Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3]/[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.O.BrN1C(=[O:30])CCC1=O>C(COC)OC>[CH3:20][C:19]([CH:18]([OH:30])[CH2:17][CH2:16]/[C:15](/[CH3:22])=[CH:14]/[CH2:13][CH2:12]/[C:2](/[CH3:1])=[CH:3]\[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)=[CH2:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C\COC1CCCCO1
Solvent: O
Solvent: COCCOC
Product: C=C(C)C(O)CC/C(C)=C/CC/C(C)=C\COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2 g (0.0065 mol) of tetrahydro-2-[[(2Z,6E)-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran dissolved in 13 ml of monoglyme and 2.6 ml of water is treated portionwise at -10° with 1.3 g of N-bromosuccinimide. The mixture is subsequently stirred at 0° for 1/4 hour and at room temperature for 2 hours. The reaction solution is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution. After drying and removing the solvent the residue, containing tetrahydro-2-[[(2Z,6E)-10-bromo-11-hydroxy-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran, is dissolved in 18 ml of methanol and treated with 600 mg of potassium carbonate. The suspension is stirred at room temperature for 1.5 hours under argon. After removing the methanol on a rotary evaporator the residue is treated 500 ml of ether and 200 ml of water. The organic phase is washed with saturated sodium chloride solution. After drying and removing the solvent the residue, containing (6E,10Z)-2,3-epoxy-2,6,10-trimethyl-12 -[(tetrahydro-2H-pyran-2-yl)oxy]-6,10-dodecadiene, is dissolved in 30 ml of toluene and treated with 1.35 g of aluminum isopropylate. The reaction mixture is boiled at reflux for 17 hours and, after cooling to room temperature, poured into 200 ml of an ice-water mixture. After acidification with 1N hydrochloric acid the mixture is extracted with 3×150 ml of hexane. The organic phase is washed with 500 ml of saturated sodium chloride solution. After drying and removing the solvent the residue is chromatographed on silica gel with a 1:2 ether-hexane mixture which additionally contains 0.1% triethylamine. There is obtained (6E,10Z)-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-1,6,10-dodecatrien-3-ol which has the following bands in the IR spectrum: 3445 cm-1, 1648 cm-1, 1441 cm-1, 1375 cm-1, 901 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3=[N:19][N:20]=[C:21](S(C)=O)[N:11]3[N:10]=2)=[CH:5][CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3=[N:19][N:20]=[C:21]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[N:11]3[N:10]=2)=[CH:5][CH:4]=1
Reactant: C1CCNC1
Reactant: COc1ccc(-c2nn3c(S(C)=O)nnc3c3ccccc23)cc1
Product: COc1ccc(-c2nn3c(N4CCCC4)nnc3c3ccccc23)cc1
Yield: 45 %

Procedure:
A mixture of 6-(4-methoxyphenyl)-3-(methylsulfinyl)-1,2,4-triazolo[3,4-a]phthalazine (3.5 g) and pyrrolidine (30 ml) is heated to 120°/140° C. in a steel bomb for 16 hours. The mixture is then cooled, and the excess of the amine is evaporated off yielding a residue which is washed carefully with a small amount of water and crystallized from 70% ethanol. Yield: 45%. M.p. 196°-98° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=2[C:19]([OH:21])=O)=[CH:5][CH:4]=1.[O:22]=[C:23]1[CH:28]([N:29]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:27][CH2:26][C:25](=[O:45])[NH:24]1>>[O:22]=[C:23]1[CH:28]([N:29]2[C:19](=[O:21])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][CH2:8][C:6]3[O:7][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=3)[C:13]2=[O:15])[CH2:27][CH2:26][C:25](=[O:45])[NH:24]1
Reactant: O=C(O)c1cccc(NCc2ccc(CO)o2)c1C(=O)O
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Product: O=C1CCC(N2C(=O)c3cccc(NCc4ccc(CO)o4)c3C2=O)C(=O)N1

Procedure:
3-[(5-Hydroxymethyl-furan-2-ylmethyl)-amino]-phthalic acid (3.04 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-Dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The solid yellow residue was purified by chromatography (SiO2, 60% ethyl acetate/hexanes) to give 0.40 g of solid which was dissolved in methylene chloride (70 ml) and washed with saturated NaHCO3 (2×100 ml), brine (1×100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated leaving 0.32 g (27%) of product as a yellow solid: mp 172-174° C.; 1H NMR (DMSO-d6) δ 11.11 (s, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 7.06 (d, J=7.0 Hz, 1H), 6.99 (t, J=6.0 Hz. 1H), 6.27 (d, J=2.9 Hz, 1H), 6.20 (d, J=2.9 Hz, 1H), 5.18 (t, J=5.7 Hz, 1H), 5.07 (dd, J=5.2 and 12.5 Hz, 1H), 4.54 (d, J=5.9 Hz, 2H), 4.33 (d, J=5.7 Hz, 2H), 2.96-2.82 (m, 1H), 2.63-2.46 (m, 2H), 2.06-1.99 (m, 1H); 13C NMR (DMSO-d6) δ 172.80, 170.07, 168.80, 167.24, 155.00, 151.10, 145.79, 136.08, 132.12, 117.57, 111.04, 109.71, 108.06, 107.60, 55.63, 48.60, 39.05, 30.98, 22.13; Anal. Calcd. For C19H17N3O6: C, 59.53; H, 4.47; N, 10.96. Found: C, 59.30; H, 4.54; N, 10.70.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)[CH2:11][CH:10]1[CH2:29][O:30][CH2:31][CH3:32])C1C=CC=CC=1>CO.[H][H].[C].[Pd]>[ClH:1].[CH2:31]([O:30][CH2:29][CH:10]1[NH:9][CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)[CH2:11]1)[CH3:32]
Reactant: [H][H]
Reactant: CCOCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Yield: 99.2 %

Procedure:
In methanol (15 ml) is dissolved 1-benzyl-2-ethoxymethyl-4-(3,4,5-trimethoxybenzoyl)piperazine hydrochloride (1.0 g) obtained in Reference Example 12. To the solution is added 10% palladium-carbon (0.3 g), and the mixture is stirred for 3 hours in hydrogen streams. The reaction mixture is subjected to filtration, and the filtrate is subjected to distillation under reduced pressure to leave crystals, followed by recrystallization from ethanol-ether to afford 3-ethoxymethyl-1-(3,4,5-trimethoxybenzoyl)piperazine hydrochloride (0.8 g) as colorless crystals, m.p 203-204° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[CH2:18].[K+].[I-].[K+].CNC=O.C1(C=CC(O)=CC=1)O>>[C:16]([O:21][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)[O-]
Reactant: O=[N+]([O-])c1cccc2c1ccn2CCCl
Agent: Oc1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Solvent: CNC=O
Product: C=C(C)C(=O)OCCn1ccc2c([N+](=O)[O-])cccc21
Reaction time: 2.5 h
Yield: 92.3 %

Procedure:
Next, into a flask of 200 ml capacity fitted with a stirrer and cooling tube, there were introduced 14.9 g of 1-(2-chloroethyl)-4-nitroindole, 18.0 g of potassium methacrylate, 6.0 g of potassium iodide, 40 ml of N, N-methyl formamide and a small quantity of hydroquinone, these then being heated to 100° C., and stirred for 2.5 hours. After the reaction had been completed, insoluble material was removed by filtration, and concentration was performed under reduced pressure. Furthermore, this reaction mixture was purified by column chromatography using silica gel, to obtain 16.8 g of 1-(2-methacryloyloxyethyl)-4-nitroindole.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH:11][C:12]([N:14]([CH3:27])[C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[C:17](=[O:26])[N:18]([CH3:25])[C:19]3=[O:24])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH:11][C:12]([N:14]([CH3:27])[C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[C:17](=[O:26])[N:18]([CH3:25])[C:19]3=[O:24])=[O:13])=[CH:6][CH:5]=1
Reactant: CN1C(=O)c2cccc(N(C)C(=O)NNc3ccc([N+](=O)[O-])cc3)c2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CN1C(=O)c2cccc(N(C)C(=O)NNc3ccc(N)cc3)c2C1=O
Yield: 87 %

Procedure:
1-p-Nitrophenyl-4-methyl-4-(2-methyl-1,3-dioxoisoindolin-4-yl)semicarbazide (2.6 g) was dissolved in 300 ml tetrahydrofuran and a catalytic amount (about 200 mg) of 10% palladium on carbon was added. The mixture was hydrogenated on a Parr hydrogenation apparatus overnight at 40 psi hydrogen pressure. The mixture was filtered and the solvent was evaporated to give 2.0 g (87% yield).
Reaction SMILES: Cl.[C:2]12([CH2:12][CH2:13][NH2:14])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH:14][CH2:13][CH2:12][C:2]12[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2)=[O:19]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Product: O=C(NCCC12CC3CC(CC(C3)C1)C2)c1ccccc1Cl

Procedure:
Prepared according to the method of Example 1 from 1-adamantaneethylamine hydrochloride (0.055 g) and 2-chlorobenzoyl chloride (0.033 ml) to give the title compound as a white solid (0.074 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:28]=[C:9]2[N:10]=[C:11]([N:15](C)[CH2:16][CH2:17]N(C)CC3C=C(C)ON=3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.N[CH2:30][CH:31]1CC[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]1.NCC1CCCN1C(OC(C)(C)C)=O>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:28]=[C:9]2[N:10]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:30][CH2:31][CH2:32][NH:33][CH2:34]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Reactant: Cc1cc(CN(C)CCN(C)c2nc(N)n3nc(-c4ccco4)nc3n2)no1
Agent: CC(C)(C)OC(=O)N1CCCC1CN
Product: Nc1nc(NCC2CCCNC2)nc2nc(-c3ccco3)nn12

Procedure:
2-Furan-2-yl-N5-piperidin-3-ylmethyl-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine was prepared in the same manner as described in Example 6(a) and (b) above, except that 3-aminomethyl-1-Boc-piperidine was used as the starting material instead of 2-aminomethyl-1-Boc-pyrrolidine (both starting materials are commercially available from Astatech, Monmouth Junction, N.J.).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[C:17]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)(=[O:19])[CH3:18]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:23]3[CH:24]=[CH:25][C:20]([C:17](=[O:19])[CH3:18])=[CH:21][CH:22]=3)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1
Product: CC(=O)c1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Yield: 86 %

Procedure:
According to Scheme 3 Method A: The title compound was prepared from 1-(4-chlorobenzyl)-5-bromopyridin-2(1H)-one (Example 2 Step 1) and 4-acetylphenylboronic acid according to the procedure described for Example 2 Step 2. Reaction conditions: 4 hours at 80° C. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 50/50 as eluent to afford 1-(4-chlorobenzyl)-5-(4-acetylphenyl)pyridin-2(1H)-one (0.29 mmol, 0.10 g, 86%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]5[C:29](=[O:37])[C:30](=[O:36])[C:31]=5[O:32]C(C)C)[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1.Cl.O>CO>[CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]5[C:31](=[O:32])[C:30](=[O:36])[C:29]=5[OH:37])[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(Nc4c(OC(C)C)c(=O)c4=O)cc23)CC1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(Nc4c(O)c(=O)c4=O)cc23)CC1
Temperature: 80 °C
Yield: 46.3 %

Procedure:
To a solution of 3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinyl]propyl]-5 [1,2-dioxo-4-(1-methylethoxy)-3-cyclobuten-3-yl]aminoindole (I-3) (0.175 g, 0.35 mmol) in 5 mL of methanol was added 0.10 mL (0.60 mmol) of 6N HCl and the mixture was heated at ca. 80° C. for 5 h. Another 0.10 mL (0.60 mmol) of 6N HCl was then added, as well as 0.20 mL of H2O, and the mixture was heated at ca. 100° C. for 18 h. On cooling to room temperature, the resulting suspension was filtered and the residue was washed (acetone, ether) and then air-dried. This solid (0.130 g) was taken up in methanol and the resulting solution was treated with charcoal, filtered and evaporated to give the hydrochloride salt of the title compound (0.075 g, 36%) as a beige solid, mp 215° C. (dec): IR (KBr) 3410 (br), 3240 (br), 1783, 1700, 1632, 1547 cm -1 ; 1H NMR (DMSO-d6, 200 MHz) δ10.88 (s, 1H), 10.37 (s, 1H), 8.56 (s, 1H), 8.19 (s, 1H), 7.62 (s, 1H), 7.29 (d, J=8.6 Hz, 1H), 7.21 (s, 1H), 7.10 (dd, J=8.6, 1.8 Hz, 1H), 4.80 (br m, 2H), 3.90 (s, 3H), 3.57 (br m, 4H), 3.13 (br m, 4H), 2.73 (m, 2H), 2.12 (m, 2H). Anal. Calcd for C24H26N6O4. 3 HCl. H2O: C, 48.86; H, 5.30; N, 14.25. Found: C, 48.81; H, 5.51; N, 14.22.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:3]=1.[CH3:21][S-:22].[Na+]>CS(C)=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:4]2[N:3]=[C:2]([S:22][CH3:21])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH2:11][CH3:12])=[CH:15][CH:16]=1
Reactant: CCn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCn1cnc2c(Nc3ccc(Cl)cc3)nc(SC)nc21
Temperature: 110 °C

Procedure:
A mixture of the product from step (ii) (0.6 g) and sodium thiomethoxide (0.45 g) in dimethylsulphoxide (15 ml) was heated at 110° C. for 4 h. The mixture was partitioned between ethyl acetate and water, the organics washed with water, dried (MgSO4) and evaporated under reduced pressure. Yield 0.45 g
Reaction SMILES: CN(C)C=O.[N+:6]([C:9]1[CH:37]=[CH:36][C:12]([CH:13]=[CH:14][C:15]2[C:24]([CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=3)=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)([O-])=O.Cl>[Fe].O>[NH2:33][C:30]1[CH:29]=[CH:28][C:27]([CH:26]=[CH:25][C:24]2[C:15]([CH:14]=[CH:13][C:12]3[CH:11]=[CH:10][C:9]([NH2:6])=[CH:37][CH:36]=3)=[N:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:23]=2)=[CH:32][CH:31]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2nc3ccccc3nc2C=Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(C=Cc2nc3ccccc3nc2C=Cc2ccc(N)cc2)cc1
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
In a solution of 40 ml of N,N-dimethylformamide and 10 ml of water, 10 g of iron powders and 5.2 g of 2,3-bis(4-nitrostyryl)quinoxaline were dispersed. While stirring, 2.4 ml of hydrochloric acid was dropwise added to the dispersion at room temperature. Stirring was continued for 15 minutes at the same temperature and then for 30 minutes on a steam bath at 70° C. The reaction liquid was transferred to a Soxhlet's extractor and extracted for 3 hours using 300 ml of acetone. The acetone extracts were poured into 500 ml of water to adjust the pH of the liquid to 9 to 10 with an aqueous sodium carbonate solution. The resulting crystals were filtered and dried to obtain 4.3 g (yield 98%) of the product having a melting point of 227° to 228° C.
Reaction SMILES: C([O:8][C:9](=[O:48])[C@H:10]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37]C(OCC1C=CC=CC=1)=O)[NH:11][C:12](=[O:32])[CH2:13][CH2:14][C@H:15]([C:29](=[O:31])[NH2:30])[NH:16][C:17](=[O:28])[C@H:18]([CH3:27])[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[C:23]([O:22][C:20]([NH:19][C@H:18]([C:17]([NH:16][C@@H:15]([C:29](=[O:31])[NH2:30])[CH2:14][CH2:13][C:12]([NH:11][C@H:10]([C:9]([OH:48])=[O:8])[CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])=[O:32])=[O:28])[CH3:27])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(N)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)N[C@@H](CCCCN)C(=O)O)C(N)=O
Yield: 89.1 %

Procedure:
In 40 ml of acetic acid was dissolved 4.00 g of Nα -(t-butyloxycarbonyl-alanyl-D-isoglutaminyl)-Nε -benzyloxycarbonyl-lysine benzyl ester, and the solution was hydrogenolyzed in the presence of palladium-on-carbon in a hydrogen stream at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated. To the residue was added diethyl ether, and the precipitated powder was recrystallized from methanoldiethyl ether to obtain 2.37 g of Nα -(t-butyloxycarbonylalanyl-D-isoglutaminyl)-lysine.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[NH:13][C@H:12]([CH3:17])[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:11][C@H:12]([CH3:17])[N:13]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=3)[C@H:14]([CH3:16])[CH2:15]2)=[O:9])=[CH:18][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: C[C@@H]1CN(C(=O)COc2ccc(Cl)cc2)C[C@H](C)N1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: C[C@@H]1CN(C(=O)COc2ccc(Cl)cc2)C[C@H](C)N1Cc1ccc(F)cc1
Yield: 61.3 %

Procedure:
To a solution of (cis)-1-((4-chlorophenoxy)methyl)carbonyl-3,5-dimethylpiperazine (0.20 g, 0.71 mmol) in anhydrous THF (2 mL) was added 4-fluorobenzyl-bromide (0.11 mL, 0.85 mmol), diisopropylethylamine (0.15 mL, 0.85 mmol) and sodium iodide (0.042 g, 0.28 mmol). The resultant mixture was stirred at ambient temperature for 2 days. At that time the mixture was poured into ether and washed with 5% aqueous NaHCO3 solution, then brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography on silica gel afforded 0.17 g of (cis)-1-((4-chlorophenoxy)methyl)carbonyl-3,5-dimethyl-4-(4-fluorobenzyI)piperazine as a pink oil; which was converted to its hydrochoride salt; NMR (CDCl3) 7.6 (m, 2), 7.3 (m, 4), 7.0-6.8 (m, 2), 5.0-2.8 (m, 10), 1.5-1.3 (m, 6) ppm.
Reaction SMILES: Cl.[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([C:18]([NH:20][C@H:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][OH:23])=[O:19])[NH2:17])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N([CH2:35][CH3:36])CC)C>C(Cl)Cl>[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([C:18]([NH:20][C@H:21]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:22][OH:23])=[O:19])[NH:17][C:22](=[O:23])[CH:21]([C:36]1[CH:35]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: O=C(NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1)OCc1ccccc1
Yield: 140 %

Procedure:
Prepared according to the method described in Example 1(d) above from (R)-N5 -(Cbz)-(R)-N-(2-hydroxy-1-phenylethyl)ornithine amide hydrochloride (2.6 g; 6.16 mmol; from step (b) above), 2-nitrophenyl diphenyl acetate (2.37 g; 7.39 mmol; see Example 1(c) above) and triethylamine (1.28 mL; 9.24 mmol) in 150 mL of CH2Cl2, yielding 2.5 g of the sub-title compound as a white, crystalline material.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH2:14][CH2:13][CH2:12][C:11]=1[N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:9].N[C:21]1C=CC=C[CH:22]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH2:14][CH2:13][CH2:12][C:11]=1[NH:15][C:19]1[CH:18]=[CH:17][CH:16]=[CH:22][CH:21]=1)=[O:9]
Reactant: Nc1ccccc1
Reactant: O=C(C1=C(N2CCCC2)CCC1)c1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(C1=C(Nc2ccccc2)CCC1)c1ccccc1Br

Procedure:
Reflux a solution of (2-bromophenyl)[2-(1-pyrrolidinyl)-1-cyclopenten-1-yl]-methanone (14.1 g) (from Preparative Example 1) in benzene (100 ml) containing aniline (4.5 ml) and p-toluenesulfonic acid monohydrate (8.8 g) for 19 hrs. Remove water continuously with a Dean-Stark trap. Wash the cooled solution with water, 1M NaHCO3 solution, and with water. Dry the benzene solution, filter it, and evaporate the solvent. Crystallize to obtain (2-bromophenyl)[2-(phenylamino)-1-cyclopenten-1-yl]-methanone, m.p. 106-5°-108.5° from CH3CN.
Reaction SMILES: C([O:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([NH2:14])=[CH:9][C:8]=1[F:15])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:14][C:10]1[C:11]([Cl:13])=[CH:12][C:7]([C:6]([OH:16])=[O:5])=[C:8]([F:15])[CH:9]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(N)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(F)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.8 %

Procedure:
4-Amino-5-chloro-2-fluorobenzoic acid tert-butyl ester (Intermediate 177; 3.0 g, 12.21 mmol) was dissolved in DCM (75 mL) and trifluoroacetic acid (25 mL) added. The mixture was stirred for 1 hour at room temperature and then concentrated to yield the title compound as a pale yellow solid (2.45 g, 100%).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C@@H:13]([NH:16][C:17]2[C:18]3[N:19]([CH:26]=[C:27]([C:29]([O:31]CC)=[O:30])[CH:28]=3)[N:20]=[CH:21][C:22]=2[C:23](=[O:25])[NH2:24])[C:12]([CH3:35])([CH3:34])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C@@H:13]([NH:16][C:17]2[C:18]3[N:19]([CH:26]=[C:27]([C:29]([OH:31])=[O:30])[CH:28]=3)[N:20]=[CH:21][C:22]=2[C:23](=[O:25])[NH2:24])[C:12]([CH3:35])([CH3:34])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1cc2c(N[C@@H]3CCN(C(=O)OC(C)(C)C)CC3(C)C)c(C(N)=O)cnn2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)O)cc23)C(C)(C)C1
Temperature: 25 °C
Yield: 101.5 %

Procedure:
A 2 M aqueous solution of sodium hydroxide (6 mL, 12.00 mmol) was added to a solution of (R)-ethyl 4-((1-(tert-butoxycarbonyl)-3,3-dimethylpiperidin-4-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate (1.187 g, 2.58 mmol) in methanol (11 mL) and tetrahydrofuran (11 mL) at room temperature. The resulting mixture was heated at reflux for 40 min and cooled to room temperature. The organic solvents were evaporated in vacuo. The residue was neutralized to pH 5 with 1 N HCl. The resulting precipitate was collected by filtration to give (R)-4-((1-(tert-butoxycarbonyl)-3,3-dimethylpiperidin-4-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid as brown solid (1.13 g, 97% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.57 (br. s., 1H), 11.16 (d, J=8.8 Hz, 1H), 8.31 (s, 1H), 8.05 (d, J=1.3 Hz, 1H), 7.23 (s, 1H), 4.12-4.00 (m, 1H), 3.87 (br. s., 1H), 3.56 (d, J=12.8 Hz, 1H), 3.01 (br. s., 2H), 1.91 (dd, J=13.5, 3.2 Hz, 1H), 1.56 (d, J=8.1 Hz, 1H), 1.41 (s, 9H), 0.98 (s, 3H), 0.92 (s, 3H); MS (ES+) m/z: 432.2 (M+H); LC retention time: 3.795 min (analytical HPLC Method H).