Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:35])[N:4]([CH2:14][C:15]([NH:17][CH:18]([CH:32]([CH3:34])[CH3:33])[CH:19]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:20]([F:23])([F:22])[F:21])=[O:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:43]1([CH2:49][C:50](Cl)=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1.C(OCC)(=O)C>[Si:25]([O:24][CH:19]([C:20]([F:23])([F:21])[F:22])[CH:18]([NH:17][C:15](=[O:16])[CH2:14][N:4]1[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=[C:2]([NH:1][C:50](=[O:51])[CH2:49][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:3]1=[O:35])[CH:32]([CH3:33])[CH3:34])([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reactant: O=C(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)Cc2ccccc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 8 h

Procedure:
A 25 mL flask was charged with 2-(3-amino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (0.301 g) dissolved in freshly distilled tetrahydrofuran (6 mL) under nitrogen. Triethylamine (0.09 mL) was added, followed by phenylacetyl chloride (0.08 mL). The cloudy, yellowish solution was stirred overnight; diluted with ethyl acetate (50 mL); washed with 10% hydrochloric acid (three times), saturated aqueous sodium bicarbonate (three times) and brine; dried; and evaporated to give an oil which solidified under vacuum. The soft solid was purified by chromatography, eluting with ethyl acetate:dichloromethane (3:97), to afford N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-(2-oxo-6-phenyl-3-phenylacetylamino-1,2-dihydro-1-pyridyl)acetamide (0.272 g); TLC: Rf =0.54, methanol:dichloromethane (1:99); MS: m/z=630(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)=[N:8]2.[NH:27]1[CH2:32][CH2:31][CH:30]([N:33]2[C:37]3=[N:38][CH:39]=[N:40][C:41]([NH2:42])=[C:36]3[CH:35]=[N:34]2)[CH2:29][CH2:28]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.CO>[CH3:1][O:2][C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:7]([C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[C:37]5=[N:38][CH:39]=[N:40][C:41]([NH2:42])=[C:36]5[CH:35]=[N:34]4)[CH2:29][CH2:28]3)=[CH:19][CH:20]=1)=[N:8]2
Reactant: COc1nccc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cc12
Reactant: Nc1ncnc2c1cnn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1nccc2nc(-c3ccc(CN4CCC(n5ncc6c(N)ncnc65)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(5-methoxy-3-phenyl-1,6-naphthyridin-2-yl)benzaldehyde (80 mg, 0.235 mmol) and 1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine-4-amine (58 mg, 0.26 mmol) in dry DMF (1 mL) containing acetic acid (70 μL, 1.25 mmol) was stirred at room temperature 16 hours. Sodium triacetoxyborohydride (91 mg, 0.43 mmol) was then added to the semi-solid mixture and stirred for three hours. The mixture was diluted with methanol and the solvent evaporated. The residue was purified by column chromatography on silica gel eluting with a 0.5 to 5% methanol/ethyl acetate (sat'd NH3) gradient. The combined fractions were concentrated and the residue was digested with acetonitrile to afford upon cooling the pure title compound. 1H-NMR (500 MHz, CDCl3): δ 8.55 (1H, s), 8.39 (1H, s), 8.23 (1H, d, J=6 Hz), 7.92 (1H, s), 7.56 (1H, d, J=6 Hz), 7.41 (2H, d, J=7.8 Hz), 7.24-7.33 (5H, m), 5.40 (2H, br s), 4.75 (1H, m), 4.17 (3H, s), 3.57 (2H, br s), 2.31-2.41 (2H, m), 2.18-2.28 (2H, m), 1.96 (2H, br d, J=10.7 Hz). m/e (m+1): 543.3.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]([NH2:12])=[NH:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[C:16](OC)(=[O:21])[CH2:17][C:18]([CH3:20])=O>CO>[C:1]1([C@@H:7]([NH:9][C:10]2[N:12]=[C:16]([OH:21])[CH:17]=[C:18]([CH3:20])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: C[C@H](NC(=N)N)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(O)nc(N[C@@H](C)c2ccccc2)n1
Reaction time: 8 h
Yield: 12.9 %

Procedure:
To a solution of (S)-1-phenylethylguanidine (1 g, 6.13 mmol, 1 eq) [prepared by condensation of (S)-1-phenylethylamine with methylthiopseudourea sulfate in refluxing aqeous sodium bicarbonate] in methanol (5.8 mL) was added a solution of 25% NaOMe in MeOH (4.2 mL, 18.39 mmol, 3 eq). To this stirred solution was added methyl acetoacetate (0.66 mL, 6.13 mmol, 1 eq) dropwise via syringe. The mixture was allowed to stir overnight. The methanol was removed by warming under a flow of air. The residue was dissolved in 20 mL water, acidified with concentrated aqueous HCL and extracted with ether and the ether layer discarded. The aqueous layer was neutralized and extracted with ethyl acetate. The organic extracts were combined and dried over anhydrous Na2SO4, filtered and concentrated. The material was purified by flash column chromatography to give 181 mg of the title compound. Mass spectrum (NH3/CI): 230.2 (M+1).
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[C:18](OCC)=[O:19])[CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].C(OCC)(=O)C>O1CCCC1.C1(C)C=CC=CC=1>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[CH2:18][OH:19])[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (1.5 g, 4.47 mmol) in tetrahydrofuran (20 mL) at 0° C. was added a 1.5 M solution of diisobutylaluminum hydride in toluene (6.3 mL, 9.39 mmol) slowly. The solution was allowed to warm slowly to ambient temperature and after 4 hours the solution was re-cooled to 0° C. and additional 1.5 M diisobutylaluminum hydride in toluene was added (6 mL, 9 mmol). The solution was allowed to stir with the flask in the ice bath for 1.5 h. Some aqueous Rochelle's salt was added dropwise followed by ethyl acetate. The mixture was stirred overnight and the phases were separated. The aqueous phase was extracted one more time with ethyl acetate. The combined organic phases were washed with Rochelle's salt, then brine, dried over MgSO4 and concentrated in vacuo to yield a white solid. (1.3 g, 98%). 1H-NMR (DMSO-d6,) 7.61-7.51 (m, 3H), 4.87 (t, J=5 Hz, 1H), 4.10 (d, J=5 Hz, 2H), 3.87 (quintet, J=9 Hz, 1H), 2.37-2.30 (m, 4H), 2.29-1.87 (m, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([C:15]2[C:16]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22]3)=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:12]1.Cl.C(OCC)C>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH:13]([C:15]2[C:16]([N:21]3[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22]3)=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Agent: Cl
Solvent: CCOCC
Product: NC1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Yield: 68.3 %

Procedure:
To a round bottomed flask was added tert-butyl (1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate (1.3145 g, 2.94 mmol) and hydrogen chloride, 1M in diethyl ether (0.089 ml, 2.94 mmol) to stir. Solvent was evaporated. The reaction mixture was diluted with saturated sodium bicarbonate and extracted with CH2Cl2. The organic extract was washed with water, saturated Na2CO3, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo to give 1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine (0.696 g, 2.009 mmol, 68.2% yield).
Reaction SMILES: [H-].[Na+].Br[C@H:4]1[C@H:9](O)[C:8]2[C:11]([O:15][CH3:16])=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][CH2:5]1.[O:17]1CCCC1>>[CH3:16][O:15][C:11]1[C:8]2[CH2:9][C:4](=[O:17])[CH2:5][O:6][C:7]=2[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc2c1[C@@H](O)[C@H](Br)CO2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COc1cccc2c1CC(=O)CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5.0 g sodium hydride in 100 ml of dry tetrahydrofuran is added with stirring a solution of 13 g of trans-3-bromo-4-hydroxy-5-methoxy-3,4-dihydro-2H-[1]-benzopyran in 150 ml of dry tetrahydrofuran in a dropwise fashion. After 30 minutes stirring at room temperature, the reaction mixture is filtered through filter-cel and the solvent is removed in vacuo. The residue is dissolved in 150 ml of toluene, 1.0 g of anhydrous zinc iodide is added and the mixture is refluxed for 15 minutes. The reaction mixture is filtered through 120 g of silica gel with methylene chloride as the eluent to afford 5-methoxy-3,4-dihydro-2H-[1]-benzopyran-3-one (5-methoxychroman-3-one) as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([Cl:15])[N:14]=1)[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([Cl:15])[N:14]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(Cl)nc(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)O)cc(Cl)n1

Procedure:
1.0 g (4.39 mmol) of methyl 2-tert-butyl-6-chloroisonicotinate [lit.: O. Isler et al., Helvetica Chimica Acta 1955, 38 (4), 1033-1046] in 17 ml of THF and 8.8 ml (8.8 mmol) of 1 M aqueous sodium hydroxide solution were heated under reflux for 30 min. After cooling, the mixture was adjusted to pH 1 with concentrated hydrochloric acid and concentrated almost completely on a rotary evaporator. The solid formed was filtered off, washed with a little water and dried. This gave 870 mg (93% of theory) of the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:11]2[C:6]([CH:7]=[CH:8][C@H:9]([CH3:29])[C@@H:10]2[CH2:12][CH2:13][C@H:14]2[O:19][C:18](=[O:20])[CH2:17][C@H:16]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:15]2)=[CH:5][CH2:4][CH2:3]1.[CH2:30]([C:32]([CH2:39][CH3:40])([CH2:36][CH:37]=[CH2:38])[C:33](Cl)=[O:34])[CH3:31]>>[CH2:30]([C:32]([CH2:39][CH3:40])([CH2:36][CH:37]=[CH2:38])[C:33]([O:1][C@@H:2]1[C@H:11]2[C:6]([CH:7]=[CH:8][C@H:9]([CH3:29])[C@@H:10]2[CH2:12][CH2:13][C@H:14]2[O:19][C:18](=[O:20])[CH2:17][C@H:16]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[CH2:15]2)=[CH:5][CH2:4][CH2:3]1)=[O:34])[CH3:31]
Reactant: C[C@H]1C=CC2=CCC[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: C=CCC(CC)(CC)C(=O)Cl
Product: C=CCC(CC)(CC)C(=O)O[C@H]1CCC=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 77.5 %

Procedure:
A procedure similar to that described in Example 6, above, was followed, but using 1.26 g (3.0 mmol) of (4R,6R)-6-{2-[(1S,2S,8S,8aR)-1,2,6,7,8,8a-hexahydro-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Japanese Patent Kokai Application No. Sho 59-175450] and 2.09 g (12.2 mmol) of 2,2-diethyl-4-pentenoyl chloride, to provide 1.30 g of the title compound.
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:8][CH:7]=1.[CH2:17]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[CH2:28][NH:29][CH3:30])[CH3:18].C1C=CC2N(O)N=NC=2C=1.O.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:29]([CH2:28][C:20]2[N:19]([CH2:17][CH3:18])[C:27]3[C:22]([CH:21]=2)=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:30])=[O:16])=[CH:8][CH:7]=1
Reactant: Nc1ccc(C=CC(=O)O)cn1
Reactant: CCn1c(CNC)cc2ccccc21
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(CN(C)C(=O)/C=C/c2ccc(N)nc2)cc2ccccc21
Reaction time: 8 h
Yield: 30.1 %

Procedure:
EDC (0.84 g, 4.38 mmole) was added to a solution of 3-(6-aminopyridin-3-yl)acrylic acid (0.72 g, 4.38 mmole), 1-ethyl-2-(methylaminomethyl)-1H-indole (0.75 g, 3.98 mmole), HOBt.H2O (0.59 g, 4.38 mmole) and diisopropylethylamine (1.40 mL, 7.96 mmole) in DMF (30 mL) at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. Flash chromatography on silica gel (5% MeOH/CHCl3) gave the title compound (0.40 g, 30%) as a light tan solid: MS (ES) m/e 335 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:21]1([CH2:27][CH2:28][C:29]2[CH:37]=[CH:36][C:32]([CH2:33][CH2:34][NH2:35])=[CH:31][CH:30]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH2:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:33][CH2:34][NH:35][C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])=[CH:36][CH:37]=1
Reactant: NCCc1ccc(CCC2CCCCC2)cc1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc(NCCc2ccc(CCC3CCCCC3)cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Reaction of 2-chloroadenosine with p-(2-cyclohexylethyl)-phenethylamine as described in Example 14 gives 2-[2-(p-2-cyclohexylethyl-phenyl)-ethylamino]-adenosine, [alpha]D25 =-25.6° in DMSO, m.p. 154°-160°.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH3:12])=[N:6][CH:5]=1.O.[OH-].[Li+]>O1CCOCC1.O>[C:16]([O:15][C:13]([N:10]([CH2:11][CH3:12])[C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][N:6]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCN(C(=O)OC(C)(C)C)c1ccc(C(=O)OC)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The crude 6-(tert-butoxycarbonyl-ethyl-amino)-nicotinic acid methyl ester is taken up in 100 mL dioxane and a solution of lithium hydroxide monohydrate (13.5 g, 0.32 mol) in 100 mL water is added and the reaction mixture is stirred at RT for 4 h. The dioxane is removed from the reaction mixture under reduced pressure, water is added and the reaction mixture is acidified to pH 6 with a solution of 10% citric acid in water. The formed precipitate is filtered off and dried in vacuo. Yield: 36 g. 1H NMR (DMSO-d6): δ 13.2 (s, 1H), 8.8 (s, 1H), 8.2 (d, 1H), 7.8 (d, 1H), 4.0 (quart, 2H), 1.5 (s, 9H), 1.2 (t, 3H).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:6][CH2:5][C:4]1=[O:19].[O:20]=[C:21]1[NH:30][C:29]2[N:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][CH:35]=O)[CH:26]=[CH:25][C:24]=2[CH:23]=[CH:22]1>>[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]2[CH2:18][CH2:17][N:16]([CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:27]3[N:28]=[C:29]4[C:24]([CH:23]=[CH:22][C:21](=[O:20])[NH:30]4)=[CH:25][CH:26]=3)[CH2:15][CH2:14]2)[CH2:6][CH2:5][C:4]1=[O:19]
Reactant: CN1C(=O)CCc2cccc(N3CCNCC3)c21
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Agent: Cl
Product: CN1C(=O)CCc2cccc(N3CCN(CCCCOc4ccc5ccc(=O)[nH]c5n4)CC3)c21

Procedure:
In a manner similar to that of other examples above, 1-methyl-8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 462.2 (Exact Mass: 461.24).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1.Cl[CH2:17][C:18]1[O:19][C:20]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:21]=2[C:22]=1[CH3:23]>C(O)C>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:9][CH:10]=1)[CH2:17][C:18]1[O:19][C:20]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:21]=2[C:22]=1[CH3:23]
Reactant: Cc1c(CCl)oc2ccc([N+](=O)[O-])cc12
Reactant: CNCCc1ccc(NS(C)(=O)=O)cc1
Solvent: CCO
Product: Cc1c(CN(C)CCc2ccc(NS(C)(=O)=O)cc2)oc2ccc([N+](=O)[O-])cc12

Procedure:
N-Methyl-4-methanesulphonamidophenethylamine (1.66 g, 7.3 mmole) and 2-chloromethyl-3-methyl-5-nitrobenzofuran (see Preparation 7B--0.82 g, 3.6 mmole) were heated at reflux temperature in ethanol (20 ml) for 3 hours. The solvent was then evaporated and the residue was purified by column chromatography on silica eluting with methylene chloride/hexane (4:1) followed by methylene chloride containing methanol (0% up to 5%). The product-containing fractions were combined and evaporated, and the residue was recrystallised from ethanol to give the title compound, yield 1.52 g, m.p. 124°-124.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH:10]=[CH2:11])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:10]([CH2:11][OH:20])[CH2:9][C:4]=2[CH:3]=1
Reactant: C=CCc1cc(Cl)ccc1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: OCC1Cc2cc(Cl)ccc2O1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-2-(prop-2-en-1-yl)phenol (17 g, crude, nominally 101 mmol) in chloroform (100 ml) was added mCPBA (17.4 g, 101 mmol, 1 eq) with stirring for 1 hour at 50° C. in an oil bath. Then the reaction mixture was concentrated under vacuum and re-dissolved in MeOH (100 ml). Potassium carbonate (27.6 g, 200 mmol, 2 eq) was added and the mixture was stirred for 5 hours at 50° C. The solids were filtered off and the filtrate was concentrated under vacuum. The crude material was purified by silica gel chromatography using 3% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford (5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol as yellow oil (6.15 g); 1H NMR (300 MHz, CDCl3): δ 7.00-7.18 (m, 2H), 6.80 (d, J=8.7 Hz, 1H), 4.88-4.97 (m, 1H), 3.85-3.90 (m, 1H), 3.70-3.79 (m, 1H), 3.19-3.27 (dd, J=9.3 Hz, 15.9 Hz, 1H), 2.98-3.05 (dd, J=7.5 Hz, 15.9 Hz, 1H), 2.10 (broad s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=[N:30][C:25]2[CH:26]=[CH:27]C=[N:29][C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NC1(C#N)CC1.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:12](=[O:14])[NH:30][C:25]2([C:24]#[N:29])[CH2:27][CH2:26]2)[CH2:10][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CC1(N)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(=O)NC2(C#N)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To a suspension of the 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylic acid (1.7 g, 8.43 mmol), HATU (3.5 g, 9.3 mmol), and 1-aminocyclopropanecarbonitrile hydrochloride (1.0 g, 8.43 mmol) in THF (34 mL) was added triethylamine (3.5 mL, 25.3 mmol). The yellow suspension was stirred at room temperature for 18 h then most of the THF was removed in-vacuo. The remaining slurry was diluted with 150 mL 10% (w/w) aqueous Na2CO3 and 150 mL EtOAc. The layers were separated and the organic phase was washed with 10% (w/w) aqueous Na2CO3 (2×100 mL). The organic phase was washed with brine (1×75 mL), dried with Na2SO4, filtered, and concentrated to afford a crude light orange solid. This solid was triturated with Et2O and the white solid was filtered off using Et2O to rinse to yield 1.8 g of [1-(1-cyano-cyclopropylcarbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester as an off-white solid, m/z 266.5 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)=[CH:10][CH:9]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>C(O)C>[CH2:21]([N:23]([CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])=[CH:10][CH:9]=1)[CH3:22]
Reactant: BrCCCCCCc1ccc(CCCCCCBr)cc1
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)CCCCCCc1ccc(CCCCCCN(CC)CC)cc1
Yield: 91.6 %

Procedure:
First, 0.42 g of 1,4-bis(6-bromohexyl)benzene and 0.44 g of diethylamine were dissolved in 5 ml of absolute ethanol, and the mixture was refluxed for 2 hours. After removing the solvent under a reduced pressure and adding chloroform, the mixture was evaporated under a reduced pressure. The residue was acidified with 1N hydrochloric acid, washed with chloroform, alkalized with 10% sodium hydroxide, subjected to salting out, and extracted with total 80 ml of chloroform. The extract was washed with water and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated under a reduced pressure to obtain 0.37 g of the title compound as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@@H:10]([O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11].C1C(=O)N([Br:27])C(=O)C1.OS([O-])=O.[Na+]>ClCCl.C(#N)C>[Br:27][C:17]1[CH:18]=[C:13]([O:12][C@H:10]([C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[C:14]([NH2:19])=[N:15][CH:16]=1
Reactant: C[C@H](Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: C[C@H](Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Yield: 82.5 %

Procedure:
(S)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-aminopyridine (12 g, 39.87 mmol) was dissolved in dichloromethane (15 mL), a solution of N-bromosuccimide (7.1 g, 39.87 m mol) in acetonitrile (20 mL) was added dropwise slowly under the cooling of ice bath, and the reaction was stirred. After TLC test has showed that reaction was completed, a small amount of NaHSO3 solution was added to quench it, and the pH was adjusted to about 8-9 using sodium carbonate solution. The mixed solution was concentrated under reduced pressure to remove dichloromethane and acetonitrile. The residue was extracted with dichloromethane, and the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, concentrated; the residue was purified via silica gel column chromatography (petroleum ether:ethyl acetate=4:1) to yield the target product as yellow solid (12.5 g, yield: 83%).