Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([NH:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[C:3]1[CH:8]=CC=CC=1.C(N(C(C)C)CC)(C)C.BrCCC1[O:31][CH2:30][CH2:29][O:28]1.CC1CC=CCC=1>C(#N)C.C(Cl)Cl>[O:28]1[CH2:29][CH2:30][O:31][CH:8]1[CH2:3][CH2:2][NH:9][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: c1ccc(CNC2CCCC2)cc1
Reactant: BrCCC1OCCO1
Agent: CC1=CCC=CC1
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C1CCC(NCCC2OCCO2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.8 %

Procedure:
To a suspension of N-benzylcyclopentanamine hydrochloride (0.986 g, 4.66 mmol) in acetonitrile (10 mL) was added di-iso-propylethylamine (2.0 mL, 11.5 mmol) and the mixture stirred at room temperature for 10 minutes. A solution of 2-(2-bromoethyl)-1,3-dioxolane (1.01 g, 5.58 mmol) in acetonitrile (5 mL) was added and the mixture heated at 80° C. for 48 hours. The reaction mixture was diluted with DCM and was washed with water, dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was loaded onto an SCX-2 cartridge and eluted with acetonitrile (4 column volumes) and then 10% triethylamine/acetonitrile (4 column volumes). The product containing fractions were combined and the solvent evaporated at reduced pressure. The residue was dissolved in ethanol (10 mL) and 10% palladium on charcoal (0.90 g) added. The mixture was stirred at room temperature for 5 minutes and then 1-methyl-1,4-cyclohexadiene (1.9 mL, 16.9 mmol) added. The reaction mixture heated to reflux and then the reaction mixture stirred under reflux for 1 hour. The reaction mixture allowed to cool and the suspension filtered. The filtrate was evaporated at reduced pressure to afford the title compound (0.249 g, 40%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].C(O[C:11](=[O:16])[CH2:12][C:13]([CH3:15])=O)C.[C:17](O)(=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[C:17]([O:1][CH2:2][CH2:3][N:4]1[C:11](=[O:16])[CH2:12][C:13]([CH3:15])=[N:7][CH2:6][CH2:5]1)(=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: NCCNCCO
Reactant: CCOC(=O)CC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 104.2 g (1 mole) of N-hydroxyethylethylenediamine and 130.1 g (1 mole) of ethylacetoacetate. At 150° to 160° C., 18 g of water and 46 g of ethanol were distilled off. Then, after addition of 282.5 g (1 mole) of oleic acid, the esterification was effected at 210° to 215° C. to distil off 18 g of water and to obtain 4-oleoyloxyethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:29]>C(#N)C.CC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[N:13]([CH3:29])[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CN1CCC(OC(c2cccc(I)c2)c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC#N
Product: CN1CCC(OC(c2cccc(I)c2)c2nc3ccccc3n2C)CC1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A solution of 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (example 51, 260 mg) in anhydrous acetonitrile (10 mL) is treated with 60% sodium hydride (47 mg) for 1 h at room temperature. The mixture is then cooled to 0° C. and iodomethane (36 μL) is introduced. After stirring for 15 h, dilution with water and extraction with ethyl acetate, the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/0.5) to afford the pure base that is then converted into its dioxalate salt in acetone to give 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1-methyl-1H-benzimidazole, dioxalate, melting at 76° C.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][C:6]=1[CH3:11]
Reactant: [H][H]
Reactant: Cc1ccnc(F)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccnc(F)c1N

Procedure:
To a solution of 10.1 g (65 mmol) of 2-fluoro-4-methyl-3-nitropyridine in 200 mL of ethyl acetate was added 25 g (0.40 mol) of acetic acid and 0.8 g of 5 percent palladium on carbon catalyst. This mixture was shaken under 50 psig (pounds per square inch gauge) (2400 kiloPascals) pressure of hydrogen for 18 hours, was filtered, and was concentrated by evaporation under reduced pressure to obtain an oil. This oil was partitioned between dilute aqueous sodium bicarbonate and ether. The organic phase was separated, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography to obtain 7.2 g (88 percent of theory) of the title compound as a colorless solid, melting at 63°-64° C. Nuclear Magnetic Resonance Spectrum (200 MHz (megaHertz), CDC13): 1H: 7.4 (d, 1H, J=5.0); 6.8 (d, 1H, J=5.0); 3.7 (br, 2H); 2.1 (s, 3H); 13C: 152.6 (d, J=229); 134.1 (d, J=8.6); 133.8 (d, J=14.5 ); 128.1 (d, J=27.1 ); 123.3, 16.4 (d, J=4.1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[NH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[SH:22]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[S:22][C:13]3[CH:14]=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]=3[N:11]=2)[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: O=Cc1ccc(O)c(Br)c1
Solvent: CN(C)C=O
Product: Oc1ccc(-c2nc3cc(C(F)(F)F)ccc3s2)cc1Br
Temperature: 100 °C

Procedure:
In a N,N-dimethylformamide (DMF) solvent, a suspension of 3-bromo-4-hydroxybenzaldehyde (1.0 eq.) and 2-amino-4-(trifluoromethyl)benzenethiol (1.0 eq.) was heated at a temperature of 100° C. After cooling, DMF was removed therefrom under reduced pressure. Methylene chloride was added to the resultant solid, and the produced precipitate was filtered, and washed with methylene chloride to obtain a solid target product.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([O:25][CH2:24][CH2:23][CH2:22][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCCCOCc1ccccc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CCCOCc3ccccc3)c2)OC1(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (5.0 g, 26 mmol), potassium carbonate (4.27 g, 30.9 mmol) and 1-bromo-3-benzyloxypropane (6.20 g, 27.0 mmol) in DMF (20 mL) was stirred at 80° C. overnight, quenched with water (20 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (2×30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO system: EtOAc/Heptane=30-70%) to afford 7.67 g of the title compound as a light-yellow oil (87%). 1H NMR (CDCl3, 400 MHz): δ=7.80 (s, 1H), 7.66 (s, 1H), 7.30-7.36 (m, 5H), 4.48 (s, 2H), 4.28 (t, J=6.8 Hz, 2H), 3.43 (t, J=5.8 Hz, 2H), 2.17 (m, 2H), 1.33 (s, 12H). MS (ES+): m/z=343.36 [MH+]. HPLC: tR=4.20 min (ZQ3: polar—5 min).
Reaction SMILES: [C:1]1([C:13]([OH:15])=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.S(Cl)(Cl)=O.[CH3:20][C:21]1[N:25]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[N:23][C:22]=1[CH2:45][NH:46]C.C(N(CC)CC)C>C(#N)C>[CH3:20][C:21]1[N:25]([C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:24]=[N:23][C:22]=1[CH2:45][NH:46][C:13]([C:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1)=[O:15]
Reactant: O=C(O)c1cn2c3c(cccc13)CCC2
Reactant: CNCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(CNC(=O)c2cn3c4c(cccc24)CCC3)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2.5 h

Procedure:
1.2 g (6.0 mmol) of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid were mixed with 15 ml of thionyl chloride and boiled for 2.5 hours. The excess of thionyl chloride was distilled off in vacuo, and toluene was added. The mixture was evaporated in vacuo again, and the residue was dissolved in 20 ml of acetonitrile. A solution of 2.2 g (6.0 mmol) of 5-methyl-4-(methylamino)methyl-1-triphenylmethyl-1H-imidazole and 1.7 ml (12 mmol) of triethyl amine in 25 ml of acetonitrile was added, the mixture was boiled for 1 hour, and evaporated in vacuo. The residue was shaken with methylene chloride and 2 N NaOH. The organic layer was washed with water and evaporated in vacuo. The residue was chromatographed on silicagel using methylene chloride/methanol (95/5) as an eluent. After evaporating the desired fractions 2.0 g of N-methyl, N-[(5-methyl-1-triphenylmethyl-1H-imidazol-4-yl)methyl]-5,6-dihydro-4H-pyrrolo [3,2,1-ij]quinoline-1-carboxamide were obtained. This product was treated as described in Example I to remove the triphenylmethyl group, and purified. 0.46 g of the desired title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[N:6][CH:7]=1
Reactant: O=Cc1cncc(F)c1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cncc(F)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
A mixture of 1.1 g of the crude 5-fluoro-3-pyridinecarbaldehyde, 1.8 g of malonic acid, 0.15 ml of piperidine, and 7 ml of pyridine is stirred at 110° C. for 2 hours. The reaction mixture is concentrated, and 20 ml of water is added. The resulting precipitate is collected and washed with cold water to give 0.5 g of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[C:15]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[S:14][C:13]=2[CH:39]=1)C1C=CC=CC=1.C[O:41][C:42](=[O:47])[CH2:43][CH2:44][CH2:45]Cl.[C:48]([O-:51])([O-:50])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:42]([OH:47])(=[O:41])[C:48]([OH:51])=[O:50].[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[C:15]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:45][CH2:44][CH2:43][CH2:42][OH:41])=[CH:34][CH:33]=3)[S:14][C:13]=2[CH:39]=1
Reactant: COC(=O)CCCCl
Reactant: COc1cc(Cc2c(-c3ccc(O)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cc2c(-c3ccc(OCCCCO)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Product: O=C(O)C(=O)O
Temperature: 80 °C

Procedure:
4-[6-Benzyloxy-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]benzo[b]thiophen-2-yl]phenol (0.10 g; 0.19 mmol), 4-chlorobutyric acid methyl ester (27 mL; 0.22 mmol) and Cs2CO3 (0.43 g; 1.31 mmol) were combined in 2 mL of DMF and heated in an oil bath maintained at 80° C. for 3 h. After cooling to room temperature, water (30 mL) was added, and extraction was carried out with EtOAc (4×25 mL). The combined organics were washed with brine and dried by passage through Na2SO4. Purification was effected by flash chromatography on silica gel, eluting with EtOAc(100-90%)/Et3N(0-5%)/MeOH(0-5%). The title product was obtained as a colorless oil (92 mg, 78%).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([CH2:16][OH:17])=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]([F:36])=[CH:27][C@H:28]1[C@H:30]([C:31](Cl)=[O:32])[C:29]1([CH3:35])[CH3:34].O>C(OCC)C>[F:25][C:26]([F:36])=[CH:27][C@H:28]1[C@H:30]([C:31]([O:17][CH2:16][C:4]2[C:5]3[CH2:11][CH2:10][CH2:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[C:6]=3[CH:1]=[CH:2][CH:3]=2)=[O:32])[C:29]1([CH3:34])[CH3:35]
Reactant: OCc1cccc2c1CCCc1ccccc1-2
Reactant: CC1(C)[C@@H](C=C(F)F)[C@@H]1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: CC1(C)[C@@H](C=C(F)F)[C@@H]1C(=O)OCc1cccc2c1CCCc1ccccc1-2

Procedure:
To a stirred solution of 6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-methanol (0.95 g, 0.043 mole) and 1 ml of dry triethylamine in 15 ml of dry diethyl ether was added 3 ml of a solution of trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride in dry diethyl ether (1.42 mmole/ml). The resultant mixture was stirred at room temperature for approximately 18 hours, then poured into 50 ml of water. The organic phase was separated and washed first with an aqueous 5% sodium bicarbonate solution and then with water. The organic solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to leave an oil. This oil was purified by column chromatography on silica gel, eluted with ethyl acetate:hexanes (5:95), to yield 0.83 g of (6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-yl)methyl trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarboxylate as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:43]=[CH:42][C:36]([C:37]([O:39]CC)=[O:38])=[CH:35][CH:34]=4)[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.O>CCO.C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[N:25][C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:33]4[CH:43]=[CH:42][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=4)[CH2:31][CH2:32]3)=[N:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(N2CCN(c3ncc(-c4cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c4)cn3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cccc(-c2cnc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
Ethyl 4-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)benzoate (451 mg) was dissolved in EtOH (5 ml) and THF (5 ml), and a 1 M aqueous NaOH solution (2 ml) was added thereto, followed by stirring at room temperature for 3 hours. After neutralization with 1 M hydrochloric acid (2 ml), water was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 4-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)benzoic acid (269 mg).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:18]([CH2:28][O:29]CC=C)[O:17][C@@H:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C@@H:6]1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)C=C.II.O>O1CCCC1.C(Cl)(Cl)Cl.[Ir]>[CH2:34]([O:33][C@@H:6]1[C@@H:5]([OH:4])[C@@H:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:18]([CH2:28][OH:29])[O:17][C@H:7]1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C=CCOC[C@H]1O[C@@H](OCCCCCCCC)[C@H](OCc2ccccc2)[C@@H](OCC=C)[C@H]1OCc1ccccc1
Agent: [Ir]
Agent: II
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCO[C@@H]1O[C@H](CO)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Yield: 84.8 %

Procedure:
Iridium complex (1,5-cyclooctadiene bis(methyldiphenylphosphine)iridium hexafluorophosphate, 172 mg, 0.15 mmol) was suspended in tetrahydrofuran (5 mL), and activated by stirring under H2 flow. Compound 15 (811 mg, 1.47 mmol) dissolved in tetrahydrofuran (5 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hour under argon gas flow. Iodine (745 mg), water (38 mL), and tetrahydrofuran (15 mL) were added thereto, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was diluted with chloroform, and then washed successively with saturated sodium thiosulfate solution, saturated aqueous sodium hydrogencarbonate, and saturated brine. The chloroform layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:EtOAc=5:2) to obtain Compound 16 (589 mg, 82.1%). Rf: 0.35 (toluene:AcOEt=2:1)
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][CH:12]3[C:16]([CH3:18])([CH3:17])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][CH:12]3[C:16]([CH3:17])([CH3:18])[CH2:15][N:14]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: CC1(C)CNCC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: CS(=O)(=O)Cl
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CN(S(C)(=O)=O)CC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A suspension of 6-bromo-4-((4,4-dimethylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (97 mg, 0.25 mmol) in DCM (3 mL), was added DIPEA (0.16 mL, 0.87 mmol) and methanesulfonyl chloride (0.04 mL, 0.5 mmol). The mixture was stirred at rt overnight. The reaction was quenched with water, extracted by dichloromethane, washed with hydrochloride (0.5N), aq. sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated. The residue was triturated in ether then filtered to give (+/−)-6-bromo-4-(4,4-dimethyl-1-(methylsulfonyl)pyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (92 mg, 86%). MS (ES+) m/z: 431.99 (M+H).
Reaction SMILES: [ClH:1].Cl.N=C[O:5]CNCCC[C@@H](C(O)=O)N.Cl.C([O:21][C:22](=[O:41])[C@H:23]([CH2:32][CH2:33][CH2:34][NH:35][CH:36]=[N:37][O:38][CH2:39][CH3:40])[NH:24]C(OC(C)(C)C)=O)(C)(C)C>>[OH2:5].[ClH:1].[ClH:1].[CH2:39]([O:38][N:37]=[CH:36][NH:35][CH2:34][CH2:33][CH2:32][C@@H:23]([C:22]([OH:41])=[O:21])[NH2:24])[CH3:40]
Reactant: N=COCNCCC[C@H](N)C(=O)O
Reactant: CCON=CNCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Product: CCON=CNCCC[C@H](N)C(=O)O
Product: O
Yield: 94 %

Procedure:
By the method described above for the preparation of N5-(iminomethoxymethyl)-L-ornithine dihydrochloride, 0.78 g (1.97 mmol) N2-(tert-butoxycarbonyl)-N5-(ethoxyiminomethyl)-L-ornithine tert-butyl ester hydrochloride was deprotected to yield 0.51 g (94%) N5-(ethoxyiminomethyl)-L-ornithine dihydrochloride monohydrate. TLC (silica gel, ammonium hydroxide:methanol/1/25) Rf=0.24. Mass spectrum (CI) 204 (MH+, 74%).
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8].S(Cl)([Cl:20])=O>N1C=CC=CC=1.C(OCC)C>[Cl:20][CH2:2][C:3]1[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCc1ccc(OC(C)C(=O)OC)c(CO)c1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCc1ccc(OC(C)C(=O)OC)c(CCl)c1
Yield: 100.8 %

Procedure:
By the method of Example 1, Step H, 26.0 grams (0.109 mole) of methyl 2-(2-hydroxymethyl-4-ethylphenoxy)propionate and 14.3 grams (0.12 mole) of thionyl chloride were reacted in the presence of two drops of pyridine in 120 mL of diethyl ether, yielding 28.21 grams of methyl 2-(2-chloromethyl-4-ethylphenoxy)propionate. The NMR spectrum was consistent with the proposed spectrum.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]([O:8][C:9]([CH2:11][S:12](Cl)(=[O:14])=[O:13])=[O:10])[CH3:7]>C1COCC1>[CH2:6]([O:8][C:9](=[O:10])[CH2:11][S:12](=[O:14])(=[O:13])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:7]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)CS(=O)(=O)NC(C)(C)C
Temperature: -20 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
tert-Butylamine (7.9 mL, 75 mmol.) was dissolved in 50 mL of THF. The solution was cooled to −20° C. and (ethoxycarbonyl)methanesulfonyl chloride dissolved in 10 mL of THF was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 24 h. The mixture was filtered, and the filtrate concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc; 2:1) to afford ethyl-2-(N-tert-butylsulfamoyl)acetate (4.1 g, 43%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[NH:17]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:18]([C:26](ON1C(=O)CCC1=O)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH2:1]([NH:9][C:26](=[O:27])[C@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:17][C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.7 %

Procedure:
To a solution of 1-octylamine (0.9 g, 6.9 mmol) and triethylamine (0.7 g, 6.9 mmol) in ethyl acetate (80 ml) was added a solution of BOC-Phe-OSu (2.5 g, 6.9 mmol) in ethyl acetate (50 ml). The mixture was stirred at room temperature for 20 hours. The organic layer was washed with water, 10% sodium carbonate, water and brine and denied on MgSO4. Evaporation of the solvent in vacuo yielded MdL080 as a white powder (2.5 g, 6.6 mmol, 96%). 1H NMR (CDCl3): δ=7.26-7.14 (m, 5H), 5.59 (bp 1H), 5.02 (bp, 1H), 4.20 (m, 1H), 3.07 (m, 4H), 1.57-1.17 (m, 21H), 0.82 (t, 3H, 3J=6.8 Hz); 13C NMR (CDCl3): δ=170.98, 136.68, 129.19, 128.60, 126.76, 65.88, 39.34, 88.71, 31.66, 29.21, 29.07, 28.16, 26.64, 22.52, 13.97.