Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:15]([N:22]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>C(O)CCC>[CH2:15]([N:22]1[CH2:26][CH2:25][CH:24]([NH:27][C:2]2[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: NC1CCN(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CN(C)c1nc(NC2CCN(Cc3ccccc3)C2)nc2ccccc12
Yield: 33.6 %

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (5.1 g, 28.9 mmol) and 1-Benzyl-pyrrolidin-3-ylamine (5.1 g, 28.9 mmol) in BuOH (8 mL) was stirred at reflux for 26 hr, poured into saturated aqueous NaHCO3, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 10% to 16% EtOAc in hexane) to give N2-(1-benzyl-pyrrolidin-3-yl)-N4,N4-dimethyl-quinazoline-2,4-diamine (3.37 g, 50%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10](=NNC(N)=O)[CH2:11][P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14])=[N:6][CH:7]=1.Cl.[OH-:24].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10](=[O:24])[CH2:11][P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14])=[N:6][CH:7]=1
Reactant: COP(=O)(CC(COc1ccc(Cl)cn1)=NNC(N)=O)OC
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COP(=O)(CC(=O)COc1ccc(Cl)cn1)OC
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of dimethyl 3-(5-chloropyrid-2-yloxy)-2-semicarbazonopropylphosphonate (400 mg.), toluene (5 ml.) and 6N hydrochloric acid (1.0 ml.) was stirred at room temperature for 4.5 hours, and the pH of the reaction mixture was adjusted to about 4 by the dropwise addition of 5N sodium hydroxide solution. The organic layer was separated and the aqueous layer was washed with ethyl acetate (6 ml). The combined organic extracts were washed with a 1:1 v/v mixture of saturated brine and water (4 ml. then 2 ml.) and dried, and the solvents were evaporated under reduced pressure to give dimethyl 3-(5-chloropyrid-2-yloxy)-2-oxopropylphosphonate, RF = 0.43 (5% v/v methanol in ethyl acetate). The n.m.r. spectrum in deuteriochloroform showed the following characteristic peaks (δ values):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[OH:24])=[CH:4][CH:3]=1.I[CH:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[O:24][CH:26]([CH3:28])[CH3:27])=[CH:4][CH:3]=1
Reactant: Oc1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)Oc1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
9-(4-Chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-ol (I-(4A-7)b; 50 mg, 0.14 mmol), 2-iodopropane (26 mg, 0.15 mmol), and cesium carbonate (50 mg, 0.15 mmol) were combined in dimethylformamide (0.7 ml) and stirred overnight. Additional 2-iodopropane (13 mg, 0.76 mmol), and cesium carbonate (25 mg, 0.76 mmol) were added and stirred an addional day. The reaction mixture was diluted with ethyl ether and then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried (Na2SO4), evaporated to dryness, and then purified on a Biotage™ Flash 12S column using 0–70% ethyl acetate in hexanes as eluant to afford title compound 31A-1 (34 mg, 56%); 1H NMR: +ESI MS (M+1) 399.4; (400 MHz, CD2Cl2) δ 8.51 (s, 1H), 7.56 (dd, J=7.5, 1.7 Hz, 1H), 7.47–7.34 (m, 5H), 7.23 (d, J=9.1 Hz, 2H), 5.71 (septuplet, J=6.2 Hz, 1H), 1.50 (d, J=6.2 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].CO[C:14](OC)([CH3:16])[CH3:15].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.N1C=CC=CC=1.CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH:7][CH:14]([CH3:16])[CH3:15]
Reactant: COC(C)(C)OC
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)Nc1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 61.5 %

Procedure:
5-chloro-2-nitroaniline (8.6 g; 0.05 mole), 2,2-dimethoxypropane (10.0 ml; 0.09 mole) and trifluoroacetic acid [TFA] (4.0 ml; 0.005 moles) were dissolved in toluene (100 ml) and stirred for 1 hr. A boron/pyridine complex (hereinafter BH3 * pyridine) (5.0 ml; 0.05 moles) was added in 1.0 ml increments. The reaction was exothermic, and the reaction progress was monitored by tlc (40% EtOAc/hexane). Additional TFA, BH3 * pyridine and 2,2-dimethoxypropane were added until the tlc indicated that the 5-chloro-2-nitroaniline was consumed. The reaction mixture was placed on a bed of silica and eluted with toluene. The product was the first major component to elute, which produced 6.6 g (61%) of a yellow crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][CH3:23].[CH2:27](Br)[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].[F-].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]([C:24]([O:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29])=[O:25])[CH2:21][CH2:22][CH3:23]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCCC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br)C(=O)O
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CCCC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br)C(=O)OCC(=O)c1ccccc1
Reaction time: 8.5 h

Procedure:
A mixture of 2.11 g. of N-[4-bromo-3-(1-carboxybutyloxy)phenyl]-3,4,5,6-tetrahydrophthalimide, 11.19 g. of phenacyl bromide, 0.64 g. of potassium fluoride and 10 ml. of acetonitrile was refluxed with stirring for 8.5 hours and the reaction mixture was cooled and the precipitate was separated by a filtration. The filtrate was concentrated under a reduced pressure and the residue was purified by a chromatography on a column of silica gel (developing solvent of benzene) to obtain 2.20 g. of Compound No. 141 shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1.CO.[OH-].[Na+].Cl>C(OCC)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OC)c(OC)c3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1OC
Yield: 23.3 %

Procedure:
A solution of methyl 6-chloro-5-(3,4-dimethoxyphenyl)-1H-indole-3-carboxylate (75 mg, 0.22 mmol), methanol (2.2 mL), and aqueous sodium hydroxide (1 M, 0.75 mL, 0.75 mmol) was heated at 75° C. for 24 hours. The reaction was acidified with 1 M HCl to pH=2 then diluted with ethyl acetate. The aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a crude solid. The crude product was dissolved in methylene chloride and methanol and silica gel was added. The solvent was removed in vacuo and the crude material adsorbed onto silica was loaded onto a column of silica gel and eluted with ethyl acetate (with 0.2% formic acid)/heptanes (1:1 to 1:0) to provide the title compound (17 mg, 24%) as a tan solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[CH:9][C:10]=1[Cl:11])[CH:2]=[CH2:3].[C:13](Cl)([Cl:15])=[S:14]>[OH-].[Na+].O.C(Cl)(Cl)Cl>[Cl:15][C:13]([O:12][C:7]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:6]=1)=[S:14]
Reactant: C=CCOc1cc(O)ccc1Cl
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CCOc1cc(OC(=S)Cl)ccc1Cl

Procedure:
3-Allyloxy-4-chlorophenol (35.0 g) was dissolved in a solution of 7.7 g of sodium hydroxide in 30 ml of water. To the solution, there was added with stirring a solution of 14.6 ml of thiophosgene in 55.0 ml of chloroform. The reaction mixture was allowed to stand for phase separation. The chloroform layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Reduced pressure distillation of the residue gave 33.0 g of O-(3-allyloxy-4-chlorophenyl) chlorothioformate as a fraction boiling at 128°-129° C./0.4 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[NH3:13]>>[NH2:13][C:6]1[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=[C:2]([F:1])[C:3]=1[C:4]#[N:5]
Reactant: N
Reactant: COc1cc(F)c(C#N)c(F)c1
Product: COc1cc(N)c(C#N)c(F)c1
Temperature: 140 °C

Procedure:
2,6-Difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst. 1989, 172) (200 mg, 1.18 mmol) was dissolved in ethanolic ammonia (2M solution, 10 ml) and the mixture was heated at 140° C. in an autoclave for 16 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate in pentane as eluant (20:80) to give the title compound as a white solid (165 mg). LRMS: m/z (ES+) 189 [MNa+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH3:16])[C:12]=1[C:13]([NH2:15])=[O:14])=O.[OH-].[Na+].CCO>O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]1[NH:15][C:13](=[O:14])[C:12]2[C:11]([CH3:16])=[CH:10][S:9][C:8]=2[N:7]=1
Reactant: COc1ccccc1C(=O)Nc1scc(C)c1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccccc1-c1nc2scc(C)c2c(=O)[nH]1
Temperature: 120 °C
Yield: 60.8 %

Procedure:
A mixture of 2-(2-methoxybenzamido)-4-methylthiophene-3-carboxamide (0.84 g, 2.9 mmol), 6 N aqueous NaOH (4.8 mL), and EtOH (4.8 mL) was heated at 120° C. for 16 h. The reaction was cooled, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under vacuum to give 2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one (0.48 g, 61% yield). LC/MS: m/z 273.1 (M+H)+ at 2.91 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:4]=2[C:5]([CH3:13])=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1C=CC=CC=1.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]2[C:4]3[C:5]([CH3:13])=[N:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([O:1][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:3]=3[O:16][N:15]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1nc(C)c2c(-c3ccc(OC)cc3)noc2c1O
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(C)c2c(-c3ccc(OC)cc3)noc2c1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.7 %

Procedure:
Ethyl 7-hydroxy-3-(4-methoxyphenyl)-4-methylisoxazolo[4,5-c]pyridine-6-carboxylate (56 mg, 0.17 mmol) and DMAP (1 mg) were added to pyridine (1 mL). Pivaloyl chloride (84 μl, 0.68 mmol) was added and the mixture was stirred at room temperature for 48 h. Saturated sodium bicarbonate solution (5 mL) and EtOAc (15 mL) were added, and the aqueous layer was extracted with additional EtOAc. The combined organic layer was dried over MgSO4, concentrated, and the residue was purified by flash chromatography (0-20% EtOAc/hexanes) to give 58 mg of the title compound. MS: (+) m/z 413.50 (M+1).
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH:13]1[CH:18]=[O:19]>>[CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:8])[CH3:9])[CH:3]([O:10][CH:17]2[O:12][CH:13]([CH:18]=[O:19])[CH2:14][CH2:15][CH2:16]2)[CH2:2]1
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: O=CC1CCC=CO1
Product: CC1CCC(C(C)C)C(OC2CCCC(C=O)O2)C1

Procedure:
Menthol may be condensed with compound 16, 3,4-dihydro-2H-pyran-2-carboxaldeyde in the presence of acid to provide compound 17, 6-menthyloxy-tetrahydro-2H-pyran-2-carboxaldehyde. A Lewis acid or a protic acid may be employed, with protic acids being preferred. Aldehyde 17 may be reduced to an alcohol 19, 6-menthyloxy-tetrahydro-2H-pyran-2-methanol, by catalytic hydrogeneration for example, over Raney nickel or a nobel metal catalyst. Compound 17 may alternatively be reduced to compound 19 using a hydride reducing agent, such as sodium borohydride or lithium aluminum hydride.
Reaction SMILES: [OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20](Cl)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:11])([F:10])[F:9])[CH2:3]1.CCN(C(C)C)C(C)C.[F:37][CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([N:40]4[CH2:41][CH2:42][CH:38]([F:37])[CH2:39]4)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:11])([F:10])[F:9])[CH2:3]1
Reactant: FC1CCNC1
Reactant: O=C(NCC1(O)CCCC(C(F)(F)F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCCC(C(F)(F)F)C1)c1c(Cl)ccc2nc(N3CCC(F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3-trifluoromethyl-cyclohexylmethyl)-amide, DIPEA and 3-fluoro-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (d, 1H), 4.72 (s, 1H), 3.80-3.58 (m, 3H), 3.26 (m, 2H), 2.59 (m, 1H), 2.22 (m, 1H), 2.08 (1H), 1.85-1.72 (m, 2H), 1.50 (m, 1H), 1.33-1.20 (m, 3H). m/z: 474 [M+H]
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[N:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]([O:36][C:37]([N:39]1[CH2:40][CH:41]=[C:42]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=3)[CH:5]=[C:4]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)[N:3]=2)[CH2:43][CH2:44]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(Cl)n2)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2nc(-c3ccc(F)c(Cl)c3)cc(N3CCN(c4ncccc4C(F)(F)F)CC3)n2)CC1

Procedure:
Heat a solution of 2-chloro-4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine (774 mg, 1.64 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (608 mg, 1.97 mmol (prepared essentially as described by Eastwood (2000) Tetrahedron Letters 41 (19):3705-3708), K3PO4 (2M, 1.64 mL) and Pd(PPh3)4 (76 mg, 0.07 mmol) in dioxane at 80° C. for 16 hours. Partition the reaction mixture between brine and EtOAc, dry the EtOAc layer (Na2SO4) and concentrate under reduced pressure. Flash chromatography (30% EtOAc in hexanes as eluent) yields 4-{4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a foam.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]([NH:23][CH2:24][CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:22]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH2:29][O:30][CH:25]([CH2:24][NH:23][CH2:21][CH3:22])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCNCC1CNCCO1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Product: CCNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(ethylaminomethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-7-[2-(ethylaminomethyl)morpholino]6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 210°-213° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][CH:9]2[C:15]3=[N:16][C:17]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][N:22]=4)=[CH:18][C:19](=[O:20])[N:14]3[CH2:13][CH2:12][NH:11][CH2:10]2)=[O:7])=[C:4]([O:29][CH3:30])[CH:3]=1.Br[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][CH:9]2[C:15]3=[N:16][C:17]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][N:22]=4)=[CH:18][C:19](=[O:20])[N:14]3[CH2:13][CH2:12][N:11]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:10]2)=[O:7])=[C:4]([O:29][CH3:30])[CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COc1cc(Cl)ccc1C(=O)NC1CNCCn2c1nc(-c1ccncn1)cc2=O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1C(=O)NC1CN(c2ccc(F)cc2)CCn2c1nc(-c1ccncn1)cc2=O
Yield: 38.4 %

Procedure:
A mixture containing 0.035 g (0.08 mmol) of (+/−)-4-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide, 0.016 g (0.09 mmol) of 4-bromofluorobenzene, 0.009 g (0.10 mmol) of sodium tert-butoxide, 0.006 g (0.03 mmol) of tri-tert-butylphosphine and 0.007 g (0.01 mmol) of tris(dibenzylideneacetone)dipalladium(0) in 1.60 mL of anhydrous toluene under argon atmosphere was stirred under reflux for 4 h30. The reaction mixture was cooled, aqueous solution of sodium carbonate was added and the resulting solution extracted with dichloromethane. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 90/10/1 to afford 0.016 g (38%) of the pure product as a powder.
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].O1CCCC1.[CH2:20]([N:23]1[C:31](=[O:32])[C:30]2[C:25](=[N:26][C:27]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]4)=[CH:36][CH:35]=3)=[N:28][CH:29]=2)[N:24]1[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH2:53])[N:48]=1)[CH:21]=[CH2:22]>O>[CH2:20]([N:23]1[C:31](=[O:32])[C:30]2[C:25](=[N:26][C:27]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]4)=[CH:36][CH:35]=3)=[N:28][CH:29]=2)[N:24]1[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([N:53]2[CH2:9][CH2:10][CH2:11][C:12]2=[O:13])[N:48]=1)[CH:21]=[CH2:22]
Reactant: O=C(Cl)CCCCl
Reactant: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n1-c1cccc(N)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n1-c1cccc(N2CCCC2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
With cooling with ice, 0.012 mL of triethylamine and 12.4 mg of 4-chlorobutyric acid chloride were added to tetrahydrofuran (1 mL) solution of 20 mg of the compound obtained in Example 50, 2-allyl-1-(6-aminopyridin-2-yl)-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, and stirred at room temperature for 1 hour. Water was added to the reaction mixture, extracted with chloroform, and the organic layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, the resulting residue was dissolved in 1 mL of N,N-dimethylformamide, and 5 mg of potassium tert-butoxide was added thereto and stirred at room temperature for 30 minutes. Saturated ammonium chloride solution was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was washed with saturated saline water and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through preparative thin-layer chromatography (chloroform/methanol=10/1) to obtain 5 mg of the entitled compound as a yellow solid.