Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[CH:8]=1)C.[CH3:15][C:16]([CH3:18])=[O:17].[H][H]>C1COCC1>[I:13][C:9]1[CH:8]=[C:7]([C:6](=[O:14])[CH2:15][C:16](=[O:17])[CH3:18])[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: CC(C)=O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
4.0 g (100 mmol) sodium hydride (60%) was added to a stirred solution of 13.8 g (50 mmol) 3-iodobenzoic acid ethyl ester and 12 mL (160 mmol) acetone in 25 mL anhydrous THF. The mixture was stirred at 25° C. for 20 min, then slowly warmed to 30° C. An exothermic reaction started, and the temperature was kept below 30° C. with water bath. After 1 h the hydrogen evolution stopped, and the mixture was cooled to 5° C., and quenched with 150 mL 3% aqueous hydrochloric acid. 200 mL ether was added to the solution, then the phases were separated. The organic phase was washed with 100 mL water three times, dried with anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was mixed with 200 mL hexane, then the precipitate was filtered, and washed with 50 mL hexane three times. The filtrate was concentrated under reduced pressure, and purified by silica gel flash chromatography with hexane(neat), then hexane-EtOAc(4:1) as eluents to yield 7.0 g of the title compound, which was crystallized from hexane at −40° C.; TLC (Hexane-EtOAc(4:1)): Rf=0.65).
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([CH3:13])[CH:7]=1>>[CH:1]1([C:6]2[CH:7]=[C:8]([CH3:13])[CH:9]=[C:10]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:11]=2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(O)cc1
Reactant: C1=CCCC1
Product: Cc1cc(C2CCCC2)c(O)c(C2CCCC2)c1
Temperature: 140 °C
Reaction time: 15 h
Yield: 36.9 %

Procedure:
840 g of cyclopentene are added dropwise to 648 g of p-cresol and 60 g of an acid-activated fuller's earth at 140° C. Next the mixture is stirred at 140° C for 15 h. After having removed the catalyst by filtration the mixture is fractionated. In the boiling range of 153°-156° C 540 g of 2,6-dicyclopentyl-4-methylphenol are obtained (0.8 mm Hg) and between 167°-170° C 422 g of a fraction (0.8 mm Hg) which is recrystallised from petroleum ether. Yield: 360 g of 2,5-dicyclopentyl-4-methylphenol. Melting point: 78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[O:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[C:26](O)=[O:27]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:26]([CH:22]3[CH2:23][CH2:24][CH2:25][O:21]3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)C1CCCO1
Solvent: CO
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)C1CCCO1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and tetrahydro-2-furancarboxylic acid, (CAN 16874-33-2) as starting materials; enantiomers were separated by chiral HPLC (ChiralPak AD, 30% ethanol/n-heptane (−) enantiomer isolated; LC-MS (UV peak area/ESI) 100%, 401.0868 (M+H)+; αD20 (MeOH)=−16.8°
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C(O[Na])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)cc2)CC1
Temperature: 85 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
A mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (Willoughby, Christopher A.; Bioorg. Med. Chem. Lett., 13, 3, 2003, 427-432) (311 mg, 1.55 mmol), 4-bromobenzonitrile (237 mg, 1.30 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), (±)-BINAP (48 mg, 0.077 mmol) and t-BuONa (136 mg, 1.42 mmol) in freshly degassed toluene (4.5 mL) was stirred at 85° C. under argon for 2 hours. Work-up and purification gave 4-(4-cyano-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as an orange solid (324 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.N1C=CC=CC=1.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>ClCCl>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19]([CH:16]2[CH2:18][CH2:17]2)=[O:20])=[CH:7][N:6]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(N)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)C2CC2)cn1
Reaction time: 1 h

Procedure:
5-Amino-2-methoxy pyridine (12.4 grams, 0.10 mole), 10 milliliter (ml) of pyridine were mixed together in 200 ml dichloromethane in a reaction flask. 9.1 ml (0.10 mole) of cyclopropane carboxylic acid chloride was added to the reaction mixture over a period of 2 minutes. The reaction was exothermic and temperature rose to 34° C. The reaction was allowed to stand for one hour at room temperature, after which the reaction mixture was washed with 200 ml of 5% sodium hydroxide and 100 ml of water. The resulting organic phase was separated and dried over magnesium sulfate crystals. Crystals formed, so the mixture was filtered and washed with 300 ml of acetone and the filtrate evaporated in vacuo to give a solid that was triturated with hexane to yield 16.7 grams, after drying. The product was identified by IR and NMR as the title compound, having a melting point of 130°-131° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([F:23])([F:22])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH:27]([CH3:33])[C:28]([N:30]([CH3:32])[CH3:31])=[O:29]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:9][C:10]([F:22])([F:23])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=1)[CH:27]([CH3:33])[C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCOc1cccc(C(F)(F)CNC(=O)OC(C)(C)C)c1
Reactant: CC(Cl)C(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1cccc(C(F)(F)CN(C(=O)OC(C)(C)C)C(C)C(=O)N(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
75 mg (0.23 mmol) of N-tert-butoxycarbonyl-2,2-difluoro-2-(3-butoxyphenyl)-ethylamine are dissolved in dry DMF (5 mL). The solution is cooled to 0° C. and NaH (6.7 mg; 1.2 eq) is added. The solution is stirred at RT for 10 min, then cooled again to 0° C. and 2-chloro-N,N-dimethylpropanamide (31 mg; 0.23 mmol) are added. After 4 hours a further 1.2 eq of NaH (6.7 mg) are added. The reaction mixture is stirred overnight at RT, then quenched with water, evaporated, the residue taken up with water and EtAc. The organic layer is separated and the water layer extracted three times with EtAc. The combined organic phases are dried over anhydrous Na2SO4, filtered and evaporated. The resulting crude residue is flash-chromatographed (eluant: petroleum ether/EtAc, 9/1 to 8/2). 2-[N-tert-butoxycarbonyl-2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylpropanamide (84 mg; 81%) is obtained as pale yellow oil.
Reaction SMILES: Cl[C:2]([C:4]1[C:5]([Cl:15])=[C:6]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:7]([O:9][CH3:10])=[O:8])=[O:3].Cl.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][O:23][NH2:24])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][O:23][NH:24][C:2]([C:4]2[C:5]([Cl:15])=[C:6]([CH:11]=[CH:12][C:13]=2[Cl:14])[C:7]([O:9][CH3:10])=[O:8])=[O:3])=[CH:20][CH:19]=1
Reactant: NOCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(Cl)c(C(=O)Cl)c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c(C(=O)NOCc2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 122.2 %

Procedure:
At about 30° C., 10.70 g (0.04 mol) of methyl 3-chlorocarbonyl-2,4-dichlorobenzoate in 50 ml of methylene chloride were slowly added dropwise to a solution of 7.76 g (0.04 mol) of O-(4-chlorobenzyl)hydroxylamine hydrochloride and 4.05 g (0.04 mol) of triethylamine in 200 ml of methylene chloride. After stirring for 12 hours at room temperature, the reaction mixture was washed with dilute phosphoric acid, dried and concentrated. Trituration of the residue with diethyl ether gave 19.00 g of methyl 3-(4-chlorobenzyloxyaminocarbonyl)-2,4-dichlorobenzoate.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].Cl>O.CO>[OH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: OCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C=Cc1ccc(OCCCCCCO)cc1
Yield: 78.7 %

Procedure:
A solution of 4.4 g of NaOH in 20 ml of distilled water was added to a solution of 7.5 g of 4-hydroxy cinnamic acid in methanol, 0.02 g of Kl was added thereto, and then 10.0 g of 6-bromo-1-hexanol was slowly added dropwise for reaction at 65° C. for 24 hours. 100 ml of distilled water was added thereto to complete the reaction, and then the mixture was cooled to normal temperature. A 10% aqueous HCl solution was added thereto, and the obtained precipitants were filtered to obtain 9.5 g of 4-((6-hydroxyhexyl)oxy)cinnamic acid. (Yield: 60%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:29]2[CH:28]=[N:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(Cl)cc3)c2c1O
Reactant: COc1ccc(B(O)O)cn1
Product: CCOC(=O)c1nc(-c2ccc(OC)nc2)c2snc(-c3ccc(Cl)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-bromo-3-(4-chloro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 2-methoxy-5-pyridineboronic acid: MS (m/z) 440.1 (M−1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[CH3:16][N:17]([CH3:34])[S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24]([OH:26])=O)(=[O:20])=[O:19]>>[CH3:34][N:17]([CH3:16])[S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:26])(=[O:19])=[O:20]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)C)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-[(dimethylamino)sulfonyl]-5-(trifluoromethyl)benzoic acid (Butt Park Ltd.). The product was purified a second time using preparative HPLC (Phenomenex Gemini® column) and a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2). Light brown foam (20%). MS (ESI): m/z=478.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.C(OC(=O)[N:14]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[N:19][CH:18]=[C:17](Cl)[N:16]=1)(C)(C)C.C(OCC)(=O)C.CCCCCCC>CN(C)C=O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([NH:14][C:15]2[CH:20]=[N:19][CH:18]=[C:17]([N:3]3[CH:7]=[CH:6][CH:5]=[N:4]3)[N:16]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Clc1ccc(Nc2cncc(-n3cccn3)n2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
Sodium hydride (60% in mineral oil, 156 mg, 3.90 mmol) was added to a suspension of pyrazole (260 mg, 3.82 mmol) in N,N-dimethylformamide (5 mL) and the mixture was heated to 50° C. for 20 minutes. (4-Chloro-phenyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl ester (260 mg, 0.76 mmol) was added and stirring was continued for 30 minutes at the same temperature. The temperature was raised to 100° C. and the mixture was stirred overnight. The reaction mixture was quenched with brine and extracted with ethyl acetate (4×15 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulphate, filtrated and evaporated to give the crude product. Flash chromatography (ethyl acetate/heptane as eluent) gave (4-chloro-phenyl)-(6-pyrazol-1-yl-pyrazin-2-yl)-amine (56 mg, 27%) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCCl
Reactant: C1COCCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCOCC1
Temperature: 60 °C
Yield: 32.9 %

Procedure:
In the manner described in Example 21C, 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.38 mmol) from Example 21B was reacted with morpholine (99 μL, 1.14 mmol), diisopropylethyl amine (199 μL, 1.14 mmol), and tetrabutyl ammonium iodide (140 mg, 0.38 mmol). After heating at 60° C. overnight the reaction was cooled to room temperature, and 10 mL of water added. The resulting precipitate was collected by filtration and purified by HPLC on a phenyl-hexyl reverse phase column eluting with an acetonitrile/water gradient 35-55% over 60 minutes. The major peak was collected, neutralized to pH-8 with saturated sodium bicarbonate and extracted twice with ethyl acetate. The extracts were combined, dried with magnesium sulfate, and concentrated to a solid. The solid was triturated with 20:1 methanol water and the solid removed by filtration and dried to give 72 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.99 (s, 1H), 8.55 (s, 1H), 7.58 (m, 2H), 7.39 (m, 2H), 7.26 (m, 1H), 6.99 (m, 1H), 6.47 (s, 1H), 4.25 (m, 2H), 3.99 (s, 3H), 3.58 (m, 4H), 2.5-2.35 (m, 6H), 1.97 (m, 2H), 1.30 (s, 9H). LC-MS (ESI) m/z 577 (M+H)+.
Reaction SMILES: ClC[C:3]1[C:12]2[C:7](=[CH:8][C:9](OC)=[C:10](OC)[CH:11]=2)[C:6](CC2C=CC(OC)=C(OC)C=2)=[N:5][CH:4]=1.COC1C=CC=CC=1C1CCNCC1.C(N(CC)CC)C>CS(C)=O.O>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=[CH:4][N:5]=1
Reactant: COc1ccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)cc1OC
Agent: COc1ccccc1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: c1ccc2cnccc2c1

Procedure:
A mixture of 5.0 g of 4-chloromethyl-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]isoquinoline, 2.49 g of 4-(2-methoxyphenyl)piperidine, and 2.63 g of triethylamine in 50 ml of dimethylsulfoxide was heated at 80° for one hour under argon and then the cooled solution was diluted with water and extracted with methylene chloride. The organic layer was washed with sodium bicarbonate solution, dried over sodium sulfate, charcoaled, and evaporated to give 7.0 g of 6,7-dimethoxy-1-}(3,4-dimethoxyphenyl)methyl}-4-[[4-(2-methoxyphenyl)-1-piperidinyl)-1-piperidinyl]methyl]isoquinoline as a yellow foam.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)=[N:4][N:3]=1.C(O)(=[O:27])C.C(N(C(C)C)CC)(C)C.O>CN1CCCCC1=O>[Cl:24][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[O:22][CH3:23])[CH2:15][NH:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=2)[C:2](=[O:27])[NH:3][N:4]=1
Reactant: CC(=O)O
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Agent: CN1CCCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(CNc2n[nH]c(=O)c3ccc(C#N)cc23)cc1Cl
Temperature: 170 °C
Reaction time: 7 h

Procedure:
1-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine (1.0 g) prepared in Example 1 was dissolved in 10 ml of N-methyl-2-piperidone, followed by the addition of 0.26 ml of acetic acid and 2.1 ml of diisopropylethylamine. The obtained mixture was stirred at 170° C. for 7 hours, followed by the addition of 100 ml of water. The crystals thus precipitated were recovered by filtration.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15](O)=[O:16])=[O:12])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:4].[NH4+].[Cl-].C1C=CC2N(O)N=[N:36]C=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([NH2:36])=[O:16])=[O:12])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:4]
Reactant: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Boc-Gly-Nleu-Pro-OH (1.1 g, 2.85 mmol.), NH4Cl (0.5 g, 8.6 mmol.) and HOBt (0.5 g, 3.7 mmol.) were dissolved in DMF and the solution was chilled to 0° C. on a water-ice bath. Triethylamine (1.4 ml) was added slowly while stirring the solution. After 10 minutes, EDC (0.73 g, 3.7 mmol.) was added to the solution and the stirring continued overnight. The DMF was removed under reduced pressure and the resulting mixture was poured into 300 ml ethyl acetate. The ethyl acetate solution was washed by H2O 2×10 ml, saturated NaHCO3 2×10 ml, brine 2×10 ml, saturated NaHSO4 2×10 ml and brine again until the pH of the brine layer was approximate 7. The organic layer was dried using Na2SO4 and the ethyl acetate was distilled under reduced pressure to obtain the product Boc-Gly-Nleu-Pro-NH2. The Boc group of this product was removed in 30 ml solution of 30% TFA in DCM. The deprotection reaction was allowed to proceed for 40 minutes. The DCM and TFA was removed under reduced pressure and benzene 3×20 ml was added and distilled to remove trace TFA. The product TFA salt of Gly-Nleu-Pro-NH2 was dissolved in 100 ml ethyl ether and the solution was chilled to 0° C. HCl/dioxane (4N) was added to the solution until no more precipitation was seen. The ether was removed by filtration to obtain the product (white solid, 0.65 g, 69%). Analytical HPLC profile, single peak, RT=10.5 min. (8-40% B in 30 min.). FAB-MS, observed (M+H)+ =285. 1H-NMR (500 MHz, DMSO-d6, 27° C., assignment by TOCSY) δ 8.15 (s, 3H, NH3+), 7.70 (s, C-terminal NH2), 7.58 (s, C-terminal NH2), 7.38 (s, C-terminal NH2), 7.26 (s, C-terminal NH2), 7.23 (s, C-terminal NH2), 6.92 (m, C-terminal NH2), 4.38 (m, Pro-α), 4.30 (s, Nleu-α), 4.26 (s, Nleu-α), 4.22-4.13 (m, Nleu-α, Pro-α), 4.10 (s, Nleu-α), 4.07 (s, Nleu-α), 3.81 (m, Gly-α), 3.73-3.63 (m, Nleu-α, Gly-α), 3.61-3.55 (m, Gly-α, Pro-δ), 3.43 (m, Pro-δ), 3.17-2.97 (m, 2H, Nleu-β), 2.23-1.62 (m, 5H, Nleu-γ, Pro-β, Pro-γ), 0.83 (m, 6H, methyl of Nleu-δ).
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[CH:17][N:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[OH-].[Na+].O>C1COCC1>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][N:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)OC)cn2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)O)cn2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 3, (570 mg, 1.31 mmoles) was dissolved in THF (6 ml) to which was added 1N NaOH (3 ml) and H2O (3 ml). The reaction mixture was stirred at room temperature under N2 overnight. The THF was removed in vacuo. The aqueous phase was washed with CHCl3. Then the aqueous phase was acidified with concentrated HCl until slightly acid (pH about 5-6). The resulting beige solid was filtered, taken up in CHCl3 (about 500 ml), and the organic solvent was dried and concentrated. The residue was triturated with ether and filtered to afford the title compound, m.p. 117°-179°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CN(C=O)C>[C:17]([NH:21][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)c1ccc(Cl)cc1
Yield: 83.8 %

Procedure:
To a stirred suspension of 4-chlorobenzoic acid (31.3 g, 200 mmol) in toluene (200 mL) was added oxalyl chloride (30 mL, 350 mmol) followed by DMF (0.1 mL). The resulting suspension was heated at reflux until all solids dissolved. The solvent was removed under reduced pressure by rotary evaporation. The resulting semi-solid residue was dissolved in ethyl acetate (200 mL) and cooled in an ice bath under nitrogen with mechanical stirring. A solution of tert-butylamine (53 mL, 500 mmol) in ethyl acetate (50 mL) was carefully added to the mixture dropwise keeping the internal temperature below 10° C. During addition the initially clear solution became thick colorless slurry. Ethyl acetate (50 mL) was added followed by sat. aq. NaHCO3 (300 mL) and the resulting mixture was stirred until two clear layers resulted. The biphasic mixture was transferred into a separatory funnel, and the organic layer was separated. The organic layer was then washed with water (100 mL), brine (100 mL), and dried over anhydrous Na2SO4. Recrystallization from ethyl acetate/hexanes afforded N-tert-butyl-4-chlorobenzamide (35.5 g, 84% yield) as colorless needles (mp 136-137° C.).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2].[N+:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][Br:31])([O-:26])=[O:25]>>[Br-:31].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1C(C)=O)C2=O
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Product: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3cccc([N+](=O)[O-])c3)cc1C(C)=O)C2=O
Product: [Br-]

Procedure:
The title compound 123 is prepared according to the procedure reported in Example 38.1 with compound 103 (62 mg, 0.2 mmol) and 3-nitrobenzyl bromide (73 mg, 0.34 mmol) as reactants. White solid. (Yield 85.1 mg, 81%).