Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:15][C@@H:16]1[CH2:18][O:17]1>C(O)C>[O:17]1[CH2:18][C@@H:16]1[CH2:15][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: ClC[C@@H]1CO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C[C@H]2CO2)CC1
Reaction time: 12 h
Yield: 94.9 %

Procedure:
Tert-butyl piperazine-1-carboxylate 7a (7.44 g, 40 mmol) and (S)-2-chloromethyl-oxirane (3.70 g, 40 mmol) were dissolved in 60 mL of ethanol. The reaction solution was stirred for 12 hours. The resulting solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[[(2S)-oxiran-2-yl]methyl]piperazine-1-carboxylate 20a (9.20 g, yield: 95.0%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8](Cl)=[O:9])=[C:5]([CH3:7])[N:6]=1.[NH2:11][C:12]1[C:20]([NH:21][C:22]([C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)=[O:23])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15].O>N1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:8]2[O:9][C:14](=[O:15])[C:13]3[CH:17]=[CH:18][CH:19]=[C:20]([NH:21][C:22]([C:24]4[CH:29]=[N:28][CH:27]=[CH:26][N:25]=4)=[O:23])[C:12]=3[N:11]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C(=O)Cl)s1
Reactant: Nc1c(NC(=O)c2cnccn2)cccc1C(=O)O
Solvent: O
Solvent: c1ccncc1
Product: Cc1nc(C)c(-c2nc3c(NC(=O)c4cnccn4)cccc3c(=O)o2)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.3 %

Procedure:
2,4-dimethylthiazole-5-carbonyl chloride 17 (104 mg, 0.58 mmol) was added to a suspension of 2-amino-3-(pyrazine-2-carboxamido)benzoic acid 16 (100 mg, 0.39 mmol) in pyridine (5 mL). The reaction mixture was stirred at room temperature for 12 h then poured into ice cooled H2O (30 mL). The resulting precipitate was collected by filtration, rinsed with H2O, and dried under vacuum to give 18 (110 mg, 81% yield).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][CH3:4].[C:13](OC(=O)C)(=[O:15])[CH3:14]>C1COCC1>[CH3:5][C:2]([C:6]1[CH:7]=[CH:8][C:9]([NH:10][C:13](=[O:15])[CH3:14])=[CH:11][CH:12]=1)([CH3:1])[CH2:3][CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C)(C)c1ccc(N)cc1
Solvent: C1CCOC1
Product: CCC(C)(C)c1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a stirred solution of 4-(1,1-dimethylpropyl)aniline (Preparation 100, 12.5 g, 0.076 mol) in THF (100 mL) was added acetic anhydride slowly at 0° C. The reaction was stirred at room temperature for 8 hours. The reaction was extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (12 g, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([Br:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:17]1([O:22][C:23]2[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:24][CH:25]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([Br:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1Cl
Reactant: OB(O)c1ccc(OC2CCCC2)cc1
Product: CCOC(=O)c1c(Cl)c2cc(Br)ccc2n1-c1ccc(OC2CCCC2)cc1

Procedure:
The sub-title compound was prepared in accordance with the procedure described in Example 8(c) using 5-bromo-3-chloro-1H-indole-2-carboxylic acid ethyl ester (see Example 3)5, Method 1, step (a)) and 4-cyclopentoxyphenylboronic acid instead of 4-isopropoxyphenylboronic acid.
Reaction SMILES: B(Br)(Br)Br.C[C:6]1[C:7]([O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[C:23]([CH:29]([CH3:31])[CH3:30])[CH:22]=2)=[C:8]2[C:12](=[CH:13][C:14]=1[CH3:15])[NH:11][C:10]([P:16]([OH:19])(=[O:18])[OH:17])=[CH:9]2.Cl[CH2:33]Cl>>[CH3:33][C:7]1([O:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH:29]([CH3:30])[CH3:31])[CH:22]=2)[CH:6]=[C:14]([CH3:15])[CH:13]=[C:12]2[C:8]1=[CH:9][C:10]([P:16]([OH:19])(=[O:18])[OH:17])=[N:11]2
Reactant: ClCCl
Reactant: COc1ccc(Oc2c(C)c(C)cc3[nH]c(P(=O)(O)O)cc23)cc1C(C)C
Agent: BrB(Br)Br
Product: CC1=CC(C)(Oc2ccc(O)c(C(C)C)c2)C2=CC(P(=O)(O)O)=NC2=C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of boron tribromide (1 M in dichloromethane, 1.3 mL, 1.3 mmol) was added to a solution of 5,6-dimethyl-4-(4′-methoxy-3′-iso-propylphenoxy)indolephosphonic acid (100 mg, 0.26 mmol) in dichloromethane (10 mL) at −78° C. The ice bath was removed and the reaction mixture was warmed to rt. After stirring at rt overnight, the reaction mixture was quenched with ice, diluted with ethyl acetate and washed with water then brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (86.3 mg, 80%): 1H NMR (300 MHz, CD3OD) δ 7.18 (s, 1H), 6.97 (d, J=3.0 Hz, 1H), 6.60 (s, 1H), 6.57 (d, J=9.0 Hz, 1H), 6.26 (dd, J=9.0, 3.0 Hz, 1H), 3.22 (heptuplet, J=6.9 Hz, 1H), 2.28 (s, 3H), 2.18 (s, 3H), 1.12 (d, J=6.9 Hz, 6H); Anal. Calcd for (C19H22NO5P+1.5H2O+0.1 C3H6O): C, 56.79; H, 6.32; N, 3.43. Found: C, 56.61; H, 5.92; N, 3.22.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[CH2:16][CH2:15]2)[CH:3]=1.[CH3:28][NH:29][CH3:30]>CO.C1COCC1>[CH3:28][N:29]([CH3:30])[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[CH2:16][CH2:15]2)[CH:3]=1
Reactant: CNC
Reactant: O=C(c1ccccc1)N1CCN(c2cc(Cl)nnc2-c2ccccc2)CC1
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1cc(N2CCN(C(=O)c3ccccc3)CC2)c(-c2ccccc2)nn1
Temperature: 60 °C

Procedure:
To (4-(6-chloro-3-phenylpyridazin-4-yl)piperazin-1-yl)(phenyl)methanone (1 g) dissolved in methanol (40 ml), and dimethyl amine in THF (10 ml) was added under nitrogen atmosphere and the reaction mixture was heated to 60° C. for 18 hrs. The progress of reaction was monitored by TLC. After consumption of starting material, reaction mixture was cooled to room temperature and neutralized with solid sodium bicarbonate. The mixture was extracted with dichloromethane (3×10 ml). The combined organic layer was dried over anhydrous sodium sulphate and concentrated to afford (4-(6-(dimethylamino)-3-phenylpyridazin-4-yl)piperazin-1-yl)(phenyl)methanone as yellow liquid.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[S:5].[C:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=O)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>CO>[N:2](=[C:16]([O:18][CH2:19][CH3:20])[C:15](=[N:2][NH:3][C:4]([NH2:6])=[S:5])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:3][C:4]([NH2:6])=[S:5]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Product: CCOC(=NNC(N)=S)C(Cc1ccccc1)=NNC(N)=S
Temperature: 25 °C
Reaction time: 11 h
Yield: 100.8 %

Procedure:
Thiosemicarbazide hydrochloride (8.30 g, 65.1 mmol) was dissolved in a mixed solvent of methanol (50 mL) and distilled water (50 mL). To the solution was added ethyl benzoylacetate (17.0 mL, 98.2 mmol) and concentrated hydrochloric acid (1.00 mL, 12.0 mmol), and the mixture was stirred at room temperature for 11 hours. The deposited solid was collected by filtration, washed (methanol) and then dried to give 3 phenyl-3-thiosemicarbazonopropionic acid ethyl ester (thiosemicarbazone) (11.1 g, 64%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[C:6]([F:13])[CH:5]=1)=[O:3].[C:14](=O)([O:17]C)[O:15][CH3:16]>>[F:13][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[O:11][CH3:12])[C:2]([CH2:1][C:14]([O:15][CH3:16])=[O:17])=[O:3]
Reactant: COc1c(F)cc(C(C)=O)cc1F
Reactant: COC(=O)OC
Product: COC(=O)CC(=O)c1cc(F)c(OC)c(F)c1
Yield: 97 %

Procedure:
This compound was prepared from 3,5-difluoro-4-methoxyacetophenone and dimethyl carbonate according to method A. Yellow solid; Yield: 97%; mp 64–67° C.; 1H-NMR (300 MHz, CDCl3) δ 3.77 (s, 3H), 3.93 (s, 2H), 4.13 (t, J=1.7 Hz, 3H), 7.52 (m, 2H). Minor tautomer: 3.81 (s, 3H), 4.06 (m, 3H), 5.58 (s, 1H), 7.34 (m, 2H), 12.47 (s, 1H); MS (ESI) m/z 243 ([M−H]−), 245 ([M+H]+); Anal. Calcd for C11H10F2O4: C: 54.10, H: 4.13. Found: C: 54.37, H: 4.08.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([CH:9]3[CH2:10][CH2:11][N:12]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=4)[CH2:13][CH2:14]3)=[N:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2[nH]c(C3CCNCC3)nc2c1
Reactant: CCc1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCc1cnc(N2CCC(c3nc4cc(Br)ccc4[nH]3)CC2)nc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 30.6 %

Procedure:
Intermediate 1 (500 mg, 1.69 mmol) and 2-chloro-5-ethylpyrimidine (264 mg, 1.86 mmol) were dissolved in propan-2-ol (25 ml). To this mixture N,N-Diisopropylethyl amine (1.8 ml, 10.1 mmol) added and stirred at 90° C. for 12 h. After completion of the reaction, propan-2-ol was removed to obtain the crude. Crude was purified by combiflash using a mixture of AcOET and Petether (40:60) as eluent to afford the titled compound (0.2 g) as a pale-yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([OH:11])[CH:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:6]=1)=O.[NH3:22]>>[OH:11][C:9]1[CH:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:6]=[C:5]([C:3]([NH2:22])=[O:2])[N:10]=1
Reactant: COC(=O)c1nc(O)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: N
Product: NC(=O)c1nc(O)cc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
4-Hydroxy-6-(3-trifluoromethylphenyl)-pyrimidine-2-carboxylic acid methyl ester (17 mg) was stirred for one hour at room temperature in aqueous ammonia (500 ul). Solvent was evaporated under reduced pressure to yield product 4-hydroxy-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carboxylic acid amide (17 mg) as a white solid. 1H NMR (DMSO): δ 8.66 (s, 1H), 8.61 (s, 1H), 8.54 (d, 1H), 8.13 (s, 1H), 7.87 (d, 1H), 7.73 (t, 1H), 7.22 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5](=O)[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:9][C:7]1([CH3:10])[CH2:8][C:3](=[O:2])[CH:4]=[CH:5][CH2:6]1
Reactant: COC1=CC(=O)CC(C)(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CC=CC(=O)C1
Reaction time: 4 h

Procedure:
A solution of 3-methoxy-5,5-dimethyl-cyclohex-2-enone (80 g, 0.52 mol) in anhydrous tetrahydrofuran (270 mL) was treated dropwise with a 1M solution of LiAlH4 in tetrahydrofuran (182 mL), under argon atmosphere and keeping the temperature of the reaction between 0° C. and 5° C. The temperature was allowed to rise to 25° C. and the mixture was stirred for 4 hours. The resulting slurry was cooled with an ice bath, quenched with ethyl acetate (30 mL) and poured with caution into a cooled 2 M H2SO4 solution. The aqueous solution was then extracted with diethyl ether (300 mL×3), dried on Na2SO4 and evaporated under reduced pressure to remove most of the solvent. The crude material contained the title compound as a low boiling point oil that was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].I[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)Cl>[CH:11]([O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])([CH3:13])[CH3:12]
Reactant: CC(C)I
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)Oc1cccc(C#N)c1
Reaction time: 8 h

Procedure:
A combination of 32 g (268 mmol, Aldrich) 3-cyanophenol, 26.9 mL (268 mmol) 2-iodopropane, and 88 g (269 mmol) cesium carbonate in 1:1 CH2Cl2:CH3CN was heated to reflux and allowed to stir overnight. HPLC/MS showed pure product so the suspension was filtered, washed with CH3CN and concentrated. The remaining oil was dissolved in CH2Cl2 and filtered thru a short pad of silica with CH2Cl2. The filtrate was concentrated to dryness to give the product. An alternative preparation uses the conditions similar to the above except that potassium carbonate is used as the base.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][C:26](B(O)O)=[CH:27][CH:28]=2)[CH:23]=[N:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([C:2]3[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=4)[N:3]=3)=[CH:27][CH:28]=2)[CH:23]=[N:22]1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1ccc2[nH]ncc2c1
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: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 43.1 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 200.0 mg, 0.68 mmol) in 1,4-dioxane (1 mL), was added 1H-indazol-5-ylboronic acid (386.0 mg, 2.38 mmol), K3PO4 (434.0 mg, 2.05 mmol), Pd(PPh3)4 (39.0 mg, 0.03 mmol) under nitrogen atmosphere and water (3 drops). After stirring for 20 min at 90° C., the reaction mixture was dissolved in water (30 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 2%-10% ethyl acetate in petroleum ether to afford methyl 2-(1H-indazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (110.0 mg, 45%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:12][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C)cnc1N
Reactant: Ic1cccnc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(C)cnc1Nc1cccnc1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
3-Amino-6-methyl-pyrazine-2-carboxylic acid ethyl ester (Example C) (800 mg, 4.4 mmol) and 3-iodopyridine (1.63 g, 8.0 mmol) were dissolved in 17 ml dry dioxane. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (510 mg, 0.88 mmol), cesium carbonate (2.30 g, 7.0 mmol) and tri(dibenzylideneacetone)dipalladium chloroform complex (460 mg, 0.44 mmol) were added and the reaction mixture was stirred for 16 hours at 130° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (heptane/ethyl acetate 9:1->heptane/ethyl acetate 1:2). The desired product was obtained as a yellow oil (455 mg, 40%), MS: m/e=259.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12]([C:22](OC2C=CC=CC=2)=[O:23])C(=O)OC2C=CC=CC=2)[CH:7]=1.[CH3:50][N:51]([CH3:62])[CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][CH:57]([NH:60][CH3:61])[CH2:56][CH2:55]1>CN(C)C=O>[CH3:50][N:51]([CH3:62])[CH2:52][CH2:53][N:54]1[CH2:55][CH2:56][CH:57]([N:60]([CH3:61])[C:22]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=5)=[O:49])[CH2:38][CH2:39]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:23])[CH2:58][CH2:59]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: CNC1CCN(CCN(C)C)CC1
Solvent: CN(C)C=O
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 65.7 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) was added N-[1-(2-dimethylaminoethyl)piperidin-4-yl]-N-methylamine (69.5 mg), followed by stirring at room temperature for 22 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (31.4 mg, 65.9%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2c([N+](=O)[O-])c(Cl)nc3ccccc23)cc1
Yield: 93.4 %

Procedure:
The method described in Part A of Example 1 was used to treat 2,4-dichloro-3-nitroquinoline (10.0 g, 40.8 mmol) in DMF (100 mL) with triethylamine (8.53 mL, 61.2 mmol) and 4-methoxybenzylamine (4.85 mL, 40.8 mmol). After the precipitate was isolated by filtration, it was dried for three hours in a vacuum oven at 60° C. to provide 13.1 g of 2-chloro-N-(4-methoxybenzyl)-3-nitroquinolin-4-amine as a brown solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[N:16]1([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[N:17]1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([N:16]3[CH:20]=[CH:19][CH:18]=[N:17]3)=[CH:28][CH:27]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc(-n3cccn3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 4-pyrazol-1-yl-benzaldehyde, of Preparation 42, using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 2 h. 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, 1H), 7.70 (d, 1H), 7.65 (d, 2H), 7.45 (d, 2H), 7.28-7.19 (m, 3H), 7.10 (d, 1H), 6.45 (dd, 1H), 3.83 (s, 2H), 3.79 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.63 (t, 2H); MS 350 (M+1).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH:9]2[CH2:11][CH2:10]2)=[O:8])[CH:2]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH:9]1([C:7]([C:3]2[CH:2]=[C:1]([CH2:12][Br:13])[CH:6]=[CH:5][CH:4]=2)=[O:8])[CH2:10][CH2:11]1
Reactant: Cc1cccc(C(=O)C2CC2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1cccc(CBr)c1)C1CC1

Procedure:
A stirred suspension of cyclopropyl m-tolyl ketone (16 g) and N-bromosuccinimide (17.8 g) in carbon tetrachloride (100 ml) was irradiated and heated under reflux by means of a tungsten lamp for 2 hours and cooled. The solid was filtered off and the filtrate evaporated. The residual oil was distilled under reduced pressure and the fraction distilling at 115°-130°/0.1 mm was collected.
Reaction SMILES: C[O:2][C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:7]([C:13]1[CH:35]=[CH:34][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:28]5=[N:29][CH:30]=[N:31][C:32]([NH2:33])=[C:27]5[CH:26]=[N:25]4)[CH2:20][CH2:19]3)=[CH:15][CH:14]=1)=[N:8]2.Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[NH2:33][C:32]1[N:31]=[CH:30][N:29]=[C:28]2[N:24]([CH:21]3[CH2:20][CH2:19][N:18]([CH2:17][C:16]4[CH:34]=[CH:35][C:13]([C:7]5[C:6]([C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=6)=[CH:5][C:4]6[C:3](=[O:2])[NH:12][CH:11]=[CH:10][C:9]=6[N:8]=5)=[CH:14][CH:15]=4)[CH2:23][CH2:22]3)[N:25]=[CH:26][C:27]=12
Reactant: COc1nccc2nc(-c3ccc(CN4CCC(n5ncc6c(N)ncnc65)CC4)cc3)c(-c3ccccc3)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Nc1ncnc2c1cnn2C1CCN(Cc2ccc(-c3nc4cc[nH]c(=O)c4cc3-c3ccccc3)cc2)CC1
Temperature: 150 °C

Procedure:
A mixture of 1-{1-[4-(5-methoxy-3-phenyl-1,6-naphthyridin-2-yl)benzyl]-piperidin-4-yl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.092 mmol) and pyridine hydrochloride 9500 mg, 4.35 mmol) was heated at 150° C. for 10 minutes. The cooled mixture was diluted with water and made neutral with sodium bicarbonate solution. The white solid was collected by filtration, dried, and then digested in acetonitrile with a little methanol. Upon cooling the pure product was isolated by filtration. 1H-NMR (500 MHz, DMSO-d6): δ 11.60 (1H, br s), 8.38 (1H, s), 8.15 (1H, s), 8.07 (1H, s), 7.50 (1H, d, J=7.3 Hz), 7.31-7.60 (5H, m), 7.24-7.28 (4H, m), 6.69 (1H, d, J=7.3 Hz), 4.57 (1H, m), 3.53 (2H, s), 2.91 (2H, m), 2.11-2.17 (4H, m), 1.80-1.87 (2H, m). m/e (m+1): 529.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([Cl:21])=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C@@H:9]3[CH2:13][C:14]4[C:19]([C@H:8]3[C:7]=2[CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4.C=O.[C:24]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH3:1][O:2][C:3]1[C:4]([Cl:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH3:24])[C@@H:9]3[CH2:13][C:14]4[C:19]([C@H:8]3[C:7]=2[CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4
Reactant: COc1cc2c(cc1Cl)CCN[C@@H]1Cc3ccccc3[C@@H]21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc2c(cc1Cl)CCN(C)[C@@H]1Cc3ccccc3[C@@H]21
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
A solution of 300 mg (1.00 mmol) of Compound P from step E was dissolved in 20 mL acetonitrile and 0.40 mL (5.3 mmol) 37% aqueous formaldehyde was added followed by 0.10 grams (1.59 mmol) sodium cyanoborohydride. After 30 minutes, the solution was brought to pH 7 by dropwise addition of glacial acetic acid then stirred an additional 1 hour and 45 minutes. The solvent was removed under reduced pressure, and the residue was taken up into 125 mL ethyl acetate. This was washed with 50 mL 10% sodium bicarbonate, dried (MgSO4) and evaporated to give an oil, which was purified by flash chromatography over silica gel, eluting with ethyl acetate to give 150 mg of trans-5,6,7,7a,8,12b-hexahydro-2-methoxy-3-chloro-7-methyl-benz[d]indeno[2,1-b]azepine (Compound Q) as an oil, 200 MHz NMR (CDCl3) d 2.17(dd,1H,J=12,Hz), 2.69(m,2H) 2.37(s,3H), 2.90-3.40(m,4H), 3.77(s,3H), 4.67(d,1H,J=9 Hz), 7.03(s,1H), 7.17(s,1H), 7.20-7.35(m,4H).