Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16](F)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1.COC1C=CC(C[NH2:29])=CC=1.CO.C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>C(O)C.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[NH2:29][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][N:15]=1)[N:12]=[CH:11][C:10]([C:20]#[N:21])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1cccc(Br)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1cnc2cnc(N)cc2c1Nc1cccc(Br)c1
Reaction time: 20 h

Procedure:
To 1.3 g of 4-(3-bromo-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile in 20 mL of absolute ethanol was added 5 ml of 4-methoxy-benzylamine. The reaction was refluxed for six days, stripped of solvents, and passed through a plug of silica gel with 5% methanol/chloroform. This crude product was dissolved in 10 mL of chloroform containing 5% anisole and 10 mL of trifluoroacetic acid was added. After stirring under an inert atmosphere for 20 hours, 10 mL of toluene was added and the solvents stripped on a rotary evaporator. The product was purified by flash chromatography with a gradient of 0-10% methanol/chloroform. The solid was extracted with hot, 5% methanol/isopropyl ether and then cooled, filtered, and dried to give 250 mg of 6-amino-4-(3-bromo-phenylamino)-[1.7]naphthyridine-3-carbonitrile as an off-white solid. mass spectrum (m/e): M+H 306.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br)([O-:16])=[O:15]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[O:10][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[N+:14]([O-:16])=[O:15])[CH:5]=[O:6]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCOc1cc(C=O)cc(Br)c1O
Product: CCOc1cc(C=O)cc(Br)c1OCc1ccccc1[N+](=O)[O-]

Procedure:
Alkylation of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (5 g) with 2-nitrobenzylbromide (4.85 g) was performed according to the method described in example 1a. Yield: 7.88 g. MS-ESI: [M+H]+=380/382
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:9][C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[C:3]([O:18][CH3:19])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH:13]4[CH2:14][CH2:15]4)[CH2:9][C:8](=[O:16])[NH:7][C:6]=3[CH:17]=2)=[N:22][CH:23]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc2c(cc1N)NC(=O)CN(CC1CC1)C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)NC(=O)CN(CC1CC1)C2
Yield: 23.9 %

Procedure:
In an analogous manner to procedure 1656g, 8-amino-4-cyclopropylmethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (150 mg, 0.57 mmol) and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (143 mg, 0.48 mmol) were coupled to afford (1S,2S,3R,4R)-3-[5-chloro-2-(4-cyclopropylmethyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (60 mg, 24%) as a mustard yellow solid following preparative tlc on silica gel (10% MeOH-DCM); 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 2H), 7.90 (s, 1H), 7.52 (s, 1H), 7.16 (d, J=8 Hz, 1H), 6.79 (s, 1H), 6.30 (m, 3H), 5.69 (s, 1H), 4.38 (t, J=8 Hz, 1H), 3.93 (s, 3H), 3.78 (m, 2H), 3.43 (m, 2H), 3.06 (s, 1H), 2.87 (s, 1H), 2.57 (m, 3H), 2.24 (d, J=9 Hz, 1H), 1.60 (d, J=9 Hz, 1H), 0.92 (m, 1H), 0.59 (m, 2H), 0.22 (m, 2H); MS (m/e) 524 (M+1); mp 152° C.
Reaction SMILES: [Na].[O:2]=[S:3]1(=[O:17])[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]([CH2:13][C:14]([O-])=[O:15])=[N:4]1.C([O:20][C:21]([C@H:23]1[C@@H:28]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C@H:27]2[CH2:38][C@@H:24]1[CH2:25][CH2:26]2)=O)C.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[O:2]=[S:3]1(=[O:17])[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]([C:13]2[C:14](=[O:15])[N:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C@@H:28]3[C@H:23]([C:21]=2[OH:20])[C@@H:24]2[CH2:38][C@H:27]3[CH2:26][CH2:25]2)=[N:4]1
Reactant: O=C([O-])CC1=NS(=O)(=O)c2cnccc2N1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cnccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
The crude sodium-(1,1-dioxo-1,4-dihydro-1λ6-pyrido[4,3-e][1,2,4]thiadiazin-3-yl)-acetate, (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6l, 0.149 g, 0.51 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (0.194 g, 0.51 mmol) were combined and dissolved in anhydrous N,N-dimethylformamide (1 mL). The mixture was stirred at 25° C. for 1 h. Triethylamine (0.35 mL, 2.6 mmol) was added and the mixture was stirred at 50° C. for 16 h. Upon cooling, the mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride solution (2×25 mL) and saturated aqueous brine solution (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm, 75% to 100% ethyl acetate in hexanes) followed trituration of the resulting oil with a 1:1 mixture of hexanes and diethyl ether (2 mL) afforded the desired product, (1R,2S,7R,8S)-5-(1,1-dioxo-1,4-dihydro-1λ6-pyrido[4,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.0184 g, 0.039 mmol, 7.7% over two steps), as a pale yellow powder. LC-MS (ESI) calculated for C23H21FN4O4S 468.13, found 469.2 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ: 1.01-1.54 (6H, m), 2.35 (1H, d, J=3.7 Hz), 2.46 (1H, s), 2.53 (1H, s), 3.26 (1H, d, J=9.5 Hz), 4.23 (1H, d, J=15.8 Hz), 4.94 (1H, d, J=15.0 Hz), 7.08-7.13 (3H, m), 7.24-7.28 (2H, m), 8.44 (1H, d, J=4.8 Hz), 8.67 (1H, s).
Reaction SMILES: [C:1]1([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[C:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:43][CH:42]=3)=[CH:37][C:12]3[S:13][C:14](/[CH:24]=[C:25](\[C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)/[C:26]([O:28]CC)=[O:27])=[C:15]([O:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C:11]=3[CH:10]=2)=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[C:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)=[CH:43][CH:42]=3)=[CH:37][C:12]3[S:13][C:14](/[CH:24]=[C:25](\[C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)/[C:26]([OH:28])=[O:27])=[C:15]([O:16][C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=4)[C:11]=3[CH:10]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)/C(=C/c1sc2cc(OCc3ccc(-c4ccccc4)cc3)c(OCc3ccc(-c4ccccc4)cc3)cc2c1Oc1ccc(Cl)cc1)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C(=C/c1sc2cc(OCc3ccc(-c4ccccc4)cc3)c(OCc3ccc(-c4ccccc4)cc3)cc2c1Oc1ccc(Cl)cc1)c1ccncc1

Procedure:
A solution containing 1.5 mmol of the product of Example 1, 3 ml of an aqueous 1N sodium hydroxide solution and 30 ml of ethanol is refluxed for 12 hours. After returning to ambient temperature, the reaction mixture is concentrated under reduced pressure and the residue is then diluted with water and subsequently taken up in ethyl ether. The organic phase is then acidified by the addition of 6 ml of 1N HCl solution. A precipitate forms, which is filtered off, rinsed with water and then dried under reduced pressure, allowing the expected compound to be obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C([Li])CCC.CCCCCC.[I:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>O1CCCC1>[C:1]([O:5][C:6](=[O:11])[CH2:7][C:8](=[O:9])[CH2:10][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([I:25])=[CH:27][CH:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccc(I)cc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CCc1ccc(I)cc1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
t-butylacetoacetate (1.5 mL, 9.2 mmol) was added dropwise over 2 minutes to a stirred suspension of sodium hydride (60% mineral oil suspension; 400 mg, 10.0 mmol) in tetrahydrofuran at 0° C. under nitrogen. After stirring for 10 minutes n-butyl lithium in hexane (1.6 M; 6.0 mL, 9.6 mmol) was added then stirring continued for a further ten minutes. The resulting solution was treated dropwise with a solution of 4-iodobenzyl bromide (2.97 g, 10.0 mmol) in tetrahydrofuran (4 mL) and then warmed to room temperature. The reaction was stirred for 40 minutes at room temperature and then quenched with 6 M HCl (5 mL). The resulting mixture was extracted with diethyl ether (3×50 mL). The organic phases were combined, washed with brine (50 mL) and dried (MgSO4) then the solvent evaporated under reduced pressure. The residue was purified via flash chromatography on silica gel (1:20 to 1:10 ethyl acetate/cyclohexane) to give the title compound (1.88 g, 54%) as a yellow oil. LC/MS: 3.66 min; z/e 375, calcd (M+1) 375. 1H NMR (400 MHz; CDCl3): 7.6 (2H), 6.93 (2H), 3.33 (2H), 2.85 (4H), 1.45 (9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:27]([O:29]CC)=[O:28])=[N:10][CH:9]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:27]([OH:29])=[O:28])=[N:10][CH:9]=1
Reactant: CCOC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(N3CCOCC3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(N3CCOCC3)ccc12
Yield: 76.8 %

Procedure:
To a solution of ethyl 4-(2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylate (94 mg, 0.224 mmol) in MeOH (5 mL) at room temperature was added 1N sodium hydroxide solution (1.121 mL, 1.121 mmol). The mixture was heated at reflux for 1 hr and then concentrated under vacuum. To the residue was added water (20 mL), and the resulting mixture was neutralized with 1 N HCl solution to pH 5. The precipitating product (68 mg, 0.172 mmol, 77% yield) was collected as a tan solid by suction filtration and dried at 50° C. under vacuum.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]#[N:19])=[CH:4][C:5]2[N:6]([C:8]([S:14](Cl)(=[O:16])=[O:15])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1.Cl.[F:21][C:22]1([F:26])[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:1][C:2]1[C:3]([C:18]#[N:19])=[CH:4][C:5]2[N:6]([C:8]([S:14]([N:24]3[CH2:25][C:22]([F:26])([F:21])[CH2:23]3)(=[O:16])=[O:15])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1
Reactant: CC(C)c1nc2cc(C#N)c(Cl)cn2c1S(=O)(=O)Cl
Reactant: FC1(F)CNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1nc2cc(C#N)c(Cl)cn2c1S(=O)(=O)N1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 93.5 %

Procedure:
6-Chloro-7-cyano-2-isopropylimidazo[1,2-a]pyridine-3-sulfonylchloride (1.00 g, 3.14 mmol) obtained in step 3 was dissolved in acetonitrile (10 mL), and the solution was stirred at room temperature for 1.25 hours after adding 3,3-difluoroazetidinehydrochloride (611 mg, 4.71 mmol) and triethylamine (1.31 mL, 9.43 mmol). A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture. The precipitated crystals were collected by filteration, and washed with water. The resulting crude product was purified by silica gel column chromatography (heptane/ethyl acetate=80/20→50/50) to give 6-chloro-3-(3,3-difluoroazetidin-1-ylsulfonyl)-2-isopropylimidazo[1,2-a]pyridine-7-carbonitrile (1.10 g, yield 93%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:16])[NH2:15])=[N:6]1.O=[C:22]([CH3:28])[CH2:23][C:24](OC)=[O:25]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:24]([OH:25])[CH:23]=[C:22]([CH3:28])[N:16]=2)=[N:6]1
Reactant: COC(=O)CC(C)=O
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Solvent: Cc1ccccc1
Product: Cc1cc(O)nc(-c2nn(Cc3ccccc3F)c3ncccc23)n1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2.00 g (7.43 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide (example I, step 5) are dissolved together with 1.04 g (8.91 mmol) of methyl 3-oxobutanoate in 10 ml of absolute toluene under argon and stirred under reflux for 8 hours. A further 8.91 mmol of methyl 3-oxobutanoate are added, and stirring under reflux temperature is continued for 24 hours. This is followed by cooling to 0° C., removal of the precipitated solid by filtration and drying under high vacuum. 1.98 g (72% of theory) of the product are obtained.
Reaction SMILES: C([NH:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[NH:11][N:10]=1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[NH2:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[NH:11][N:10]=1
Reactant: Clc1cccc(Nc2ncnc3[nH]nc(NCc4ccccc4)c23)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
In order to remove residual water, some solvent is distilled off from a suspension of 75.8 g (216 mmol) of 3-benzylamino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]-pyrimidine in 1.5 liters of benzene. Then, with exclusion of moisture, the suspension is introduced into 84 g of aluminum chloride (Fluka, Buchs/Switzerland) in 500 ml of benzene. The reaction mixture is heated at 80° C. for 2.5 hours and then cooled to RT. The supernatant benzene phase is poured into 2 kg of ice-water (leaving behind a green, oily residue) and the solid that precipitates is filtered with suction and rinsed thoroughly with water (→K1). Using a rotary evaporator, the benzene is evaporated off from the filtrate, and the aqueous phase that remains is added, together with 1 kg of ice, to the green, oily residue and hydrolysis is carried out for 2 hours at 40° C. The crystalline product is filtered with suction and rinsed with water (→K2). K1 and K2 are taken up in 1 liter of methanol, acidified with 4N aqueous HCl and partially concentrated by evaporation. Water is added and the methanol is evaporated off completely. The crystals are filtered off and rinsed with water. The same purification procedure is repeated with semi-saturated Na2CO3 solution/methanol and water/methanol. Stirring at 50° C. in methanol, precipitation with diethyl ether, filtering and drying yield 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 232-234° C.; TLC: Rf =0.50 (ethyl acetate).
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.C(N(CC)CC)C.[OH:25][N:26]=[C:27]([Cl:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH2:35]([N:38]1[C:50]2[C:49]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[N:43]=[C:42]([Cl:51])[C:41]=2[N:40]=[C:39]1[CH2:52][O:53][CH2:54][CH3:55])[CH:36]=[CH2:37]>CN(C=O)C.ClCCl>[OH:25][N:26]=[C:27]([Cl:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl:51][C:42]1[C:41]2[N:40]=[C:39]([CH2:52][O:53][CH2:54][CH3:55])[N:38]([CH2:35][CH:36]3[O:9][N:8]=[C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:37]3)[C:50]=2[C:49]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[N:43]=1
Reactant: C=CCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Reactant: ON=Cc1ccccc1
Agent: O=C1CCC(=O)N1Cl
Agent: ON=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1CC1CC(c2ccccc2)=NO1
Reaction time: 8 h

Procedure:
N-Hydroxybenzenecarboximidoyl chloride (13.7 g) was prepared according to the method described in Part D of Example 1 by reacting benzaldehyde oxime (11.5 g, 94.9 mmol) in DMF (20 mL) with N-chlorosuccinimide (12.6 g, 94.9 mmol) and was obtained as a white solid. Triethylamine (0.69 mL, 4.97 mmol) was added to a solution of N-hydroxybenzenecarboximidoyl chloride (644 mg, 4.14 mmol) and 1-allyl-4-chloro-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline (prepared as described in Part C of Example 1, 1.00 g, 3.32 mmol) in dichloromethane (50 mL) at room temperature. The solution was stirred overnight and then was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel to afford 4-chloro-2-(ethoxymethyl)-1-[(3-phenyl-4,5-dihydroisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline as a pale yellow solid (1.19 g).
Reaction SMILES: [NH2:1][C@:2]([CH3:13])([CH2:5][CH2:6][C:7]1[N:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)[CH2:3][OH:4].[C:14](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:15].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:13][C@@:2]1([CH2:5][CH2:6][C:7]2[N:8]([CH3:12])[CH:9]=[CH:10][CH:11]=2)[CH2:3][O:4][C:14](=[O:15])[NH:1]1
Reactant: Cn1cccc1CC[C@@](C)(N)CO
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cccc1CC[C@]1(C)COC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
The obtained (2R)-2-amino-2-methyl-4-(1-methylpyrrol-2-yl)butan-1-ol 1/2 D-(−)-tartrate (41.4 mg, 0.16 mmol) was suspended in methylene chloride (1.6 mL) and di-t-butyl dicarbonate (0.176 g, 0.810 mmol), triethylamine (0.225 mL, 1.62 mmol) and 4-dimethylaminopyridine (2.0 mg, 0.016 mmol) were added thereto, followed by stirring of the mixture at room temperature for 30 minutes. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate 3:2-2:1) to obtain (4R)-4-methyl-4-[2-(1-methylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (17.7 mg, yield: 53%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[C@H:23]1[CH2:28][CH2:27][O:26][C:24]1=[O:25]>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C@H:23]1[CH2:28][CH2:27][O:26][C:24]1=[O:25])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1OCC[C@@H]1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1OCC[C@@H]1OS(=O)(=O)C(F)(F)F
Reaction time: 0.08 h
Yield: 61.2 %

Procedure:
Trifluoromethanesulfonic anhydride (1.65 mL) was gently added to a solution of pyridine (0.83 mL) in dichloromethane mL) at 0° C., and the mixture was stirred for 5 minutes at the same temperature. Subsequently, (S)-2-hydroxybutyrolactone (1.0 g) was added dropwise thereto over 10 minutes at 0° C., followed by stirring for 12 hours at the same temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane/ethyl acetate=2/1), to thereby yield a colorless oil (1.40 g, 61.2%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:12][C:13]([C:15]1[C:19]2[CH:20]=[C:21]([C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([OH:35])=O)[C:22]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:18]=2[O:17][C:16]=1[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)=[O:14])[CH3:11].[C:46]1([C:52]([NH2:55])([CH3:54])[CH3:53])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[F:45][C:42]1[CH:41]=[CH:40][C:39]([C:16]2[O:17][C:18]3[CH:23]=[C:22]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])[C:21]([C:30]4[CH:38]=[CH:37][CH:36]=[C:32]([C:33](=[O:35])[NH:55][C:52]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)([CH3:54])[CH3:53])[CH:31]=4)=[CH:20][C:19]=3[C:15]=2[C:13]([O:12][CH2:10][CH3:11])=[O:14])=[CH:44][CH:43]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(C(=O)O)c3)cc12
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Reaction time: 1 h
Yield: 81.2 %

Procedure:
DIEA (51 μL, 0.293 mmol) was added to a stirring solution of 3-(3-(ethoxycarbonyl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)benzoic acid (50 mg, 0.098 mmol), 2-phenylpropan-2-amine (26 mg, 0.195 mmol), HATU (56 mg, 0.147 mmol) in DMF (1 mL) at 25° C. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the titled compound (50 mg, 81%). LC-MS retention time: 1.82 min; m/z (MH+): 629. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O[N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28]>C1COCC1>[C:23]1(=[O:28])[NH:22][C:26](=[O:27])[CH2:25][CH2:24]1.[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1CCC(=O)N1O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: C1CCOC1
Product: O=C1CCC(=O)N1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Dicyclcohexylcarbodiimide (24.1 g, 117 mmol) dissolved in THF is added to a solution of oleic acid (30 g, 106.2 mmol) in 150 ml of THF at 0° C. After 20 minutes, N-hydroxysuccinimide (13.5 g, 117 mmol) is added to the mixture. The mixture is slowly warmed to room temperature. After 18 hours at room temperature, cooling to 0° C. is effected, and the precipitate is sucked off. The filtrate is concentrated and purified on a silica gel column using ethyl acetate/heptene (1:3). Yield: 83% of a colorless wax.
Reaction SMILES: [C:1]([NH:24][C@@H:25]([CH3:45])[C:26]([O:28][C@H:29]([CH3:44])[C@H:30]([NH:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=1)[C:31]([O:33][CH3:34])=[O:32])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\CC.C(O)(=O)CCC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CC>>[C:1]([NH:24][C@@H:25]([CH3:45])[C:26]([O:28][C@H:29]([CH3:44])[C@H:30]([NH:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=1)[C:31]([O:33][CH3:34])=[O:32])=[O:27])(=[O:23])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N[C@@H](C)C(=O)O[C@H](C)[C@H](NC(=O)c1cccnc1)C(=O)OC
Agent: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](C)C(=O)O[C@H](C)[C@H](NC(=O)c1cccnc1)C(=O)OC

Procedure:
The same synthetic sequence outlined above for the preparation of (2S,3R)-methyl 3-((S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoyloxy)-2-(nicotinamido)butanoate was used, except that (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoic acid (EPA) was used instead of DHA. MS calculated for C34H47N3O6: 593.35. found: [M+H]+ 594.