Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.Br.[NH2:12][CH2:13][CH2:14]Br.C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[S:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[NH:12][CH2:13][CH2:14]1
Reactant: COC(=O)c1sccc1S
Reactant: NCCBr
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1NCCSc2ccsc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(aca) Method A: 17.4 g of methyl 3-mercapto-thiophene-2-carboxylate were dissolved in 350 ml of toluene under an inert gas atmosphere, whereupon the solution was treated with 20.5 g of 2-aminoethyl bromide hydrobromide and then with 100 ml of 3N sodium methylate solution in methanol. The mixture was stirred at room temperature for 30 minutes and thereafter heated under reflux until the reaction finished. The mixture was evaporated in vacuo, the residue was taken up in 300 ml of water, acidified with 2N hydrochloric acid and the crystals were removed by filtration. By recrystallization from chloroform there was obtained 3,4-dihydro-thieno[2,3-f][1,4]thiazepin-5-(2H)-one as white crystals of m.p. 186°-188°.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].I[CH:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:25]([CH3:27])[CH3:26])=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:22][CH:23]=1)#[N:2]
Reactant: CC(C)I
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OC(C)C)cc1F

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-hydroxy-phenyl)-2-methoxy-acetamide was alkylated with 2-iodopropane and cesium carbonate in DMF to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-isopropoxy-phenyl)-2-methoxy-acetamide. Light yellow oil. MS 357.2 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5](F)[C:6]2[C:10]=1[N:9]=[CH:8][C:7]=2[C:11](=[O:15])[C:12]([O-:14])=O.[K+].[C:18]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([N:26]1[CH2:31][CH2:30][N:29]([C:12](=[O:14])[C:11]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][N:5]=3)[NH:9][CH:8]=2)=[O:15])[CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C([O-])C(=O)c1cnc2c(Cl)ccn(F)c1-2
Reactant: O=C(c1ccccc1)N1CCNCC1
Agent: [K+]
Product: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1c[nH]c2c(Cl)ccnc12

Procedure:
Precursor 5p, 1-benzoyl-4-[(7-chloro-4-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a starting from Potassium (7-chloro-4-fluoro-4-azaindol-3-yl)oxoacetate, Precursor 4e, and 1-benzoyl-piperazine. 1H NMR (500 MHz, CD3OD) δ8.83 (s, 1H), 8.63 (d, 1H, J=5.35 Hz), 7.91 (d, 1H, J=5.75 Hz), 7.47 (m, 5H), 3.80-3.30 (m, 3H). MS m/z: (M+H)+ Calc'd for C20H18ClN4O3: 397.11; Found 397.02. HPLC retention time: 1.20 minutes (column A).
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([O:18]C)=[O:17])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[Li+].[OH-].CO.Cl>O>[O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([OH:18])=[O:17])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylate (3.30 g; 12.25 mmol), 1 N LiOH (15 mL), and methanol (60 mL) was stirred at 0° C. for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 2.80 g (87%) of snow-white solid which did not require further purification. 1H NMR (CDCl3): δ0.89 (t, 3H); 1.21, 1.24 (s, 3H each); 1.42-1.85 (m, 7H); 2.35 (m, 1H); 3.22 (d, 1H); 3.42(m, 1H); 5.31 (d, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].C(N(C(C)C)CC)(C)C.Br[CH2:50][CH2:51][CH2:52][C:53]#[N:54]>C(#N)C>[C:53]([CH2:52][CH2:51][CH2:50][NH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33])#[N:54]
Reactant: N#CCCCBr
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](NCCCC#N)c3ccccc3)c2=O)c1F
Yield: 93.9 %

Procedure:
Compound 1f (110 mg, 0.2 mmol) was dissolved in acetonitrile (5 mL) and diisopropylethyl amine (52 mg, 0.4 mmol) was added, followed by the addition of 4-bromobutyronitrile (90 mg, 0.6 mmol). The reaction mixture was refluxed for 16 hours. Volatiles were evaporated and the residue was purified by flash chromatography (silica, 5% MeOH/CH2Cl2) to give compound 3a (115 mg, 94% ). MS (CI) m/z 613.3 (MH+).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:8])[O:9][C@@H:10]4[O:16]3)[CH2:4][CH2:3]1
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@@]4(C)CC[C@@H]1[C@]32OO4
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Reaction time: 1 h

Procedure:
To a solution of 4 g (0.014 m) of qinghaosu (I) in 200 ml of methanol, was added 4 g of sodium borohydride in small portions, keeping the reaction mixture at 0°-5°. After stirring for 60 min, the mixture was neutralized with glacial acetic acid, concentrated and diluted with water. The white precipitate formed was collected and dried. Recrystallization of the solid from acetone-hexane afforded white needles mp: 153°-58° C., 3.2 g (80).
Reaction SMILES: O[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4]1.S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4]1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cnn(CO)c1
Solvent: ClCCl
Product: COC(=O)c1cnn(CCl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.38 g of 1-(hydroxymethyl)-4-methoxycarbonyl-1H-pyrazole was dissolved to 10 ml of dichloromethane. 1 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 1.59 g of 1-(chloromethyl)-4-methoxycarbonyl-1H-pyrazole.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: CN1CCNCC1
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCN(C)CC3)s2)c(C)[nH]c1=O
Yield: 63.3 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 1-methylpiperazine as described in Steps 5 and 6, Example 24 to give the title compound as a solid (63.3% yield). LC/MS: RT 2.07 min; m/e 382 (M+H); 1H NMR (δ, ppm): 11.8 (1H, s), 11.3 (1H, s), 7.7 (1H, d); 7.4 (1H, s); 7.32 (1H, d), 4.8 (2H, m), 3.5 (2H, d), 3.2 (2H, m), 2.9 (2H, t), 2.75 (3H, s), 2.4 (2H, q), 2.36 (3H, s), 1.1 (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([OH:11])=[C:4]([O:12][CH3:13])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>S1(CCCC1)(=O)=O.O>[CH2:20]([O:11][C:5]1[C:4]([O:12][CH3:13])=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[N+:8]([O-:10])=[O:9])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: COc1cc(Br)cc([N+](=O)[O-])c1OCc1ccccc1
Reaction time: 24 h
Yield: 80.7 %

Procedure:
A mixture of 4-bromo-2-methoxy-6-nitrophenol (7.0 g), anhydrous potassium carbonate (2.12 g) and benzyl chloride (3.93 g) in dry sulpholane (70 ml) was stirred at 90°-95° C. for 24 hours. The mixture was then diluted with water (300 ml) and the resulting oil was extracted with diethyl ether (3×50 ml). The combined ethereal extracts were washed with aqueous sodium carbonate solution (2 N; 2×50 ml) and then with water (3×20 ml), dried over anhydrous sodium sulphate and evaporated in vacuo to give a solid, which was recrystallised from ethanol to give 2-benzyloxy-5-bromo-3-methoxynitrobenzene (7.7 g), m.p. 74°-76° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:41]=[C:35]5[CH2:36][N:37]([CH3:40])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:42])[N:27]([CH3:43])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:41]=[C:35]5[CH2:36][N:37]([CH3:40])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:42])[N:27]([CH3:43])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)cc2C1
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a solution of 128e (158 mg, 0.27 mmol) in methanol/dichloromethane (5/5 mL) was added NaBH4 (31 mg, 0.82 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was complete. The reaction was quenched with water (10 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 128 (95 mg, 60%) as a white solid. MS-ESI: [M+H]+ 585.3. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=5.0 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.00 (d, J=2.5 Hz, 1H), 7.58-7.54 (m, overlap, 4H), 7.44 (s, 1H), 5.70 (s, 1H), 4.52-4.39 (m, 2H), 4.10-4.09 (m, 3H), 3.70 (s, 3H), 3.59 (s, 2H), 2.88-2.86 (m, 2H), 2.47 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=2[F:20])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([F:20])=[C:12]([F:19])[C:13]([F:18])=[C:14]([F:17])[C:15]=2[F:16])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(-c2c(F)c(F)c(F)c(F)c2F)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2c(F)c(F)c(F)c(F)c2F)cc1
Yield: 89.5 %

Procedure:
4-Nitro-2′,3′,4′,5′,6′-pentafluorobiphenyl (10 g, 0.0345 mol) was dissolved in absolute ethanol (750 mL) and stirred under a hydrogen atmosphere (1 atm.) over Pd/C (0.3 g) until absorption of hydrogen ceased. The solution was filtered and the solvent was removed. The crude product was purified by column chromatography to give 4-amino-2′,3′,4′,5′,6′-pentafluorobiphenyl as a white powder (8.0 g, 89% yield).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:10]=[C:9]1[CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)(=O)=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.CN(C)C=O>ClCCl.C(=O)(O)[O-].[Na+]>[N:32]1([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]2[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCOS(C)(=O)=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCN2CCCC2)CC1
Temperature: 50 °C
Yield: 93 %

Procedure:
Combine tert-butyl 4-(1-(2-(methylsulfonyloxy)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (2.02 g, 4.42 mmol), pyrrolidine (1.1 mL, 3.0 eq), and dimethylformamide (19 mL). Heat the reaction mixture to 50° C. overnight. Dilute with dichloromethane and saturated aqueous sodium bicarbonate. Separate the layers. Wash the organics with water. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to ethyl acetate to 10% methanol in dichloromethane, to give the title compound as a yellow oil (1.79 g, 93%). MS (ES) m/z=433 [M]+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18](Cl)[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[NH2:25][CH2:26][CH2:27][CH2:28][OH:29]>>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Reactant: NCCCO
Product: OCCCNc1cc(-c2ccnc(Nc3cccc(C(F)(F)F)c3)n2)ccn1

Procedure:
50 mg (0.143 mmol) of N-(3-trifluoromethyl-phenyl)-4-(2-chloro4-pyridyl)-2-pyrimidineamine are stirred for 44 h at 100° in 1 ml of 3-amino-1-propanol. Concentration by evaporation and chromatography (methylene chloride:methanol=9:1) give N-(3-trifluoromethyl-phenyl)-4-[2-(3-hydroxy-propyl-amino)-4-pyridyl]-2-pyrimidineamine; Rf =0.1 (methylene chloride:methanol=95:5), FAB-MS: 390, m.p. 158°-163°.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:12]>O1CCCC1>[CH:1]1([CH2:6][CH2:7][S:8]([NH2:12])(=[O:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: O=S(=O)(Cl)CCC1CCCC1
Solvent: C1CCOC1
Product: NS(=O)(=O)CCC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(cyclopentyl)ethanesulfonyl chloride (14.1 g, 71.4 mmol) in dry tetrahydrofuran (40 ml) was saturated with gaseous ammonia at 0° C. The resulting solution was stirred at room temperature under nitrogen for 2 hours and then concentrated under vacuum. The residue was dissolved in ethyl acetate (50 ml) and water (50 ml) and the aqueous phase was then acidified to pH 2 with 2.0 M aqueous hydrochloric acid. The organic phase was separated and then washed with water (2×30 ml), dried (sodium sulfate) and concentrated under vacuum. Purification of the residue by chromatography on silica (500 g) using 65/35 pentane/ethyl acetate as eluant gave the title compound as an off-white solid (6.48 g), Rf 0.7 (pentane/ethyl acetate 1:1).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:30]1[CH2:31][CH2:32][CH:27]([N:12]2[C:13]3[C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[C:17]=4[N:16]=[CH:15][C:14]=3[C:25](=[O:26])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[C:11]2=[O:33])[CH2:28][CH2:29]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCN(C(C)=O)CC3)c12

Procedure:
1-(1-Acetyl-piperidin-4-yl)-3-(3-chloro-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (45 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.1 mmol) and acetyl chloride. LCMS: m/z 479 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.59 (s, 1H), 7.58 (m, 1H), 7.52 (m, 1H), 7.42 (m, 1H), 7.24 (m, 1H), 7.10-7.18 (m, 2H), 6.48 (m, 1H), 5.18 (m, 1H), 4.82 (m, 1H), 4.12 (s, 3H), 3.95 (m, 1H), 3.20 (m, 1H), 3.58-3.78 (m, 3H), 2.08 (s, 3H), 1.78 (m, 2H) ppm.
Reaction SMILES: [CH3:1][CH3:2].[F:3][C:4]([F:12])([F:11])[C:5]([C:7]([F:10])([F:9])[F:8])=[O:6]>>[F:3][C:4]([F:12])([F:11])[C:5]([C:7]([F:10])([F:9])[F:8])([OH:6])[CH2:1][CH2:2][C:5]([C:7]([F:10])([F:9])[F:8])([C:4]([F:12])([F:11])[F:3])[OH:6]
Reactant: CC
Reactant: O=C(C(F)(F)F)C(F)(F)F
Product: OC(CCC(O)(C(F)(F)F)C(F)(F)F)(C(F)(F)F)C(F)(F)F

Procedure:
By starting the experiment with a 1:1 molar ratio of ethane to hexafluoroacetone, 47.3 g 1,1-bis(trifluoromethyl)propanol-1, b.p. 75°-80° C/705 mm. and 6.0 g of 1,1,4,4-tetrakis(trifluoromethyl) butan-1,4-diol, m.p. 96°-98° C, were obtained. From these data it will become apparent that increasing the molar ratio of ethane to hexafluoroacetone will increase the yield of the propanol-1 with respect to the diol. The converse is also true. That is, the more hexafluoroacetone one uses with respect to ethane, the more diol one will achieve with respect to the monofunctional alcohol. When an excess of ethane is used, i.e., when it is desired to form primarily 1,1-bis(trifluoromethyl) propanol-1, the amount of excess used is immaterial. That is, ten or even a hundred moles of ethane can be used for every mole of hexafluoroacetone with excellent results. On the other hand, it has been found that it is not advisable to use more than about twelve moles of hexafluoroacetone per mole of ethane if one wishes to have the diol as the predominant product. If a larger excess than this of the hexafluoroacetone is used, by-products begin to predominate and it becomes difficult to separate the diol from them.
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl[C:9]1[CH:14]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:20][CH:21]=3)[CH2:16]2)[N:12]=[C:11]([NH2:32])[N:10]=1.[N:33]1(C(OC(C)(C)C)=O)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:25][CH:24]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)=[CH:20][CH:21]=2)[CH2:16][N:15]1[C:13]1[CH:14]=[C:9]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[N:10]=[C:11]([NH2:32])[N:12]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(N2CCNCC2)nc(N)n1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 118 starting from 4-chloro-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and tert-butyl piperazine-1-carboxylate (Aldrich, Cat. No. 343536). LCMS (M+H)+: m/z=405.2.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8](Br)=[N:7][N:6]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=2)[C:5]1=[O:22])[CH:2]=[CH2:3].[Na].[CH3:24][OH:25]>>[CH2:1]([N:4]1[C:9](=[O:10])[C:8]([O:25][CH3:24])=[N:7][N:6]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=2)[C:5]1=[O:22])[CH:2]=[CH2:3]
Reactant: CO
Reactant: C=CCn1c(=O)c(Br)nn(-c2cccc(NC(C)=O)c2)c1=O
Agent: [Na]
Product: C=CCn1c(=O)c(OC)nn(-c2cccc(NC(C)=O)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
According to Scheme 3 Step 3: To a solution of compound 6(B) (800 mg, 2.19 mmol) in MeOH (10 mL) was added a solution of sodium methoxyde 2M in methanol (1.1 mL, 2.19 mol). After 1 h of stirring at room temperature, the mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were successively washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 10 g SiO2) using CH2Cl2/MeOH 98/2 as eluant to afford N-(3-(4-allyl-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 6(C) (600 mg, 86%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3](O)[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[NH2:12][C@H:13](CO)[CH2:14][CH:15]([CH3:17])[CH3:16]>C1C=CC=CC=1>[CH2:14]([C@H:13]1[CH2:1][O:2][CH:3]([C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])[NH:12]1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C[C@H](N)CO
Reactant: COC(O)C(F)(F)C(F)(F)F
Solvent: c1ccccc1
Product: CC(C)C[C@H]1COC(C(F)(F)C(F)(F)F)N1

Procedure:
Pentafluoropropanal methyl hemiacetal (14.9 g, 82.8 mmol) and L-leucinol (9.7 g, 82.8 mmol) were dissolved in 100 mL of benzene and heated to reflux overnight in a flask equipped with a Dean-Stark tube. The resulting solution was cooled and concentrated to provide the title compound as an oil which was used directly in the following step.
Reaction SMILES: [O:1]=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH2:13]1CCN2C(=NCCC2)CC1.IC.Cl>CN(C=O)C>[O:1]=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:13])=[O:4]
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(=O)Cc1ccccc1
Temperature: 0 °C

Procedure:
2-Oxo-3-phenylpropanoic acid (20 g), DMF (100 ml) and DBU (18.2 ml) were combined at 0° C. under N2 atmosphere, and the mixture was stirred at 0° C. for an hour. Then iodomethane (15.2 ml) was added to the solution at 0° C. The reaction mixture was stirred at r.t. for 3 hours, and poured into 1N—HCl. The mixture was extracted with AcOEt (twice). The combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with CHCl3/AcOEt (30:1) as an eluent, and triturated with IPE/n-Hexane to give methyl 2-oxo-3-phenylpropanoate (11.2 g) as a pale yellow wax.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][CH:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:21]([OH:25])[C:22]([NH2:24])=[O:23].CCN(C(C)C)C(C)C>>[NH2:24][C:22](=[O:23])[CH:21]([OH:25])[CH:20]([NH:19][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[N:18][C:10]=1[C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)c1cccnc1-c1nc2ccccc2o1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1nc2ccccc2o1
Yield: 85.9 %

Procedure:
Coupling of 2-(benzo[d]oxazol-2-yl)nicotinic acid (190 mg, 0.791 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (169 mg, 0.780 mmol) was performed by analogy to the method described for example 1.2 using DIPEA instead of triethylamine. The reaction yielded 279 mg of the title compound; ESI-MS [M+H+]=417.1.