Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH:17]=1)=[O:10])(=[O:4])=[O:3].[H-].[Na+].[CH3:37]I.O>CN(C=O)C>[CH3:37][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH:17]=1)=[O:10]
Reactant: CI
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(NS(C)(=O)=O)c3)ccc2C)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N(C)S(C)(=O)=O)c3)ccc2C)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of N-[5-(3-methanesulphonylaminobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide (0.3 g) in DMF (5 ml) was added portionwise to a stirred mixture of sodium hydride (0.025 g) in DMF (5 ml). The resultant mixture was stirred at ambient temperature for 40 minutes. Methyl iodide (0.088 g) was added and the mixture was stirred at ambient temperature for 3 hours. The mixture was poured into water (150 ml). The resultant precipitate was isolated, washed in turn with water and diethyl ether and dried under vacuum at 60° C. There was thus obtained the title compound (0.18 g); m.p. 168-169° C.; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.99 (s, 3H), 3.82 (s, 6H), 7.07 (d, 1H), 7.21 (d, 1H). 7.59 (m, 5H), 7.79 (s, 1H), 7.87 (d, 1H), 7.93 (s, 1H), 9.75 (br s, 1H), 10.25 (br s, 1H); Mass Spectrum: M+H+ 498.
Reaction SMILES: C[O:2]C(=O)C1C=CC=CC=1N.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1.O=S(Cl)Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:21])=[O:2])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(O)Cc1ccc(F)cc1

Procedure:
First, 2-amino-benzoic acid methyl ester (1.00 g, 6.61 mmol) was dissolved in purified CH2Cl2, and DMAP (0.04 g, 0.33 mmol) was added thereto at 0° C. Then, the mixture was added to the reaction vessel containing (4-fluorophenyl)-acetyl chloride produced from reaction of (4-fluoro-phenyl)-acetic acid (1.53 g, 9.90 mmol) with SOCl2, and then reacted at normal temperature for 10 hours. After adding cold sodium bicarbonate solution containing ice, the reaction mixture was extracted with CH2Cl2, and then concentrated under reduced pressure to obtain 1.50 g (79%) of the compound 2-[2-(4-fluorophenyl)-acetylamino]-benzoic acid methyl ester as the solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[BH4-].[Na+].CC(C)=O>CO.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(C)=O
Product: COc1ccc(CO)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a mixed solution of 100 g of 3-bromo-para-anisaldehyde in MeOH (700 ml) and THF (100 ml), on ice, was added 7.50 g of NaBH4. After the solution was warmed to room temperature and stirred for two hours, acetone was added. The reaction solution was concentrated under reduced pressure, water and EtOAc were added to the residue, and liquid separation was performed. The organic layer was washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/1; v/v) to obtain 99.8 g of the title compound (colorless solid).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.S(=O)(=O)(O)N.N[CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:10]1[C:9]([NH2:20])=[N:8][C:6]2[N:7]=[C:2]([NH:1][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:3]=[CH:4][C:5]=2[CH:11]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: NCCCN1CCOCC1
Agent: NS(=O)(=O)O
Product: Nc1nc2nc(NCCCN3CCOCC3)ncc2cc1-c1c(Cl)cccc1Cl

Procedure:
A mixture of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine (4.00 g) from Example 1, sulfamic acid (2.53 g) and aminopropylmorpholine (30 mL) was reacted as in Example 53. In this instance, the crude residue was washed with hot ethyl acetate followed by diethyl ether to afford 3.95 g of the title compound 6-(2,6-dichlorophenyl)-N2 -(3-morpholin-4-yl-propyl)-pyrido[2,3-d]pyrimidine-2,7-diamine, CIMS (1% NH3 in CH4): 461=M+ +C2H5, 433=M+ +H (Base), 346, 332; mp 224°-230.5° C.
Reaction SMILES: [F:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[CH:6](Cl)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CC(C)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[CH:6]([N:25]3[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: Fc1cc2c(cc1Cl)C(Cl)Cc1ccccc1S2
Reactant: OCCN1CCNCC1
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: OCCN1CCN(C2Cc3ccccc3Sc3cc(F)c(Cl)cc32)CC1

Procedure:
A mixture of 7-fluoro-8,10-dichloro-10,11-dihydrodibenzo(b,f)thiepine (the preparation of which is described in Example 19) (4.5 g), 1-(2-hydroxyethyl)piperazine (4.1 g) and chloroform (5 ml) was refluxed for 7.5 hours. The reaction mixture was then diluted with chloroform (50 ml) and the solution washed with water. The chloroform was evaporated the residue dissolved in benzene (200 ml) and the solution shaken with 3 N-HCl (60 ml). The separated hydrochloride was filtered, suspended in the aqueous layer of the filtrate and the suspension made basic with ammonium hydroxide. The liberated base was taken up in chloroform and isolated as usual; m.p. 150°-152° C. (acetone), yield 4.8 g (81%).
Reaction SMILES: Cl[S:2]([C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])=[O:3].[NH2:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C(=O)(O)[O-].[Na+].C(=O)(O)[O-]>ClCCl.O>[CH3:21][Si:20]([CH3:22])([NH:19][S:2]([C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])=[O:3])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)N
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1S(=O)(=O)N[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.3 %

Procedure:
A suspension of ethyl 2-(chlorosulfonyl)-3-nitrobenzoate (14.7 g), amino-t-butyldimethylsilane (15.4 g), and sodium bicarbonate (3.5 g) in dichloromethane (300 mL) was stirred at room temperature in a stoppered flask for 4 days. Water (90 mL) and saturated aqueous bicarbonate (45 mL) were added, and the mixture was stirred. The dichloromethane phase was dried over magnesium sulfate, filtered, concentrated, and chromatographed on silica gel eluted with 20% ethyl acetate in hexanes to give 12.9 g of the title compound as a white solid, m.p. 101-102° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]([CH:17]1[CH2:22][CH2:21][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:30]([CH3:36])=[N:31][CH:32]=[N:33][C:34]=2[CH3:35])=[O:28])[CH2:19][CH2:18]1)[C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)#[N:2].[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[O:13])=[CH:10][CH:9]=1)[CH:17]1[CH2:18][CH2:19][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:34]([CH3:35])=[N:33][CH:32]=[N:31][C:30]=2[CH3:36])=[O:28])[CH2:21][CH2:22]1)#[N:2]
Reactant: C1CNCCN1
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)N3CCNCC3)cc2)CC1
Yield: 31.2 %

Procedure:
Using general procedure E, 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid (see EXAMPLE 133) (54 mg, 0.10 mmol) and piperazine (26 mg, 0.30 mmol) afforded COMPOUND 135 as a white solid (19 mg, 31%). 1H NMR (CDCl3) δ 0.83-1.13 (m, 2H), 1.03 (d, 3H, J=6.3 Hz), 1.49-1.79 (m, 5H), 2.20 (t, 1H, J=11.7 Hz), 2.51 (s, 6H), 2.60 (t, 1H, J=10.8 Hz), 2.76-2.86 (m, 7H), 3.29-3.37 (m, 1H), 3.58-3.72 (m, 4H), 3.82-3.88 (m, 1H), 3.96 (s, 2H), 6.52 (d, 2H, J=8.7 Hz), 7.25-7.26 (m, 2H), 7.44-7.56 (m, 4H), 8.54 (br s, 1H), 8.90 (s, 1H). 13C NMR (CDCl3) δ 13.46, 21.97, 29.16, 30.38, 30.82, 39.97, 41.22, 42.71, 43.57, 46.25, 48.11, 51.94, 55.66, 60.20, 112.14, 112.70, 118.91, 124.15, 129.38, 129.45, 129.70, 130.77, 130.90, 141.23, 149.34, 157.56, 163.12, 166.27, 170.60. ES-MS m/z 609 (M+H). Anal. Calcd. for C35H44N8O2.0.5CH2Cl2.0.1H2O: C, 65.29; H, 6.98; N, 17.16. Found. C, 65.22; H, 7.12; N, 16.78.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].C(OC(Cl)=O)C.[NH2:20][CH2:21][C:22]1[C:27]([CH2:28][CH3:29])=[N:26][C:25]2[N:30]([CH2:33][CH3:34])[N:31]=[CH:32][C:24]=2[C:23]=1[NH:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(Cl)Cl>[CH2:33]([N:30]1[C:25]2=[N:26][C:27]([CH2:28][CH3:29])=[C:22]([CH2:21][NH:20][C:8]([C:7]3[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=3)[C:3]([O:2][CH3:1])=[O:4])=[O:10])[C:23]([NH:35][CH:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[C:24]2[CH:32]=[N:31]1)[CH3:34]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.8 %

Procedure:
To 3-(methoxycarbonyl)benzoic acid (1.261 g, 7.00 mmol) in DCM (35 mL) was added TEA (2.439 mL, 17.50 mmol), EtOCOCl (0.739 mL, 7.70 mmol) at 0° C. after which 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (2.379 g, 7.00 mmol) was added. This mixture was then stirred for 1 h at room temperature. The reaction mixture was diluted with DCM (35 mL) then washed with HOAc (2×20 mL, 10%), NaHCO3 (20 mL, 10%), and water (20 mL), concentrated, The residue washed with EtOAc/Hexane (10 mL, 1:1) to afford the title compound (3.5138 g, 94.2%). LC-MS m/z 466 (M+H)+.
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][C:6]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>CO>[OH:5][C:6]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH3:1])=[O:9]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cccc(O)c1O
Solvent: CO
Product: COC(=O)c1cccc(O)c1O
Temperature: 25 °C
Yield: 99 %

Procedure:
Prepare a reaction flask with 300 mL methanol and add 30 mL of acetyl chloride, under argon, in an ice bath. Add 2,3-dihydroxy-benzoic acid (21.70 g, 0.1418 mole) and stir while heating at reflux overnight. Chill in an ice bath and bubble through hydrogen chloride gas for about 10 minutes. Heat the mixture and stir at reflux overnight. Cool to ambient temperature, then concentrate to an off-white solid. Dissolve and separate into diethyl ether and water. Isolating the ether portion and extract twice with 250 mL 5% sodium bicarbonate. Separate, wash with brine and dry over magnesium sulfate. Filter and condense on a rotary evaporator to give the title compound as an off-white solid (21.1 g, 99%). m.p. 79°-81° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH2:26][NH:25][CH2:24][CH2:23]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:20]([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=5)[CH:21]=4)[CH2:26]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: c1ccc(-c2ccc3c(c2)CCNC3)nc1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2cc(-c3ccccn3)ccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Pyridin-2-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=2)[C:10]([C:24]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)=[O:25])=[CH:9][N:8]=1.O>CN(C)C=O>[CH3:1][N:2]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=2)[C:10]([C:24]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)=[O:25])=[CH:9][N:8]=1)[CH2:3][CH2:4][OH:5]
Reactant: COc1ccc(CNc2nc(Cl)ncc2C(=O)c2cc(OC)c(OC)c(OC)c2)cc1Cl
Reactant: CNCCO
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNc2nc(N(C)CCO)ncc2C(=O)c2cc(OC)c(OC)c(OC)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A solution of 2-methylaminoethanol 100 mg in dimethylformamide 1 ml is added at room temperature to a solution of 2-chloro-5-(3,4,5-trimethoxyphenylcarbonyl)-4-(3-chloro-4-methoxybenzylamino)pyrimidine (120 mg) prepared in above Example 1-(3) in dimethylformamide (1 ml). The mixture is stirred at room temperature for 1 hour and thereto is added water 50 ml. The mixture is extracted with ethyl acetate-chloroform and the extract is subjected to silica gel chromatography (solvent: chloroform-methanol 5%) to give 2-(N-methyl-N-(2-hydroxyethyl)amino)-5-(3,4,5-trimethoxyphenylcarbonyl)-4-(3-chloro-4-methoxybenzylamino)pyrimidine 110 mg as white crystals. mp 166.5–168° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([OH:19])=[O:18])[CH:3]=1.[CH3:20][O-:21].[Na+]>CN(C=O)C.CCOCC>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:5]1[N:6]=[N:7][C:2]([O:21][CH3:20])=[CH:3][C:4]=1[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(C(=O)O)c(Nc2ccc(I)cc2F)nn1
Temperature: 135 °C

Procedure:
To solid 6-chloro-3-(2-fluoro-4-iodo-phenylamino)-pyridazine-4-carboxylic acid (34 mg, 0.09 mmol) in DMF was added NaOMe (0.43 mmol, 0.5 M in MeOH). The mixture was heated at 135° C. for 3 h. The mixture was diluted with ether and extracted with NaOH (1N). The aqueous layer was acidified by concentrated HCl. The desired product was precipitated and was collected by vacuum filtration. LC/MS [8.08 min; 390 (M+1)].
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCC=O)C=CC=CC=1.[Cl:20][CH2:21][CH2:22][CH2:23]I.ClCCI>>[Cl:20][CH2:21][CH2:22][CH2:23][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCI
Reactant: O=CCc1ccccc1
Agent: ClCCI
Agent: O=CCCc1ccccc1
Product: O=C(CCCCl)Cc1ccccc1

Procedure:
When in the procedure of Example 2 0.10 mole of phenylacetaldehyde is substituted for 3-phenylpropionaldehyde, and 0.10 mole of 1-chloro-3-iodopropane is substituted for 1-chloro-2-iodoethane, 5-chloro-1-phenylpentan-2-one is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39]>>[F:32][C:33]1[CH:34]=[C:35]([C:12]2[N:11]=[CH:10][C:9]3[O:8][C:5]4[C:4]([C@:15]5([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[CH:7][CH:6]=4)[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: OB(O)c1cccnc1
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3)ccc1Oc1cnc(-c3ccc(F)c(F)c3)cc12

Procedure:
The title compound was synthesized by steps analogous to those described in Method A1, but using Intermediate 10B, pyridin-3-ylboronic acid, and 3,4-difluorophenylboronic acid. MS m/z=457.2 [M+H]+. Calculated for C26H18F2N4O2: 456.14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl[S:21]([OH:24])(=O)=[O:22].[NH3:25]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[CH:16][C:17]([S:21]([NH2:25])(=[O:24])=[O:22])=[CH:18][CH:19]=1
Reactant: N
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccccc2)C1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(N)(=O)=O)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3 %

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed chlorosulfonic acid (4 mL). This was followed by the dropwise addition of a solution of 6,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (1.6 g, 5.5 mmol, 1.00 equiv) in dichloromethane (30 mL) at 0° C. The resulting solution was stirred for 1 h at 0° C. in a water/ice bath and for an additional 1 h at 25° C. in an oil bath. To this was added chlorosulfonic acid (16 mL) dropwise at 25° C. The resulting solution was stirred for an additional 1 h at 25° C. To the resulting mixture was cooled to 0° C. and aqueous ammonia (120 mL) was added dropwise. The resulting solution was stirred for an additional 3 h 90° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 20 mL of water. The resulting solution was extracted with dichloromethane (3×30 mL) and the combined organic layers concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (100:1). The crude product (0.5 g) was purified by preparative HPLC to give 53 mg (3%) of the title compound as a TFA salt. 1H-NMR (300 MHz, CDCl3, ppm): 7.89 (1H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 7.30 (1H, m), 6.77 (1H, s), 4.87 (1H, s), 4.39 (1H, s), 3.69 (2H, m), 2.98 (1H, t), 2.67 (1H, dd), 2.55 (3H, s). MS (ES, m/z): 371 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Na].[CH2:6]([O:8][C:9](=[O:15])[CH2:10][C:11]([CH2:13]Cl)=[O:12])[CH3:7].C(O)(=O)C>C(O)C.O1CCCC1>[CH2:6]([O:8][C:9](=[O:15])[CH2:10][C:11]([CH2:13][O:3][CH2:2][CH3:1])=[O:12])[CH3:7]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOCC(=O)CC(=O)OCC
Temperature: 25 °C
Yield: 71 %

Procedure:
2.2 mol of sodium ethylate in ethanol -- prepared from 55.2 g (2.2 mols) of sodium and 500 ml of ethanol -- were diluted with 500 ml of tetrahydrofuran. 164.5 g (1 mol) of γ-chloroacetoacetic acid ethyl ester were added to the solution, at room temperature, sufficiently rapidly that the reaction temperature rose to 50° C. The mixture was then cooled to room temperature, 72 g (1.2 mols) of glacial acetic acid were added, the solvent was evaporated off on a rotary evaporator in vacuo, the residue was shaken with 200 ml of water, the mixture was extracted twice with 250 ml of methylene chloride each time, and the combined organic phases were dried over magnesium sulphate. The solvent was stripped off in vacuo and the residue was distilled. 123.7 g (71% of theory) of γ-ethoxyacetoacetic acid ethyl ester of boiling point 75° C./3 mm Hg were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=O)[O:25]C2C=CC=CC=2)=[C:19]([Cl:33])[CH:18]=1)(=[O:3])[NH2:2].[CH:34]1([NH2:37])[CH2:36][CH2:35]1.O.C(O)C>CN(C)C=O>[Cl:33][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:37][CH:34]1[CH2:36][CH2:35]1)=[O:25])[O:16][C:7]1[C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: NC1CC1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)c2cc1C(N)=O
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (17.5 g, 37.7 mmol) disclosed in WO 02/32872 was dissolved in N,N-dimethylformamide (350 mL), and then cyclopropylamine (6.53 mL, 94.25 mmol) was added to the reaction mixture under a nitrogen atmosphere, followed by stirring overnight at room temperature. To the mixture was added water (1.75 L), and the mixture was stirred. Precipitated crude crystals were collected by filtration, washed with water, and dried at 70° C. for 50 min. To the obtained crude crystals was added ethanol (300 mL), and then the mixture was heated under reflux for 30 min to dissolve, followed by stirring overnight to cool slowly down to room temperature. Precipitated crystals was collected by filtration and dried under vacuum, and then further dried at 70° C. for 8 hours to give the titled crystals (12.91 g; 80.2%).
Reaction SMILES: [O:1]1[C:5]([CH2:6][CH2:7][OH:8])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[Na+]>>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:8][CH2:7][CH2:6][C:5]1[O:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[CH:4]=1
Reactant: BrCCCCCBr
Reactant: OCCc1cc2ccccc2o1
Agent: [Na+]
Agent: [OH-]
Product: BrCCCCCOCCc1cc2ccccc2o1
Reaction time: 21 h

Procedure:
A mixture of 2-benzo(b)furanethanol (2.00 g), 1,5-dibromopentane (6 ml), 50% sodium hydroxide (7 ml) and TAB (0.2 g) was vigorously stirred at 24° for 21 h, then partitioned between water (50 ml) and ether (60 ml). The organic phase was washed with brine (50 ml), dried and evaporated in vacuo. The oily residue was purified by FCC eluting with hexane-diethyl ether (97:3) to give the title compound as a colourless oil (2.70 g), t.l.c. (hexane-diethyl ether 4:1) Rf 0.54.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.N1C=[CH:37][C:36]([C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)=N1.[NH2:46][C:47]1C=CC(C(=O)CC2C=CC=CC=2)=CC=1>>[CH2:47]1[C:40]2[C:39](=[CH:45][CH:44]=[C:42]([NH:43][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:41]=2)[CH2:36][CH2:37][NH:46]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: Nc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: Nc1ccc(-c2cc[nH]n2)cc1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 1-(4-aminophenyl)-2-phenylethanone 4-(1H-pyrazol-3-yl)aniline by a procedure similar to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 4.32 (s, 2H), 6.70 (d, 1H, J=5.2 Hz), 7.17-7.37 (m, 8H), 7.42 (d, 1H, J=7.7 Hz), 7.51-7.65 (m, 3H), 7.86 (d, 1H, J=8.8 Hz), 7.92 (d, 2H, J=9.0 Hz), 8.00 (d, 2H, J=8.8 Hz), 8.06 (s, 1H), 8.40 (d, 1H, J=5.4 Hz), 8.53 (d, 1H, J=9.0 Hz), 8.91 (d, 1H, J=6.8 Hz), 10.09 (s, 1H), 10.98 (s, 1H); ESIMS (M+H)+=636.