Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CCCCCC.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:14][CH:15]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (50% w/w dispersion in mineral oil, 3.7 g) was treated under argon with repeated washes of hexane. The oil-free residue was suspended in dry DMF (100 ml) and 4-hydroxyphenylacetic acid (13.0 g) was added portionwise to the stirred cooled (4° C.) mixture. After 30 minutes, benzyl bromide (9.2 ml) was added dropwise and, after a further 1 hour at 4° C., stirring was continued overnight at ambient temperature. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The aqueous phase was re-extracted with further ethyl acetate and the combined organic extracts washed with water and brine, then dried (MgSO4) and evaporated. The crystalline residue gave benzyl 4-hydroxyphenylacetate, 17.8 g, as off-white crystals: m.p. 70°-72° C.; NMR (CDCl3) δ 7.32(5H, m), 7.14(2H, d), 6.76(2H, d), 5.12(2H, s), 3.59(2H, s); m/e 242 (M.)+.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:7][CH:8]=[CH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.Cl>CCCCC>[Br:1][C:9](=[CH:8][O:7][CH2:3][CH2:4][CH2:5][CH3:6])[C:10](=[O:15])[C:11]([F:13])([F:14])[F:12]
Reactant: BrBr
Reactant: CCCCOC=CC(=O)C(F)(F)F
Agent: Cl
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: CCCCOC=C(Br)C(=O)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h

Procedure:
8.0 g (0.05 mole) of bromine, dissolved in 100 ml pentane, are added dropwise to a solution of 9.75 g (0.05 mol) of 4-n-butoxy-1,1,1-trifluorobut-3-en-2-one in 50 ml of pentane cooled to -20° C. After stirring for 1 hour at -20° C., a solution of 6.0 g (0.06 mole) of triethylamine in 100 ml pentane is added dropwise at the same temperature. After being allowed to stand overnight at 25° C., the mixture is poured into ice water and acidified by means of 1N hydrochloric acid and the phases are separated. Conventional work-up gives 12.1 g of almost homogeneous crude 3-bromo-4-n-butoxy-1,1,1-trifluorobut-3-en-2-one, which is freed from the small amount of impurities by distillation under reduced pressure. Boiling point 113°-115° C./16 mbar, nD20 =1.4640.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.Br[CH2:11][CH:12]([OH:15])[CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1([CH:13]([OH:14])[CH:12]([OH:15])[CH3:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OCC(O)CBr
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(O)C(O)n1cnc2ccccc21
Yield: 68.7 %

Procedure:
Benzimidazole (590 mg, 5.0 mmol) and 3-bromo-1,2-propanediol (0.52 mL, 6.0 mmol) were dissolved in anhydrous acetonitrile (50 mL) and dry potassium carbonate (2.07 g, 15 mmol) was added. The solution was then heated to reflux for 3 days. Upon cooling the mixture was filtered and the filtrates were concentrated, giving the desired N-benzimidazolyl-1,2-propanediol (0.66 g, 69%) as a pale yellow solid. 1H NMR (CDCl3) δ 3.60 (m, 2H), 3.78 (m, 2H), 4.17 (m, 1H), 4.27 (m, 2H), 7.25 (m, 2H), 7.42 (d, 1H, J=6 Hz), 7.67 (d, 1H, J=6 Hz), 7.87 (s, 1H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:37]([CH2:38][CH2:39]O)=[CH:36][CH:35]=1.[C:43]1(=[O:49])[NH:47][C:46](=[O:48])[CH:45]=[CH:44]1>>[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:37]([CH2:38][CH2:39][N:47]2[C:43](=[O:49])[CH:44]=[CH:45][C:46]2=[O:48])=[CH:36][CH:35]=1
Reactant: COc1ccc(CCO)cc1
Reactant: O=C1C=CC(=O)N1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(CCN2C(=O)C=CC2=O)cc1

Procedure:
Reagents: Ph3P (1.31 g, 5 mmol), DEAD (0.8 ml, 5 mmol), p-methoxyphenethyl alcohol (1.2 g, 7.5 mmol) and maleimide (0.48 g, 5 mmol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: CCOC(=O)CCCN
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 5 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A suspension of 4-chloro-3-nitro[1,5]naphthyridine (10.0 g, 47.7 mmol) and ethyl 4-aminobutyrate hydrochloride (9.6 g, 57 mmol) in dichloromethane (200 mL) was cooled to 5° C. Triethylamine (16.6 mL, 119 mmol) was added, and the reaction was allowed to warm to ambient temperature and stirred for two hours. The mixture was diluted with dichloromethane (200 mL) and washed with saturated aqueous sodium bicarbonate (2×150 mL). The combined aqueous fractions were extracted with dichloromethane (100 mL), and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 14.5 g of ethyl 4-(3-nitro[1,5]naphthyridin-4-ylamino)butanoate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:35])=[CH:8][C:9](=[O:34])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:35])=[CH:8][C:9](=[O:34])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)cc(C)c3ccc(OC)cc32)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(CCCn2c(=O)cc(C)c3ccc(OC)cc32)CCNCC1
Reaction time: 14 h

Procedure:
To 2 mL of a chloroform solution containing 0.45 g of 1-tert-butyl 4-ethyl 4-(3-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylate, 1 mL of trifluoroacetic acid was added, and the mixture was stirred for 14 hours. The solvent was removed under reduced pressure, and water and diethyl ether were added thereto. The aqueous layer was separated, ethyl acetate was added thereto, and the resultant solution was adjusted to pH 12.5 with a 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and the extract were combined, and the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.29 g of a yellow oily substance, ethyl 4-(3-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate.
Reaction SMILES: [CH2:1]([O:5][CH:6]([C:10]([F:13])([F:12])[F:11])[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH3:4].O.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[CH2:1]([O:5][CH:6]([C:10]([F:11])([F:12])[F:13])[C:7]([O:9][CH2:15][CH3:16])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCOC(C(=O)O)C(F)(F)F
Solvent: O
Solvent: CCO
Product: CCCCOC(C(=O)OCC)C(F)(F)F
Reaction time: 12 h
Yield: 750.2 %

Procedure:
A mixed solution of (+)-2-butoxy-3,3,3-trifluoropropionic acid (1.2 g) obtained in Example 6, ethanol (40 ml) and p-toluenesulfonic acid monohydrate (0.1 g) was heated with stirring for 12 hours, followed by distilling off the solvent under normal pressure, extracting the residue with ether, neutralizing, washing with water and concentrating to obtain (+)-ethyl 2-butoxy-3,3,3-trifluoropropionate (0.9 g). [α] +24.1 (cl. 06, CHCl3).
Reaction SMILES: O=[C:2]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][C:12]2([CH3:22])[CH3:21])[CH:3]([CH3:8])[CH2:4][C:5](O)=[O:6].O.[NH2:24][NH2:25]>C(O)C>[CH3:8][CH:3]1[C:2]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][C:12]3([CH3:22])[CH3:21])=[N:25][NH:24][C:5](=[O:6])[CH2:4]1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc2c(c1)C(C)(C)CC(=O)N2C
Solvent: CCO
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc2c(c1)C(C)(C)CC(=O)N2C
Yield: 76.5 %

Procedure:
A mixture of 20 g of 4-oxo-4-(1,4,4-trimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-methylbutanoic acid, 10 g of hydrazine hydrate and 200 ml of ethanol was heated under reflux for one hour. After cooling, the precipitated crystals were filtered off and recrystallized from ethanol to give 15.1 g of 6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-2-one, melting at 238°-241° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11](NCCC)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]([CH2:9][CH2:10][CH2:11][NH:12][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCNC1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCCNS(C)(=O)=O)CCC2c2ccc(F)cc2)cc1

Procedure:
Reaction of (2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propylamine with methanesulfonyl chloride according to the general method of example 1d yielded the title compound as a white solid, m.p. 123° C. and MS: m/e=455.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH3:25])[C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]#[C:15][CH2:16][CH2:17][O:18]C2CCCCO2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1>CO>[C:1]([O:5][C:6](=[O:26])[N:7]([C@H:8]1[CH2:9][CH2:10][C@H:11]([C:14]#[C:15][CH2:16][CH2:17][OH:18])[CH2:12][CH2:13]1)[CH3:25])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCCOC2CCCCO2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCCO)CC1

Procedure:
A solution of 3.45 g (9.44 mmol) of trans-Methyl-{4-[4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-cyclohexyl}-carbamic acid tert-butyl ester and 0.7 g (2.83 mmol) of pyrimidium toluene-4-sulfonate in 25 ml MeOH was stirred at 55° C. for 1.5 h. The reaction was partitioned between aqueous solution of 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl, dried over Na2SO4 and evaporated to give 2.85 g (quantitative) of trans-[4-(4-Hydroxy-but-1-ynyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, MS: 281 (M).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][CH2:31]Br)[C:14]1=[O:33])=[O:11].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(OC(C)C)(C)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][CH2:31][N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)[C:14]1=[O:33])=[O:11]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCBr)C1=O)c1cc2ccccc2[nH]1
Reactant: CN1CCNCC1
Solvent: CC(C)OC(C)C
Product: CN1CCN(CCN2C(=O)C(NC(=O)c3cc4ccccc4[nH]3)N=C(c3ccccc3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-1-(2-bromoethyl )-5-phenyl-2H-1,4-benzodiazepine-2-one (0.3 g) and 1-methylpiperazine (3.0 ml) was stirred for 4.0 hours at room temperature and diisopropyl ether (20 ml) was added thereto. The resultant precipitates were collected by filtration and dissolved in diluted hydrochloric acid. The solution was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and the resultant precipitates were collected by filtration to give (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-1-[2-(4-methyl-1-piperazinyl)ethyl ]-5-phenyl-2H-1,4-benzodiazepine-2-one (0.20 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15](OCC)=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH3:22]>C(O)C>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([NH2:22])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N
Reactant: CCOC(=O)COc1ccc(OCCn2ccnc2)cc1
Solvent: CCO
Product: NC(=O)COc1ccc(OCCn2ccnc2)cc1
Reaction time: 20 h

Procedure:
A mixture of ethyl 4-[2-(1-imidazolyl)ethoxy]phenoxyacetate free base (1.0 g), ethanol (10 ml) and concentrated ammonia solution (20 ml) was allowed to stand at room temperature for 20 hours to give a clear solution. The solution was evaporated and the residue was crystallized twice from 2-butanone to give 4-[2-(1-imidazolyl)ethoxy]phenoxyacetamide (0.38 g), m.p. 123°-124° C. Found: C, 59.70; H, 5.77; N, 16.26. C13H15N3O3 requires: C, 59.76; H, 5.79; N, 16.08%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14](=[O:25])[CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N+:16]([O-])=O)[C:9]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.C1CCCCC=1>CO.[C].[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14](=[O:25])[CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH2:16])[C:9]=2[C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1)C(c1ccccc1)[N+](=O)[O-]
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CO
Product: NC(C(=O)Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1)c1ccccc1
Yield: 78.4 %

Procedure:
11 mg of 5-(4-fluorophenyl)-3-(2-nitrophenylacetylamino)-4-(4-pyridyl)pyrazole was dissolved in 5 ml of methanol. Then, 100 mg of cyclohexene and 20 mg of 5% palladium-carbon were added thereto, followed by heating under reflux for 1 hour. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to obtain 8 mg (79% yield) of the title compound as a light-brown powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17](=[O:30])[CH2:18][CH2:19][C:20]([O:22]CC2C=CC=CC=2)=[O:21])[CH:9]=1)([O-])=O>O1CCOCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17](=[O:30])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:9]=1
Reactant: O=C(CCC(=O)n1cc(Cc2cccc([N+](=O)[O-])c2)c2ccccc21)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cccc(Cc2cn(C(=O)CCC(=O)O)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
To a solution of benzyl 4-[3-(3-nitrobenzyl)indol-1-yl]-4-oxobutyrate (320 mg) in a mixture of 1,4-dioxane (6 ml) and methanol (3 ml) was added 10% palladium on activated carbon (60 mg), and the mixture was shaken under hydrogen atmosphere (3 atm) at 25° C. for 1.5 hours. The catalyst was filtered off and the filtrate was evaporated. The crude crystals were washed with hot chloroform and hot ethyl acetate to give 4-[3-(3-aminobenzyl)indol-1-yl]-4-oxobutyric acid (157 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:17]#[N:18].C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:17]#[N:18])[CH:12]=[N:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cncc(OCc2ccccc2)c1
Reactant: N#C[Cu]C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cncc(OCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
3-(Benzyloxy)-5-bromopyridine (5.38 g, 20.4 mmol, Harrowven et al. Tetrahedron, 2001, 57, 4447-4454) in DMF (33 mL) was stirred with copper cyanide (2.9 g, 32.6 mmol) at 160° C. for 7 hours. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate was added and the formed suspension was stirred at 50° C. for 15 minutes. After filtration the liquid phases were separated. The precipitate was triturated with 10% DMF in ethyl acetate (500 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL) at 50° C. and filtration and phase separation were performed. The treatment of the precipitate with saturated aqueous sodium hydrogen carbonate solution and 10% DMF in ethyl acetate was repeated two times and the combined organic phases washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane, 0 to 65%) to yield 3.13 g 5-(benzyloxy)pyridine-3-carbonitrile.
Reaction SMILES: [CH:1]1([N:4]2[C:9]([NH2:10])=[C:8]([NH2:11])[C:7](=[O:12])[NH:6][C:5]2=[O:13])[CH2:3][CH2:2]1.[C:14](O)(=O)[CH3:15]>>[CH:1]1([N:4]2[C:9]3[N:10]=[C:14]([CH3:15])[NH:11][C:8]=3[C:7](=[O:12])[NH:6][C:5]2=[O:13])[CH2:3][CH2:2]1
Reactant: Nc1c(N)n(C2CC2)c(=O)[nH]c1=O
Reactant: CC(=O)O
Product: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2C1CC1
Reaction time: 1 h

Procedure:
A solution of 6.4 g of 1-cyclopropyl-5,6-diamino-2,4-(1H,3H)-pyrimidinedione (IV) in 20 ml of acetic acid was refluxed for 2 hours. The solution was evaporated. The received oil was refluxed in 40 ml of 2N NaOH and 10 ml of 5N NaOH for 1 hour and then neutralized with 5N HCl. The crystals were filtered off. Yield 1.85 g (26%) (XXXVI) NMR (see Table I).
Reaction SMILES: [C:1]1([NH:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][CH2:12][CH2:13][Cl:14]>CC(C)=O>[Cl:14][CH2:13][CH2:12][CH2:11][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:8]=[O:9]
Reactant: O=CNc1ccccc1
Reactant: ClCCCBr
Solvent: CC(C)=O
Product: O=CN(CCCCl)c1ccccc1
Yield: 85.4 %

Procedure:
To a mixture of phenylformamide (49.6 g, 410 mmol), 1-bromo-3-chloropropane (75.4 g, 490 mmol) in acetone (400 mL) was added CsCO3 (156.4 g, 480 mmol) and the resulting mixture was stirred at reflux temperature for 14 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate (400 mL) and water (150 mL) were added to the residue and the organic layer was washed with brine (150 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate, 1/0 to 10/3, v/v) to give 3-chloropropyl(phenyl)formamide (69.1 g, 350 mmol) as pale yellow oil. Yield: 85%. To a solution of this pale yellow oil (36.2 g, 180 mmol) in 2-propanol (140 mL) was added conc. HCl (25 mL) and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was cooled to r.t. and diisopropyl ether (140 mL) was added. The resulting mixture was allowed to stand at r.t. for 12 hours, that led precipitation of crystals. The crystals were collected by filtration and washed with diisopropyl ether (10 mL×2) to give N-(3-chloropropyl)aniline hydrochloride (13.7 g, 57 mmol) as colorless needles. The combined filtrates were concentrated under reduced pressure and recrystallized from diisopropyl ether-2-propanol (1/2, v/v) to give N-(3-chloropropyl)aniline hydrochloride (19.5 g, 81 mmol). Yield: 76%. From N-(3-chloropropyl)aniline hydrochloride (5.0 g, 21 mmol), using a similar procedure to that described for reference example 57, the title compound (7.0 g, 19 mmol) was obtained as colorless crystals. Yield: 90%.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](Cl)[C:11]=2[Cl:17])=[C:5]([C:18]([F:21])([F:20])[F:19])[N:4]=1.[Cl:22]C1C=C(Cl)C=CC=1CC#N>>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:22])=[CH:12][C:11]=2[Cl:17])=[C:5]([C:18]([F:21])([F:20])[F:19])[N:4]=1
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(C(F)(F)F)n1
Agent: Cl
Product: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(C(F)(F)F)n1

Procedure:
This compound was prepared in a manner analogous to the compound of Example 14 from 2,4-dichlorophenylacetonitrile (Aldrich): mp. 220.5°-221° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH:45]1([CH2:51][CH2:52][NH2:53])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>CN(C=O)C>[CH:45]1([CH2:51][CH2:52][NH:53][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: NCCC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCCC4CCCCC4)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl 4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3 dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2-cyclohexylethylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(2-cyclohexylethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:9][CH:8]=1)=O.[NH2:30]N.Cl>C(O)C>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:9][CH:8]=2)=[N:30]1
Reactant: CN(C)/C=C/C(=O)c1ccc(OCCCCN2C(=O)c3ccccc3C2=O)cc1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: NCCCCOc1ccc(-c2cc[nH]n2)cc1

Procedure:
A suspension of 21.2 g of (E)-2-[4-[4-[3-(dimethylamino)-1-oxo-2-propenyl]phenoxy]butyl]-1H-isoindole-1,3(2H)-dione (Example 48) in 300 ml of boiling ethanol is treated with 6 ml of anhydrous hydrazine. A suspension quickly develops, necessitating addition of 200 ml more ethanol to permit stirring. While stirring 35 ml of concentrated HCl is then added, the mixture refluxed a further hour, and filtered hot. The insolubles are washed with 200 ml of boiling water. The combined filtrates are taken to dryness in vacuo, leaving the hydrochloride salt of the title compound as shown by mass spectrometry. The product is utilized for synthesis without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI-MS (m/z): 460 [M+1]+.