extraction using ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The target compound was thus obtained as a colorless oil (133 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:9]=[C:8]([NH2:19])[C:7]=1[NH2:20].[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O>>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][C:6]1[C:7]2[N:20]=[C:30]([C:26]3[S:25][CH:29]=[CH:28][N:27]=3)[NH:19][C:8]=2[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=1
Reactant: O=Cc1nccs1
Reactant: COc1ccccc1Oc1cc(Oc2cccnc2)cc(N)c1N
Product: COc1ccccc1Oc1cc(Oc2cccnc2)cc2[nH]c(-c3nccs3)nc12

Procedure:
The entitled compound was obtained as a yellow solid in the same method as in Example 67 or in accordance with the method or by combining it with an ordinary method but using 3-(2-methoxyphenoxy)-5-(pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 67 (step 3) and 2-thiazolecarboxaldehyde.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[C:7]([CH3:15])[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[NH:5][C:4](=[O:16])[CH2:3]1>C(O)C.[Ni]>[CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[C:7]([CH3:15])[CH:8]=[C:9]([NH2:12])[CH:10]=2)[NH:5][C:4](=[O:16])[CH2:3]1
Reactant: Cc1cc([N+](=O)[O-])cc2c1NC(=O)CC2(C)C
Agent: [Ni]
Solvent: CCO
Product: Cc1cc(N)cc2c1NC(=O)CC2(C)C
Yield: 38.4 %

Procedure:
A solution of 3,4-dihydro-4,4-dimethyl-6-nitro-8-methyl-2-(1H)-quinolone (9.46 g) in absolute ethanol (80 cm3) was hydrogenated at 60° and 60 p.s.i. (4.13×105Pa) pressure over Raney nickel (0.9 g) for 6 hours. The cooled solution was then filtered through "Solkafloc" (Trade mark for a cellulose based filtering aid) and evaporated in vacuo to give a solid which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:chloroform, 1:33 by volume. Combination and evaporation of appropriate fractions gave the title compound (3.17 g) which was characterised spectroscopically and used directly in Preparation 22 without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].ClCCl>O>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:6][CH2:5]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(CCO)CC1

Procedure:
A mechanically-stirred solution of 1-(2-hydroxyethyl)piperazine (10.0 g, 9.4 mL, 0.07 mol) in 30 mL of deionized water is cooled to 0 C. Then portions of 4N sodium hydroxide (total 28 mL) and portions of benzyl chloroformate (18.8 g, 15.7 mL, 0.11 mol) are added over 15 minute periods, keeping the temperature at 0 C. to 5 C. At the end of the additions, 4N sodium hydroxide solution is added to bring the pH of the reaction mixture to 10. After 1 hour dichloromethane (200 mL) is added and the layers are separated. The organic solution is dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 1-(2-hydroxyethyl)-4-carbobenzyloxypiperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:22])[N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[Br:25][CH2:26][C:27](O)=[O:28]>C1COCC1>[Br:25][CH2:26][C:27]([N:19]1[CH2:18][CH2:17][N:16]([C:15](=[O:22])[CH2:14][C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=3)[S:10][CH:11]=2)[CH2:21][CH2:20]1)=[O:28]
Reactant: O=C(O)CBr
Reactant: O=C(Nc1nc(CC(=O)N2CCNCC2)cs1)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(Nc1nc(CC(=O)N2CCN(C(=O)CBr)CC2)cs1)c1ccc(Cl)cc1

Procedure:
55.1 Using general method A, with THF instead of DMF as solvent, 4-chloro-N-[4-(2-oxo-2-piperazin-1-yl-ethyl)-thiazol-2-yl]-benzamide (example 54.2) was coupled with bromoacetic acid to give N-(4-{2-[4-(2-bromo-acetyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-4-chloro-benzamide. Amorphous white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([OH:21])=[C:16]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.C(OCC)C>CN1C(=O)CCC1>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([O:21][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1)=[C:16]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[CH:15]=[CH:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1c(-c2ccc(F)cc2)ccc2cc(OCc3ccccc3)ccc12
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: O=Cc1ccc(Oc2c(-c3ccc(F)cc3)ccc3cc(OCc4ccccc4)ccc23)cc1
Temperature: 165 °C
Yield: 70 %

Procedure:
Add sodium hydride (400 mg, 10 mmol) into a solution of 6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-ol in NMP (40 mL). Add the above alkoxide suspension into a solution of 4-fluorobenzaldehyde (2 mL, 19 mmol) in NMP (30 mL) at 165° C. Heat at 165° C. for 1 hour. Cool and add buffer solution (pH=7, 10 mL). Add diethyl ether (1 L). Separate the layers and wash the aqueous layer with diethyl ether (2×200 mL). Combine the organic layers, dry with magnesium sulfate and concentrate in vacuo. Chromatograph the residue on a biotage column eluting the material with a step gradient of methanol/dichloromethane (0 to 10%) to obtain 2.9 g (70%) of 4-[6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yloxy]-benzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[NH:16][C:15]2=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:31][C:32]([F:36])([F:35])[CH2:33]I>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[N:16]([CH2:33][C:32]([F:36])([F:35])[F:31])[C:15]2=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(F)ccc32)CC1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)n(CC(F)(F)F)c3cc(F)ccc32)CC1
Temperature: 45 °C

Procedure:
Solid 1-tert-butoxycarbonyl-4-(5-fluoro-2-oxo-1-benzimidazolinyl)piperidine (9.7 g, 28.9 mmol.) was dissolved in anhydrous DMF (72 mL) under an inert atmosphere and cesium carbonate (10.6 g, 32.5 mmol.) was added followed by excess 2,2,2-trifluoroethyl iodide (14.3 mL, 145 mmol.). This reaction mixture was gently warmed at 40-50° C. for an extended period (1-2 days), periodically adding additional 2,2,2-trifluoroethyl iodide (4 mL, 4 mmol in four portions) to drive the alkylation to completion. The cooled reaction mixture was diluted with EtOAc and washed with aq. NaHCO3 and water (3×). The organic layer was dried (Na2SO4) and filtered through a pad of charcoal and the solvent then evaporated. The solid residue was triturated with Et2O and collected to give 1-tert-butoxycarbonyl-4-(5-fluoro-3-(2,2,2-tri-fluoroethyl)-2-oxo-1-benzimidazolinyl)piperidine as a nearly pure white solid. This material was crystallized from CH2C2 to remove a slightly less polar impurity affording the product, mp: 172-173° C.
Reaction SMILES: C([O:8][C:9](=[O:42])[CH:10]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:11]([N:13]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([N:13]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[C:11](=[O:12])[CH:10]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:9]([OH:42])=[O:8])[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: COc1ccc(N(CCc2ccc(C(F)(F)F)cc2)C(=O)C(C(=O)OCc2ccccc2)c2ccccc2)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(N(CCc2ccc(C(F)(F)F)cc2)C(=O)C(C(=O)O)c2ccccc2)cc1OC

Procedure:
0.35 g (0.62 mmol) N-(3,4-Dimethoxy-phenyl)-2-phenyl-N-[2-(4-trifluoromethyl-phenyl)-ethyl]-malonamic acid benzyl ester in 20 mL ethyl acetate and 0.37 mL acetic acid was hydrogenated over Pd/C with atmospheric pressure of H2 for 16 h at room temperature. The catalyst was filtered off and the and the filtrate evaporated to dryness. The acid was used without further purification in the consecutive step. MS(m/e): 488.2 (MH+).
Reaction SMILES: [CH:1]1([C@H:4]([NH:6][CH2:7][C:8]2[NH:9][C:10](=[O:18])[C:11]3[CH2:17][O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH3:5])[CH2:3][CH2:2]1.[F:19][C:20]1[CH:37]=[CH:36][C:23]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1>>[CH:1]1([C@H:4]([N:6]([CH2:7][C:8]2[NH:9][C:10](=[O:18])[C:11]3[CH2:17][O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[C:33](=[O:34])[CH2:32][N:29]2[CH2:30][CH2:31][CH:26]([C:24](=[O:25])[C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:37][CH:36]=3)[CH2:27][CH2:28]2)[CH3:5])[CH2:3][CH2:2]1
Reactant: C[C@@H](NCc1nc2c(c(=O)[nH]1)COCC2)C1CC1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: C[C@H](C1CC1)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (9 mg) from (R)-2-((1-cyclopropylethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C27H33FN4O4 496.6. found 497.6 (ESI, M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.98-8.21 (m, 2H) 7.40 (t, J=8.84 Hz, 2H) 4.25-4.54 (m, 5H) 3.84 (ddd, J=17.31, 5.56, 5.43 Hz, 3H) 3.70 (d, J=6.06 Hz, 1H) 3.56 (br. s., 2H) 3.23 (br. s., 1H) 2.99-3.20 (m, 2H) 1.99 (br. s., 4H) 1.00-1.29 (m, 4H) 0.68-0.94 (m, 1H) 0.46-0.68 (m, 1H) 0.38 (d, J=5.05 Hz, 1H) 0.24-0.34 (m, 1H) 0.15-0.24 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:23]=[O:24])C>C1COCC1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:23]=[O:24])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc(Br)cc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 4′,4-dibromobiphenyl (3.12 g, 10 mmol) in dry THF (50 mL) at −78° C. was added dropwise a solution of n-BuLi (1.6M in hexane, 10 mmol). After addition, the mixture was stirred for 30 minutes at −78° C. Anhydrous DMF (50 mL) was then added and the mixture was allowed to stir at room temperature for 2 hours. The solvent was removed under high vacuum and the residue was taken in water and extracted with dichloromethane (2×50 mL). The combined organic layer were dried (MgSO4) and concentrated. Purification by flash chromatography (ethyl acetate/hexane: 2/8) gave the title compound 152 55% yield. MS (ESI)=261 (MH+).
Reaction SMILES: Br.Br[CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=O.[NH2:18][C:19]([NH2:21])=[S:20].C(N(CC)CC)C>C(#N)C>[C:12]1([C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1cccnc1)C(Br)c1ccccc1
Reactant: NC(N)=S
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1nc(-c2cccnc2)c(-c2ccccc2)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
To a mixture of 2-bromo-2-phenyl-1-(3-pyridyl)ethanone hydrobromide (2.00 g) and thiourea (432 mg) in acetonitrile (30 mL), was added triethylamine (0.80 mL) dropwise and the resulting mixture was stirred at 80° C. for 3 h. The solvent was removed under reduced pressure and an aqueous saturated solution of sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The organic phases were washed with water, dried and concentrated under reduced pressure to give the amorphous title compound (1.10 g, yield 84%).
Reaction SMILES: C([C:5](C1C=CC=CC=1)(C1C=CC=CC=1)[C@@:6](O[SiH3])([N:8]1[C:13]2=[N:14][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16][CH:17]=[C:12]2[CH2:11][N:10]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:9]1=[O:33])[CH3:7])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:66]1CCCC1>>[OH:66][CH2:5][C@H:6]([N:8]1[C:13]2=[N:14][C:15]([NH:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:16][CH:17]=[C:12]2[CH2:11][N:10]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:9]1=[O:33])[CH3:7]
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@](C)(O[SiH3])C(c3ccccc3)(c3ccccc3)C(C)(C)C)C2=O)cc1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@H](C)CO)C2=O)cc1
Reaction time: 2 h

Procedure:
(R)-1-(2-tert-Butyl-diphenyl-silanyloxy-1-methyl-ethyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.55 g, 0.80 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL) and treated with tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 3.2 mL, 3.20 mmol) (Aldrich) at 40° C. for 3 hours and then at room temperature for 2 hours. The reaction was concentrated. The residue was redissolved in ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by flash chromatography (Biotage 40M, ethyl acetate-hexanes gradient [75–85% ethyl acetate]) followed by crystallization from ethyl acetate-hexanes gave (R)-(−)-1-(2-hydroxy-1-methyl-ethyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid. (Yield 0.26 g, 79.9%). Melting Point: 156–163° C.