Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[S:18][C:17]([C:19]4[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1.[OH:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[S:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:21][CH:20]=4)=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(Nc2ncnc3cc(-c4ccc(Br)cc4)sc23)c1
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cccc(Nc2ncnc3cc(-c4ccc(OCCN5CCOCC5)cc4)sc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 28.4 %

Procedure:
N-(3-methoxyphenyl)-6-(4-bromophenyl)thieno[3,2-d]pyrimidine-4-amine (0.26 g, 0.76 mmol) was dissolved in 5 ml of degassed dimethylformamide and added with 4-(2-hydroxyethyl)morpholine (0.12 ml, 0.92 mmol) and triphenylphosphine (241 mg, 0.92 mmol). The mixture was further added with DIAD (0.18 ml, 0.92 mmol) at 0° C. and stirred at room temperature for 15 hours. It was extracted with 50 ml saturated sodium bicarbonate and 50 ml of ethylacetate and the organic layer was washed with 50 ml of water twice, dried with magnesium sulfate and filtered. After concentration under vacuum, column chromatography (dichloromethane/methanol, 15/1) was done. The title compound (100 mg, 29%) was obtained as ivory colored solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.Br[CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[S:17][C:18]([C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[O:23])=[C:19]([CH3:21])[N:20]=2)[C:12]1=[O:33]>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:24][C:22]([C:18]2[S:17][C:16]([N:13]3[CH2:14][CH2:15][CH:11]([NH:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:12]3=[O:33])=[N:20][C:19]=2[CH3:21])=[O:23])=[CH:27][CH:28]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(N2CCC(Br)C2=O)sc1C(=O)NCc1ccc(F)cc1
Product: Cc1nc(N2CCC(NCc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 85 %

Procedure:
Following the procedure as described in Example 5, making variation as required to use (4-fluorophenyl)methanamine in place of 2-cyclopropylethanamine to react with 2-(3-bromo-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 85% yield: mp 123-124° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.35-7.21 (m, 4H), 7.06-6.92 (m, 4H), 6.07 (t, J=5.6 Hz, 1H), 4.50 (d, J=5.6 Hz, 2H), 4.20 (t, J=5.6 Hz, 1H), 3.97-3.76 (m, 3H), 3.68 (t, J=8.6 Hz, 1H), 2.60 (s, 3H), 2.53-2.37 (m, 1H), 2.11-1.89 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 173.6, 162.3, 162.2, 162.1, 155.2, 152.8, 135.0, 133.7, 129.8, 129.6, 118.8, 115.6, 115.4, 58.5, 51.0, 44.8, 43.3, 27.1, 17.3; MS (ES+) m/z 457.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2C)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccccc1C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5- dimethyl-8-(2-methylphenyl)-2-naphthalenyl)ethynyl]- benzoate (Compound 3) 80.0 mg (0.190 mmol) in 3 ml of EtOH and 2 ml of THF was added 60.0 mg (1.50 mmol, 1.50 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCI. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.89(2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.4 Hz), 7.46 (2H, s), 7.29-7.14 (4H, m), 6.59 (1H, s), 5.90 (1H, t, J=4.7 Hz), 2.39 (2H, m), 2.60 (3H, s), 1.39 (3H, s), 1.29 (3H, s).
Reaction SMILES: [CH3:1][N:2]([C:7]12[CH2:16][CH:12]([CH2:13][CH2:14][CH2:15]1)[CH:11]1[CH2:17][CH:8]2[CH2:9][CH2:10]1)[C:3](=[O:6])[CH2:4]Cl.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K]>>[CH3:1][N:2]([C:7]12[CH2:16][CH:12]([CH2:13][CH2:14][CH2:15]1)[CH:11]1[CH2:17][CH:8]2[CH2:9][CH2:10]1)[C:3](=[O:6])[CH2:4][N:22]1[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]2[C:18]1=[O:28]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C(=O)CCl)C12CCCC(C1)C1CCC2C1
Agent: [K]
Product: CN(C(=O)CN1C(=O)c2ccccc2C1=O)C12CCCC(C1)C1CCC2C1
Yield: 83 %

Procedure:
Under the same reaction conditions as described in section (A) of Example 7, N-methyl-N-(1-tricyclo[4.3.1.12,5 ]undecyl)-2-chloroacetamide was reacted with potassium phthalimide to obtain N-methyl-N-(1-tricyclo[4.3.1.12,5 ]undecyl)-2-phthalimidoacetamide in a yield of 83%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:12][CH3:13])=[N:8][NH:9][C:10]=1[OH:11])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:21]([CH3:32])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:23].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:12][CH3:13])=[N:8][NH:9][C:10]=1[O:11][CH:21]([CH3:32])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CC)n[nH]c1O
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CC)n[nH]c1OC(C)C(=O)c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-ethyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (1.5 g, 8.14 mmol) in DMF (10 ml) is added K2CO3 (1.15 g, 8.14 mmol). The mixture is heated to 50° C. and treated with a solution of 2-bromo-1-(2,4-dichloro-phenyl)-propan-1-one (Intermediate AA) (2.53 g, 8.96 mmol) in DMF (10 ml). Stirring continues at 50° C. for 1 hour and after cooling to RT, the reaction mixture is poured into water (300 ml, pre-cooled to 10-15° C.) which is subsequently allowed to reach ambient temperature over 3 h (with stirring). The resulting suspension is filtered, washed with water and the solid dried in vacuo overnight. The resultant crude product is triturated in diethyl ether (approx. 15 ml) for 20 mins. then dried in vacuo to yield 5-[2-(2,4-dichloro-phenyl)-1-methyl-2-oxo-ethoxy]-3-ethyl-1H-pyrazole-4-carboxylic acid ethyl ester: yield: MS: m/z 385.13 [M+H]+
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[NH:9][C:10](=[O:18])[C:11]([O:14][C:15](=[O:17])[CH3:16])([CH3:13])[CH3:12])(=[O:3])[NH2:2].C1C(=O)N([Br:26])C(=O)C1>CC(O)=O.O>[Br:26][C:7]1[S:6][C:5]([NH:9][C:10](=[O:18])[C:11]([O:14][C:15](=[O:17])[CH3:16])([CH3:12])[CH3:13])=[C:4]([C:1](=[O:3])[NH2:2])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OC(C)(C)C(=O)Nc1sccc1C(N)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC(C)(C)C(=O)Nc1sc(Br)cc1C(N)=O
Temperature: 25 °C

Procedure:
Intermediate 10 (46.5 g, 172 mmol) is dissolved in AcOH (700 mL). To the resulting suspension, NBS (32.2 g, 181 mmol) is added. The mixture is stirred at room temperature, after which it is evaporated to give a slurry. This slurry is taken up in water to give a suspension that is filtered. Resulting precipitate is dried in the vacuum oven and used as such.
Reaction SMILES: C([O:3][C:4](=[O:11])[CH:5](Br)[CH2:6][CH2:7][CH2:8][CH3:9])C.NC(N)=[S:14].[OH-].[Ba+2].[OH-]>C(O)C>[SH:14][CH:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([OH:3])=[O:11]
Reactant: NC(N)=S
Reactant: CCCCC(Br)C(=O)OCC
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Product: CCCCC(S)C(=O)O
Reaction time: 20 h
Yield: 81 %

Procedure:
A mixture of 100 g (0.44 mole) of 2-bromohexanoic acid ethyl ester (Aldrich) and 39.0 g (0.51 mole) of thiourea (Fisher) in 600 mL of ethanol was stirred and heated on a steam bath for 2 hr. The solvent was evaporated under reduced pressure to give a solid residue. The solid was treated with 75 g (0.44 mole) of barium hydroxide in 1 L of 20% aqueous ethanol and the reaction mixture was stirred and heated at reflux for 20 hr. An additional 30.0 g (0.18 mole) of barium hydroxide was added and stirring and heating was continued for 20 hr. The reaction mixture was filtered and the filtrate pH was adjusted to 2 with concentrated hydrochloric acid. The mixture was extracted with three 500 mL portions of ethyl ether. The ethereal extracts were washed twice with 300 mL portions of water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to yield 52.8 g (80%) of 2-mercaptohexanoic acid as a light-yellow, viscous oil that has a sharp onion smell.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]1[CH2:18][CH:17]1[CH2:19][CH2:20][NH2:21]>>[CH2:16]1[CH2:18][CH:17]1[CH2:19][CH2:20][NH:21][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: NCCC1CC1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Product: O=C(NCCC1CC1)c1ccc(-c2ccccc2)cc1

Procedure:
Using Preparation Method 1, 4-phenylbenzoic acid was reacted with (2-cyclopropyl)ethylamine. The resulting reaction mixture was purified using SiO2 with CH2Cl2 100%. A white crystalline solid was obtained (29%). NMR 1H (ppm, CDCl3): 7.82 (d, J3=8.2 Hz, 2H), 7.64 (d, J3=8.4 Hz, 2H), 7.60 (d, J3=7.5 Hz, 2H), 7.47-7.34 (m, 3H), 6.26 (br. s., 1H), 3.60-3.53 (m, 2H), 1.54 (quart., J3=6.8 Hz, 2H), 0.76-0.71 (m, 1H), 0.51-0.48 (m, 2H), 0.13-0.11 (m, 2H).
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][C:13]2[C:8](=[CH:9][C:10]([CH2:24][CH3:25])=[N:11][C:12]=2[CH2:22][CH3:23])[N:7]=1>O.Cl>[CH2:22]([C:12]1[N:11]=[C:10]([CH2:24][CH3:25])[CH:9]=[C:8]2[C:13]=1[CH:14]=[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6](=[O:2])[NH:7]2)[CH3:23]
Reactant: O=N[O-]
Reactant: CCc1cc2nc(N)c(-c3ccccc3)cc2c(CC)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCc1cc2[nH]c(=O)c(-c3ccccc3)cc2c(CC)n1
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A solution of sodium nitrite (3.2 g) in water (64 ml) was added dropwise over 45 minutes to a solution of compound B (2.0 g) in 2M hydrochloric acid (150 ml). The mixture wa stirred for a further 1 hour and then the suspended white solid was collected by filtration and dried under vacuum to give 5,7-diethyl-3-phenyl-1,6-naphthyridin-2(1H)-one (1.0 g); m.p. >260° C.; NMR (d6 -DMSO): 1.32(t, 3H), 1.33(t, 3H), 3.07(q, 2H), 3.47(q, 2H), 7.41(s, 1H), 7.43-7.55(m, 3H), 7.74-7.85(m, 2H), 8.31(s, 1H); mass spectrum (+ve FAB, methanol/NBA): 279 (M+H)+ ; microanalysis, found: C, 76.9; H, 6.6; N, 9.7%; C18H18N2O.0.25H2O requires: C, 76.4; H, 6.5; N, 9.9%.
Reaction SMILES: CCOCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[CH3:15][N:16]([CH3:29])[C:17]1(C#N)[CH2:26][CH2:25][C:20]2([O:24][CH2:23][CH2:22][O:21]2)[CH2:19][CH2:18]1>C1COCC1>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:17]2([N:16]([CH3:29])[CH3:15])[CH2:26][CH2:25][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:19][CH2:18]2)=[CH:8][CH:9]=1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: COc1ccc(Br)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2(N(C)C)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Magnesium (3.65 g, 150 mmol) and an iodine crystal were provided in a nitrogen atmosphere and heated. Abs. ether (10 mL) was then added and a solution of 4-bromoanisole (18.8 mL, 150 mmol) in abs. ether (150 mL) was added in drops so that the ether lightly boiled. The solution formed was subsequently stirred for 1 h at RT and then mixed in drops with a solution of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (10.5 g, 50.0 mmol) in abs. THF (100 mL), and the solution heated to 37-40° C. until boiling during the addition. A precipitate separated out and the batch was stirred overnight at RT. The solution was mixed with NH4Cl solution with ice cooling, the phases were separated, the aqueous phase extracted three times with ether, the combined organic phases washed with saturated NaCl solution and water, dried over Na2SO4 and concentrated to low volume in a vacuum. Flash chromatography of the residue with ethyl acetate/methanol (20:1→9:1→4:1→1:4→MeOH) gave the desired product.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[NH:16])[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6].CN(C)[CH:20]=[CH:21][C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=O.[OH-].[Na+]>C(O)(C)C>[N+:5]([C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:17]=[C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:21]=[CH:20][N:16]=2)[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc(Nc2nccc(-c3cccnc3)n2)c1
Reaction time: 0.5 h

Procedure:
41.3 g (0.17 mol) of 3-nitrophenyl-guanidine nitrate, made into a slurry in 50 ml of isopropanol, are added to a solution of 30 g (0.17 mol) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one [described in EP-A-0 233 461] in 250 ml of isopropanol. After the addition of 7.49 g (0.19 mol) of sodium hydroxide, the yellow suspension is boiled at reflux for 8 hours. After cooling to 0°, the mixture is filtered and washed with 200 ml of isopropanol. The filtration residue is made into a sherry in 300 ml of water and stirred for 30 minutes, filtered and washed with 200 ml of water. After again making into a slurry in 200 ml of ethanol and washing with 200 ml of ethanol/diethyl ether (1:1) there is obtained N-(3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine; m.p. 212°-213° , Rf =0.75 (chlorofoform:menthol=9:1).
Reaction SMILES: C([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[N:13]([CH3:23])[C:12]2=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:27].[H][H]>CO.[Pd]>[ClH:27].[CH3:23][N:13]1[C:12](=[O:24])[C:11]2([CH2:10][CH2:9][NH:8][CH2:26][CH2:25]2)[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]1=[O:22]
Reactant: [H][H]
Reactant: CN1C(=O)N(c2ccccc2)C2(CCN(Cc3ccccc3)CC2)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN1C(=O)N(c2ccccc2)C2(CCNCC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of 8-benzyl-3-methyl-1-phenyl-1,3,8-triazaspiro[4,5]decane-2,4-dione (470 mg, 1.3 mmol), from Step D, in methanol (100 mL) were added concentrated aqueous hydrochloric acid (0.12 mL, 1.4 mmol) and wet 20% palladium on carbon (0.47 g). The reaction vessel was pressurized with hydrogen (4 atmospheres) and shaken on a Parr apparatus at ambient temperature for 2 hours. The reaction mixture was then filtered sequentially through a paper filter and through a PTFE (polytetrafluoroethylene) filter membrane (0.45μ), rinsing with methanol. The filtrate was concentrated under reduced pressure and then the residue was dried to give 0.34 g (89% yield) of the title compound as a white solid, m.p.>330° C. (dec); MS (DCl/NH3) M/Z: 260 (M+H)+, 277 (M+NH4)+ ; 300 MHz 1H NMR (CDCl3) δ2.02 (td, J=5, 14 Hz, 2H), 2.31 (d, J=15 Hz, 2H), 3.08 (s, 3H), 3.34-3.43 (m, 2H), 3.72 (td, J=3, 12 Hz, 2H), 7.29-7.35 (m, 2H), 7.49-7.58 (m, 3H).
Reaction SMILES: [OH:1][NH:2][C:3]([NH2:5])=[O:4].CO.[CH3:8][C:9](=O)[CH2:10][C:11](=O)[CH2:12][CH3:13].O.[ClH:17]>>[ClH:17].[CH2:12]([C:11]1[CH:10]=[C:9]([CH3:8])[N:5]=[C:3]([OH:4])[N+:2]=1[O-:1])[CH3:13]
Reactant: CCC(=O)CC(C)=O
Reactant: NC(=O)NO
Agent: Cl
Solvent: CO
Solvent: O
Product: CCc1cc(C)nc(O)[n+]1[O-]
Temperature: -15 °C
Reaction time: 2 h

Procedure:
0.12 mol (9.13 g) hydroxy urea were dissolved in 50 ml 2 M HCl, 20 ml of methanol were added and 0.10 mol (11.41 g) 2,4-hexanedione were added dropwise under cooling by approximately −15° C. Further 30 ml of water and 10 ml of methanol were added. The two-phase reaction mixture was allowed to warm up slowly to room temperature and was stirred at room temperature for further 2 h, then evaporated until dryness. The residue was suspended with 50 ml of acetone, the mixture was cooled in an ice/ethanol bath, the solid filtered off and washed with a little ice-cold acetone. After drying 7.88 g crude product were obtained which were recrystallized from 45 ml ethanol wherefrom first an insoluble salt compound was hot filtered off and the product was subsequently recrystallized from the filtrate at −18° C. 3.0 g product were obtained which were again recrystallized from 28 ml ethanol. Finally 2.26 g of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2.Cl.Cl[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:1]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]3)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1cc2c(N)cccc2[nH]1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(N3CCNCC3)cccc2[nH]1
Temperature: 110 °C
Reaction time: 16 h
Yield: 37.8 %

Procedure:
A mixture of the product of Example 3 (9.5 g, 0.051 mol), bis(2-chloroethyl)amine hydrochloride (10.6 g, 0.06 mol), and potassium carbonate (8.3 g, 0.06 mol) in anhydrous dimethylformamide (30 ml) was heated at 110° C. under argon. Further addition of bis(2- chloroethyl)amine hydrochloride (5.5 g. 0.031 mol) and potassium carbonate (4.2 g, 0.031 mol) were made after 7 h and 16 h. After another 6 h,the reaction mixture was poured into dilute potassium carbonate solution (400 ml) and extracted with ether (3×300 ml) and ethyl acetate (2×250 ml). The extracts were combined, dried (MgSO4), and washed with water (2×200 ml). Evaporation of the solvent in vacuo gave a solid which was recrystallised from ether to give the product (5.0 g) as off-white crystals, m.p. 177°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Oc1ccc(Cl)cc1
Product: COc1ccc2c(Oc3ccc(Cl)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-chloro-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-Chloro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 382(MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[CH:23]([O:26][CH3:27])[O:24][CH3:25])[C:8]([NH:10][C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:9].CN(CCN(C)C)C.CN([CH:39]=[O:40])C>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:22]([CH:23]([O:26][CH3:27])[O:24][CH3:25])=[CH:21][CH:20]=[C:7]2[C:6]=1[CH:39]([OH:40])[N:10]([C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])[C:8]2=[O:9]
Reactant: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1C(OC)OC
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COCOc1c(C(OC)OC)ccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 76 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-methoxymethoxy-4-dimethoxymethyl-N-(1-methyl-1-phenylethyl)benzamide (3.61 g, 9.67 mmol) was dissolved in THF (100 mL), and the solution was treated with TMEDA (4.70 mL, 31.0 mmol), sec-butyl lithium-hexane solution (1.03 mol/L, 30.0 mL, 30.9 mmol) and DMF (1.65 mL, 21.3 mmol), followed by purification by slurry using chloroform and hexane to obtain 4-methoxymethoxy-5-dimethoxymethyl-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (2.95 g, yield 85%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[OH:18][N:17]=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:9][C:2]=1[OH:1]
Reactant: O=Cc1ccc(N2CCOCC2)cc1O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1ccc(N2CCOCC2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
A solution of 2-hydroxy-4-morpholin-4-yl-ben zaldehyde (0.135 g, 0.65 mmol) in pyridine (5 mL) was treated with hydroxylamine hydrochloride (45 mg, 0.65 mmol) and stirred for 30 min at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 5% sodium bicarbonate. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the product as a pale yellow solid (51 mg, 35%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>CN(C=O)C>[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:17]([C@H:14]1[CH2:13][CH2:12][C@@H:11]([CH2:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:16][CH2:15]1)=[O:19]
Reactant: NCc1ccccc1F
Reactant: O=C(O)[C@H]1CC[C@@H](Cc2nc3ccccc3[nH]2)CC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCc1ccccc1F)[C@H]1CC[C@@H](Cc2nc3ccccc3[nH]2)CC1

Procedure:
To a solution of (E) cis-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid (271 mg, 1.05 mmol), EDC (200 mg, 1.05 mmol) and HOAt (142 mg, 1.05 mmol) in anhydrous DMF (4 mL) was added 2-fluorobenzylamine (131 mg, 1.05 mmol) and the reaction mixture was stirred for lh. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc and the organic layer washed 2× with water. The EtOAc was dried with MgSO4 and concentrated to give a yellow solid. The crude material was triturated with 2:2:1 water/CH3CN/DMSO and the resultant white solid filtered off. Repetitive concentration and trituration of the filtrate in the same manner gave cis-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid 2-fluoro-benzylamide (F) (230 mg, 60%) as a white solid. The (F) compound was stirred in 1M HCl/ether (10 ML) for 1 h and concentrated to give the HCl salt of Ex. 7 (250 mg): 1H NMR (400 MHz, CD3OD) δ 7.50 (br s 2H), 7.35-7.25 (m, 2H), 7.22-7.05 (m, 4H), 4.43 (s, 2H), 2.92 (d, 2H), 2.41 (m, 1H), 2.23 (m, 1H), 1.93 (m, 2H), 1.60 (m, 6H); mass spectrum m/z 366 [(M+H)+; calcd for C22H25N3OF: 366].
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][CH:10]=2)[N:5](C(=O)C(F)(F)F)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:1][C:2]1([CH3:34])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:19][CH2:20]3)=[O:14])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCN(C(=O)C(F)(F)F)c2cc(NC(=O)N3CCN(c4ncccc4Cl)CC3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1(C)CCNc2cc(NC(=O)N3CCN(c4ncccc4Cl)CC3)ccc21
Temperature: 50 °C

Procedure:
A suspension of N-(4,4-dimethyl-1-trifluoroacetyl-1,2,3,4-tetrahydroquinol -7-yl)-4-(3-chloro-2-pyridyl)-piperazine-1-carboxamide (125 mg, 0.253 mmol) and potassium carbonate (105 mg, 0.758 mmol) in methanol (5 ml) and water (5 ml) was heated at 50° C. for 3 h. After this period, the solvents were evaporated in vacuo and the residue partitioned between DCM (50 ml) and water (50 ml). The aqueous layer was re-extracted with DCM (2×50 ml) and then the combined organic layers dried (Na2SO4) and the solvents evaporated in vacuo to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.19 (dd, 1H), 7.61 (dd, 1H), 7.07 (d, 1H), 6.87 (dd, 1H), 6.75 (d, 1H), 6.41 (dd, 1H), 6.19 (br, 1H), 3.85-3.95 (br, 1H), 3.60-3.70 (m, 4H), 3.30-3.40 (m, 4H), 3.25-3.35 (m, 2H), 1.65-1.75 (m, 2H), 1.26 (s, 6H). MS (ES): MH+ 400/402.