Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:19]2[C:18]([CH3:17])=[CH:22][N:21]=[CH:20]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cncn1-c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of p-nitrofluorobenzene (2 g, 14 mmol) in DMF (20 mL) was treated with potassium carbonate (8 g, 58 mmol) and 4-methylimidazole (1.2 g, 14.mmol). After refluxing for 18 h, the reaction mixture was cooled down and concentrated at reduced pressure. The residue was treated with water and the mixture was extracted with ethyl acetate and dried over magnesium sulphate. The organic layer was concentrated and the residue was purified by flash-chromatography (methanol/methylene chloride, 0.5:9.5) affording 1.8 g(62%) of p-nitro-4 (5)-methyl-imidazol-1-yl as 7:1 mixture of regioisomers.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[C:12]([C:14]2[N:18]=[CH:17][NH:16][N:15]=2)=[O:13])[CH:7]=[CH:6][N:5]=1.CI.[C:25](=O)([O-])O.[Na+]>CN(C)C=O.O>[Br:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[C:12]([C:14]2[N:18]=[CH:17][N:16]([CH3:25])[N:15]=2)=[O:13])[CH:7]=[CH:6][N:5]=1
Reactant: O=C(c1nc[nH]n1)N(Cc1ccnc(Br)c1)C1CCC1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cnc(C(=O)N(Cc2ccnc(Br)c2)C2CCC2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (186 mg) was added to a solution of N-[(2-bromopyridin-4-yl)methyl]-N-cyclobutyl-1H-1,2,4-triazole-3-carboxamide (1.3 g) in dimethylformamide (10 mL), and the mixture was stirred at room temperature for 15 min. Methyl iodide (0.25 mL) was added thereto and the mixture was stirred at room temperature for 17.5 hr. Saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, followed by extraction with ethyl acetate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=75:25-0:100) to afford the title compound (748 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[F:14][B-:15]([F:18])([F:17])[F:16].[H+].[N:20](OCCCCC)=O>C(O)C.C(OCC)C>[F:14][B-:15]([F:18])([F:17])[F:16].[N+:1](=[C:2]1[CH:7]=[N:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[C:4]([CH3:13])[CH2:3]1)=[N-:20]
Reactant: CCCCCON=O
Reactant: Cc1cc(N)cnc1CCCCN
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Solvent: CCOCC
Product: CC1=C(CCCCN)N=CC(=[N+]=[N-])C1
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) mixture of 5-amino-2-[4-aminobutyl]-3-methylpyridine (0.86 g) and fluoroboric acid (5 ml) in ethanol (30 ml) was reacted with amyl nitrite (3 ml) over 15 minutes and then stirred for a further 15 minutes, diluted with diethyl ether at 0° C. to give 5-diazo-2-(4-aminobutyl)-3-methylpyridine fluoroborate (1.88 g) m.p. 80°-120° C. (dec).
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@H:19]2[C@:10](C(OCC)=O)([C:11](=[O:25])[NH:12][C:13]3[C:14]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31]>O1CCOCC1>[ClH:31].[CH2:1]([N:8]1[CH2:20][C@H:19]2[C@H:10]([C:11](=[O:25])[NH:12][C:13]3[C:14]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@]12CN(Cc3ccccc3)C[C@@H]1c1cccc(C(F)(F)F)c1NC2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1Nc2c(cccc2C(F)(F)F)[C@H]2CN(Cc3ccccc3)C[C@@H]12
Temperature: 90 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
To a solution of (±)-cis-ethyl 2-benzyl-4-oxo-6-(trifluoromethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,4-c]quinoline-3a-carboxylate from Example 1, Part D (45 mg, 0.11 mmol) in 6 mL of 1,4-dioxane was added 4 mL of 3N HCl. The reaction was stirred at 90° C. for 18 h. The reaction was allowed to cool and was concentrated in vacuo. The residue was partitioned between ethyl acetate and sat'd aq NaHCO3. The organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was taken up in 3 mL of diethyl ether and then there was added HCl (0.10 mL of a 4N solution in 1,4-dioxane, 0.40 mmol). A solid settled out of solution. The solvents were decanted and the remaining solid was triturated twice with diethyl ether and dried in vacuo to afford 30 mg (73%) of the title compound of Example 2 as an off-white solid. LRMS (ESI): 347.26 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[Cl:26][C:27]1[N:32]=[N:31][C:30]([N:33]2[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:39]([CH:36]3[CH2:37][CH2:38][N:33]([C:30]4[N:31]=[N:32][C:27]([Cl:26])=[CH:28][CH:29]=4)[CH2:34][CH2:35]3)=[O:40])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(c2ccc(Cl)nn2)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(c3ccc(Cl)nn3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound rac-[(3R,4S)-1-[1-(6-Chloro-pyridazin-3-yl)-piperidine-4-carbonyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-(6-chloro-3-pyridazinyl)-4-piperidinecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 608.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:6]=[C:5]([NH:16][NH2:17])[N:4]=1)[CH3:2].[C:18](OCC)(OCC)(OCC)[CH2:19][CH3:20]>>[CH2:19]([C:20]1[N:4]2[C:3]([CH2:1][CH3:2])=[N:8][C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[CH:6][C:5]2=[N:16][N:17]=1)[CH3:18]
Reactant: CCc1nc(NN)cc(N2CCN(C)CC2)n1
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc2cc(N3CCN(C)CC3)nc(CC)n12
Yield: 37 %

Procedure:
A mixture of 8.3 g (0.045 mole) of 2-ethyl-6-hydrazinyl-4-(4-methyl-1-piperazinyl)pyrimidine and 75 ml of triethyl orthopropionate was heated at reflux for 48 hours. After cooling the mixture was evaporated in vacuo. Diethyl ether was added to the residue and the mixture was cooled. The precipitate was collected by filtration to provide 4.5 g (37%) of 3,5-diethyl-7-(4-methyl-1-piperazinyl)-1,2,4-triazolo[4,3-c]pyrimidine. Recrystallizations from ethyl acetate-hexane and ethyl acetate-cyclohexane provided white crystalline product, m.p. 128°-131° C. Analysis for C14H22N6 : Calculated: %C, 61.3; %H, 8.1; %N, 30.6; Found: %C, 59.8; %H, 8.2; %N, 30.1. The structural assignment was confirmed by nuclear magnetic resonance and infrared spectral analyses.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:19]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:28][O:29][CH2:30][C:31]([OH:33])=O)(=[O:21])=[O:20])=[C:14]([CH3:34])[CH:13]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:58]1[CH:63]=[CH:62][CH:61]=[C:60]([C:64]2([O:71][CH2:72][CH2:73][N:74]3[CH2:78][CH2:77][CH2:76][CH2:75]3)[CH2:70][CH2:69][CH2:68][NH:67][CH2:66][CH2:65]2)[CH:59]=1>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:19]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:28][O:29][CH2:30][C:31]([N:67]2[CH2:68][CH2:69][CH2:70][C:64]([C:60]3[CH:59]=[N:58][CH:63]=[CH:62][CH:61]=3)([O:71][CH2:72][CH2:73][N:74]3[CH2:78][CH2:77][CH2:76][CH2:75]3)[CH2:65][CH2:66]2)=[O:33])(=[O:21])=[O:20])=[C:14]([CH3:34])[CH:13]=1
Reactant: c1cncc(C2(OCCN3CCCC3)CCCNCC2)c1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)N2CCCC(OCCN3CCCC3)(c3cccnc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
DIPEA (2.5 eq.) was added to a cooled solution (0° C.) of (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid [acid D] in methylene chloride (5 ml/mmol), followed by HOBt (1 eq.) and EDCl (1.5 eq.). The reaction mixture was stirred at room temperature for 10 min and cooled to 0° C. and 4-(pyridin-3-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)azepan hydrochloride [amine K] (1.2 eq.) was added. The reaction mixture was then stirred at room temperature for 16 h. In this time, the educts reacted completely (TLC control). The reaction mixture was diluted with methylene chloride (20 ml) and washed with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium bicarbonate solution and finally with sat. sodium chloride solution again. The organic phase was dried over sodium sulfate and concentrated to dryness on a rotary evaporator. The crude product was purified by means of column chromatography (silica gel, 2% methanol in methylene chloride). Yield: 46%. MS, Rt=2.8 min, m/z=643.4 [MH]+
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:18][CH3:19])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)[CH3:3].[H][H]>CO.[Pd]>[ClH:1].[ClH:1].[CH2:18]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)[CH3:19]
Reactant: CCN(CC)CCCOc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN(CC)CCCOc1ccc(N)cc1

Procedure:
Hydrogenate a solution of 8.5 g (29.4 mmol) of N,N-diethyl-3-(4-nitrophenoxy)propanamine hydrochloride in 100 mL of methanol over 0.92 g of 10% palladium on carbon catalyst at 40-45 psi at room temperature. When hydrogen uptake ceases remove the catalyst by filtration and add 5 mL of concentrated hydrochloric acid. Remove the solvent in vacuo. Recrystallize the residue from ethanol to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[OH-].[NH4+:17]>O1CCCC1>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH2:17])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(F)cc2)C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)N1CC(Oc2ccc(F)cc2)C1
Temperature: 25 °C

Procedure:
A solution of 5.52 g (0.022 mole) of crude 3-(4-fluorophenoxy)-1-azetidine carbonyl chloride in 20 ml of tetrahydrofuran was treated with 10 ml of concentrated ammonium hydroxide while stirring. The exothermic reaction mixture was stirred for 18 hr as it cooled to ambient temperature. The reaction mixture was diluted with 400 ml of ice water to produce a phase separation. Upon standing, the oily phase solidified and was collected by filtration yielding 12.5 g of crude wet product. Recrystallization from aqueous ethanol after charcoal treatment produced an oil which slowly crystallized. The sample was recrystallized from methylene chloride, yield 1.6 g (35%) of amorphous-like powder, m.p. 185°-188° C.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[NH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=2)[N:15]([CH3:23])[N:14]=1>>[F:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:23])[N:14]=[C:13]2[NH:12][C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cn1nc(N)c2cc(F)ccc21
Reactant: COC(=O)c1ccncc1Br
Product: Cn1nc(Nc2cnccc2C(=O)O)c2cc(F)ccc21
Yield: 23 %

Procedure:
The title compound was prepared in 23% yield from methyl 3-bromoisonicotinate and 3-amino-5-fluoro-1-methyl-indazole according to the general procedure for Example 6. 1H NMR (400 MHz, DMSO-d6): δ 4.01 (3H, s), 7.31-7.41 (2H, m), 7.67 (1H, dd, J=9.1, 4.1 Hz), 7.78 (1H, d, J=5.0 Hz), 8.16 (1H, d, J=5.0 Hz), 9.49 (1H, s), 10.33 (1H, br s). [M+H] calc'd for C14H11FN4O2, 287; found 287.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[CH3:26][O:27][CH2:28][C:29]#[CH:30].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O.[Cu]I.C(Cl)(Cl)Cl>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:30]#[C:29][CH2:28][O:27][CH3:26])[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: C#CCOC
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)cc(N2CCOCC2)n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COCC#Cc1cc(N2CCOCC2)nc(-n2c(C(F)F)nc3ccccc32)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1-[4-Chloro-6-(morpholin-4-yl)pyrimidin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (100 mg) was dissolved in dimethylformamide (1 mL), and 3-methoxyprop-1-yne (45 μL), tetrakistriphenylphosphine palladium (0) (16 mg), copper (I) iodide (1.3 mg), and potassium carbonate (227 mg) were added thereto, followed by stirring in a microwave reactor at 80° C. for 1 hour. An aqueous ammonium chloride solution and chloroform were added thereto, and the organic layer was extracted, washed with saturated brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:40). A mixed solvent of diisopropyl ether and hexane was added thereto, and the resulting solid was collected by filtration and further washed with hexane to obtain 2-(difluoromethyl)-1-[4-(3-methoxyprop-1-yn-1-yl)-6-(morpholin-4-yl)pyrimidin-2-yl]-1H-benzimidazole (10 mg) as a yellow powder.
Reaction SMILES: [Na+].[F:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([O-])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:23])=O>CN(C)C=O>[F:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([Cl:23])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)([O-])c1ccc(OCc2ccc(F)cc2)cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(OCc2ccc(F)cc2)cc1

Procedure:
To a stirred solution of 4-hydroxybenzenesulfonic acid sodium salt dihydrate (5.13 g, 22.1 mmol) in 23 mL of 1 N sodium hydroxide was added a solution of 4-fluorobenzyl bromide (3.3 mL, 26.5 mmol) in 20 mL of ethanol. The mixture was heated at reflux for two days, then cooled to ambient temperature (22° C.), whereupon a white precipitate formed. The flaky white solids were collected by filtration, rinsed with ethyl acetate and diethyl ether, and dried to give 4.95 g of 4-(4-fluoro-benzyloxy)-benzenesulfonic acid sodium salt. A stirred solution of 4-(4-fluoro-benzyloxy)-benzenesulfonic acid sodium salt (13.0 g, 42.7 mmol) in 50 mL of thionyl chloride and two drops of dimethylformamide was heated at a gentle reflux for 8 hours. The mixture was concentrated to a yellow solid which was suspended in ethyl acetate and filtered. The filtrate was concentrated to 11.2 g of 4-(4-fluorobenzyloxy)benzenesulfonyl chloride as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.95-7.98 (m, 2 H), 7.38-7.41 (m, 2 H), 7.06-7.12 (m, 4 H), 5.12 (s, 2 H).
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH3:15])=[N:9][C:8]=2[N:7]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.[K+].[Br-]>>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[C:10]([CH3:15])=[N:9][C:8]=2[N:7]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCn1c(=O)c2[nH]c(C)nc2n(CCCC)c1=O
Agent: [Br-]
Agent: [K+]
Product: CCCCn1c(=O)c2c(nc(C)n2S(=O)(=O)c2ccc(C)cc2)n(CCCC)c1=O
Yield: 75 %

Procedure:
The title compound was prepared according to the procedure of example 3 except that 1,3-dibutyl-8-methyl-3,7-dihydro-purine-2,6-dione was used in place of 1,3-dibutyl-3,7-dihydro-purine-2,6-dione and p-toluenesulfonyl chloride was used in place of methanesulfonyl chloride. Yield: 75%; mp: 111-113° C.; 1H NMR (300 MHz, CDCl3): δ 0.89-0.96 (m, 6H), 1.29-1.37 (m, 4H), 1.58-1.65 (m, 2H), 1.67-1.72 (m, 2H), 2.48 (s, 3H), 2.86 (s, 3H), 3.93 (t, J=7.6 Hz, 2H), 4.11 (t, J=7.1 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 8.13 (d, J=8.5 Hz, 2H); IR (KBr, cm−1): 2960m, 2865m, 1709s, 1674s, 1593m, 1528s, 1479m, 1181m, 1121s, 938m, 760m, 595m; MS (ES) m/z (relative intensity): 433 (M++H, 100).
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])=[CH:4][CH:3]=1.[NH4+].[Cl-].[CH2:19]1COC[CH2:20]1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:19]([C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])=[CH:4][CH:3]=1)#[CH:20]
Reactant: C1CCOC1
Reactant: C[Si](C)(C)CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [NH4+]
Product: C#Cc1ccc(C(=O)OCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (trimethylsilyl)ethyl 4-iodobenzoate (2.5 g, 7.2 mmol), (tributyltin)acetylene (2.5 mL, 8.6 mmol) and THF (50 mL) was purged with argon for 10 min, and then treated with bis(triphenylphosphine)palladium (II) chloride (126 mg, 0.18 mmol). The suspension was stirred overnight at room temperature and then for 1 hour at 50 ° C. The solution was treated with NH4Cl and the product extracted with 50% ethyl acetate and hexane solution. The layers were separated and the aqueous layer extracted twice more with the same organic solution. The combined organic layers were washed with brine, and dried (MgSO4), and filtered and the solvents were removed under reduced pressure. The residue was purified by silica gel chromatography (98:2, hexane:ethyl acetate) to give the title compound as a yellow oil.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:17]=C(C(OC)=O)C=1>C(O)(=O)C>[CH2:10]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:17]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=1)[CH3:11]
Reactant: CCOC(=O)C(=O)CC(=O)CC
Reactant: COC(=O)c1cc(C)n(Cc2ccc(C)cc2)n1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)n(Cc2ccc(C)cc2)n1

Procedure:
A solution of ethyl 2,4-dioxohexanoate (Step 1, 2.0 g, 11.6 mmol) and 4-(methylbenzyl)-hydrazine dihydrochloride (Step 3 of Intermediate A, 2.67 g, 12.8 mmol) in acetic acid (15 mL) was stirred for 4 h at 90° C. After removal of the solvent (rotavapor), the residue was subjected to MPLC (silica, cyclohexane/ethyl acetate 5:1) to afford the title compound as a highly viscous oil (1.93 g, 61%): 1H NMR (400 MHz, CDCl3) δ 7.10 (d, 2H), 6.98 (d, 2H), 6.62 (s, 1H), 5.33 (s, 2H), 4.40 (quart, 2H), 2.48 (quart, 2H), 2.31 (s, 3H), 1.40 (t, 3H), 1.18 (t, 3H); DCI(NH3)-MS m/z 273 (MH)+; HPLC RT (Method I) 4.75 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[C:21]1([CH2:27][CH2:28][C:29]([N:31]2[C@@H:35]([CH:36]([CH3:38])[CH3:37])[CH2:34][O:33][C:32]2=[O:39])=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[CH2:27]([C@H:28]([C@@H:40]([OH:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:29]([N:31]1[C@@H:35]([CH:36]([CH3:37])[CH3:38])[CH2:34][O:33][C:32]1=[O:39])=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)CCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@H](Cc1ccccc1)[C@@H](O)c1ccccc1
Reaction time: 1 h

Procedure:
1.55 ml (11 mmol) of diisopropylamine is dissolved in 20 ml of absolute THF under argon and 7.75 ml (12 mmol) of n-butyllithium solution (1.55M in n-hexane, Aldrich) are added at -20° C. with stirring. The mixture is stirred at this temperature for 10 minutes and the freshly prepared solution of lithium diisopropylamide prepared in this way is then added dropwise to a solution of 2.61 g (10 mmol) of (4S)-3-(3-phenylpropionyl)-4-(2-propyl)-oxazolidin-2-one (J.J. Plattner et al., J. Med. Chem. 1988, 31 (12), 2277-2288) cooled to -70° C. in 30 ml of absolute THF. The mixture is subsequently stirred at -70° C. for 30 minutes and 1.32 ml (13 mmol) of benzaldehyde are injected into the mixture via a septum. After one hour at this temperature, the mixture is hydrolyzed by adding 100 ml of saturated ammonium chloride solution and allowed to come to room temperature, and 100 ml of diethyl ether are added. The organic phase is separated off and the aqueous phase is extracted with 100 ml of diethyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=4[CH3:28])[C:21]([O:23]C)=O)[CH:14]=3)[C:9]2=[O:29])=[CH:5][CH:4]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1.C([Mg]Cl)(C)C>O1CCCC1>[CH:32]1([NH:35][C:21](=[O:23])[C:20]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:18]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[C:9](=[O:29])[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=3)[CH:17]=[CH:16]4)[CH:19]=2)[CH2:34][CH2:33]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)n(Cc4ccc(OC)cc4)ccc3c2)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(Cn2ccc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-4-methyl-benzoic acid, methyl ester (product of step v)) (1.0 g) and cyclopropylamine (0.71 g) in tetrahydrofuran (3 mL) was treated with isopropylmagnesium chloride (2M in THF, 0.77 mL) and stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous ammonium chloride and extracted into ethyl acetate. The organic phase was dried, filtered and evaporated to yield the title compound as a solid (850 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[NH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1>CCOCC>[Cl:5][CH2:4][CH2:3][CH2:2][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: ClCCCBr
Reactant: C1CCNC1
Solvent: CCOCC
Product: ClCCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To the solution of about 186 g (1.18 mol) of 1-bromo-3-chloropropane in about 200 ml of ether was added about 2 equivalent of pyrrolidine at about 0° C. After addition, the mixture was allowed to warm to room temperature and stirred overnight. The resulting white solid residue was removed and to the clear solution was added ice-cold 10% hydrochloric acid. The ether layer was discarded and the acid layer was basified with ice-cold 20% NaOH, extracted with ether and dried over Na2SO4. Ether was removed and the residue was distilled under vacuum (95° C./30 mmHg). About 91 g of product having formula (VIII) was obtained in a form of a pale yellow liquid. The yield was about 53%.
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[C:7]([F:10])[C:5]([NH2:6])=[C:4]([F:11])[C:3]=1[F:12].[CH2:13]([O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)[CH2:14][CH2:15][CH3:16]>>[CH2:13]([O:17][C:18]1[CH:23]=[C:22]([C:2]2[C:8]([F:9])=[C:7]([F:10])[C:5]([NH2:6])=[C:4]([F:11])[C:3]=2[F:12])[CH:21]=[CH:20][CH:19]=1)[CH2:14][CH2:15][CH3:16]
Reactant: Nc1c(F)c(F)c(Br)c(F)c1F
Reactant: CCCCOc1cccc(B(O)O)c1
Product: CCCCOc1cccc(-c2c(F)c(F)c(N)c(F)c2F)c1
Yield: 64.9 %

Procedure:
The title compound (250 mg) was prepared from 4-bromo-2,3,5,6-tetrafluoroaniline (300 mg, 1.23 mmol) and 3-butoxyphenylboronic acid (310 mg, 1.59 mmol) as a yellow liquid.