Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14](=[O:27])[CH2:15]CN1CCC2C(=CC=CC=2)C1.Cl.C(O)C>>[C:14]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1[CH3:2])(=[O:27])[CH3:15]
Reactant: Cc1c(C(=O)CCN2CCc3ccccc3C2)cnn1-c1ncccn1
Agent: Cl
Solvent: CCO
Product: CC(=O)c1cnn(-c2ncccn2)c1C

Procedure:
2.42 g of 4-acetyl-1-(2-pyrimidinyl)-5-methylpyrazole, 2.89 g of the compound obtained in the above (1) and 12 ml of a 1N hydrochloric acid/ethanol solution were dissolved in 150 ml of ethanol and heated under reflux for 32 hours. During this period, 10 g of paraformaldehyde was added thereto in portions. The reaction mixture was evaporated and the residue was neutralized by adding an aqueous solution of sodium hydroxide. After extracting with chloroform, the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to thereby give 2.17 g of the title compound in the form of a solid product. 1H-NMR (CDCl3) δ: 2.67 (t, 4H, J=5 Hz), 2.88 (t, 2H, J=7 Hz), 3.00 (s, 3H), 3.09 (t, 2H, J=7 Hz), 3.21 (t, 4H, J=5 Hz), 6.83 (dd, 1H, J=8, 2 Hz), 6.95 (ddd, 1H, J=8, 2, 1 Hz), 7.03 (t, 1H, J=2 Hz), 7.10 (t, 1H, J=8 Hz), 7.35 (t, 1H, J=5 Hz), 8.15 (s, 1H), 8.86 (d, 2H, J=5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:32])[C:15](=[O:31])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([O:26][CH2:27][CH2:28][O:29]C)[CH:17]=2)=[C:4]([O:33][CH3:34])[CH:3]=1.BrCCO.C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:32])[C:15](=[O:31])[C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([O:26][CH2:27][CH2:28][OH:29])[CH:17]=2)=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: COCCOc1cc(C(=O)N(C)c2cnccc2-c2ccc(F)cc2OC)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: OCCBr
Agent: [Cl-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(OCCO)cc(C(F)(F)F)c1

Procedure:
To a suspension of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-3-hydroxy-N-methyl-5-(trifluoromethyl)benzamide (0.06 g, 143 μmol, Example 236, intermediate) in acetonitrile (2 mL) were added 2-bromoethanol (21.4 mg, 12.1 μL, 171 μmol) and potassium carbonate (23.7 mg, 171 μmol) and the light brown suspension was heated to reflux for 24 hours before another batch of 2-bromoethanol (21.4 mg, 12.1 μL, 171 μmol) and potassium carbonate (29.6 mg, 214 μmol) were added. After heating at reflux for another 20 hours the reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered and evaporated. The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless foam (0.021 g; 31%). MS (ESI): m/z=465.14 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([OH:33])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:32])([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>ClCCl>[C:41]([O:33][C@H:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14](/[CH:13]=[CH:12]/[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([OH:32])([CH3:31])[CH3:30])(=[O:43])[CH3:42]
Reactant: CC(C)(O)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H](CCc1ccccc1C(C)(C)O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 2-[2-[3(S)-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-3-hydroxy propyl]phenyl]-2-propanol (100 gm) in dichloromethane (500 ml) at 25-30° C. 4-di(methyl amino)pyridine (5.32 gm) was added and cooled to 0° C. To the reaction mixture Triethylamine (26.4 gm) was added at 0° C. Acetic anhydride (26.7 gm) was added slowly at temp. 0-5° C. over 30-60 min and maintained the reaction at temp. 0-5° C. over 30 min. Reaction completion was monitored by TLC. After reaction completion the reaction mass was quenched into 7% NaHCO3(500 ml) and stirred for 15 min. Temperature was raised to 25-30° C. and maintained for 30 min. Reaction mass was settled for 15 min and separated the organic layer. Aq.layer was extracted with dichloromethane (250 ml). The combined organic layer was washed with 25% NH4Cl solution (500 ml). Organic layer was distilled below 40° C. to get the desired product as residue.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]([C:19]([OH:21])=O)=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27].C(OCC)(=O)C>C(Cl)Cl.CCCCCC>[CH2:26]([N:28]([CH2:29][CH3:30])[C:19]([C:12]1[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])=[CH:16][CH:15]=[C:14]([O:17][CH3:18])[CH:13]=1)=[O:21])[CH3:27]
Reactant: COc1ccc(-c2ccccc2OC(C)C)c(C(=O)O)c1
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cc(OC)ccc1-c1ccccc1OC(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 66.2 %

Procedure:
Prepare a solution of 2'-isopropoxy-4-methoxy-biphenyl-2-carboxylic acid (4.80 g, 0.0168 mole) in 125 mL methylene chloride (dichloromethane). Under an argon atmosphere, at ambient conditions, add thionyl chloride (2.99 g, 0.0356 mole, 1.835 mL). Continue stirring for about 45 minutes, observing the color change to light brown. Cool the reaction mixture to 0° C. and dropwise add diethylamine (22.00 mL, 15.627 g, 0.21 mole), ensuring the temperature does not exceed 25° C. Continue stirring for 30 minutes after addition of the amine is complete. Dilute the reaction to 150 mL of methylene chloride and wash the organic phase with water, separate and wash twice with 100 mL 5% sodium bicarbonate. Separate and wash with brine (sat'd NaCl) and dry over magnesium sulfate. Filter through celite and evaporate on a rotary evaporator to give a viscous light brown liquid. Chromatography (30% ethyl acetate: 70% hexane) gives a pale yellow liquid. Place under near vacuum to give a waxy solid of the title compound (3.80 g, 66%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29].C(N(CC)CC)C>ClCCl>[CH:31]([O:30][C:28]([N:23]1[CH2:24][CH2:25][CH:20]([C@@:18]2([CH3:26])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:29])([CH3:33])[CH3:32]
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC([C@]2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine by treatment with isopropyl chloroformate in the presence of triethylamine using dichloromethane as a solvent. LC (method 6): tR=0.96 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(Cl)Cl)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:26][CH2:27][N:28]([S:31]([C:34]3[CH:35]=[C:36]([OH:41])[C:37]([OH:40])=[CH:38][CH:39]=3)(=[O:33])=[O:32])[CH2:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[O:40][C:37]3[CH:38]=[CH:39][C:34]([S:31]([N:28]4[CH2:27][CH:26]=[C:25]([C:22]5[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=5)[CH2:30][CH2:29]4)(=[O:33])=[O:32])=[CH:35][C:36]=3[O:41]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(Cl)(Cl)c2ccc(Cl)cc2)cc1
Reactant: O=S(=O)(c1ccc(O)c(O)c1)N1CC=C(c2ccc(F)cc2)CC1
Product: Cc1ccc(C2(c3ccc(Cl)cc3)Oc3ccc(S(=O)(=O)N4CC=C(c5ccc(F)cc5)CC4)cc3O2)cc1

Procedure:
Using 4-chlorophenyl-4-methylphenyl-dichloromethane (57 mg, 0.2 mmol) and 4-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonyl]-benzene-1,2-diol (69 mg, 0.2 mmol) as a starting material, the title compound was obtained as an off-white crystalline solid (90 mg, 80%) after taking the residue up in hexane/ethyl acetate (4/1), stirring for 10 minutes, filtering the solid and drying.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([Si:17]([CH3:24])([CH3:23])[O:18][CH2:19][C@@H:20]1[CH2:22][O:21]1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([Si:17]([CH3:24])([CH3:23])[O:18][CH2:19][C@@H:20]([OH:21])[CH2:22][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CO1
Product: CC(C)(C)[Si](C)(C)OC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2

Procedure:
Starting from 6-amino-4H-benzo[1,4]oxazin-3-one and tert-butyl-dimethyl-((S)-1-oxiranylmethoxy)-silane and using a procedure analogous to that of Example 201, step 201.ii, the title compound was obtained as a pale brown foam (5.2 g, 66% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:22][N:23](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)#[N:23]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C#N)cn2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 4-(5-bromopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (compound 26.1, 1 g, 2.80 mmol, 1.00 equiv), zinc cyanide (400 mg, 3.42 mmol, 1.22 equiv), Pd(PPh3)4 (200 mg, 0.17 mmol, 0.06 equiv) in DMF (50 mL) was stirred under nitrogen for 2 h at 100° C. After cooling to room temperature, the reaction was then quenched by careful addition of 300 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×100 mL of ethyl acetate. The combined organic layers were washed with 1×100 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:4) yield 0.5 g (58%) of the title compound as a yellow oil.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][C:7](=[O:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].O.Cl>CO>[OH:15][CH:7]([CH2:6][CH2:5][O:4][CH3:3])[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: COCCC(=O)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCC(O)C(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
At 0° C., 1.05 g (27.6 mmol) of sodium borohydride were added a little at a time to a solution of 5.20 g (27.6 mmol) of tert-butyl 4-methoxy-2-oxobutanoate in 68.5 ml of methanol. The reaction mixture was stirred for another 5 min, 5 ml of water were added and the pH was adjusted to 6 using aqueous hydrochloric acid (1N). Methanol was removed under reduced pressure at 30° C. and the aqueous phase that remained was extracted three times with 50 ml of diethyl ether. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure (25° C., 70 mbar). Yield: 4.48 g (77% of theory)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C@@H:8]([NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[CH:17][CH:16]=1)[CH2:7][CH2:6]2)=O.C1COCC1.[CH2:34]([NH:38][CH3:39])[CH:35]([CH3:37])[CH3:36].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH2:34]([N:38]([CH2:1][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C@@H:8]([NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[CH:17][CH:16]=1)[CH2:7][CH2:6]2)[CH3:39])[CH:35]([CH3:37])[CH3:36]
Reactant: O=Cc1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Reactant: CNCC(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CN(C)Cc1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of N-((S)-6-formyl-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (0.50 g), THF (5 ml), methanol (2 ml), isobutylmethylamine (0.23 g) and acetic acid (0.24 g) was added polymer-bound sodium cyanoborohydride (2.7 mmol), and the suspension was agitated at room temperature for 12 hours. The polymer was filtered off with suction and the filtrate was concentrated. The residue was purified by preparative HPLC. The product was thus obtained with the molecular weight of 450.63 (C28H38N2O3); MS (ESI): 451 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]([O:16][C:17]([NH:19][C@H:20]([C:22](O)=[O:23])[CH3:21])=[O:18])([CH3:15])([CH3:14])[CH3:13].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[C:12]([O:16][C:17]([NH:19][C@H:20]([C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)=[O:23])[CH3:21])=[O:18])([CH3:14])([CH3:15])[CH3:13]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc2c(c1)CC(=O)N2
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 5-amino-2-oxindole (800 mg, 5.4 mM) and N-tert-butoxycarbonylalanine (1020 mg, 5.4 mM) in dichloromethane (50 ml) were added benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (2800 mg, 5.6 mM) and N-methylmorpholine (1.2 ml, 11 mM). The mixture was stirred for 15 h at room temperature. Then the solvent was evaporated under vacuum, the residue suspended in water and extracted 3 times with ethyl acetate. The collected extracts were evaporated and then purified by flash chromatography on silica gel using as eluant cyclohexane/ethylacetate 1:9. Thus pure 5-(N-tert-butoxycarbonylalanylamino)-2-oxindole was obtained (600 mg). A solution of the above compound (250 mg, 0.97 mM) in trifluoroacetic acid (15 ml) was maintained for 1 h at room temperature. Then the solution was concentrated under vacuum and ether added to precipitate 5-(alanylamino)-2-oxindole.
Reaction SMILES: [I:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=1.[NH2:24][NH2:25]>CCO>[I:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:24][NH2:25])=[O:19])=[CH:16][CH:15]=1
Reactant: NN
Reactant: COC(=O)c1ccc(-c2nc(-c3ccccn3)n(C)c2I)cc1
Solvent: CCO
Product: Cn1c(-c2ccccn2)nc(-c2ccc(C(=O)NN)cc2)c1I
Temperature: 25 °C

Procedure:
Methyl 4-(5-iodo-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzoate (Step 3, 2 g, 1.9 mmol) was suspended in 10 mL of EtOH and 3 mL of anhydrous hydrazine, and heated at reflux for 2 h. After the reaction was cooled to rt, the solid product was filtered, washed with hexanes, and air-dried to give 750 mg of 4-(5-iodo-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzohydrazide. LCMS: [M+1]=420.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)#[CH:9].[CH3:21][C:22]([CH3:43])([CH3:42])[CH2:23][C:24]([NH:26][C:27]1[C:35](C2C=NC=CC=2)=[C:30]2[N:31]=[CH:32][CH:33]=[CH:34][N:29]2[N:28]=1)=[O:25]>O1CCCC1.C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.[Cu]I>[CH3:21][C:22]([CH3:43])([CH3:42])[CH2:23][C:24]([NH:26][C:27]1[C:35]([C:9]#[C:8][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)=[C:30]2[N:31]=[CH:32][CH:33]=[CH:34][N:29]2[N:28]=1)=[O:25]
Reactant: C#Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)CC(=O)Nc1nn2cccnc2c1-c1cccnc1
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(=O)Nc1nn2cccnc2c1C#Cc1ccc(OC(F)(F)F)cc1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
Triethylamine (3 mL) was added to a mixture of bis(tri-t-butylphosphino)palladium (9.6 mg, 0.019 mmol; Strem), 1-ethynyl-4-trifluoromethoxybenzene (0.12 mL, 0.75 mmol), CuI (3.6 mg, 0.019 mmol) and the product from Example 110B (117 mg, 0.38 mmol) in anhydrous tetrahydrofuran (3 mL). The mixture was purged with a nitrogen stream for 2 minutes, and then stirred at 85° C. for 18 hours in a sealed tube. The reaction mixture was cooled and partitioned between dichloromethane (2×50 mL) and 1.0 M sodium carbonate (100 mL). The combined organic extracts were dried (sodium sulfate), filtered, and concentrated under vacuum. The resulting residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-100% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 9.12 (dd, J=6.9, 1.7 Hz, 1H), 8.65 (dd, J=4.1, 1.7 Hz, 1H), 7.58-7.60 (m, 2H), 7.41-7.44 (m, 2H), 7.17 (dd, J=6.9, 4.1 Hz, 1H), 2.29 (s, 2H), 1.07 (s, 9H); MS (APCI) m/z 417 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2)=[O:4].[CH3:16][C@@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][NH:18]1>>[CH3:16][C@H:17]1[NH:18][CH2:19][CH2:20][N:21]([CH2:2][C:3]([NH:5][C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH:8]=[CH:9][CH:10]=[N:11]3)=[O:4])[CH2:22]1
Reactant: C[C@@H]1CNCCN1
Reactant: O=C(CCl)Nc1cccc2ncccc12
Product: C[C@@H]1CN(CC(=O)Nc2cccc3ncccc23)CCN1

Procedure:
The subtitle compound was prepared from 2-chloro-N-(quinolin-5-yl)acetamide (1 g) (J Indian Chem Soc, 1940, 17, 619-621) and (R)-2-methylpiperazine (0.5 g) by the method of Example 58 step (i) as a white solid. Yield: 1.4 g
Reaction SMILES: C[N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]2[C:11]([CH2:21][C:22]([OH:24])=O)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:13]=[C:3]12.[CH3:25][O:26][CH2:27][CH2:28][NH2:29]>O1CCCC1>[CH3:25][O:26][CH2:27][CH2:28][NH:29][C:22](=[O:24])[CH2:21][C:11]1[N:4]2[C:3]([NH:2][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=32)=[N:13][C:12]=1[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1
Reactant: Cc1ccc(-c2nc3n(C)c4ccccc4n3c2CC(=O)O)cc1
Reactant: COCCN
Solvent: C1CCOC1
Product: COCCNC(=O)Cc1c(-c2ccc(C)cc2)nc2[nH]c3ccccc3n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.3 %

Procedure:
A suspension of 3.5 g (0.11 mol) of 9-methyl-2-(4-methylphenyl)-9H-imidazo[1,2-a]benzimidazole-3-acetic acid is prepared in 70 ml of dry tetrahydrofuran, 2.67 g (0.165 mol) of N,N'-carbonyldiimidazole are added in small portions, over 10 min, and the mixture is stirred at room temperature for 1 h. It is cooled in an ice-cold water bath, and 1.65 g (0.165 mol) of 2-methoxyethylamine in solution in 4 ml of dry tetrahydrofuran are added. Stirring is continued for 1 h at cold temperature, and then at room temperature for 4 h. The solvent is evaporated under reduced pressure. The residue is crystallized from water. The solid is collected by filtration, washed, dried and recrystallized from ethanol. 2.9 g of compound are finally obtained. Melting point: 189°-190° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11]S)=[CH:2]1.C1C=CC2NC=C(CCO)C=2C=1.[C:25]([OH:32])(=[O:31])[CH2:26][CH2:27][C:28]([CH3:30])=[O:29].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1C=CC=CC=1>[CH3:30][C:28]1([CH2:27][CH2:26][C:25]([OH:32])=[O:31])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][O:29]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: SCCc1c[nH]c2ccccc12
Reactant: CC(=O)CCC(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: OCCc1c[nH]c2ccccc12
Solvent: c1ccccc1
Product: CC1(CCC(=O)O)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of the starting material of formula II, tryptophol (500 mg.), levulinic acid (580 mg.), 75 ml. of benzene, 1.7 g. of phosphorus pentoxide and about 0.5 g. of diatomaceous earth (Celite) is stirred magnetically at room temperature for 15 minutes and then at 70° C. for 11/2 hr. The reaction mixture is filtered. The filtrate is washed three times with 5N NaOH; the combined aqueous phase is washed twice with ether and then rendered acidic with cold 50% HCl. The aqueous phase is extracted with chloroform. The chloroform extract is dried (Na2SO4) and evaporated to dryness. The residue is crystallized from ethyl acetate-petroleum ether to afford the title compound, m.p. 104° - 110° C., nmr (CDCl3) δ1.47 (3H), 2.18 (4H), 2.74 (2H), 3.96 (2H), 7.18 (1H), 9.60 (1H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CC(=O)CC>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH3:29]
Reactant: Oc1ccc(OCc2ccc(F)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(OCc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A solution of 3 g of 4-(4-fluoro-benzyloxy)-phenol in 40 ml of 2-butanone was treated with 2.5 g potassium carbonate and 1.6 ml of ethyl bromoacetate. The mixture was stirred at 80° C. during 3 h, then, in order to complete the reaction, 1.7 g of potassium carbonate and 1.9 ml of ethyl bromoacetate were added successively in four portions during a period of 24 h. For the working-up, the reaction mixture was cooled to room temperature, then treated with water and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulphate and evaporated under reduced pressure. There were obtained 2.95 g (71% of theory) of [4-(4-fluoro-benzyloxy)-phenoxy]-acetic acid ethyl ester as brownish crystals which were pure enough to be used in the next step without further purification; MS: m/e=304 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15][C:16]([O-])=[O:17])[C:12]([CH3:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Li+].[BH4-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15][CH2:16][OH:17])[C:12]([CH3:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(C)c(CC(=O)[O-])n2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C)c(CCO)n2)cc1

Procedure:
Following the same procedure described for the preparation of Example 470 and starting from [6-(4-methoxyphenyl)-3-methyl-2-pyridinyl]acetate (Example 479, 0.25 g, 0.88 mmol), LiBH4 (0.88 mL, 2 M in THF, 1.75 mmol) in THF (4.4 mL), the title compound was obtained (0.18 g, 84%). 1H NMR (400 MHz, CD2Cl2) δ 7.87 (d, 2H), 7.55-7.45 (m, 2H), 6.98 (d, 2H), 4.18-4.08 (m, 2H), 3.85 (s, 3H), 3.06-2.95 (m, 2H), 2.29 (s, 3H).