Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](N(CC)C(C)C)(C)[CH3:2].[NH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:28]=[C:27]([CH2:29][CH2:30][C:31]4[C:36]([CH2:37][C:38]([NH2:40])=[O:39])=[CH:35][CH:34]=[CH:33][N:32]=4)[C:26]([C:41]([F:44])([F:43])[F:42])=[CH:25][N:24]=3)=[CH:18][CH:17]=2)[CH2:11]1.BrCC>CN(C=O)C>[CH2:1]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:28]=[C:27]([CH2:29][CH2:30][C:31]4[C:36]([CH2:37][C:38]([NH2:40])=[O:39])=[CH:35][CH:34]=[CH:33][N:32]=4)[C:26]([C:41]([F:42])([F:44])[F:43])=[CH:25][N:24]=3)=[CH:18][CH:17]=2)[CH2:11]1)[CH3:2]
Reactant: NC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCCNC3)cc2)ncc1C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCBr
Product: CCN1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(N)=O)n3)cc2)C1
Reaction time: 0.08 h
Yield: 35.6 %

Procedure:
N,N-Diisopropylethylamine (18.0 μL, 0.103 mmol) was added to a solution of 2-(2-(2-(2-((4-(Piperidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetamide (39) (17 mg, 0.034 mmol) in DMF (5 mL). The mixture was stirred for 5 min then bromoethane (4.0 μL, 0.051 mmol) was added and stirring was continued for 24 h at room temperature. A further portion of bromoethane (4.0 μL, 0.051 mmol) was added and the reaction mixture was stirred for an additional 16 hours at room temperature. The volatiles were evaporated in vacuo and the residue partitioned between ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) and dried over Na2SO4. Filtration then removal of the solvent under reduced pressure afforded a beige solid which was purified by mass-directed preparative HPLC to afford the title compound (40) (6.2 mg, 36%) as a white solid; 1H NMR (400 MHz, d4-MeOH) δ 8.54 (s, 1H), 8.38 (dd, J=4.8, 1.5 Hz, 1H), 7.69-7.66 (m, 3H), 7.28-7.19 (m, 3H), 3.68 (s, 2H), 3.59-3.46 (m, 2H), 3.38-3.22 (m, partially obscured by d4-MeOH), 3.19-3.08 (m, 2H), 3.04-2.80 (m, 3H), 2.12-1.99 (m, 2H), 1.99-1.70 (m, 2H), 1.34 (t, J=7.3 Hz, 3H). LCMS Method C: rt=4.20 min, m/z=513.2 [M+H]+, 511.2 [M−H]−.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[NH3:10]>>[NH2:10][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8]
Reactant: N
Reactant: Cc1noc(C)c1CCl
Product: Cc1noc(C)c1CN

Procedure:
4-Chloromethyl-3,5-dimethylisoxazole (700 mg, 4.8 mmol) is suspended in concentrated aqueous ammonia at 20–25 degrees C., and vigorously stirred overnight. The reaction mixture is extracted with isopropyl alcohol/chloroform (10/90, 2×). The combined organic phases are concentrated under nitrogen flow. The residue is purified by flash chromatography methanol/methylene chloride (5–20%, 1% triethylamine) to give the title compound, MR (CDCl3, 300 MHz) delta 3.62, 2.37, 2.29, and 1.44.
Reaction SMILES: C([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:23][CH3:24])=[CH:10][CH:9]=1)(=O)CC.[Li+].[OH-]>CO.C1COCC1>[CH2:23]([C:15]1[N:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][OH:5])=[CH:13][CH:12]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1)[CH3:24]
Reactant: CCC(=O)OCCc1ccc(-n2c(CC)nc3ccccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1nc2ccccc2n1-c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86356.6 %

Procedure:
To a solution of 2-[4-(2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate (1.3 g, 4 mmol) in methanol/THF (v/v, 1:1, 32 mL) was added 4N aqueous LiOH (8 mL, 8 mmol) and the resulting mixture was stirred at room temperature. After 3 h, the mixture was concentrated. The residue was dissolved in water (30 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 2:1 to 0:1) to afford 920 g (86%) of the title compound as pale brown solids: 1H-NMR (CDCl3)δ1.26 (3H, t, J=7.5 Hz), 2.80 (2H, q, J=7.5 Hz), 3.00 (2H, t, J=6.5 Hz), 3.98 (2H, t, J=6.5 Hz), 7.25-7.08 (3H, m), 7.31 (2H, d, J=8.3 Hz), 7.45 (2H, d, J=8.3 Hz), 7.81-7.75 (1H, m).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][C:27]([OH:30])([CH3:29])[CH3:28])C>>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[CH:25]=[C:26]([C:27]([OH:30])([CH3:29])[CH3:28])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C#CC(C)(C)O
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Product: CC(C)(O)c1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 4-hydroxy-4-methyl-pent-2-ynoic acid ethyl ester employing the procedure described in Example 105.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(Cl)Cl.CN1CCOCC1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([S:28]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 906.3 %

Procedure:
To 4.6 g (3.03 mmol) of the methyl 3-aminobenzoate prepared in Example 1 in 30 mL of methylene chloride containing 4.0 mL (36 mmol) of N-methylmorpholine was added 4.0 mL (33 mmol) of benzenesulfonyl chloride. After stirring at room temperature for 1 hr the reaction mixture was quenched with water (100 mL). The suspension was dissolved in ethyl acetate/ether combination. The organic phase was washed sequentially with 2N HCl and then sodium bicarbonate. The organic phase was dried (MgSO4), and concentrated and triturated from ethyl acetate/hexane ether to give 8.0 g (90%) of the title compound as a colorless solid: NMR (DMSO-d6 ; 300 MHz) δ 10.58 (s, 1H), 7.75-7.84 (m, 3H), 7.52-7.72 (m, 4H), 7.35-7.45 (m, 2H), and 3.82 ppm (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1.[CH3:21][P:22]([C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28]([NH2:33])=[CH:27][CH:26]=1)([CH3:24])=[O:23].Cl>COCCO.C(O)C>[CH3:24][P:22]([C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28]([NH:33][C:2]2[CH:3]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:5]=[CH:6][N:7]=2)=[CH:27][CH:26]=1)([CH3:21])=[O:23]
Reactant: COc1nc(P(C)(C)=O)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncn1
Agent: Cl
Solvent: COCCO
Solvent: CCO
Product: COc1nc(P(C)(C)=O)ccc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)ncn1

Procedure:
To a solution of 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0.250 mmol) in 1 mL of 2-methoxyethanol is added 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (50.0 mg, 0.250 mmol) and 0.15 mL of 2.5 M HCl in ethanol. The mixture is heated in a sealed tube at 90° C. until formation of the desired compound. The mixture is basified with 1N NaOH solution, and extracted with ethyl acetate. The organic layers can be combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue can be purified by silica gel chromatography.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([NH:9][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=2)[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ncc(N)cc1I
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 5-iodo-6-methylpyridin-3-amine (125 mg, 0.534 mmol) in methylene chloride (1 mL) was added triethylamine (0.087 mL, 0.627 mmol) and cooled at 0° C. Into the reaction was added 3-(trifluoromethyl)benzoyl chloride (0.0812 mL, 0.538 mmol) dropwise and stirred at 0° C. for 45 minutes and at 25° C. for 16 hours. The reaction was extracted with EtOAc and the organic extracts were washed with water saturated Na2CO3, saturated NaCl, dried (MgSO4) and stripped in vacuo. The product was used in the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[NH:8][C:9]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:10][C:6]2=[N:5][C:4](=[O:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29](I)[CH3:30]>CN(C)C=O>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:10]=[C:6]2[N:5]([CH2:29][CH3:30])[C:4](=[O:22])[CH:3]=1
Reactant: COc1ccc(COCc2nc3nc(=O)cc(N)n3[nH]2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(=O)cc(N)n2nc(COCc3ccc(OC)cc3)nc12
Temperature: 25 °C
Reaction time: 36 h

Procedure:
145.6 g of 7-amino-2-[(4-methoxybenzyloxy)methyl]-s-triazolo[1,5-a]pyrimidin-5-one is dissolved in 1500 ml of dimethylformamide and mixed with 76.8 g of potassium carbonate. After the addition of 45.2 ml of ethyl iodide the mixture is stirred for about 1.5 days at ambient temperature. For working up, the dimethylformamide is distilled off in vacuo and the residue remaining is taken up in 500 ml of water (distilled), 500 ml of saturated NaCl solution and 1000 ml of dichloromethane. After separation of the organic phase the aqueous phase remaining is extracted three more times with 200 ml of dichloromethane. The combined organic phases are dried over magnesium sulphate and then freed from solvent. About 180 g of a solid remain, which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:4]([P:10]([OH:13])([OH:12])=[O:11])([P:6]([OH:9])([OH:8])=[O:7])[OH:5])[CH2:2][NH2:3].[OH-].[Na+:15].[OH-].[K+]>>[CH2:1]([C:4]([P:10]([O-:13])([OH:12])=[O:11])([P:6]([O-:8])([OH:9])=[O:7])[OH:5])[CH2:2][NH2:3].[Na+:15].[Na+:15]
Reactant: NCCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: NCCC(O)(P(=O)([O-])O)P(=O)([O-])O

Procedure:
In another embodiment, the invention is directed to a method for preparing a packaged liquid pamidronate alkaline salt composition by (a) combining a sugar with water; (b) combining the mixture of step (a) with pamidronic acid to form a pamidronic acid slurry; (c) adding to the pamidronic acid slurry sufficient aqueous solution of sodium hydroxide or potassium hydroxide to yield a solution having a pH of about 8.5; (d) adding to the resultant solution a pharmaceutically acceptable acid in an amount sufficient to lower the pH of the solution to about 6.5; (e) transferring the solution having a pH of about 6.5 into a vessel having an inner surface which does not react with the solution; and (f) sealing the vessel. Alternatively, a pamidronic acid aqueous slurry can be treated with aqueous sodium hydroxide or potassium hydroxide to form an aqueous solution of pamidronate disodium or pamidronate dipotassium. This solution can then be combined with mannitol and the resulting solution acidified to a pH of about 6.5 with, for example, phosphoric acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:21]=[N:22][CH:23]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][C:13]=1[F:20])=[O:4].[OH-].[Na+]>>[F:20][C:13]1[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:12]=1[NH:11][C:10]1[N:9]2[CH:21]=[N:22][CH:23]=[C:8]2[CH:7]=[CH:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2cncn2c1Nc1ccc(SC)cc1F
Agent: [Na+]
Agent: [OH-]
Product: CSc1ccc(Nc2c(C(=O)O)ccc3cncn23)c(F)c1
Temperature: 65 °C
Yield: 76.3 %

Procedure:
To a solution of 5-(2-fluoro-4-methylsulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (150 mg, 0.45 mmol) in IMS (10 mL) was added sodium hydroxide (0.5 mL, 1M aqueous solution, 0.5 mmol), the reaction mixture heated at 65° C. for 1.5 hours. The reaction mixture was concentrated in vacuo then taken up in water (ca. 15 mL), the aqueous solution was washed with diethyl ether before the pH was adjusted to pH 3 using 1M HCl, resulting in precipitation of a brown solid. The precipitate was extracted using ethyl acetate, the organic phase was isolated and washed with water followed by brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford the title compound as a brown solid (109 mg, 76%). 1H NMR (CD3OD): 7.67 (1 H, s), 7.44 (1 H, d, J=9.53 Hz), 7.39 (1 H, d, J=0.83 Hz), 7.24 (1 H, dd, J=9.57, 0.80 Hz), 7.15 (1 H, dd, J=11.47, 2.12 Hz), 7.02-7.01 (1 H, m), 6.76 (1 H, t, J=8.49 Hz), 2.49 (3 H, s).
Reaction SMILES: [C@@H:1]1([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:32])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C@@H:27]([C:29]([OH:31])=[O:30])[NH2:28])=[O:21])[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].O=C1CCC(=O)N1[O:40][C:41](=O)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:51]([O:50][C:48](=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][C:41]([NH:28][C@H:27]([C:29]([OH:31])=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:15]([NH:14][CH2:13][CH2:12][O:11][C@@H:1]1[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3])=[O:32])=[O:40])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C(CCCCCCC(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](N)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](NC(=O)CCCCCCC(=O)OCc2ccccc2)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N6-[6-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-6-oxohexanoyl]-L-lysine (310 mg, 0.669 mmol) in DMF (20 mL) at 0° C. was added benzyl 8-[(2,5-dioxopyrrolidin-1-yl)oxy]-8-oxooctanoate (242 mg, 0.669 mmol), followed by the addition of DIPEA (0.117 ml, 0.669 mmol). The reaction was warmed to 25° C. and stirred at this temp for 18 hr. The reaction mixture was concentrated, and the residue was purified by flash chromatography on C18 reverse phase silica gel, eluting with 0-30% CAN in water, to give the title compound. UPLC Method B: m/e=710.423 [M+1]; Rt=4.59 min.
Reaction SMILES: [OH:1][CH:2]([C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)[CH2:3][CH:4]=[CH2:5].[N+](=[CH2:20])=[N-].O>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C@H:6]([CH:2]([OH:1])[CH2:3][CH:4]2[CH2:20][CH2:5]2)[CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=CCC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](C(O)CC2CC2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
Add palladium (II) acetate (50.0 mg; 0.22 mmol) to a stirred solution of (3S)-tert-butyl 3-(1-hydroxybut-3-enyl)pyrrolidine-1-carboxylate (S-mix) (3.0 g, 12.43 mmol) and freshly prepared diazomethane (50 mL, about 23.8 mmol in diethyl ether) in THF (20 mL) under nitrogen at 0° C. (Caution: vigorous gas evolution). Stir at 0° C. for 10 minutes. Warm to room temperature, pour into water and extract with ethyl acetate (3×). Wash the combined organics with water and brine. Dry (MgSO4), filter and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 0-100% ethyl acetate in hexane to afford 2.9 g (91%) of the title compound. MS (m/z)=200.0 (M−55)
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([O:10][C:11](=[O:25])[CH:12]([CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13](=O)[CH3:14])[CH3:9].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.CCOCC>[CH2:8]([O:10][C:11]([C:12]1[CH:16]=[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13]=1[CH3:14])=[O:25])[CH3:9]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cc(-c2ccccc2)n(C2CCCCC2)c1C

Procedure:
Cyclohexylamine (5 mmol, 0.5 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g) and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting residue was resuspended in ether, then washed with water and brine. The organic layer was dried over MgSO4, and the solids were separated and the solvents removed under vacuum. Purification of the oil yielded the named product, 1H-NMR (CDCl3, ppm): 1.0 bm (2H), 1.23 t (3H), 1.6-1.7 bm (8H), 2.66 s (3H), 4.16 q (2H), 6.39 s (1H), and 7.25 bm (5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH2:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:24][CH:25]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: COc1ccccc1-c1cccn2nc(N)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: COc1ccccc1-c1cccn2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc12

Procedure:
[8-(2-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(2-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.312 mmol) and 1-(4-Bromo-phenyl)-4-methyl-piperazine (90.0 mg, 0.353 mmol) with 2,2′-Bis-dicyclohexylphosphanyl-biphenyl (34.0 mg, 0.0622 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a pale yellow foam (0.063 g, 49%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.39 (d, J=6.2 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.51 (d, J=6.9 Hz, 1H), 7.45 (d, J=7.5 Hz, 2H), 7.40 (t, J=7.8 Hz, 1H), 7.09 (t, J=7.3 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.95 (d, J=7.6 Hz, 2H), 6.91-6.86 (m, 1H), 6.65 (s, 1H), 3.81 (s, 3H), 3.17-3.12 (m, 4H), 2.61-2.56 (m. 4H), 2.36 (s, 3H). MS=415 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([O:17]CC)=[O:16])=[CH:11][N:10]1[CH3:20].O1CCCC1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([OH:17])=[O:16])=[CH:11][N:10]1[CH3:20]
Reactant: CCOC(=O)c1cn(C)n(-c2ccc(F)cc2F)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(C(=O)O)c(=O)n1-c1ccc(F)cc1F
Yield: 81.4 %

Procedure:
In the same manner as in Reference Example 65 and using ethyl 2-(2,4-difluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (2.4 g, 8.7 mmol), tetrahydrofuran (6 mL), methanol (5 mL) and 4N aqueous sodium hydroxide solution (8 mL) as starting materials, the title compound (1.8 g, 83%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[OH-].[Na+].O.Cl[CH2:14][CH:15]([OH:19])[CH2:16][CH2:17][Cl:18]>C(O)(C)C>[Cl:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: OC(CCl)CCCl
Reactant: COc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: COc1ccccc1OCC(O)CCCl

Procedure:
To a mixture of 2 moles (248.26 g.) of 2-methoxyphenol, 4 moles (160 g.) of sodium hydroxide, 250 ml. of water and 1 liter of isopropanol was added with stirring 2.2 moles (314.64 g.) of 1,4-dichloro-2-butanol. The mixture was refluxed gently overnight. The reaction mixture was extracted with 1 liter of isopropyl ether, dried over sodium sulfate and distilled under reduced pressure. The distillate which was collected at 136°-138° C./0.015 mm. (396.8 g.) solidified to a white crystalline solid which melted at 48°-50° C.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:16][CH2:17][CH2:18][NH2:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C>[CH2:1]([N:19]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:18][CH2:17][NH:16][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: NCCNC(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: c1ccc(CN(CCNC(c2ccccc2)c2ccccc2)Cc2ccccc2)cc1

Procedure:
A solution of 2.9 g of benzyl chloride in 25 ml of acetonitrile is added to 5.6 g of N-diphenylmethyl-ethylenediamine in 30 ml of boiling acetonitrile. The mixture is heated under reflux for 12 hours, concentrated and partitioned between diethyl ether and 10% sodium hydroxide solution. The organic phases are dried over sodium sulphate and concentrated by evaporation. The residue can be recrystallised from methanol or diisopropyl ether. N,N-dibenzyl-N'-diphenylmethyl-ethylenediamine having a melting point of 89°-91° C. is obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.Br[C:17]1[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:22][N:21]1[C:17]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=3)[C:10]2=[O:13])=[CH:18][N:19]=[CH:20]1
Reactant: Cn1cncc1Br
Reactant: O=C1NCCc2ccc(C(F)(F)F)cc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cncc1N1CCc2ccc(C(F)(F)F)cc2C1=O
Yield: 24.7 %

Procedure:
Using analogous conditions as described for the preparation of Example 1A above, 7-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one (I-4-d: 150 mg, 0.6849 mmol) was reacted with 5-bromo-1-methyl-1H-imidazole (165 mg, 1.0273 mmol), 1,4-dioxane (3 mL), copper iodide (13.01 mg, 0.0685 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (29.17 mg, 0.205 mmol) and potassium phosphate (434.6 mg, 2.05 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 50 mg of the product (24.75% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])/[CH:11]=N/O)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH:15]S(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:11](=[O:15])[C:10](=[O:14])[NH:9]2)=[C:6]([F:8])[CH:7]=1
Reactant: O=C(/C=N/O)Nc1cc(F)cc(Br)c1
Reactant: O=S(=O)(O)O
Product: O=C1Nc2cc(Br)cc(F)c2C1=O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
(E)-N-(3-bromo-5-fluorophenyl)-2-(hydroxyimino)acetamide (6.13 g, 23.6 mmol) was slowly added to a solution of conc. H2SO4 (30 mL) in an ice bath. The temperature of the reaction mixture was maintained below 50° C. After completion of the addition, the solution was heated to 90° C. for 1 h. After it was cooled to rt, the mixture was poured into ice-water and stirred vigorously for 1 h. The insoluble solid was filtered and washed with water, dried under vacuum to provide 7.4 g of crude product, which was used into the next step without further purification. MS (ESI): 242, 244 (MH−).