Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17](I)[CH:18]=1)[CH3:11].[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][C:29]#[CH:30])([CH3:24])([CH3:23])[CH3:22]>C1COCC1.CCN(CC)CC.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][C:29]#[C:30][C:17]1[CH:16]=[N:15][C:14]([NH2:20])=[C:13]([O:12][CH:10]([C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[CH:18]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(Oc1cc(I)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Oc1cc(C#CCNC(=O)OC(C)(C)C)cnc1N)c1c(Cl)ccc(F)c1Cl
Yield: 29.2 %

Procedure:
To a solution of 3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine (7.1 g, 16.6 mmol) and prop-2-ynyl-carbamic acid tert-butyl ester (3.1 g, 20.0 mmol) in THF (60 mL) and Et3N (60 mL) was added CuI (63 mg, 0.3 mmol) and Pd(PPh3)4 (384 mg, 0.3 mmol). The mixture was stirred under nitrogen and monitored by TLC until the reaction was complete. The mixture was extracted with EtOAc and washed by water. The crude product was purified on a silica gel column eluting with 20-40% EtOAc in hexanes to provide (3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester (2.2 g, 29% yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[O:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:29]3[CH2:28][CH2:27][N:26]([CH:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[CH2:31][CH2:30]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CCN(C3CCOCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (165 mg, 0.59 mmol), 1-(tetrahydropyran-4-yl)piperazine (110 mg, 0.65 mmol) and molecular sieves (4 Å, powdered, 750 mg) in DCE (10 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (170 mg, 0.80 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH, 100:0 to 98:2 to 95:5 to 90:10) to afford 2-Chloro-9-methyl-6-morpholin-4-yl-8-[4-(tetrahydropyran-4-yl)piperazin-1-ylmethyl]-9H-purine as a white solid (250 mg, 98%). 1H NMR (CDCl3, 400 MHz) δ 4.27 (m, 4 H), 4.01 (dd, J=11.5, 4.2 Hz, 2 H), 3.81 (m, 7 H), 3.69 (s, 2 H), 3.36 (dd, J=12.5, 10.9 Hz, 2 H), 2.55 (m, 8 H), 2.40 (m, 1 H), 1.75 (d, J=12.5 Hz, 2 H) and 1.56 (m, 2 H)
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].Cl.[CH:23]1([CH2:29][NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:23]1([CH2:29][N:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:12](=[O:14])[CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCCCCCCNCC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCN(CC1CCCCC1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.108 g, 0.36 mmol) in methylene chloride (3.6 mL) were added N-(cyclohexylmethyl)-N-heptylamine hydrochloride (0.090 g, 0.36 mmol) and DMAP (0.098 g, 0.80 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.070 g, 0.36 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (25 mL) and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL) and brine (25 mL), dried over Na2SO4 and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 5 g Si/25 mL) with methanol (0-1% gradient) in methylene chloride as the eluent yielded 0.103 g (58%) of a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21]Br)[C:9]=2[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:9]=2[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2]
Reactant: NCc1cccnc1
Reactant: CCOC(=O)c1oc2cccc(OCCCBr)c2c1C1CC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1oc2cccc(OCCCNCc3cccnc3)c2c1C1CC1
Temperature: 70 °C

Procedure:
To a solution of 4-(3-bromo-propoxy)-3-cyclopropyl-benzofuran-2-carboxylic acid ethyl ester (92 mg) in ethanol (4 ml) was added 3-aminomethylpyridine (500 μl) and heated at 70° C. overnight. The mixture was diluted with ethyl acetate (10 ml) and washed with saturated aqueous ammonium chloride solution (5 ml) and water (5 ml), then dried over anhydrous sodium sulfate, concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol to give 3-cyclopropyl-4-{3-[(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-carboxylic acid ethyl ester as a pale yellow oil (108 mg). ESI-MS: m/z 395 (MH+); 1H-NMR (CDCl3): δ 0.95-1.08 (4H, m), 1.44 (3H, t, J=7.3 Hz), 2.10 (2H, quintet, J=6.3 Hz), 2.54-2.60 (1H, m), 2.89 (2H, t, J=6.3 Hz), 3.85 (2H, s), 4.17 (2H, t, J=6.3 Hz), 4.45 (2H, q, J=7.3 Hz), 6.63 (1H, d, J=7.9 Hz), 7.13 (1H, d, J=7.9 Hz), 7.21-7.34 (2H, m), 7.68 (1H, d, J=7.9 Hz), 8.48 (1H, dd, J=1.7 Hz, 4.9 Hz), 8.56 (1H, d, J=1.7 Hz).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@@H:3]1[S:4][C@@:5]([N:23]1[CH2:27][CH2:26][N:25]([NH2:28])[C:24]1=[O:29])([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])[CH2:6]2.Cl.[O-:31][C:32]#[N:33].[Na+].C(=O)([O-])O.[Na+]>O.CO>[NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@@H:3]1[S:4][C@:5]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)=[O:11])([N:23]1[CH2:27][CH2:26][N:25]([NH:28][C:32]([NH2:33])=[O:31])[C:24]1=[O:29])[CH2:6]2
Reactant: N#C[O-]
Reactant: N[C@@H]1C(=O)N2C[C@@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(N3CCN(N)C3=O)S[C@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)NN1CCN([C@]2(C(=O)OCc3ccc([N+](=O)[O-])cc3)CN3C(=O)[C@@H](N)[C@H]3S2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
In a mixed solvent consisting of 30 ml of water and 30 ml of methanol was suspended 5.00 g of (3R,5R,6R)-6-amino-3-(3-amino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane. To suspension was added 2.96 ml of concentrated hydrochloric acid with water cooling. To the resulting solution was added 1.36 g of sodium cyanate in 10 minutes, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered. To the filtrate were added 50 ml of ethyl acetate and 50 ml of water. The aqueous layer was separated. The organic layer was extracted three times each with 30 ml of water. The extracts were combined with the aqueous layer obtained previously. The combined aqueous solution was adjusted to pH 6.9 with sodium hydrogencarbonate. The solvent was removed by distillation under reduced pressure. The residue was dehydrated by four times of azeotropy with ethanol. To the resulting residue was added a mixed solvent consisting of 50 ml of methylene chloride and 10 ml of methanol. The insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/methanol=10/1 to 5/1) to obtain 4.29 g (yield: 77.9%) of (3R,5R,6R)-6-amino-3-(p-nitrobenzyloxycarbonyl)-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH3:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1OCC(O)=O>ClCCl.CN(C)C=O>[CH3:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[O:3][CH2:2][C:1]([Cl:6])=[O:5]
Reactant: Cc1ccccc1OCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1OCC(=O)Cl
Reaction time: 16 h

Procedure:
Oxalyl chloride (2.2 mL, 25 mM) was added to a stirred solution of (2-methylphenoxy)acetic acid (3.32 g, 20 mM) in dichloromethane (10 mL). Dry N,N-dimethylformamide (1 drop) was added to catalyse the reaction and the mixture was stirred for 16 hours. The solvent was removed by evaporation to leave (2-methylphenoxy)acetyl chloride as a pale yellow oil, which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:14]([NH:21][C:22]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26](Br)[N:25]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.C(OCC)(=O)C.[Cu](Cl)Cl>[CH2:14]([NH:21][C:22]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:25]=1)=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: COc1cc(Br)nc(C(=O)NCc2ccccc2)c1
Agent: Cl[Cu]Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NCc2ccccc2)c1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
1.04 g (0.0029×2.2 mol) of 3-(trifluoromethyl) phenol was dissolved in about 10 ml of DMF. The obtained solution was further mixed with 0.24 g (ca. 60% in mineral oil; 0.0029×2.0 mol) of NaH and then with 0.94 g (0.0029 mol) of N-benzyl-6-bromo-4-methoxy-2-pyridine carboxamide. After adding 0.15 g (0.0029×0.5 mol) of copper chloride (I), the solution was stirred at about 120° C. for about 5 hours, and then allowed to stand for cooling to room temperature. After the reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, the organic phase of the solution was washed with saturated brine and dried with anhydrous sodium sulfate, followed by concentration thereof. Thereafter, the concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH3:16])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[C:17](=[O:19])=[O:18].Cl>CCCCCC.O1CCCC1>[CH3:15][O:14][C:12]1[CH:11]=[C:10]([CH3:16])[CH:9]=[C:8]([O:7][CH3:6])[C:13]=1[C:17]([OH:19])=[O:18]
Reactant: COc1cc(C)cc(OC)c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C)cc(OC)c1C(=O)O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
104 ml of 1.6M n-butyllithium solution in hexane are added to 200 ml of tetrahydrofuran, followed by dropwise addition of 25 ml of 3,5-dimethoxytoluene, at a temperature between 0° and 5° C. The reaction medium is stirred at 5° C. for 1 h 30, followed by introduction of excess gaseous CO2 over 30 minutes. The mixture is introduced into 200 ml of aqueous 0.5N HCl solution and the aqueous phase is extracted with ethyl acetate. The residue is concentrated and chromatographied on a silica column (eluent: dichloromethane/methanol - 93/7).
Reaction SMILES: [PH2:1](=[O:3])[O-:2].[NH4+].C[Si](C)(C)N[Si](C)(C)C.[CH2:14]=[C:15]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>ClCCl>[OH:3][PH:1]([CH2:14][CH:15]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[O:2]
Reactant: C=C(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=[PH2][O-]
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCC(C[PH](=O)O)C(=O)OC(C)(C)C
Temperature: 105 °C
Yield: 99.8 %

Procedure:
A mixture of ammonium phosphinate (162.6 g, 1.96 mol) and 1,1,1,3,3,3-hexamethyldisilazane (316 g, 1.96 mol) was heated to 105° C. for 2 hours. The reaction mixture was cooled in an ice bath and di-tert-butyl 2-methylenepentane-1,5-dioate (251 g, 0.979 mol) dissolved in dichloromethane (1000 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was then quenched with distilled water (500 ml) and the organic layer was retained. The aqueous layer was washed a second time with dichloromethane and the combined organic layers were dried over magnesium sulfate. Then the solvent was removed under reduced pressure leaving a slightly yellow oil (315 g, 100%) This product was found to be of sufficient purity for use in the next reaction. 1H NMR (CDCl3) δ 1.4 (m, 18H), 1.9 (m, 3H), 2.1 (m, 1H), 2.3 (m, 2H), 2.7 (m, 1H), 6.5 & 7.9 (d, 1H, the P-H), 11.0 (s, 1H).
Reaction SMILES: [BH3-]C#N.[Na+].[N:5]1([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH:24]1([CH:27]=O)[CH2:26][CH2:25]1>CCO>[CH:24]1([CH2:27][N:8]2[CH2:7][CH2:6][N:5]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[CH2:10][CH2:9]2)[CH2:26][CH2:25]1
Reactant: O=CC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNCC2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: C1CC(N2CCN(CC3CC3)CC2)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.26 g (20.0 mmol) NaBH3CN were added in 4 batches at RT to a solution of 1.71 g (5.0 mmol) tert. butyl 4-piperazin-1-yl-piperidine-1-carboxylate and 0.75 mL (10.0 mmol) cyclopropanecarbaldehyde in 100 mL of EtOH and the reaction mixture was stirred overnight at RT. The mixture was evaporated down i.vac., the residue was taken up in saturated NaHCO3 solution, extracted exhaustively with EtOAc and the organic phase was dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, EtOAc/MeOH/NH3 90:10:0.5).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[H-].[Na+].C([Li])CCC.[C:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>CCCCCC.O1CCCC1>[CH3:20][CH:19]([CH3:21])[CH2:18][CH2:17][C:16]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:22][C:1](=[O:6])[CH:2]=[CH:3][CH2:5]1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)CCC(=O)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)CCC1(c2ccccc2)CC=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6M n-butyl lithium in hexane, 25 mmol of isohexanophenone and 70 mL of tetrahydrofuran. Upon concentrating the reaction a solid precipitated out which was triturated with ether and filtered (m.p. 134°-136° C.). 1H NMR (CDCl3) δ0.83 (dd, 6H), 1.1-1.3 (m, 2H), 1.4-1.6 (m, 1H), 1.9-2.1 (m, 2H), 2.90 (d, 1H), 2.92 (d, 1H), 3.25 (d, 1H), 3.35 (d, 1H), 7.2-7.5 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:31])=[CH:12][C:13]([C:15]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)([CH3:23])[CH2:16][CH2:17][CH2:18]CCCC)=[CH:14][C:4]=2[O:3]1.[ClH:33].[N:34]1([CH2:39][CH2:40][CH2:41][C:42](O)=[O:43])[CH2:38][CH2:37][CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:33].[CH3:32][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:31][C:42](=[O:43])[CH2:41][CH2:40][CH2:39][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:12][C:13]([C:15]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)([CH3:23])[CH2:16][CH2:17][CH3:18])=[CH:14][C:4]=2[O:3]1
Reactant: CCCCCCCC(C)(c1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Reactant: O=C(O)CCCN1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCC(C)(c1ccc(F)cc1)c1cc(OC(=O)CCCN2CCCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
3.21 g. (9.37 mmole) of 4,4-Dimethyl-9-hydroxy-7-(4-fluorophenyl-1-methyloctyl)-1,2,3,4-tetrahydrocyclopenta [c][1]benzopyran are combined with 1.82 g. (9.37 mmole) of γ-pyrrolidinobutyric acid hydrochloride and 2.06 g. (10.0 mmole) of dicyclohexylcarbodiimide in 150 ml. of methylene chloride and stirred at room temperature for 21/2 hours. The insoluble by-product of dicyclohexylurea is removed by filtration and the filtrate is evaporated to give a residue which crystallized upon standing. The material is triturated with ether and filtered. Recrystallization from benzene/ether gives the product as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([CH3:17])[C:14](=[O:16])[NH:15][C:8]=23)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[CH3:17][N:13]1[C:9]2=[N:10][CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:18]=[CH:19][C:2]([NH:1][C:28]([NH:27][C:24]4[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=4)=[O:29])=[CH:3][CH:4]=3)=[C:8]2[NH:15][C:14]1=[O:16]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cn1c(=O)[nH]c2c(Oc3ccc(N)cc3)ccnc21
Product: Cn1c(=O)[nH]c2c(Oc3ccc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3)ccnc21
Yield: 83.7 %

Procedure:
Method H2 was used with 7-(4-aminophenoxy)-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (20 mg, 0.08 mmol) and 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (17 mg, 0.08 mmol) to afford the title compound as a solid (32 mg, 84%). 1H-NMR (δ, ppm, DMSO-d6): 3.30 (s, 3H, CH3), 6.40 (d, 1H, HPy,5, J=5.55 Hz), 7.13 (d, 2H, Harom,Ph,3+5, J=8.05 Hz), 7.54 (d, 2H, Harom,Ph,2+6), 7.61-7.65 (m, 2H, Harom′), 7.84 (d, 1H, HPy,6), 8.11 (s, 1H, Harom′), 8.97 (s, 1H, NHurea1), 9.20 (s, 1H, NHurea,3), 11.48 (s, 1H, NHPy3).
Reaction SMILES: C([O:3][C:4]([C:6]1([F:22])[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[F:22][C:6]1([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1
Reactant: CCOC(=O)C1(F)CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCC(F)(C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
4-Fluoro-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid ethyl ester (2.08 g) was dissolved in MeOH (70 ml) at RT and under an argon atmosphere and 3M aqueous NaOH (8.42 ml) was added at RT and the mixture was stirred for 12 h at RT. The solvent was evaporated and 3M HCl was slowly added to adjust the pH between 1-2. The mixture was then extracted twice with AcOEt, the organic layers were collected, washed with brine, dried over sodium sulphate and concentrated to give crude 4-fluoro-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (1.9 g) as a light brown solid which was used in next reaction step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:30]=[CH:29][C:12]3[NH:13][C:14]([NH:16][C:17]([C:19]4[N:20]=[C:21]5[CH:26]=[CH:25][C:24](Cl)=[N:23][N:22]5[CH:28]=4)=[O:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH:31]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]1.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:30]=[CH:29][C:12]3[NH:13][C:14]([NH:16][C:17]([C:19]4[N:20]=[C:21]5[CH:26]=[CH:25][C:24]([N:31]6[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]6)=[N:23][N:22]5[CH:28]=4)=[O:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1CCNCC1
Reactant: O=C(Nc1nc2cc(-c3cc(F)cc(Cl)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1nc2cc(-c3cc(F)cc(Cl)c3)ccc2[nH]1)c1cn2nc(N3CCC(O)CC3)ccc2n1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 39.9 %

Procedure:
To a solution of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide (0.07 g) in N-methylpyrrolidone (1 mL), was added piperidin-4-ol (0.08 g) and the mixture was heated to 80° C. for 12 hours. After cooling the reaction mixture, 10 mL of water was added and the reaction mixture was stirred for 10 minutes. The reaction was then filtered through a fine fritted funnel and the crude product was washed with water. After air drying, purified by column chromatography (pre-packed silica column) using a gradient of 0 to 10% 2M ammonia-methanol in DCM to obtain 6-(4-hydroxy-piperidin-1-yl)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide (32 mg). LCMS (m/z): 506.7. 1H NMR (400 MHz, DMSO-d6) δ 8.64 (1H, s) 7.93 (1H, d) 7.80-7.86 (1H, m) 7.48-7.65 (4H, m) 7.35-7.43 (2H, m) 4.79 (1H, br. s.) 3.95 (2H, ddd) 3.70-3.80 (1H, m) 3.18-3.45 (2H, m) 1.79-1.90 (2H, m) 1.39-1.53 (2H, m).
Reaction SMILES: [C:1]([CH2:24][C:25](=O)[CH2:26][C:27](=[O:49])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[BH4-].[Na+].[OH2:53]>>[C:1]([CH:24]([OH:53])[CH2:25][CH2:26][C:27](=[O:49])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)CC(=O)CC(=O)CCCCCCCCCCC/C=C\CCCCCCCC
Reactant: O
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)CCC(O)C(=O)CCCCCCCCCCC/C=C\CCCCCCCC

Procedure:
A triacylglycerol containing oil having an EOE content of at least 50% based on total triacylglycerol composition can be chemically synthesized using 1,3 dihydroxyacetone and free erucic and oleic fatty acids as starting materials. Oils chemically synthesized as described herein have EOE contents of 80% or greater, and preferably greater than 90%. In the first step, 1,3 dihydroxyacetone dimer and erucic acid can be reacted in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine to form 1,3 dierucoylpropanone. The ketone group of 1,3 dierucoylpropanone can be reduced using, for example, sodium borohydride and water to form 1,3 dierucoylpropanol. EOE can be produced by reacting 1,3 dierucoylpropanol and oleic acid in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine to form 1,3 dierucoyl 2-oleoyl propane.