Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K+].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:25][C:24]([C:26]4[CH:34]=[CH:33][CH:32]=[C:31]5[C:27]=4[CH:28]=[CH:29][NH:30]5)=[N:23][C:22]=3[C:35]([O-])=[O:36])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].O.OC1C2N=N[NH:45]C=2C=CC=1.Cl.CN(C)CCCN=C=NCC.N.O1CCOCC1>C(Cl)Cl.CN(C=O)C>[C:35]([C:22]1[N:23]=[C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH:28]=[CH:29][NH:30]3)[O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:7]([O:6][C:2]([CH3:4])([CH3:5])[CH3:3])=[O:8])[CH2:10][CH2:11]2)=[CH:16][CH:17]=1)(=[O:36])[NH2:45]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4cccc5[nH]ccc45)nc3C(=O)[O-])cc2)CC1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4cccc5[nH]ccc45)nc3C(N)=O)cc2)CC1
Yield: 66.7 %

Procedure:
To a solution of 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-2-(1H-indol-4-yl)oxazole-4-carboxylic acid potassium salt (0.045, 0.09 mmol) in DCM (0.9 ml) and DMF (0.7 ml) was added hydroxybenzotriazole monohydrate (0.018 g, 0.12 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.027 g, 0.14 mmol) and 0.5M ammonia in dioxane (0.9 ml, 0.45 mmol) and the resultant mixture stirred overnight at room temperature. The solvent was then removed in vacuo and the residue purified by preparative HPLC to afford tert-butyl 4-(4-(4-carbamoyl-2-(1H-indol-4-yl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.027 g, 0.06 mmol, 65%). LCMS (2) Rt: 3.33 min; m/z (ES+) 488.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:29][CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: NCCc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCCc3ccccc3)c3ccccc3nc21
Temperature: 80 °C
Yield: 79 %

Procedure:
A mixture of 1-ethyl- 4-chloro-1H-pyrazolo[3,4-b]quinoline (11.6 g, 0.05 mol), DMSO (20 ml) and phenethylamine (12.1 g, 0.1 mol) was heated at 80° C. overnight. The reaction mixture was poured into water (1 L) and the precipitate which formed was collected by filtration and washed with water. The solid was dissolved in hot ethyl acetate, and then the solution was dried over MgSO4, filtered and evaporated to a small volume. Hexane was added and then the mixture was cooled in an ice-bath and then the product which crystallized was collected by fitration, washed with hexane and dried to afford 12.5 g of 1-ethyl-N-(phenylethyl)-1H-pyrazolo[3,4-b]quinoline-4 amine, m.p. 157°-158° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1F.[NH2:17][C:18]1[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>C(OCC)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Reactant: Cc1ccccc1N
Solvent: CCOCC
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1C
Temperature: 25 °C
Reaction time: 36 h
Yield: 68 %

Procedure:
4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4 (12.0 g, 51.7 mmol) is suspended in xylenes (60 mL) and ortho-toluidine is added (55.2 mL, 517 mmol). The reaction mixture is heated to reflux with stirring under a nitrogen atmosphere. After 36 hours, the reaction mixture is cooled to room temperature, diluted with diethyl ether and washed with 10% aqueous HCl solution. The aqueous washings are extracted with diethyl ether. The combined organic extracts are concentrated under reduced pressure. The residue is dissolved in methylene chloride and filtered through silica gel in a fitted funnel, rinsing with methylene chloride. Three fractions are recovered. The first (2 liter) is nearly clean by HPLC. The second (1 liter) and third (1 liter) fractions are only partially pure. The first fraction is concentrated under reduced pressure and triturated with diethyl ether to give 11.2 g (68%) of clean desired product as a bright yellow solid: MS APCI (−) m/z 318 (M−1) detected.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.O.C(Cl)[Cl:16]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([Cl:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 4-tert-butyl-phenol (40.0 g, 0.27 mol) and SO2Cl2 (37.5 g, 0.28 mol) in CH2Cl2 was added MeOH (9.0 g, 0.28 mol) at 0° C. After addition was complete, the mixture was stirred overnight at room temperature and then water (200 mL) was added. The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (Pet. Ether/EtOAc, 50:1) to give 4-tert-butyl-2-chloro-phenol (47.0 g, 95%).
Reaction SMILES: [CH3:1][C:2]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][C:16]=2[C:21]2[CH:22]=[C:23]3[C:32](=[CH:33][CH:34]=2)[C:31]2[N:27]([CH:28]=[C:29]([C:35]4[N:39]([CH:40]([CH3:42])[CH3:41])[N:38]=[C:37]([CH3:43])[N:36]=4)[N:30]=2)[CH2:26][CH2:25][O:24]3)[CH2:10]1)([CH3:8])[C:3](OCC)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH:40]([N:39]1[C:35]([C:29]2[N:30]=[C:31]3[C:32]4[CH:33]=[CH:34][C:21]([C:16]5[CH:17]=[N:18][N:19]([CH3:20])[C:15]=5[CH:11]5[CH2:12][CH2:13][CH2:14][N:9]([C:2]([CH3:1])([CH3:8])[CH2:3][OH:4])[CH2:10]5)=[CH:22][C:23]=4[O:24][CH2:25][CH2:26][N:27]3[CH:28]=2)=[N:36][C:37]([CH3:43])=[N:38]1)([CH3:42])[CH3:41]
Reactant: CCOC(=O)C(C)(C)N1CCCC(c2c(-c3ccc4c(c3)OCCn3cc(-c5nc(C)nn5C(C)C)nc3-4)cnn2C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCN(C(C)(C)CO)C4)cc2OCC3)n(C(C)C)n1
Yield: 30.6 %

Procedure:
To a solution of ethyl 2-methyl-2-[3-(1-methyl-4-{4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}-1H-pyrazol-5-yl)piperidin-1-yl]propanoate (35 mg, 0.060 mmol) in dry THF (2 ml), was added LiAlH4 (11.4 mg, 0.300 mmol) in small portions at room temperature. The resulting mixture was heated to reflux for 1 h. Water (1 mL) was added to quench the reaction. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford 248 (10 mg, 31% yield). LCMS (ESI): RT=4.72 min, m/z: 545.4 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.39 (d, J=8.5 Hz, 1H), 7.91 (s, 1H), 7.43 (s, 1H), 7.09-7.08 (m, 1H), 6.93 (d, J=1.5 Hz, 1H), 5.86-5.83 (m, 1H), 4.53 (d, J=6.0 Hz, 4H), 4.27-4.25 (m, 1H), 3.89 (s, 3H), 3.28-3.25 (m, 2H), 2.99-2.96 (m, 3H), 2.44-2.40 (m, 2H), 2.26 (s, 3H), 2.08-2.06 (m, 1H), 1.58-1.70 (m, 3H), 1.47-1.45 (m, 6H), 0.93-0.91 (m, 6H)
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.S(Cl)(Cl)=O.[CH:25]1([C:31]2[CH:36]=[CH:35][C:34](O)=[C:33]([NH2:38])[CH:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C.CS(O)(=O)=O.C(=O)([O-])O.[Na+]>O.O1CCCC1>[CH:25]1([C:31]2[CH:36]=[CH:35][C:34]3[O:20][C:18]([C:16]4[CH:15]=[CH:14][C:6]5[N:7]([CH:8]6[CH2:9][CH2:10][O:11][CH2:12][CH2:13]6)[C:3]([CH3:2])=[N:4][C:5]=5[CH:17]=4)=[N:38][C:33]=3[CH:32]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Reactant: Nc1cc(C2CCCCC2)ccc1O
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1nc2cc(-c3nc4cc(C5CCCCC5)ccc4o3)ccc2n1C1CCOCC1
Yield: 49.2 %

Procedure:
To 2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (182 mg, 0.612 mmol) was added thionyl chloride (2 mL), and this was stirred at reflux for 3 hours. After the reaction was complete, concentration at reduced pressure gave a residue that was added to 4-cyclohexyl-2-aminophenol (117 mg, 0.612 mmol), triethylamine (309 mg, 3.06 mmol) and tetrahydrofuran (5 mL), and this was stirred at room temperature for 14 hours. After the reaction was complete, this was concentrated, and to a dioxane (5 mL) solution of the residue obtained was added methanesulfonic acid (353 mg, 1.46 mmol), and this was heated to reflux for 18 hours. After the reaction solution was cooled, water and saturated aqueous sodium hydrogen carbonate solution were added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (125 mg, 49% yield) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)[CH3:2].CN(C)CCN(C)CCN(C)C.[Li]CCCC.CN([CH:31]=[O:32])C>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[C:8]([CH:9]=1)[CH:31]=[O:32])[CH3:2]
Reactant: CCOc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(C=O)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 1-ethoxy-4-fluorobenzene (1.1 g, 7.9 mmol) and pentamethyl diethylene triamine (2 mL) in anhydrous THF (6 mL) was added BuLi dropwise (1.38 M, 5.98 mL, 8.3 mmol) at −78° C. After addition, the reaction mixture was warmed up to −40° C. and stirred for 30 min, the reaction mixture was then cooled to −78° C. and DMF (0.7 mL) was added. The solution was warmed to rt, and stirred for 1 h. The reaction mixture was then partitioned between EtOAc and sat. NH4Cl, the organic layer was dried over (Na2SO4), filtered and concentrated. The residue was subjected to chromatographic purification (0-10% EtOAc/hexanes gradient), 600 mg (55%) of Intermediate 53.1 was obtained. 1H NMR (CDCl3) δ 1.40 (t, 3H), 4.08 (q, 2H), 6.81 (m, 1H), 7.15 (m, 1H), 7.29 (m, 1H), 10.33 (s, 1H).
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].[C:30]([O:34][C:35](=[O:45])[NH:36][CH2:37][C:38]1[N:43]=[CH:42][C:41](Cl)=[CH:40][N:39]=1)([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C(O)(C)C.O>[C:30]([O:34][C:35](=[O:45])[NH:36][CH2:37][C:38]1[N:43]=[CH:42][C:41]([C:15]2[CH:16]=[CH:17][C:12]([C@H:8]3[O:7][C:6]([CH3:27])([CH3:28])[N:5]([C:3](=[O:4])[CH:2]([F:29])[F:1])[C@@H:9]3[CH2:10][F:11])=[CH:13][CH:14]=2)=[CH:40][N:39]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: CC(C)(C)OC(=O)NCc1ncc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCc1ncc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 140 °C
Yield: 36.4 %

Procedure:
To a stirred solution of 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (0.286 g, 0.694 mmol) and (5-Chloro-pyrimidin-2-ylmethyl)-carbamic acid tert-butyl ester (0.2 g, 0.694 mmol) in isopropylalcohol:water (2:1, 6 mL) is added K2CO3 (0.287 g, 2.083 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 20 minutes followed by addition of Pd(dppf)Cl2.CH2Cl2 (0.028 g, 0.035 mmol). The resulting reaction mixture is heated to 140° C. for 20 minutes in a microwave. Solvent is evaporated in vacuo and the crude material is diluted using water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by column chromatography using Combi-flash eluting with 75% ethyl acetate in hexane to afford the title compound (0.125 g): 1H NMR (400 MHz, DMSO-d6) δ: 1.40 (s, 9H), 1.52 (s, 3H), 1.60 (s, 3H), 4.36 (d, J=6.16 Hz, 2H), 4.54-4.58 (m, 0.5H), 4.66-4.73 (m, 1H), 4.82-4.85 (m, 0.5H), 4.91-4.95 (m, 1H), 5.28 (d, J=3.52 Hz, 1H), 6.64 (t, J=52.44 Hz, 1H), 7.32 (t, J=6.04 Hz, 1H), 7.62 (d, J=8.04 Hz, 2H), 7.86 (d, J=8.04 Hz, 2H), 9.10 (s, 2H). LC-MS (m/z): [M+H]=495.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1.C([BH3-])#N.[Na+].Cl.[OH-].[K+]>CO>[O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)C1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CO
Product: CCOC(=O)C1CCN(Cc2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 69.5 %

Procedure:
To a stirred solution of 5.0 grams (0.025 mole) of 4-phenoxybenzaldehyde and 4.0 grams (0.025 mole) of ethyl piperidin-4-ylcarboxylate in 25 mL of methanol was added 1.6 grams (0.025 mole) of sodium cyanoborohydride in one portion. Upon completion of addition, a methanolic solution saturated with hydrogen chloride was added dropwise until the pH of the reaction mixture was about 6.0. The reaction mixture was then stirred at ambient temperature for about 22 hours, after which the pH was again adjusted to about 5.5-6.0 with additional methanolic hydrogen chloride solution. The reaction mixture was poured into 350 mL of aqueous 0.1M potassium hydroxide solution. The mixture was extracted with three 125 mL portions of diethyl ether, and the combined extracts were washed with one portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with 1:1 ethyl acetate/hexane as the eluant. The product-containing fractions were combined and concentrated, yielding 5.9 grams of ethyl N-(4-phenoxyphenylmethyl)piperidin-4-ylcarboxylate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:25][NH:26][O:27][CH3:28].CN1CCOCC1>C(Cl)Cl>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([N:26]([O:27][CH3:28])[CH3:25])=[O:17])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNOC
Reactant: O=C(O)Cc1ccc(OC2CCCCC2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)Cc1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (4-cyclohexyloxy-phenyl)-acetic acid (181 mmol, 42.4 g) in anhydrous DCM (200 mL) at 0° C. was added oxalyl chloride (362 mmol, 36.6 mL) and continued stirring for 12 h during which time the reaction mixture slowly attained room temperature. The reaction mixture was concentrated in vacuo to remove volatile impurities and dried under high vacuum. To a stirred solution of N,O-dimethylhydroxylamine hydrochloride (226 mmol, 22.1 g) and N-methylmorpholine (407 mmol, 44.8 mL) in anhydrous DCM (200 mL) at 0° C. was added the acid chloride obtained above, dissolved in DCM (50 mL) dropwise. The reaction mixture was stirred for 12 h allowing it to slowly attain room temperature. The reaction mixture was washed with water (2×200 mL), brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified on a 330 g SiO2 cartridge with 20-30% ethyl acetate in hexanes to provide 2-(4-cyclohexyloxy-phenyl)-N-methoxy-N-methyl-acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:33])[C:11]([C:31]#[N:32])=[C:12]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:13]([C:14]3[CH:19]=[CH:18]C=CC=3)=[C:8]2[S:7][CH2:6]1)=[O:4].COC([C@H]1N2C(=O)C(Br)=C(CC3C4C(=CC=CC=4)C=CC=3)C(C3C=CC=CC=3)=C2SC1)=O.COC(C1N2C(=O)C(Br)=C(CC3C4C(=CC=CC=4)C=CC=3)C(C3CC3)=C2SC1)=O>>[CH3:1][O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:33])[C:11]([C:31]#[N:32])=[C:12]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:13]([CH:14]3[CH2:18][CH2:19]3)=[C:8]2[S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Agent: COC(=O)C1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(Br)c(=O)n21
Agent: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(Br)c(=O)n21
Product: COC(=O)C1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Yield: 88 %

Procedure:
By following the procedure described for the preparation of 6a from 5a, 5b (100 mg, 0.21 mmol) gave 6b as a white foam (78 mg, 88%). [α]D−44 (c 1.0, CHCl3); IR λ 3004, 2954, 2360, 2213, 1747, 1644, 1481, 1213, 1164, 792; 1H NMR (400 MHz, CDCl3) 8.12 (d, J=8.2 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.62-7.51 (m, 2H), 7.34 (t, 1H), 6,89 (d, J=7.1 Hz, 1H) 5.74 (dd, J=6.7, 2.2 Hz, J=9.8, 2.2 Hz, 1H), 1.27-1.21 (m, 1H), 0.69-0.65 (m, 2H); 0.55-0.53 (m, 2H): 13C NMR (100 MHz, CDCl3) (167.7, 162.9, 158.6, 155.6, 133.8, 132.4, 131.7, 128.9, 127.6, 126.4, 125.9, 125.5, 124.1, 122.8, 115.2, 114.5, 101.7, 63.5, 53.6, 34.8, 31.7, 11.3, 7.7, 7.2; HRMS (FAB+) calcd for C24H21N2O3S 417.1267, obsd 417.1289.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([CH2:8][OH:9])[CH2:6][C@H:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4]1)[CH3:2].I([O-])(=O)(=O)=[O:17].[Na+]>CC#N.O.CCOC(C)=O.O.[Ru](Cl)(Cl)Cl>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C@H:5]1[CH2:6][C@H:7]([C:8]([OH:17])=[O:9])[C@H:3]([CH2:1][CH3:2])[CH2:4]1)[CH3:15]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(=O)C[C@@H]1C[C@@H](CC)[C@@H](CO)C1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H]1C[C@@H](CC)[C@@H](C(=O)O)C1
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a solution of ethyl 2-((1R,3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentyl)acetate (0.140 g, 0.653 mmol) in MeCN (2 mL), water (4 mL) and EtOAc (2 mL) was added sodium periodate (0.349 g, 1.633 mmol) followed by ruthenium(III) chloride hydrate (0.0015 g, 0.0065 mmol). After about 2 h, the reaction mixture was diluted with EtOAc (20 mL) and water (10 mL). The organic layer was separated and extracted with aqueous NaOH (1 N, 10 mL). The pH of the aqueous layer was adjusted to about 1 with concd HCl and extracted with EtOAc (20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concd in vacuo to provide (1S,2R,4R)-4-(2-ethoxy-2-oxoethyl)-2-ethylcyclopentanecarboxylic acid (0.150 g, 101%) as an oil which was used without further purification. 1H NMR (600 MHz, CDCl3) δ 10.68 (bs, 1H), 4.13 (q, J=7.1 hz, 2H), 2.99-2.95 (m, 1H), 2.76-2.64 (m, 1H), 2.31 (d, J=7.6 Hz, 2H), 2.24 (ddd, J=13.5, 8.7, 4.8 Hz, 1H), 2.18-2.11 (m, 1H), 1.81 (dt, J=13.0, 8.4 Hz, 1H), 1.55-1.45 (m, 3H), 1.31-1.27 (m, 1H), 1.25 (t, J=7.0 Hz, 3H), (t, J=7.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:10][C:11]1([CH3:35])[CH2:20][CH2:19][C:18]2[N:17]=[CH:16][N:15]=[C:14]([N:21]3[CH2:27][C:26]4[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:25]=4[O:24][CH2:23][CH2:22]3)[C:13]=2[CH2:12]1>>[CH3:10][C:11]1([CH3:35])[CH2:20][CH2:19][C:18]2[N:17]=[CH:16][N:15]=[C:14]([N:21]3[CH2:27][C:26]4[CH:28]=[C:29]([C:2]5[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=5)[CH:30]=[CH:31][C:25]=4[O:24][CH2:23][CH2:22]3)[C:13]=2[CH2:12]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: COc1cncc(Br)c1
Product: COc1cncc(-c2ccc3c(c2)CN(c2ncnc4c2CC(C)(C)CC4)CCO3)c1

Procedure:
Prepared according to the method of example 5 by using 3-bromo-5-methoxypyridine and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, DMSO-d6): 8.49 (s, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 7.75 (s, 1H), 7.59 (m, 2H), 7.07 (d, 1H), 4.65 (s, 2H), 4.35 (m, 2H), 3.90 (s, 3H), 3.84 (m, 2H), 2.67 (t, 2H), 2.44 (s, 2H), 1.57 (t, 2H), 0.82 (s, 6H); MS (EI) for C25H28N4O2: 417 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([CH:20]=[O:21])=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=CC)C.[OH:28]P([O-])(O)=O.[K+].Cl([O-])=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([C:20]([OH:28])=[O:21])=[C:9]1[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=P([O-])(O)O
Reactant: Cc1c(C=O)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Agent: CC=C(C)C
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC#N
Product: Cc1c(C(=O)O)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 101.1 %

Procedure:
To a suspension of 1-benzyl-2-methyl-5-nitro-1H-indole-3-carboxaldehyde (Compound 50, 150 mg, 0.51 mmol) in acetonitrile (6 ml), tert-butanol (6 ml) and H2O (6 ml) was added 2-methyl-2-butene (4 ml), potassium phosphate monobasic (1.4 g, 10.2 mmol), sodium chlorite (80%, 1.15 g, 10.2 mmol). The mixture was stirred at room temperature for 20 h, more potassium phosphate monobasic (0.35 g, 2.6 mmol) and sodium chlorite (80%, 0.29 g, 2.6 mmol) were added and stirred at room temperature for 24 h. The solvent was removed under reduced pressure. The residue solid was washed with H2O (×3) and filtered, dissolved in acetone and filtered to yield 1-benzyl-2-methyl-5-nitro-1H-indole-3-carboxylic acid (Compound 51) as a yellow powder (160 mg, 100%). 1H-NMR (ACETONE-d6) δ 2.83 (s, 3 H), 5.68 (s, 2 H), 7.06-7.15 (m, 2 H), 7.25-7.41 (m, 3 H), 7.68 (d, J=9.1 Hz, 1 H), 8.10 (dd, J =9.1, 2.3 Hz, 1 H), 9.11 (d, J=2.3 Hz, 1 H).
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:25](N1C=CN=C1)([N:27]1[CH:31]=[CH:30]N=[CH:28]1)=O.CCOC(C)=O.CCCCCC.CN(CCO)C>CC#N.CN(C)C1C=CN=CC=1>[C:1]([O:24][CH2:30][CH2:31][N:27]([CH3:28])[CH3:25])(=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)O
Agent: CN(C)CCO
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)OCCN(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a solution of docosahexaenoic acid (0.986 g, 3.0 mmol) in CH3CN (6.0 mL) was added carbonyldiimidazole (0.535 g, 3.3 mmol) in one portion at 0° C. The mixture was allowed to warm to room temperature and stirred at room temperature for 30 min. TLC showed a complete reaction (1:1 EtOAc/hexane). N,N-dimethylaminoethanol (0.89 g, 10.0 mmol) was added dropwise followed by addition of 4-dimethylaminopyridine (0.073 g, 0.60 mmol) The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation and the residue was purified on silica gel using 72% EtOAc/hexane, 80% EtOAC/hexane and 100% EtOAc with 0.5% MeOH each to provide the product, 2-dimethylaminoethyl docosahexaenoate (1.098 g, 92%), as a light yellow oil. The product was stored at -20° C. with small amount of β-carotene.