Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[N:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18]CC)=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1>C1(C)C(C)=CC=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:16](=[O:18])[C:3]3=[CH:4][NH:5][C:6]4[C:7]([O:14][CH3:15])=[N:8][C:9]([O:12][CH3:13])=[CH:10][C:11]=4[C:2]3=[N:29]2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cnc2c(OC)nc(OC)cc2c1Cl
Reactant: NNc1ccc(Cl)cc1
Solvent: Cc1ccccc1C
Product: COc1cc2c3nn(-c4ccc(Cl)cc4)c(=O)c-3c[nH]c2c(OC)n1

Procedure:
A mixture of 2.25 g of ethyl 4-chloro-6,8-dimethoxy-1,7-naphthyridin-3-carboxylate and 1.2 g of p-chlorophenylhydrazine in 180 ml of xylene is heated at reflux overnight, then cooled and extracted with 1N sodium hydroxide (300 ml). The aqueous alkali phase is separated, washed with ether and neutralized with 20 g of ammonium chloride to precipitate a solid. The solid is collected and washed with ethanol to yield 2-(4-chlorophenyl)-6,8-dimethoxy-pyrazolo[4,3-c][1,7]naphthyridin-3(5H)-one, m.p. 318°-321°.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:9](C)=[C:10]([CH:13]=[CH:14][CH:15]=2)C#N)=[O:7])=[CH:4][CH:3]=1.[C:19]([OH:22])(=[O:21])[CH3:20].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:9]([CH3:10])=[C:20]([CH:13]=[CH:14][CH:15]=2)[C:19]([OH:22])=[O:21])=[O:7])=[CH:17][CH:18]=1
Reactant: Cc1c(C#N)cccc1C(=O)c1ccc(Cl)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
A mixture of 28 g of 3-p-chlorobenzoyl-2-methyl-benzonitrile, 210 cc of glacial acetic acid, 210 cc of water and 210 cc of concentrated sulfuric acid was refluxed overnight and after cooling to 80° C., the reaction mixture was added to a water-ice mixture. The mixture was vacuum filtered and the resulting precipitate was washed with water until the wash waters were neutral and then dried under reduced pressure to obtain 29.9 g of 3-p-chlorobenzoyl-2-methyl-benzoic acid melting at 205° C. The product was soluble in ethanol and chloroform and slightly soluble in ethyl ether. After crystallization from methanol for analysis, the product melted at 206° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]2[NH:10][CH:11]=[CH:12][C:7]2=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1.[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl>CN(C)C=O>[Cl:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[CH:11]=[CH:12][C:7]2=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=[N+]([O-])c1cc(Cl)nc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c([N+](=O)[O-])cc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C. and under an atmosphere of argon, 1.34 g (28.3 mmol) of sodium hydride (60% in mineral oil) are added in small portions to a solution of 5.6 g (28.3 mmol) of 6-chloro-4-nitro-1H-pyrrolo[2,3-b]pyridine in dimethylformamide (50 ml), and the suspension is stirred at RT for 30 minutes. The mixture is once more cooled to 0° C., 5.3 ml (29.8 mmol of 2-(trimethylsilyl)ethoxymethyl chloride are added dropwise and the mixture is allowed to stir at room temperature for 2 h. The suspension is poured into ice-water (250 ml) and stirred until the mixture has reached RT. The mixture is then extracted with ethyl acetate (three times 50 ml) and the organic phase is washed with saturated sodium chloride solution. The solution is dried over magnesium sulfate and concentrated. The residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 6:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[C:13](=[O:16])([O-])[O-].[K+].[K+].O>C(COC)OC>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:2]=[CH:3][CH:4]=[C:13]([OH:16])[CH:9]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(Br)c2c1C(=O)NC2
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(-c2cccc(O)c2)c2c1C(=O)NC2
Yield: 176.3 %

Procedure:
In a similar manner to Step 1 of Example 152, 7-amino-4-bromoisoindolinone (150 mg, 0.661 mmol) was dissolved in dimethoxyethane (10.5 mL), and the solution was treated with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenol (291 mg, 1.32 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (43 mg, 0.053 mmol), potassium carbonate (455 mg, 3.31 mmol) and water (0.24 mL), followed by purification by slurry using chloroform to obtain 7-amino-4-(3-hydroxyphenyl)isoindolinone (140 mg, yield 88%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[NH4+:11]>CO>[Br:1][C:2]1[C:3]([NH2:11])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.7 %

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (8.54 g, 37.48 mmol) in methanol (12 mL) was added dropwise over 10 minutes to an ice-bath cooled solution of 7M ammonium hydroxide (60 mL, 420 mmol) in methanol (60 mL) and the resulting solution was stirred at room temperature for 24 hours. The mixture was concentrated and water was added. The solid was filtered and dried under reduced pressure to give the title compound (6.23 g, 73%) as a white solid.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)[O:5][N:4]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[F:17][CH:2]([F:1])[C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[S:13][C:12]([C:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:16])=[CH:11][CH:10]=2)[O:5][N:4]=1
Reactant: C1CCNCC1
Reactant: Cc1c(C(F)F)noc1-c1ccc(C(=O)O)s1
Product: Cc1c(C(F)F)noc1-c1ccc(C(=O)N2CCCCC2)s1
Yield: 72 %

Procedure:
Prepared from 5-(3-Difluoromethyl-4-methyl-isoxazol-5-yl)-thiophene-2-carboxylic acid (Preparative Example 27) and piperdine by the method described in Example 2 Method B. The reaction mixture was evaporated in vacuo, then chromatographed on silica gel with EtOAc/hexanes (30 then 40%) as eluant to afford product as a colorless solid (110 mg, 72%). 1H NMR (CDCl3) 1.66-1.72 (6, 3 H), 2.35 (s, 3 H), 3.67-3.71 (m, 4 H), 6.79 (t, J=53.2, 1 H), 7.31 (d, J=4.0, 1 H), 7.45 (d, J=4.0, 1 H). 13C NMR 7.7, 24.7, 26.3, ˜46 (br), 39.8 (br), 108.7, 110.3 (t, J=236), 126.8, 128.8, 130.6, 140.6, 158.6 (q, J=30), 162.1, 162.5. 19F NMR −117.4 (J=53.5). LC/MS 6.36 min, [M+1]+ 327.
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[O:21][C:20]=2[C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)=[CH:15][CH:14]=1)C1C=CC=CC=1>C(Cl)Cl>[OH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:23](=[O:24])[C:22]([CH3:25])([CH3:26])[O:21][C:20]=2[C:27]2[CH:28]=[CH:29][C:30]([C:31]#[N:32])=[CH:33][CH:34]=2)=[CH:17][CH:18]=1
Reactant: CC1(C)OC(c2ccc(C#N)cc2)=C(c2ccc(OCc3ccccc3)cc2)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)OC(c2ccc(C#N)cc2)=C(c2ccc(O)cc2)C1=O
Reaction time: 1 h
Yield: 93.6 %

Procedure:
Boron tribromide (3.4 g, 15.8 mmol) was added to a solution of 4-(3-(4-(benzyloxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (2.5 g, 6.3 mmol) in DCM at 0° C. & the mixture was stirred for 1 h (reaction was monitored by TLC). Upon complete consumption of the starting material, the mixture was quenched with chilled water and extracted with DCM, The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 4-(3-(4-hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (1.8 g, 93.2%,) as yellow solid. 1H NMR: 500 MHz, CDCl3: δ 9.6 (s, 1H), 7.95 (d, 2H), 7.75 (d, 2H), 7.0 (d, 2H), 6.75 (d, 2H), 1.5 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:41]=[CH:40][S:39][CH:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.C([O-])(O)=O.[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:27][C:21]1[NH:20][C:19](=[O:28])[C:18]([CH2:17][NH:16][C:14]([C:4]2[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=[C:2]([C:37]3[CH:41]=[CH:40][S:39][CH:38]=3)[CH:3]=2)=[O:15])=[C:23]([CH2:24][CH2:25][CH3:26])[CH:22]=1
Reactant: CC1(C)OB(c2ccsc2)OC1(C)C
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccsc2)cc2c1cnn2C(C)C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 6-bromo-N-((1,2-dihydro-6-methyl-2-oxo-4-propylpyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide (0.2 g, 0.44 mmol) in DMF (10 mL) was added 4,4,5,5-tetramethyl-2-(thiophen-3-yl)-1,3,2-dioxaborolane (0.113 g, 0.53 mmol) followed by PdCl2(PPh3)2 (0.06 g, 0.08 mmol) and the reaction mixture was stirred for 5 min. Sodium carbonate (0.119 g, 0.940 mmol) dissolved in water (2 mL) was added and the contents were stirred at 120° C. for 3 h. The reaction mixture was diluted with NaHCO3 solution and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by silica gel chromatography (eluent: 4% MeOH\EtOAc) to afford the title compound as an off white solid (75 mg, 38%). 1H NMR (DMSO-d6, 400 MHz): δ 0.883 (t, J=7.2 Hz, 3H), 1.491-1.550 (m, 8H), 2.13 (s, 3H), 2.501 (s, 2H), 4.419 (d, J=3.6 Hz, 2H), 5.130 (t, J=6.4 Hz, 1H), 5.912 (s, 1H), 7.691 (s, 1H), 7.766 (d, J=4.4 Hz, 1H), 7.930 (s, 1H), 8.041 (s, 1H), 8.171 (s, 1H), 8.353 (s, 1H), 8.563 (s, 1H), 11.530 (s, 1H). LCMS (ES+) m/z: 449.09.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:23])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17](N(OC)C)=[O:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][Mg+].[Br-]>C1COCC1>[C:17]([C:10]1[C:11](=[O:16])[C:12]([O:14][CH3:15])=[CH:13][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=2[F:23])[N:9]=1)(=[O:18])[CH3:24]
Reactant: COc1cn(-c2cccc(Br)c2F)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cccc(Br)c2F)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of 1-(3-bromo-2-fluorophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (4.22 g, 10.9 mmol) in THF (218 mL) was added MeMgBr (1.0 M in THF, 16.4 mL, 16.4 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 2 h. The reaction was quenched with saturated NH4Cl aqueous solution at −78° C. The mixture was diluted with NaHCO3 aqueous solution, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (EtOAc/MeOH=100/0 to 50/50) to yield the title compound (3.48 g, 93% yield) as a yellow solid: 1H-NMR (DMSO-d6, 300 MHz): δ ppm 2.50 (3H, s), 3.80 (3H, s), 7.36-7.46 (1H, m), 7.77-7.85 (1H, m), 7.89-7.99 (1H, m), 8.57 (1H, d, J=1.9 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](Cl)=[N:15][CH:14]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[CH3:22].C(OC(=O)C1C=CC(N2CCN(C3C=CC(C(=O)NC4C=CC(C)=C(I)C=4)=CN=3)CC2)=CC=1)C>CCOC(C)=O>[CH2:21]([O:23][C:24](=[O:37])[C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:32][CH2:33][N:34]([C:16]3[CH:17]=[CH:18][C:13]([C:12](=[O:20])[NH:11][C:7]4[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[CH:9][N:8]=4)=[CH:14][N:15]=3)[CH2:35][CH2:36]2)=[CH:29][CH:30]=1)[CH3:22]
Reactant: CC(C)(C)c1ccnc(NC(=O)c2ccc(Cl)nc2)n1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4nccc(C(C)(C)C)n4)cn3)CC2)cc1

Procedure:
4-{4-[5-(4-tert-Butyl-pyrimidin-2-ylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester was prepared from N-(4-tert-butyl-pyrimidin-2-yl)-6-chloro-nicotinamide and 4-(piperazin-1-yl)-benzoic acid ethyl ester following a method similar to the one described in the synthesis of 4-{4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester above. The product was isolated after silica gel column with 30-100% EtOAc in hexanes. HRMS m/z calcd for C27H32N6O3 [M+H]+: 489.2609. Found: 489.2609.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].C(Cl)Cl.[CH2:18]1[C:20]2([CH2:25][N:24]([C:26]3[N:27]([CH2:48][C:49]([F:52])([F:51])[F:50])[C:28]4[C:33]([N:34]=3)=[C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:31]=[C:30]([C:41]3[CH:42]=[N:43][C:44]([NH2:47])=[N:45][CH:46]=3)[N:29]=4)[CH2:23][CH2:22][NH:21]2)[CH2:19]1>C(Cl)Cl.CO>[C:8]([N:21]1[CH2:22][CH2:23][N:24]([C:26]2[N:27]([CH2:48][C:49]([F:52])([F:51])[F:50])[C:28]3[C:33]([N:34]=2)=[C:32]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[N:31]=[C:30]([C:41]2[CH:42]=[N:43][C:44]([NH2:47])=[N:45][CH:46]=2)[N:29]=3)[CH2:25][C:20]21[CH2:19][CH2:18]2)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNC5(CC5)C4)n(CC(F)(F)F)c3n2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CC12CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
Triethylamine (56.8 μl, 0.41 mmol) and acetic anhydride (19.2 μl, 0.20 mmol) were added to a methylene chloride solution (3.0 ml) of 5-[8-(4,7-diazaspiro[2.5]oct-7-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (83.3 mg, 0.17 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then the reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (44.0 mg, 49%) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:27])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].CO.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:27])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:20][CH:21]=2)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(CC(C)(C)C)cc1)C(O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)Cc1ccc(CC(C(=O)O)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-(4-neopentylbenzyl)propionate (3.756 g, 9.657 mmol), sodium hydroxide (0.77 g, 19.3 mmol), methanol (20 ml), water (10 ml) and tetrahydrofuran (20 ml) was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water, acidified with hydrochloric acid, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give a crude product of (2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-(4-neopentylbenzyl)propionic acid as a white solid.
Reaction SMILES: O=C(C)C[N:4]1[C:8]([NH:9][C:10]([C:23]2C=CC=CC=2)([C:17]2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=[N:5]1.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[CH3:23][C:10]1[NH:9][C:8]2[N:4]([CH:17]=1)[N:5]=[CH:6][CH:7]=2
Reactant: CC(=O)Cn1nccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn2nccc2[nH]1
Reaction time: 2 h

Procedure:
To a solution of 1-(2-oxopropyl)-5-triphenylmethylaminopyrazole (0.75 g) in methanol was added conc. hydrochloric acid (0.75 ml). The mixture was stirred for 2 hours. The reaction mixture was added to a mixture of ethyl acetate, tetrahydrofuran and ice-cold water, and the mixture was adjusted to pH 8 with sodium bicarbonate. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was pulverized with diisopropyl ether to give 2-methyl-1H-imidazo[1,2-b]pyrazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[NH2:27][OH:28].C(N(CC)CC)C.CC(O)=O>CCO.CCOC(C)=O.CCCCCC>[NH2:2][C:1](=[N:27][OH:28])[C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:18]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1ccc(CNC(=O)c2cccc(C#N)c2)cc1
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc(CNC(=O)c2cccc(C(N)=NO)c2)cc1
Temperature: 88 °C
Reaction time: 5 h
Yield: 102 %

Procedure:
A solution of the compound of Example 12 (0.476 g, 1.3 mmol), hydroxylamine hydrochloride (0.089 g, 1.3 mmol), and triethylamine (0.18 mL, 1.3 mmol) in absolute EtOH (10 mL) was heated to reflux (86-90° C.). After 5 hours, TLC [1:1 EtOAc/hexane (10 mL)+5 drops of AcOH] showed that starting material was still present. Additional hydroxylamine hydrochloride (0.04 g, 0.6 equivalent) and triethylamine (0.09 mL) was added. After 40 minutes, the TLC showed no change. The reaction was concentrated in vacuo and the residue was dissolved in H2O (30 mL). The aqueous layer was extracted with EtOAc (40 mL). The organic layer was collected, dried over MgSO4, and concentrated in vacuo to give a white solid (0.49 g). NMR was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][O:22][C:21]2=[O:30])[CH2:16][CH2:15]1)[C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[O:6].[CH3:31][S:32](Cl)(=[O:34])=[O:33].N1C(C)=CC=CC=1C>ClCCl>[CH3:9][CH:8]([NH:7][C:5](=[O:6])[C:4]1[CH:11]=[CH:12][C:13]([N:14]2[CH2:15][CH2:16][CH:17]([N:20]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH2:23][O:22][C:21]3=[O:30])[CH2:18][CH2:19]2)=[C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[CH:3]=1)[CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)NC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(N)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)NC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound was prepared from the product of example 160 (0.1 g) and methanesulphonylchloride (0.02 ml) in dichloromethane (10 ml) at 0° C. in the presence of 2,6-lutidine (0.085 ml). The reaction mixture was stirred at room temperature for 16 h. The mixture was evaporated, dissolved in ethyl acetate, washed with water, dried, and evaporated under reduced pressure. Purification was by chromatography eluting with (3:1) ethyl acetate/isohexane. Yield 0.066 g as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:37]=[CH:36][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:27]=[CH:26][N:25]=4)[CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:38]1([S:44]([OH:47])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:27]=[CH:26][N:25]=4)[CH:17]=3)=[O:14])=[CH:36][CH:37]=2)[CH2:4][CH2:3]1.[C:38]1([S:44]([O-:47])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=S(=O)(O)c1ccccc1
Agent: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Solvent: Cc1ccccc1
Product: O=S(=O)([O-])c1ccccc1

Procedure:
4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide (4.94 g, 10 mmol) is added to a solution of benzenesulphonic acid (Fluka, Buchs, Switzerland; 1.61 g, 10 mmol) in hot toluene (40 mL). The solution is evaporated to dryness under reduced pressure and the resulting residue is re-crystallized from ethanol-ethylacetate. The product is filtered-off and dried to afford 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide, benzenesulphonate as a pale-yellow crystalline solid, having the following analytical properties: Analysis found: C, 64.19; H, 5.68; N, 14.93; S, 4.87%; H2O, 0.34%. Calculated for C35H37N7O4S-0.12 H2O: C, 64.28; H, 5.74; N, 14.99; S, 4.90%; H2O, 0.33%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[F:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: OCCCBr
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCOc1cccc(F)c1
Yield: 82.7 %

Procedure:
A stirred mixture of 24.3 grams (0.174 mole) of 3-bromopropanol, 20.6 grams (0.180 mole) of 3-fluorophenol, and 37.0 grams (0.270 mole) of potassium carbonate in 300 mL of acetone was heated at reflux for about 18 hours. The reaction mixture was then cooled and concentrated under reduced pressure to a residue, which was stirred with water and extracted with diethyl ether. The ether extract was washed with an aqueous 10% sodium hydroxide solution and then with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 24.5 grams of 3-(3-fluorophenoxy)propanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:23][CH2:22][CH2:21][N:20]4C(OC(C)(C)C)=O)=[CH:15][C:14]=3[F:31])[NH:9][C:8]=2[CH:7]=[C:6]([F:32])[CH:5]=1)(=[O:3])[NH2:2]>ClCCl.FC(F)(F)C(O)=O>[F:32][C:6]1[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:23][CH2:22][CH2:21][NH:20]4)=[CH:15][C:14]=3[F:31])[NH:9][C:8]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cc(F)cc3[nH]2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc(F)cc2[nH]c(-c3ccc(C4CCCN4)cc3F)nc12

Procedure:
A solution of EXAMPLE 55A (360 mg) in dichloromethane (25 mL) and trifluoroacetic acid (5 mL) was stirred for 1 hour and concentrated. The concentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobile phase A: 0.1% TFA in water; B: 0.1% TFA in CH3CN; 0-100% gradient). 1H NMR (CD3OD) δ 2.20-2.37 (m, 3H), 2.56-2.62 (m, 1H), 3.47-3.57 (m, 2H), 4.76 (dd, J=9.31, 7.17 Hz, 1H), 7.50-7.54 (m, 3H), 7.71 (dd, J=10.37, 2.44 Hz, 1H), 8.43 (t, J=7.93 Hz, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[CH:33][CH:32]=2)=[CH:26][CH:25]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:40]1[CH2:39][CH2:38][N:37]([C:34]2[CH:33]=[CH:32][C:31]([CH2:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)=[CH:36][CH:35]=2)[CH2:42][CH2:41]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCCBr)Nc1ccccc1Cc1ccccc1
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Product: O=C(CCCCCN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1)Nc1ccccc1Cc1ccccc1

Procedure:
The compound (12) synthesized in Reference Example 12 and the compound (5) synthesized in Reference Example 5 were used to produce the above compound in the same way as Example 1.