Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])=[CH:4][C:5]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([N:23]2[C:24](=[O:33])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]2=[O:32])=[CH:4][C:5]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:11])=[C:6]([CH:7]=1)[O:8][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]
Reactant: O=C1c2ccccc2C(=O)N1c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(O)cc1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(Cl)c(N2C(=O)c3ccccc3C2=O)cc1S(=O)(=O)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-chloro-2-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl-sulfonyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)phenol (0.26 g) and potassium carbonate (0.11 g) in N,N-dimethylformamide (3 mL) was added ethyl bromoacetate (0.078 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=9/1−1/9) to give ethyl 2-[5-chloro-2-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl-sulfonyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)phenoxy]acetate (0.29 g). To this material were added tetrahydrofuran (10 mL), methanol (5 mL), water (5 mL) and lithium hydroxide monohydrate (0.21 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). To the solution was added 1,1′-carbonyldiimidazole (0.16 g), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added methylamine (40% methanol solution, 2.5 mL), and the mixture was stirred at room temperature for 5 hours, and then stirred at 50° C. for 1 hour. The reaction mixture was poured into 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate) to give the title compound (0.14 g).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(OCC)=[O:2].C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:2][CH2:1][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)CCCCCN1CCCC(NCc2ccccc2OC)C1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1CNC1CCCN(CCCCCCO)C1c1ccccc1
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
Under a nitrogen atmosphere in a round-bottom flask were placed 95 mg (0.22 mmol) of the title compound of Example 97 and 1 ml of THF. The system was cooled in an ice/acetone bath, 0.44 ml (0.44 mmol) of 1M lithium aluminum hydride in ether was added to the system and the mixture was stirred fro 10 minutes. The cold bath was removed, the mixture was stirred at room temperature for 20 minutes and the cold bath was replaced. The the system was added cautiously ca. 0.4 ml of 2M aqueous sodium hydroxide, and the mixture was stirred at room temperatre for 20 minutes. Sodium sulfate was added tothe system, the mixture was stirred for 30 minutes, solides were removed by suction filtration and the filtrate was concentrated. The crude material was purified by flash column chromatography (5 g of silica gel) usign 3:47 methanol/chloroform as the eluant to obtain 49 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1.[CH3:28][NH2:29]>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:29][CH3:28])[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)c(N)c2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-Amino-1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (23 mg) and a 40% aqueous solution (60 mg) of methylamine were added to pyridine (240 mg), and the mixture was stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure, and ethanol (0.5 ml) was added to the residue. Deposits were collected by filtration and washed successively with ethanol and diisopropyl ether to obtain the title compound (6 mg) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[N:22]=1>>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([NH:19][C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH2:12][CH2:11][CH:10]([N:13]5[CH2:17][CH2:16][CH2:15][CH:14]5[CH3:18])[CH2:9]4)=[CH:7][C:2]=3[CH3:1])=[O:34])=[CH:31][CH:30]=2)[N:22]=1
Reactant: Cc1cc(C)nc(Nc2ccc(C(=O)O)cc2)n1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(C)nc(Nc2ccc(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)cc2)n1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-(4,6-dimethyl-pyrimidin-2-ylamino)benzoic acid. MS: 485.3 (M+H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([CH:18]=[N:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][NH:24]2)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl.Cl[Ti](Cl)(Cl)Cl>[F:14][C:10]1[C:9]([O:15][CH3:16])=[C:8]2[C:13](=[CH:12][CH:11]=1)[CH:18]([NH:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=1[CH:22]=[N:23][NH:24]3)[C:3]([C:2]([F:29])([F:1])[F:30])([OH:17])[CH2:4][C:5]2([CH3:7])[CH3:6]
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=Nc1cccc2[nH]ncc12)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1c(F)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2[nH]ncc12
Temperature: -22.5 °C
Yield: 81.1 %

Procedure:
1.32 g (3.117 mmol) of the above-described imine, 1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol, is dissolved in 22.8 ml of dichloromethane. 9.35 ml of a 1 M solution of TiCl4 in dichloromethane (3 equivalents) is added to this solution at −30° C., specifically under nitrogen within 15 minutes. The reaction mixture is stirred for three and one-half hours at −30 to −15° C. The batch is mixed drop by drop with saturated sodium bicarbonate solution at −30° C. After dilution with ethyl acetate, it is stirred for 15 minutes at room temperature. After 2× extraction with 150 ml each of ethyl acetate, the organic phases are washed (water, brine), dried (Na2SO4), and the solvent is spun off. After chromatography on silica gel (mobile solvent dichloromethane/methanol), 1.07 g (81.1%) of the desired product is obtained as a racemate. The product is separated into its enantiomers (Chiralpak AD 5μ; mobile solvent hexane/ethanol). The (+)-enantiomer shows an angle of rotation of [α]D=+1.6° (c=1, MeOH), and the (−)-enantiomer shows an angle of rotation of [α]D=−1.3° (c=1, MeOH).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[OH-].[CH2:8]([N+:15]([CH3:18])([CH3:17])[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(C)=O.CO>[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[CH2:8]([N+:15]([CH3:18])([CH3:17])[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:8]([N+:15]([CH3:18])([CH3:17])[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)C(=O)O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: O=C([O-])C(=O)[O-]

Procedure:
Oxalic acid in an amount of 10.78 g (0.120 mol) was dissolved in acetone, making a total of 100 g. The resultant solution was mixed with 100 g of 40% by weight solution of benzyltrimethylammonium hydroxide (0.261 mol) in methanol (produced by Tokyo Kasei Kogyo Co., Ltd.), and then 1500 g of acetone was added to the resultant mixture to form white precipitate. Subsequently, the precipitate was collected by means of suction filtration method, dispersed in 500 g of acetone and filtered to collect cake. The resultant cake was subjected to drying treatment under vacuum at 80° C. for 24 hours to form 33.9 g (0.0941 mol) of bis(benzyltrimethylammonium) oxalate at a yield of 78.4% based on the fed oxalic acid. The resultant bis(benzyltrimethylammonium) oxalate, in which a melting point was not recognized, was thermally decomposed in a stream of nitrogen at about 240° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH:38]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:38][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32]
Reactant: O=Cc1ccco1
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NCc1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
3-(4-Amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.229 mmol), 2-furaldehyde (0.027 mL, 0.321 mmol), sodium triacetoxyborohydride (193 mg, 0.916 mmol) and glacial acetic acid (55 mg, 0.916 mmol) were mixed with 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to adjust the pH to about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol/ammonium hydroxide (95:5:0.2) as mobile phase to give 3-{4-[(2-furylmethyl)amino]-3-methoxyphenyl}-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (57 mg, 48%). 1H NMR (DMSO-d6) 6 1.45 (m, 2H), 1.71 (m, 2H), 1.87 (m, 4H), 2.14 (s, 3H), 2.28 (m, 5H), 2.80 (m, 2H), 3.01 (m, 2H), 3.86 (s, 1H), 4.37 (d, J=3.13, 1H), 6.76 (d, J=8.62, 1H), 7.07 (m, 2H), 7.57 (s, 1H), 8.19 (s, 1H). LCMS (Finigan-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.0 mL/min.): MH+ 517.3, Rt=2.28 min.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:11])([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.Cl[C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:20]([NH:2][C:3]([CH3:11])([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:27])[CH3:26]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCOC(=O)CC(C)(C)N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)NC(C)(C)CC(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Ethyl 3-amino-3-methylbutanoate hydrochloride (0.87 g, 4.79 mmol) was suspended on methylene chloride (12 mL) and triethylamine (1.4 mL, 2.1 eq.). The mixture was cooled to 0° C. and treated dropwise with ethyl 3-chloro-3-oxopropanoate (0.64 mL, 1.05 eq.). The reaction was kept at room temperature for 2 hours, diluted with methylene chloride, washed with 1 N HCl and then with 5% NaHCO3, dried over Na2SO4 and evaporated to dryness to obtain ethyl 3-[(3-ethoxy-3-oxopropanoyl)amino]-3-methylbutanoate (1.2 g, Y=97%) as a red oil.
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:20]1=[O:39])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:40](N(CC)C(C)C)([CH3:42])[CH3:41].C(Br)C=C>C(Cl)Cl>[CH2:42]([N:33]([C:34]1[S:35][CH:36]=[CH:37][N:38]=1)[S:30]([C:27]1[CH:28]=[CH:29][C:24]([N:21]2[CH2:22][CH2:23][C@@H:19]([O:18][Si:1]([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:20]2=[O:39])=[CH:25][CH:26]=1)(=[O:31])=[O:32])[CH:40]=[CH2:41]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)[Si](O[C@@H]1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C1=O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: C=CCBr
Product: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2=O)cc1
Yield: 83.9 %

Procedure:
Synthesized according to General procedure 5. The reaction was set up with (R)-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl)-N-(thiazol-2 yl)benzene-sulfonamide (50.0 g, 86.6 mmol), CH2Cl2 (200 mL), N,N-diisopropylethylamine (30.2 mL, 173.2 mmol), and allylbromide (15.0 mL, 173.2 mmol). The residue was purified via silica gel using 50% EtOAc in hexanes to give the desired sulfonamide as a white solid (45.0 g, 72.7 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ. 7.85-7.79 (m, 6H), 7.70 (dd, J=1.6, 7.7 Hz, 2H), 7.49-7.40 (m, 6H), 7.36 (d, J=4.7 Hz, 1H), 6.93 (d, J=4.7 Hz, 1H), 5.90-5.82 (m, 1H), 5.16 (dd, J=1.3, 10.3 Hz, 1H), 4.97 (d, J=1.3 Hz, 1H), 4.56-4.52 (m, 3H), 3.76-3.72 (m, 1H), 3.56-3.48 (m, 1H), 2.28-2.25 (m, 1H), 2.19-1.98 (m, 1H), 1.11 (s, 9H).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH2:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=2[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Reactant: Cc1ccc(CN)cc1Cl
Product: Cc1ccc(CNC(=O)c2nc(-c3c(F)cccc3F)n(C)c(=O)c2O)cc1Cl

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3-chloro-4-methylbenzylamine (78 mg, 0.5 mmol). The title product was obtained as an off-white solid (35.3 mg, 84% yield). 1HNMR (500 MHz, CDCl3) δ: 12.27 (1H, s), 7.78 (1H, br s), 7.53–7.45 (1H, m), 7.31–7.03 (5H, m), 4.52 (2H, d, J=3.96 Hz), 3.41 (3H, s), 2.33 (3H, s). HRMS (ESI) calcd for C20H17ClF2N3O3 (M+H): 420.0926; found: 420.0929.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BrH:10].BrBr>[H][H].BrBr>[BrH:10].[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: [H][H]
Reactant: CC(=O)c1ccncc1
Agent: Br
Agent: BrBr
Product: O=C(CBr)c1ccncc1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
4-Acetylpyridine (10 g) was combined with 48% hydrogen bromide solution (18 ml) and heated to 70° C. Bromine (4.7 ml) dissolved in 48% hydrogen bromine solution (5 ml) was then added dropwise and heating then continued for 2.5 h. The precipitate which formed was collected by filtration, washed with 1:1 methanol:hexane (20 ml) and dried in vacuo to give a cream solid (19.5 g) as 2:1 mixture of product:starting material by 1H nmr. mp 170-172° C.
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=[C:5]([NH2:16])[C:4]=2[N:3]=1.[CH2:17]([O:19][CH2:20][CH2:21][C@H:22]1[CH2:27]N[CH2:25][CH2:24][NH:23]1)[CH3:18]>>[CH2:17]([O:19][CH2:20][CH2:21][C@@H:22]1[NH:23][CH2:24][CH2:25][N:16]([C:5]2[C:4]3[N:3]=[C:2]([CH3:1])[S:11][C:10]=3[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=2)[CH2:27]1)[CH3:18]
Reactant: CCOCC[C@H]1CNCCN1
Reactant: Cc1nc2c(s1)Nc1ccccc1N=C2N
Product: CCOCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)nc32)CCN1

Procedure:
In a manner similar to that described in Example 300, combine 2-methyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-ylamine (0.534 g, 2.01 mmol) and (S)-2-(2-ethoxyethyl)piperazine (0.635 g, 4.01 mmol) to obtain the title compound: Exact Mass, Calc: 372.1858; Found: 372.1867.
Reaction SMILES: [C:1]1(B(O)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Br[C:11]1[CH:16]=[C:15]([C:17]2[CH2:18][CH2:19][N:20]([O:23][CH3:24])[CH2:21][CH:22]=2)[CH:14]=[CH:13][C:12]=1[NH2:25]>>[C:1]1([C:13]2[CH:14]=[C:15]([CH:17]3[CH2:22][CH2:21][N:20]([O:23][CH3:24])[CH2:19][CH2:18]3)[CH:16]=[CH:11][C:12]=2[NH2:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CON1CC=C(c2ccc(N)c(Br)c2)CC1
Reactant: OB(O)C1=CCCCC1
Product: CON1CCC(c2ccc(N)c(C3=CCCCC3)c2)CC1
Yield: 76.8 %

Procedure:
The title compound was then prepared according to Suzuki coupling procedure of Example 12, step (d) using cyclohex-1-enyl boronic acid (27.9 mg, 1.00 mmol) and 2-bromo-4-(1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamine (as prepared above, 44 mg, 0.15 mmol) and chromatographed on silica (20-50% EtOAc/hexanes) afforded 2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenylamine (33 mg, 74%). Mass spectrum, (ESI, m/z): Calcd. for C18H26N2O, 287.2 (M+H), found 286.8.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[C:14](Cl)(=[O:16])[CH3:15]>>[CH3:1][C:2]1[CH:13]=[C:12]2[C:5](=[CH:4][CH:3]=1)[NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH:11][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2[nH]cc(CCN)c2c1
Product: CC(=O)NCCc1c[nH]c2ccc(C)cc12

Procedure:
Working in the same manner as for the amidation reaction of Example 1, but using 5-methyltryptamine (Preparation 6) and acetyl chloride as reactants, the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.ClCl>COCCO.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18]
Reactant: CN1CCNCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Agent: ClCl
Solvent: CN(C)C=O
Solvent: COCCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCN(C)CC3)cc21
Reaction time: 6 h
Yield: 53 %

Procedure:
A solution of 4.3 g (0.015 mol) of 6,7-dichloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and 9 g of 1-methylpiperazine in a mixture of methyl cellosolve (45 cm3) and dimethylformamide (10 cm3) was heated to reflux temperature. After 6 hours, 75% of the theoretical amount of ionized chlorine (1 atom) had been released into the mixture. Heating was continued for a further 2 hours. The solution was concentrated to dryness in vacuo. The residue was taken up in 20 cm3 of ethanol. The solid, which was filtered off and recrystallised from methyl cellosolve, gave 2.78 g of 6-chloro-1-ethyl-7-(4-methylpiperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 260° C., which was identical to the compound described in Example 1.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[CH2:11]([C:13]1[C:14]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)[CH3:12].[OH-].[Na+]>O>[OH:19][C:15]1[C:14]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[C:13]([CH2:11][CH3:12])[CH:18]=[CH:17][C:16]=1[CH:4]=[O:5]
Reactant: CN(C)C=O
Reactant: CCc1cccc(O)c1NCCNC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1ccc(C=O)c(O)c1NCCNC(C)=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A scrupulously dry flask was charged with anhydrous DMF (15 ml) and cooled in ice under argon. Phosphorus oxychloride, POCl3, 1.5 ml (1.15 eq) was added slowly dropwise to the stirred solution. After the addition was complete, the flask was removed from the ice bath and allowed to reach ambient temperature. This was accompanied by a color change to yellow. The flask was heated in a 40° C. bath for one hour. It was removed from the heat, and once at ambient temperature, a DMF solution of 3-(ethyl)(2-acetylaminoethyl)aminophenol (8; 3.2 g, 14 mmol) was added via addition funnel. After the addition was complete, the flask was returned to the 40° C. bath and stirred overnight. The reaction was cooled to 0° C. and 25 ml 10% NaOH was added, the mixture was allowed to warm to ambient temperature and was then placed in a 40° C. bath. Additional NaOH was added to achieve pH >10. Water (50 ml) was added. After 15 minutes the flask was removed from the bath and the pH adjusted to 5-5.5 with 1N HCl. The mixture was transferred to a separatory funnel and extracted with 4×100 ml ethyl acetate. The pooled organic fractions were washed with water (1×75 ml), predried with Na2SO4, and then dried with MgSO4 overnight. The solution was collected by filtration and the volatiles removed by rotary evaporation to yield the crude product (2.9 g). The material was purified by flash chromatography on silica, 45×150 mm column, eluting with 200 ml each of 2.5%, 5%, and 10% methanol/chloroform purified yield of(2-hydroxy-4-(ethyl)(2-acetylaminoethyl)aminobenzaldehyde) (9) was 1.52 g (45%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14](=[O:16])[CH3:15])=[CH:10][NH:11]2)=[CH:7][CH:6]=1.C(C1C2C(=CC=C(OC(F)(F)F)C=2)N([CH2:35][C:36]([OH:38])=[O:37])C=1)(=O)C>>[C:14]([C:9]1[C:8]2[C:12](=[CH:13][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:17])=[CH:6][CH:7]=2)[N:11]([CH2:35][C:36]([OH:38])=[O:37])[CH:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Reactant: COC(=O)Cc1ccc2c(C(C)=O)c[nH]c2c1
Product: COC(=O)Cc1ccc2c(C(C)=O)cn(CC(=O)O)c2c1

Procedure:
was prepared from (3-acetyl-1H-indol-6-yl)-acetic acid methyl ester in a similar manner as described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. Brown solid. MS: 290 [M+H]+; tR (HPLC conditions k): 2.83 min.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)=[C:8]([CH3:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].O.NN>CO>[CH2:1]([C:5]1[C:9]([CH2:10][NH2:11])=[C:8]([CH3:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(C)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: CCCCc1noc(C)c1CN
Temperature: 55 °C
Yield: 81.7 %

Procedure:
2-(3-Butyl-5-methyl-isoxazol-4-ylmethyl)-isoindole-1,3-dione (1.20 g, 4.0 mmol) was dissolved in MeOH (20 mL) then hydrazine hydrate (1.51 g, 30.1 mmol) was added and the reaction mixture heated at 55° C. After 2 h the reaction mixture was cooled and filtered. The filtrate was evaporated then purified by chromatography (silica, 2 to 10% methanol in dichloromethane) to give the title compound (550 mg, 81%) as a yellow liquid. MS: m/e=348.5 [M+H]+.