Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:12]=[CH:11][C:10]([O:13][C@@H:14]3[CH2:18][CH2:17][NH:16][C:15]3=[O:19])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][C:27]2=[O:30])=[C:23]([F:31])[CH:22]=1>O1CCOCC1>[CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:12]=[CH:11][C:10]([O:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:21]4[CH:29]=[C:28]5[C:24](=[C:23]([F:31])[CH:22]=4)[CH2:25][CH2:26][C:27]5=[O:30])[C:15]3=[O:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=C1NCC[C@H]1Oc1ccc(OCCC2CC2)nc1
Reactant: O=C1CCc2c(F)cc(Br)cc21
Solvent: C1COCCO1
Product: O=C1CCc2c(F)cc(N3CC[C@@H](Oc4ccc(OCCC5CC5)nc4)C3=O)cc21
Temperature: 85 °C

Procedure:
A mixture of (R)-3-[6-(2-cyclopropyl-ethoxy)-pyridin-3-yloxy]-pyrrolidin-2-one (100 mg), 6-bromo-4-fluoro-2,3-dihydro-1H-inden-1-one (87 mg) and 1,4-dioxane (2 mL) was purged with argon. N,N′-Dimethyl-ethylene-diamine (336 mg), cesium carbonate (248 mg) and copper(I) iodide (7 mg) were added. The mixture was heated to 85° C. for 3 hours. After cooling to r.t. the mixture was filtered and the filtrate purified by preparative HPLC to provide Example 1-08. 1H-NMR (400 MHz, DMSO) 67.99 (1H, dd, J=11.3, 1.8 Hz), 7.97 (1H, d, J=3.1 Hz), 7.77 (1H, d, J=1.8 Hz), 7.53 (1H, dd, J=9.0, 3.1 Hz), 6.77 (1H, d, J=9.0 Hz), 5.22 (1H, dd, J=8.3, 8.3 Hz), 4.24 (2H, t, J=6.8 Hz), 3.96 (1H, m), 3.86 (1H, m), 3.10 (2H, m), 2.72 (2H, m), 2.69 (1H, m), 2.14 (1H, m), 1.60 (2H, dt, J=6.8, 6.8 Hz), 0.80 (1H, m), 0.42 (2H, m), 0.10 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.N1CCCCC1>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:13]3[NH:12][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1Cc2ccc(Br)cc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Br)ccc2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
A solution of 6-bromo-1,3-dihydro-2H-indol-2-one (100 mg, 0.47 mmol), 1H-pyrrole-2-carbaldehyde (49.2 mg, 0.52 mmol), and piperidine (0.02 mL, 0.2 mmol) in methanol (3 mL) was stirred at 65° C. for 2 hours, cooled to room temperature, and filtered. The filter cake was washed with hexanes to provide the desired product (65 mg, 48%). MS (DCI/NH3) m/z 290 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][CH2:12]OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl>CCN(CC)CC>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: COCOC
Reactant: Oc1ccc(Br)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1ccc(Br)cc1Br
Yield: 85.5 %

Procedure:
Into a 500-mL round bottom flask equipped with a soxlet and a condensor were placed 2,4-dibromophenol (32.0 g, 0.13 mole), dimethoxymethane (200 mL, 2.26 mole), p-toluenesulfonic acid monohydrate (2.24 g, 12.0 mmol) and CH2Cl2 (200 mL). The soxlet extractor was filled with 3 A and 4 A molecular sieves. The reaction mixture was heated to reflux for 24 h after which time the soxlet extractor was filled with freshly activated sieves. The reaction mixture was heated to reflux for another 24 h. After this period of time, Et3N (10 mL) was added. The reaction mixture was stirred for 5 mn, and concentrated to dryness. The residue was dissolved in CH2Cl2 (400 mL) and the resulting solution was washed with 5% NaOH (400 mL), H2O (400 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc; 6:1) to yield 2,4-Dibromo-1-methoxymethoxybenzene [9](32.9 g, 88%) as a light yellow oil; 1H NMR (CDCl3, 300 MHz) δ7.67 [s, ArH(3)], 7.33 [d, J=8.7 Hz, ArH(5)], 7.02 [d, J=8.7 Hz, ArH(6)], 5.21 [s, OCH2OCH3 ], and 3.49 [s, OCH3 ]; LRMS (EI) m/z 298 (M+, 3), 296 (M+, 5), 294 (M+, 3), and 45 (100)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])N=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:27]=[CH:26][C:25]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][N:23]=2)=[CH:18][C:17]=1[F:35].[H-].[Na+].Br[CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42].[CH2:44]1COCC1>>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C:6]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[CH:24][C:25]([N:28]([CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:26][N:27]=3)=[CH:18][C:17]=1[F:35])=[CH:7][CH:8]=[CH:44]2
Reactant: CC(C)CCBr
Reactant: COc1cc2nccc(Oc3ccc(-c4ncc(Nc5ccccc5)cn4)cc3F)c2cc1OC
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COc1cc2cccc(Oc3ccc(-c4ncc(N(CCC(C)C)c5ccccc5)cn4)cc3F)c2cc1OC
Temperature: 50 °C

Procedure:
In a 10 mL dry flask with stirring bar was placed {2-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-pyrimidin-5-yl}-phenyl-amine (Example 39, 0.030 g, 0.06 mmol) under N2. Anhydrous THF (1.5 mL) was added, followed by the addition of NaH (60% dispersion, 0.10 g, 2.5 mmol). The resulting yellow mixture was heated at 50° C. for 20 min, then cooled to RT. 1-Bromo-3-methylbutane (0.20 mL) was added, and the resulting yellow mixture was heated at 50° C. for 4.5 h. The reaction was quenched with NH4Cl (half sat.) and the slurry was filtered, then washed with H2O. The brown solid was dissolved in CH2Cl2 and was purified on silica (50%-100% EtOAc in hexanes) to afford the title compound as a yellow solid. MS (ESI pos. ion) m/z: 539. Calc'd for C32H31FN4O3: 538.24.
Reaction SMILES: C(C1N([CH2:14][C:15]2[CH:32]=[CH:31][C:18]3/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH2:22][CH2:23][C:17]=3[CH:16]=2)C2=NC(C)=CC(C)=C2N=1)C.C(N(CC)CC)C.CS([Cl:44])(=O)=O.[Cl-].[Li+]>C1COCC1.C(OCC)(=O)C>[Cl:44][CH2:14][C:15]1[CH:32]=[CH:31][C:18]2/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[CH2:22][CH2:23][C:17]=2[CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#C/C=C1\c2ccccc2CCc2cc(CCl)ccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
(E)-(2-Hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile (JP-B-2526005; 2.61 g, 10.0 mmol) was dissolved in THF (26 mL), triethylamine (2.09 mL, 15.0 mmol), methanesulfonyl chloride (1.16 mL, 15.0 mmol) and lithium chloride (0.636 g, 15.0 mmol) were added, and the mixture was stirred at 50° C. for 2 hr. Ethyl acetate was added to the mixture, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Isopropyl ether (30 mL) was added to the obtained residue, and the mixture was filtered to give the title compound (2.59 g, 93%).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:35])[C:12]([CH3:34])([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[CH:15]=1)[CH3:13])=[O:5])C.[OH-].[Na+]>CO.O>[CH3:34][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[CH:15]=1)([CH3:13])[C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[C:4]([OH:5])=[O:3])=[O:35]
Reactant: CCOC(=O)[C@H]1CCCN1C(=O)C(C)(C)c1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(C(C)(C)C(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 16 h

Procedure:
To a stirred solution of title D compound, (R)-{2-methyl-2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionyl}-pyrrolidine-2-carboxylic acid ethyl ester (0.47 g, 0.99 mmol) in methanol (25 mL) is added sodium hydroxide (0.16 g, 3.95 mmol) in water (5 mL) at RT. The reaction mixture is stirred for 16 h. The reaction mixture is concentrated at reduced pressure, poured into water, the aqueous layer is separated, washed with ethyl acetate twice, acidified with concentrated HCl and extracted three times with ethyl acetate. The combined ethyl acetate extract is dried and concentrated to give (R)-1-{2-methyl-2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionyl}-pyrrolidine-2-carboxylic acid as a white solid: MS m/z 447.3 [M−1]−.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].O=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S([CH2:33][N+:34]#[C-:35])(=O)=O)=CC=1>C(O)C>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([N:7]2[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:35][N:34]=[CH:33]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(N)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cncn1-c1ccc(CC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Ethylaniline (2.08 mL, 16.6 mmol) and ethyl oxoacetate (50% solution in toluene, 3.30 mL, 16.6 mmol) were combined in ethanol (40 mL) and stirred at room temperature for 3 hours. Potassium carbonate (5.75 g, 41.6 mmol) and isocyanomethyl 4-methylphenyl sulfone (98%, 3.98 g, 20.0 mmol) were added and the reaction mixture was heated to reflux for 3 hours. After cooling to room temperature, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo, dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 0% to 33% ethyl acetate in heptane) afforded the product as a clear brown oil that solidified upon standing. Yield: 3.03 g, 12.4 mmol, 75%. LCMS m/z 245.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.24 (t, J=7.1 Hz, 3H), 1.29 (t, J=7.6 Hz, 3H), 2.73 (q, J=7.6 Hz, 2H), 4.21 (q, J=7.1 Hz, 2H), 7.27 (br AB quartet, JAB=8.6 Hz, ΔνAB=24 Hz, 4H), 7.66 (d, J=1.1 Hz, 1H), 7.85 (d, J=1.1 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]([C:8]([CH3:10])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-][CH2:12]C.[Na+].BrC[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:1][C:2]([CH3:12])([C:8]([CH3:10])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: CC[O-]
Reactant: CCOC(=O)CCCCCBr
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCCCCC(C)(C(C)=O)C(=O)OCC

Procedure:
A mixture of 25 g of ethyl 2-methylacetoacetate, 64 mL of a 21% sodium ethoxide solution in ethanol and 34 mL of ethyl 6-bromohexanoate is refluxed in 200 mL of ethanol overnight. The mixture is filtered and solvent is evaporated. The residue is partitioned between 1 M HCl and chloroform. The organic layer is dried over magnesium sulfate and purified on silica gel using 1:10 ethyl acetate/hexanes as eluant to yield 22 g of ethyl 2-(5-carbethoxypentyl)-2-methylacetoacetate.
Reaction SMILES: [Mg].II.Cl[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10].[CH:11]1([CH2:14][O:15][C:16]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:17]=2[C:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)=[O:19])[CH2:13][CH2:12]1>C1COCC1>[CH:11]1([CH2:14][O:15][C:16]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:17]=2[C@:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:21]2)([OH:19])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(F)c2OCC2CC2)C1
Reactant: COCCCCCl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1cccc(F)c1OCC1CC1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A flame dried 50 mL three-necked flask was charged with magnesium turnings (380 mg, 15.8 mmol) and a small crystal of iodine in THF (5 mL). The flask was evacuated and refilled with N2. Then a solution of 1-chloro-4-methoxybutane (1.6 g, 13.2 mmol) in THF (10 mL) was added dropwise slowly to the mixture. The reaction mixture was stirred under reflux for 2.5 h and most of the magnesium was consumed. The resulting Grignard reagent was used as follows. To another 100 mL three-necked flask was added (R)-tert-butyl 3-(2-(cyclopropylmethoxy)-3-fluorobenzoyl)piperidine-1-carboxylate (0.5 g, 1.32 mmol) and THF (10 mL). The flask was evacuated and refilled with N2. The mixture was cooled with a dry ice-acetone bath and the Grignard reagent (250 mL) was added. The reaction mixture was allowed to warm slowly to rt while stirring overnight. The mixture was quenched with sat'd aq NH4Cl (10 mL), extracted with EtOAc (3×), and the combined organic layers were dried over Na2SO4. Evaporation of the solvent and purification by flash column chromatography, eluting with 10% EtOAc/PE afforded (R)-tert-butyl 3-((S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (560 mg, 91%). 1H NMR (400 MHz, CDCl3): 0.35 (m, 2H), 0.63 (m, 2H), 1.05 (m, 1H), 1.43 (s, 9H), 1.55-1.20 (m, 9H), 1.85 (m, 1H), 2.55 (m, 1H), 2.67 (m, 1H), 3.27 (s, 3H), 3.33 (m, 2H), 3.85 (m, 1H), 4.05 (m, 2H), 4.25 (m, 1H), 6.97 (m, 3H). MS (E/Z): 466 (M+H+).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:10].Cl[C:25]1[N:30]=[C:29]([CH3:31])[C:28]([F:32])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:32][C:28]1[C:29]([CH3:31])=[N:30][C:25]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=4[N:19]4[N:20]=[CH:21][CH:22]=[N:23]4)=[O:10])[CH2:3]3)[CH2:6]2)=[N:26][CH:27]=1
Reactant: Cc1nc(Cl)ncc1F
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(-n2nccn2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C(=O)N2CC3CN(c4ncc(F)c(C)n4)CC3C2)c(-n2nccn2)c1

Procedure:
(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Example 288—step B, 33 mg, 0.10 mmol), 2-chloro-5-fluoro-4-methylpyrimidine (Intermediate 55, 15 mg, 0.10 mmol) and DIPEA (54 μL, 0.3 mmol) in ACN (1 mL) were heated in a microwave reactor for 2 h at 200° C. Then the reaction mixture was concentrated and purified via prep HPLC (Agilent, basic) gave the title compound as a clear oil. MS (ESI) mass calcd. C21H22FN7O2, 423.45; m/z found 424.2 [M+H]+. 1H NMR (CDCl3): 8.06 (d, J=1.8 Hz, 1H), 7.74 (s, 2H), 7.50 (d, J=5.8 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 6.95 (dd, J=8.5, 2.5 Hz, 1H), 3.93-3.76 (m, 5H), 3.71-3.59 (m, 2H), 3.53 (dd, J=11.4, 5.2 Hz, 1H), 3.44-3.30 (m, 2H), 3.07-2.87 (m, 3H), 2.37 (t, J=4.9 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28]O)=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:28][CH2:27][O:26][C:25]1[CH:30]=[CH:31][C:22]([O:21][CH2:20][CH2:19][OH:18])=[CH:23][CH:24]=1)=[O:15])[CH:7]=[CH:6]2
Reactant: OCCOc1ccc(OCCO)cc1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2cc([C@H](C)C(=O)OCCOc3ccc(OCCO)cc3)ccc2c1
Yield: 79.1 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.27 g, 18.5 mmol), hydroquinone bis(2-hydroxyethyl) ether (10.6 g, 53.3 mmol), N,N-dimethylaminopyridine (DMAP, 2.71 g, 22.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.34 g, 48.7 mmol) and NEt3 (13 mL, 93.3 mmol) in DMF (100 mL) was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness under vacuum and the residue was partitioned between HCl (3N, 100 mL) and CH2Cl2 (200 mL). The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. The product was separated by silica gel column chromatography eluting with EtOAc/hexane (1:1, Rf=0.15) and then recrystalized from ethyl ether and hexane to give the title compound as a white solid (6.01 g, 31% yield). Mp 76-78° C. 1H NMR (CDCl3) δ 7.7-7.64 (m, 3H), 7.42-7.38 (m, 1H), 7.15-7.08 (m, 2H), 6.74-6.72 (m 4H), 4.45-4.36 (m, 2H), 4.1-3.85 (m, 7H), 3.90 (s, 3H), 2.13 (br. t, 1H), 1.58 (d, J=7.2 Hz, 3H). 13C NMR (CDCl3) δ 174.6, 157.5, 153.0, 152.8, 135.4, 133.6, 129.2, 128.8, 127.1, 126.1, 125.9, 118.8, 115.7, 115.3, 105.5, 69.7, 66.6, 63.1, 61.4, 55.2, 45.2, 18.4. MS(API) m/z 428 (M+NH4)+. Anal. calcd. for C24H26O6: C, 70.23; H, 6.38. Found: C, 70.01; H, 6.39.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:12](CC3C=CC(OC)=CC=3)[CH2:11][CH2:10][CH2:9][C:8]([C:22]([O:24][CH3:25])=[O:23])=[CH:7][C:6]=2[CH:26]=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][CH2:11][CH2:10][CH2:9][C:8]([C:22]([O:24][CH3:25])=[O:23])=[CH:7][C:6]=2[CH:26]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2ccc(OC)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(Br)ccc2NCCC1
Temperature: 65 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a solution of methyl 8-bromo-1-(4-methoxybenzyl)-1,2,3,4-terahydro-1-benzoazocine-5-carboxylate (10.0 g), in toluene (50 ml) was added trifluoroacetic acid (50 ml), and the mixture was stirred at 65° C. for 2 hours. After distilling off the solvent under reduced pressure, water was added at 0° C. and the reaction mixture was neutralized with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and saturated brine, after which it was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=9:1). The resulting solid was washed with hexane to give methyl 8-bromo-1,2,3,4-terahydro-1-benzoazocine-5-carboxylate (6.59 g) as yellow crystals.
Reaction SMILES: [C:1]([C:3]1(O[Si](C)(C)C)[CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:9][C:8]2[N:7]([CH3:17])[N:6]=[C:5]([CH3:18])[C:4]1=2)#[N:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([C:3]1[C:4]2[C:5]([CH3:18])=[N:6][N:7]([CH3:17])[C:8]=2[CH2:9][CH2:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:2]
Reactant: CCOC(=O)C1CCc2c(c(C)nn2C)C1(C#N)O[Si](C)(C)C
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C1=C(C#N)c2c(C)nn(C)c2CC1
Reaction time: 5 h
Yield: 53.1 %

Procedure:
A solution of ethyl 4-cyano-4,5,6,7-tetrahydro-1,3-dimethyl-4-(trimethylsilyloxy)-1H-indazole-5-carboxylate (28.1 g, 0.119 mol) in pyridine is mixed with phosphorus oxychloride (43.0 mL, 0.461 mol), stirred for 5 hours at reflux temperature and concentrated in vacuo. The resultant black residue is diluted with ethyl acetate and water and treated with sodium bicarbonate to pH 6. The phases are separated, the organic phase is set aside, and the aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with aqueous sodium bicarbonate and water, dried (MgSO4) and concentrated in vacuo to give a black residue. The residue is triturated under ethyl acetate to give the title product as a tan solid (15.5 g, 52.9%), identified by 1HNMR and IR spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[C].[Pd].C1COCC1.CCO>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(N)c(O)c1
Reaction time: 1 h

Procedure:
To the flask was added THF/EtOH (1:1, 30 mL) followed by Ethyl 2-(3-hydroxy-4-nitrophenyl)propanoate (900 mg, 3.76 mmol) and 10% palladium carbon (93 mg) at room temperature. The reaction mixture was hydrogenated and stirred for 1 hrs at 46 psi then filtered through celite bed, and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:2) as eluant.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][NH:10][C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl[C:22]([O:24][CH3:25])=[O:23]>O1CCCC1>[CH3:8][O:9][N:10]([C:22]([O:24][CH3:25])=[O:23])[C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)Cl
Reactant: CCCCCCCCC(=O)NOC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)N(OC)C(=O)OC
Temperature: 25 °C

Procedure:
A 100 mL round-bottom flask equipped with a magnetic stir bar, argon inlet and pressure equalizing addition funnel is charged with tetrahydrofuran (14.0 mL), triethylamine (2.13 g, 1.5 eq) and N-methoxynonanamide (1.96 g, 1 eq). The reaction is cooled in an ice bath and methyl chloroformate (1.88 g, 1.4 eq) is added dropwise. The reaction is allowed to warm to room temperature overnight. The tetrahydrofuran is removed under vacuum and the residue is diluted with methylene chloride (25 mL). The reaction is washed with 0.1 M hydrochloric acid solution (1×20 mL), saturated aqueous sodium bicarbonate (3×20 mL)and brine (1×20 mL). The organic layer is dried over sodium sulfate, filtered and concentrated under vacuum.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[C@H:12]2[O:13][CH2:14][C@@H:15]([OH:16])[C@H:11]2[O:10][CH2:9]1.[N+:17]([O:20][C@H:21]([CH2:28][O:29][N+:30]([O-:32])=[O:31])[CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])([O-:19])=[O:18].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[C@H:12]2[O:13][CH2:14][C@@H:15]([O:16][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C@H:21]([O:20][N+:17]([O-:19])=[O:18])[CH2:28][O:29][N+:30]([O-:32])=[O:31])[C@H:11]2[O:10][CH2:9]1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OC1CCCCO1
Reactant: O=C(O)CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OC1CCCCO1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
To a solution of (3R,3aR,6R,6aR)-6-(tetrahydro-2H-pyran-2-yloxy)-hexahydrofuro[3,2-b]furan-3-ol (2.96 g, 12.9 mmol) in DCM (40.8 mL) a solution of the crude (S)-5,6-di(nitrooxy)hexanoic acid (3.06 g, 12.85 mmol) (Step D) in DCM (9.15 mL) was added followed by EDAC (3.69 g, 19.28 mmol) and 4-dimethylaminopyridine (175 mg, 1.28 mmol). The reaction mixture was stirred at rt for 16.5 hrs. The solvent was removed under reduced pressure. The crude residue was purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 10 to 60%), affording the title product as pale yellow oil.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH3:24][OH:25]>>[CH3:24][O:25][C:3]1([CH2:2][OH:1])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: CO
Reactant: C1CC2(CCO1)CO2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: COC1(CO)CCOCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1,6-dioxaspiro[2.5]octane (600 mg, 5.26 mmol) in methanol (10 ml) at 0° C. (ice-water) under nitrogen was added camphorsulfonic acid (50 mg, 0.21 mmol) and the resulting mixture was stirred at about 0° C. for 2 hours. The mixture was concentrated in vacuo and the crude residue was used in the next step without purification. The desired product was obtained as a light yellow oil (707 mg).