Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(CC(O)=O)C.[C:7]([N:14]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:15]([C:22](O)=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C[N:33]1CCOCC1.ClC(OCC(C)C)=O.C(OC[C@@H](N)CC(C)C)C>C(OCC)(=O)C>[C:7]([N:14]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[C@H:15]([C:22]([NH2:33])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CCOC[C@@H](N)CC(C)C
Solvent: CCCC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](Cc1c[nH]cn1)C(N)=O
Reaction time: 0.25 h

Procedure:
A mixture of Nα -Nim -bis-BOC-histidine ethyl acetate solvale (1.92 g, 5.0 mmol), 4-methylmorpholine (0.55 mL, 5.0 mmol) and isobutyl chloroformate (0.65 mL, 5.0 mmol) in ethyl acetate (50 mL) was stirred in an ice bath under N2 for 15 minutes. A solution of (S)-1-ethoxy-2-amino-4-methylpentane (0.73 g, 5.0 mmol) in ethyl acetate (2 mL) was then added and the reaction stirred at room temperature for 20 hours. After washing with 10% citric acid, brine, saturated NaHCO3 solution and brine, the ethyl acetate extract was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was flash chromatographed over silica gel. Elution with a mixture of 2% methanol and 98% chloroform afforded pure BOC-protected histidineamide (0.90 g).
Reaction SMILES: O.[NH2:2][NH2:3].[OH:4][C:5]1[C:10]([C:11]([O:13]C)=O)=[CH:9][CH:8]=[CH:7][N:6]=1>C(O)C>[O:4]=[C:5]1[C:10]([C:11]([NH:2][NH2:3])=[O:13])=[CH:9][CH:8]=[CH:7][NH:6]1
Reactant: COC(=O)c1cccnc1O
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc[nH]c1=O

Procedure:
Hydrazine hydrate (0.192 mL, 3.92 mmol) was added to a solution of the methyl 2-hydroxy-3-pyridinecarboxylate (400 mg, 2.61 mmol, commercially available from e.g. Apollo or Butt Park) in ethanol (10 mL) and the reaction was heated to reflux for 16 hrs. The reaction was cooled and the solvent was evaporated to afford an off-white solid in 395 mg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][Si](C(C)(C)C)(C)C)[CH:15]=2)[C:10]([Cl:25])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]([O:5][C:6](=[O:26])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([Cl:25])=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1cc(Cl)c2ccc(O[Si](C)(C)C(C)(C)C)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CC(C)(C)OC(=O)Cn1cc(Cl)c2ccc(O)cc21

Procedure:
In analogy to the procedure described in example 3 b], [6-(tert-butyl-dimethyl-silanyloxy)-3-chloro-indol-1-yl]-acetic acid tert-butyl ester was treated with tetrabutylammonium fluoride hydrate to obtain (3-chloro-6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester as colorless gum.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
To a mixture of 4.0 g of 4-trifluoromethoxy phenol and 25 ml of acetic acid, a mixture of 2.02 g of 70% nitric acid and 10 ml of acetic acid was added dropwise with the temperature kept at 10-15° C. The reaction mixture was stirred for five hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over sodium sulfate, and then concentrated under reduced pressure to give 4.53 g of 4-trifluoromethoxy-2-nitrophenol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[S:5][CH:6]=1.Br[C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25]([CH3:30])=[CH:24]3)[CH:12]=1>>[CH3:30][C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([NH:20][C:17]1[CH:16]=[CH:15][N:14]=[C:13]3[CH:12]=[C:11]([C:4]4[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=4)[S:19][C:18]=13)=[CH:29][CH:28]=2
Reactant: Cc1csc(B(O)O)c1
Reactant: Cc1cc2cc(Nc3ccnc4cc(Br)sc34)ccc2[nH]1
Product: Cc1csc(-c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)c1

Procedure:
The title compound was prepared from 4-methyl-2-thiopheneboronic acid and (2-bromothieno[3,2-b]pyridin-7-yl)-(2-methyl-1H-indol-5-yl)-amine by the procedure analogous to example 2 above. 1H NMR (400 MHz, CD3OD) δ8.00 (d, 1H), 7.25 (m, 3H), 7.10 (s, 1H), 6.95 (s, 1H), 6.94 (dd, 1H), 6.52 (d, 1H), 6.08 (s, 1H), 2.39 (s, 3H), 2.18 (s, 3H); RP18-HPLC RT: 6.41 minutes; API MS: 376 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([F:45])[CH:38]=1)[CH3:36]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:34]=[C:35](/[C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([F:45])[CH:38]=3)\[CH3:36])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: COc1ccc(C(C)=CBr)cc1F
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(Cl)ccc42)CCN(C)CC3)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (80 mg, 0.34 mmol) was dissolved in DMF (6 mL). Copper (I) iodide (6 mg, 0.034 mmol), L-proline (8 mg, 0.068 mmol) and K3PO4 (145 mg, 0.68 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-Bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100 mg, 0.34 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 46 mg. 1HNMR (CD3OD, Oxalate salt) δ (ppm): 7.58 (s, 1H), 7.42 (m, 2H), 7.16 (m, 3H), 6.95 (s, 1H), 3.90 (s, 3H), 3.60 (m, 4H), 3.25 (m, 4H), 3.05 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:17][C:18](O)=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14](O)=[O:15]>O1CCCC1>[OH:15][CH2:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:17][CH2:18][OH:19]
Reactant: O=C(O)Cc1ccccc1CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1ccccc1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium aluminum hydride (0.332 mol) and tetrahydrofuran (THF, 175 mL) are placed in a dry 500-mL three-necked round-bottom flask fitted with a condenser, addition funnel, nitrogen inlet, and magnetic stirrer. The mixture is cooled with an ice bath and 1,2-phenylene diacetic acid (0.165 mol) in THF (100 mL) is added dropwise to the stirring mixture. After the addition is complete, the flask is removed from the ice bath and allowed to warm to room temperature. The reaction mixture is heated at reflux for two hours, then stirred overnight at room temperature. After cooling the mixture with an ice bath, water (12.6 mL) is added dropwise, followed by the successive dropwise addition of 15 percent aqueous sodium hydroxide (12.6 mL) and water (38 mL). The resulting mixture is warmed to room temperature, and the solids separated by vacuum filtration. The filtrate is placed on a rotary evaporator to remove the solvent. The remaining solid is recrystallized from toluene-hexane to give the 1,2-di(hydroxyethyl)benzene.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH2:14])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(OS(C)(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(CCN)cc1
Yield: 99.8 %

Procedure:
4-{2-[(tert-Butoxycarbonyl)amino]ethyl}phenyl methanesulfonate (3.98 g, 12.62 mmol) was dissolved in DCM (12 mL) and TFA (10 mL) and stirred at rt for 4 h. The reaction mixture was concentrated and redissolved in EtOAc, washed with saturated aqueous K2CO3, and the organic phase was dried with Na2SO4, filtered and evaporated affording the title compound (2.71 g, 99.8%). 1H NMR (500 MHz, CD3OD): δ 2.79 (t, 2H), 2.89 (t, 2H), 3.21 (s, 3H), 7.26 (d, 2H), 7.32 (d, 2H); 13C NMR (125 MHz, CD3OD): δ 36.24, 38.34, 42.95, 122.11, 130.19, 139.44, 148.28; Mass Spectrum: M+H+ 216.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:19]([N:21]([CH2:36][CH3:37])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:20]>>[CH2:36]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=4)=[CH:10][CH:11]=3)[NH:15][C:14]2=[O:18])[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:37]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2ccc(-c3cc(Cl)cc(Cl)c3)cc2N1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cc(-c4cc(Cl)cc(Cl)c4)ccc32)c1C
Yield: 44.6 %

Procedure:
6-(3,5-Dichlorophenyl)-1,3-dihydroindol-2-one (64 mg, 0.23 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (60 mg) to give 53 mg (44%) of the title compound as a light brown solid.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:9][Si:10]([CH3:15])([CH3:14])[CH2:11]CO>>[C:1]([O:7][CH2:8][CH2:9][Si:10]([CH3:15])([CH3:14])[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: COC(=O)CC(C)=O
Reactant: C[Si](C)(C)CCO
Product: CC(=O)CC(=O)OCC[Si](C)(C)C
Yield: 98 %

Procedure:
10.66 gm (91.8 mMol) methyl acetoacetate and excess 2-(trimethylsilyl)ethanol were heated together at reflux.Methanol was distilled (68° C.) from the reaction mixture andheating was continued until the head temperature dropped below 65° C. The reaction mixture was then concentrated under reduced pressure at 40° C. to provide 18.24 gm (98%) of the desired compound as a pale yellow oil.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6]>S(Cl)(Cl)=O>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([Cl:1])=[O:6]
Reactant: O=C(O)c1ccc(OC2CCN(C3CCC3)CC2)cc1Cl
Agent: Cl
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(OC2CCN(C3CCC3)CC2)cc1Cl
Yield: 199.4 %

Procedure:
2-Chloro-4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoic acid hydrochloride (D35) (0.20 g) was dissolved in thionyl chloride (10 ml) and heated under reflux for 1.5 h. The thionyl chloride was removed by evaporation and the residue evaporated from DCM (3×10 ml) to give the title compound (D36) (0.21 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[O:5])[CH3:2].CC([Li])CC.C1CCCCC1.Cl[Si:25]([CH3:28])([CH3:27])[CH3:26]>C1COCC1.C(OCC)(=O)C.O>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:5])[CH3:12]
Reactant: CCN(CC)C(=O)c1ccsc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccsc1[Si](C)(C)C
Yield: 33.4 %

Procedure:
To a solution of 3 g (16.4 mmol) of 3-thiophenecarboxylic acid, N,N-diethylamide, from step 2a above, in 20 mL of THF cooled to -78° C. and stirred under N2 was added 1.68 g (2.1 mL, 16.4 mmol) of N,N,N',N'-tetramethylenediamine (TMEDA), followed by 12.6 mL of a 1.3M solution of 2-butyl lithium in cyclohexane (16.4 mmol), and the reaction was stirred for 1 hour. Chlorotrimethylsilane (1.78 g, 2.1 mL, 16.4 mmol) was added, and the solution was stirred for 45 min, then poured into 100 mL of water. The mixture was extracted 3× with methylene chloride, and the solvent was washed with brine, dried over MgSO4, concentrated, and purified by flash chromatography, eluting with 3:1 hexane:ethyl acetate to afford 1.4 g (38% yield) of the title product as an oil. MS 256 (M+H)+. NMR (CDCl3) δ:7.51 (d, 1 H, J=5 Hz), 7.10 (d, 1 H, J=5 Hz), 3.60-3.50 (bm, 2H), 3.3-3.10 (bm, 2H), 1.30-1.20 (bm, 3H), 1.15-1.05 (bm, 3H), 0.34 (s, 9H).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][C:26](O)=[O:27])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1.C(CN)O.CCOC(C)=O>[C:1]([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][OH:27])[N:22]=[CH:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: B
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: NCCO
Product: OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(1-Trityl-1H-imidazol-4-yl)acetic acid (65 g, 0.17 mol) is suspended in THF (400 mL) and cooled to 0° C. To this is added BH3.THF solution (350 mL, 1.0 M). The clear solution obtained is stirred at 0° C. for 30 min before warming to room temperature until LCMS indicated completion of the reaction. The solution is cooled again to 0° C. and quenched carefully with water (250 mL). The resulting solution is diluted with EtOAc (300 mL) and transferred to a separatory funnel and the aqueous layer is extracted with EtOAc. The organic phase is dried over anhydrous Na2SO4 and evaporated to give a sticky residue which is taken up in ethanolamine (800 mL) and heated to 90° C. for 2 h. The reaction is transferred to a separatory funnel, diluted with EtOAc (1 L) and washed with water (3×600 mL). The organic phase is dried over anhydrous Na2SO4 and evaporated to give 2-(1-trityl-1H-imidazol-4-yl)-ethanol as a white solid that is used as is without further purification. MS (ESI) m/z 354.8 (M+H) (prepared by alternate method in J. Med. Chem. 1996, 39(19), 3806)
Reaction SMILES: ICC.[CH:4]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:9]=1[NH2:15])(C)[CH3:5]>>[CH2:4]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:9]=1[NH2:15])[CH3:5]
Reactant: CC(C)Oc1cccc(N)c1N
Solvent: CCI
Product: CCOc1cccc(N)c1N

Procedure:
Prepared from iodoethan in analogy to 3-isopropoxy-benzene-1,2-diamine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:3]=1[CH:4]=O.[CH3:13][Si:14]([CH3:21])([CH3:20])[C:15]#[C:16][CH2:17][CH2:18][NH2:19]>>[Cl:1][C:2]1[C:3]2[C:6]([CH:7]=[CH:8][CH:9]=1)=[N:10][N:19]([CH2:18][CH2:17][C:16]#[C:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[CH:4]=2
Reactant: O=Cc1c(Cl)cccc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C#CCCN
Product: C[Si](C)(C)C#CCCn1cc2c(Cl)cccc2n1
Yield: 42.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 149(A), from 2-chloro-6-nitro-benzaldehyde (210 mg, 1.13 mmol) and 4-trimethylsilanyl-but-3-ynylamine (210 mg, 1.50 mmol). The crude product was purified by flash chromatography (cyclohexane/AcOEt 92.5:7.5) to yield 4-chloro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (134 mg, 0.48 mmol, 43%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:4]=1[C:5]([C:7](=[CH:13]OCC)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])[CH3:2].[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH2:1]([C:3]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:4]=1[C:5]([C:7](=[CH:13][NH:28][CH:25]1[CH2:27][CH2:26]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(F)c(F)c(F)c1CC
Reactant: NC1CC1
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(F)c(F)c(F)c1CC

Procedure:
Employing ethyl 2-(2-ethyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate and cyclopropylamine, the procedure of Reference Example 21 is repeated to give ethyl 2-(2-ethyl-3,4,5,6-tetrafluorobenzoyl)-3-cyclopropylaminoacrylate.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]2[CH2:33][CH2:32]2)[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[O:28][CH:27]=[N:26][CH:25]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]2[CH2:33][CH2:32]2)[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[O:28][CH:27]=[N:26][CH:25]=1)=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(-c3cnco3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC2CC2)c(=O)c2ccc(-c3cnco3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a solution of tert-butyl[4-butoxy-2-cyclopropylmethyl-6-(1,3-oxazol-5-yl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.19 g, 0.4 mmol) in ethyl acetate (5 mL) was added a solution of 4N hydrogen chloride in ethyl acetate (5 mL) and the obtained solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were recrystallized from methanol-diethyl ether to give 3-(aminomethyl)-4-butoxy-2-cyclopropylmethyl-6-(1,3-oxazol-5-yl)-1(2H)-isoquinolinone hydrochloride (0.15 g, 93.8%) as crystals.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH2:18][OH:19])([CH2:8][O:9][CH2:10][C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:12][OH:13])[CH2:6][OH:7].[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:52])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[CH:22][CH2:23][CH2:24][CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:52])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[CH:22][CH2:23][CH2:24][CH2:25][O:13][CH2:12][C:11]([CH2:16][OH:17])([CH2:10][O:9][CH2:8][C:5]([CH2:18][OH:19])([CH2:6][OH:7])[CH2:4][OH:3])[CH2:14][OH:15]
Reactant: CC(=CCCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)CCCC(C)C
Reactant: OCC(CO)(CO)COCC(CO)(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=CCCCOCC(CO)(CO)COCC(CO)(CO)CO)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
0.37 g (60%, 9.2 mmol) of sodium hydride was added to a solution of 2.35 g (9.24 mmol) of dipentaerythritol in dry N,N-dimethylformamide (6 mL) with cooling on ice. After the mixture was stirred for 1 hour at 50° C., the above (5,9,13,17-tetramethyloctadec-4-enyl)tosylate was added dropwise thereto, with additional stirring for 20 hours at 60° C. After addition of water at 0° C., the reaction mixture was extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain 494 mg of the title compound (19% yield in 2 steps) as a white solid. The results of NMR analysis of the thus obtained compound are as shown below.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[NH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH3:32][O:31][C:28]1[N:27]=[CH:26][C:25]([NH:24][C:17]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:23][C:20]([CH2:21][N:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)=[CH:19][N:18]=2)=[CH:30][CH:29]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COc1ccc(Nc2ncc(CN3CCCCC3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (264 mg, 0.457 mmol) and piperidine (Aldrich, St. Louis, Mo.) (67.7 μL, 0.686 mmol). 1H NMR (400 MHz, CDCl3) δ 11.64 (s, 1H); 8.72 (d, J=2.35 Hz, 1H); 8.35 (d, J=2.54 Hz, 1H); 8.21 (d, J=2.35 Hz, 1H); 8.14 (dd, J=8.90, 2.84 Hz, 1H); 6.77 (d, J=9.00 Hz, 1H); 5.56 (br. s., 2H); 3.94 (s, 3H); 3.45 (s, 2H); 2.56 (s, 3H); 2.41 (br. s., 3H); 1.60 (dt, J=10.95, 5.48 Hz, 5H); 1.39-1.46 (m, 2H). m/z (ESI, +ve ion) 407.0 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:9]=[CH:8][O:7][N:6]=1.O.[NH2:12][NH2:13]>C(O)C>[O:7]1[CH:8]=[CH:9][C:5]([CH2:4][C:3]([NH:12][NH2:13])=[O:2])=[N:6]1
Reactant: NN
Reactant: COC(=O)Cc1ccon1
Solvent: O
Solvent: CCO
Product: NNC(=O)Cc1ccon1
Yield: 78 %

Procedure:
As described for example 112a, isoxazol-3-yl-acetic acid methyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) at rt for 16 h. After evaporation of the solvent the residue was chromatographed (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) to afford the title compound as a white solid (yield: 78%). MS: m/e=142.1 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13](=[O:30])[NH:14][C:15]1[CH:28]=[CH:27][C:26]2[NH:25][C:24](=[O:29])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=1)(C)(C)C.[ClH:32]>ClCCl.O1CCOCC1>[ClH:32].[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]([NH:14][C:15]1[CH:28]=[CH:27][C:26]2[NH:25][C:24](=[O:29])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)NCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
(3-{[(6-oxo-5,6-dihydro-phenanthridin-2-ylcarbamoyl)-methyl]-amino}-propyl)-carbamic acid tert-butyl ester (32 mg, 0.075 mmol) was dissolved in dichloromethane (1 mL) and 4N hydrochloric acid in dioxane (1 mL) was added. The reaction mixture was stirred at room temperature overnight and then evaporated, affording 32 mg (97% yield) of the title compound.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH:15]([CH3:19])[CH2:16][CH2:17]O>CCOCC>[Br:2][CH2:17][CH2:16][CH:15]([C:8]1[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=1[O:6][CH3:5])[CH3:19]
Reactant: COc1ccc(OC)c(C(C)CCO)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: COc1ccc(OC)c(C(C)CCBr)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of phosphorous tribromide (5.7 ml., 0.06 mole) in ether (30 ml.) is added to a solution of 3-(2,5-dimethoxyphenyl)-1-butanol (30.0 g., 0.143 mole) in ether (20 ml.) at -5° C. to -10° C. and the reaction mixture stirred at -5° C. to -10° C. for 2.5 hours. It is then warmed to room temperature and stirred for an additional 30 minutes. The mixture is poured over ice (200 g.) and the resulting mixture extracted with ether (3×50 ml.). The combined extracts are washed with 5% sodium hydroxide solution (3×50 ml.), saturated sodium chloride solution (1×50 ml.) and dried (Na2SO4). Removal of the ether and vacuum distillation of the residue affords the title compound.