Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14]C(=O)C=CC1C=CC=CC=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[C:25](=[O:28])([O-])[O-].[K+].[K+]>CC(CC)=O>[OH:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:1]([CH2:2][C:25](=[O:28])[CH:2]=[CH:1][C:4]1[CH:5]=[CH:6][CH:11]=[CH:12][CH:13]=1)=[O:3]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(OC(=O)C=Cc2ccccc2)c(C(C)=O)c1
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(O)c(C(=O)CC(=O)C=Cc2ccccc2)c1
Yield: 135.1 %

Procedure:
Methyl 3-acetyl-4-cinnamoyloxy-benzoate (46.2 g; m.p. 97°-99° C) was dissolved in methyl-ethyl-ketone (350 ml). After addition of anhydrous potassium carbonate (37 g), the mixture was refluxed for 6 hours. After cooling, dilution with petroleum ether (500 ml) and filtration, the collected precipitate was dissolved in water, acidified with acetic acid, extracted with ethylacetate. The organic phase was washed with potassium carbonate 5% and water, then evaporated to dryness. After crystallisation from methanol, (2-hydroxy-5-carbomethoxy-benzoyl)-cinnamoyl-methane (31.2 g; m.p. 138°-140° C) was obtained, which was refluxed for 15 minutes with formic acid 99% (140 ml). After cooling, dilution with water (l. 1) and filtration, the collected precipitate was crystallised from acetone to obtain 6-carbomethoxy-2-(β-phenyl-vinyl)-chromone (27.8 g; m.p. 175°-177° C) which was hydrolysed with a solution of potassium hydroxide 1% (600 ml) in ethanol 95% at reflux temperature for 45 minutes. After cooling, acidification with acetic acid, concentration under vacuum and dilution with water, the precipitate was collected and washed with water to give, after crystallisation from acetone, 6-carboxy-2-(β-phenyl-vinyl)-chromone (16.1 g; m.p. 273°-275° C).
Reaction SMILES: C(CP(=O)(OCC)OCC)(=O)N.[F:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][C:21]2=O)=[CH:16][CH:15]=1.C(OP([CH2:33][C:34](=[O:39])[NH:35][CH:36]1[CH2:38][CH2:37]1)(=O)OCC)C>>[CH:36]1([NH:35][C:34](=[O:39])/[CH:33]=[C:21]2\[CH2:20][CH2:19][CH2:18][C:17]3[C:22]\2=[CH:23][C:14]([F:13])=[CH:15][CH:16]=3)[CH2:38][CH2:37]1
Reactant: CCOP(=O)(CC(=O)NC1CC1)OCC
Reactant: O=C1CCCc2ccc(F)cc21
Agent: CCOP(=O)(CC(N)=O)OCC
Product: O=C(/C=C1\CCCc2ccc(F)cc21)NC1CC1
Yield: 35.7 %

Procedure:
This compound was prepared in an analogous manner to Example 27d with the replacement of 6-chloro-1-indanone and diethyl carbamoylmethylphosphonate with 7-fluoro-1-tetralone (7.76 g, 0.05 mol) and diethyl(cyclopropylcarbamoyl)methylphosphonate (11.1 g, 0.05 mol). Chromatography on Silica gel using ethyl acetate:hexanes (1:2) as eluent gave 4.38 g (37%) of (E)-N-Cyclopropyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide, m.p., 122.8°-123.3° C.; NMR (DMSO-d6): d 8.00 (d, J=4.0 Hz, 1H), 7.32 (dd, J=11.2 Hz, 1H), 7.04-7.23 (m, 2H), 6.33 (s, 1H), 3.06 (m,2H), 2.69 (m, 3H), 1.70 (m, 2H), 0.66 (m, 2H), 0.40 (m, 2H); steady-state nOe: irradiation at 6.39 d, observed significant nOe at 7.32 d.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([N:35]5[CH2:36][CH2:37][N:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33][CH2:34]5)=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: CS(=O)(=O)N1CCN(C(=O)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 1-methanesulfonylpiperazine via General Procedure B. The product was purified via reverse phase HPLC to give 19.2 mg of 262. MS (Q1) 527.7 (M)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[O:47])[C@H:11]([CH:44]([CH3:46])[CH3:45])[CH2:12][C@H:13]([OH:43])[C@@H:14]([NH:35]C(OC(C)(C)C)=O)[CH2:15][C@@H:16]([CH:32]([CH3:34])[CH3:33])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=2)[CH2:3][CH2:2]1.[ClH:48]>O1CCOCC1>[ClH:48].[ClH:48].[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[O:47])[C@H:11]([CH:44]([CH3:46])[CH3:45])[CH2:12][C@H:13]([OH:43])[C@@H:14]([NH2:35])[CH2:15][C@@H:16]([CH:32]([CH3:33])[CH3:34])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=2)[CH2:3][CH2:2]1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](C(=O)NCCN2CCOCC2)C(C)C)C(C)C)ccc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COCCCOc1cc(C[C@@H](C[C@H](N)[C@@H](O)C[C@H](C(=O)NCCN2CCOCC2)C(C)C)C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.09 g of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid N-(2-morpholinoethyl)amide are dissolved in 40 ml of 4N hydrochloric acid in dioxane at 0° C. and the solution is stirred at 0° C. for 2 hours. The reaction mixture is lyophilised and the title compound is obtained: Rf (dichloromethane/methanol=8:2)=0.27; HPLC Rt =9.52 minutes; HR FAB-MS (M+H)+ =566.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:10]3[C:15](=[O:16])[NH:14][C:12](=[O:13])[C:11]=3[C:17]3[NH:21][CH:20]=[N:19][CH:18]=3)=[CH:8][NH:9][C:4]2=[CH:3][CH:2]=1.[OH-].[Na+]>CC(=O)CC.CCOC(C)=O>[CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][C:8]3[N:21]4[C:17](=[CH:18][N:19]=[CH:20]4)[C:11]4[C:12]([NH:14][C:15](=[O:16])[C:10]=4[C:7]=3[C:5]=2[CH:6]=1)=[O:13]
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1cnc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: O=C1NC(=O)c2c1c1c3ccccc3[nH]c1n1cncc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.1 %

Procedure:
To a stirred solution of didemnimide A (32.6 mg, 0.117 mmol) in 2-butanone (7.0 mL) at rt is added sequentially 4Å molecular sieves (˜100 mg) and CUCl2 (79 mg, 0.59 mmol). The reaction mixture was stirred for 15 h at rt. The dark purple solution was treated with 10% solution of NaOH until the pH was neutral and diluted with EtOAc (30 mL). The phases were separated and the aqueous layer was extracted with EtOAc (5×10 mL). The combined organic extracts were washed with brine (10 mL), dried (MgSO4) and concentrated. Flash chromatography (15 g of silica gel, 15:1 CH2Cl2—MeOH) of the crude material afforded 19.5 mg (60%) of recovered didemnamide A as well as 12.3 mg (38%, 95% based on recovered starting material) of iso-granulatimide (5) as a purple solid.
Reaction SMILES: CCOC(C)=O.[CH3:7][C:8]1[CH:9]=[CH:10][C:11](S(O)(=O)=O)=[CH:12][CH:13]=1.O.[O:19]1C=CC=[N:20]1.[F-].[K+]>O>[O:19]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:7]=[N:20]1
Reactant: c1cnoc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc2oncc2c1
Temperature: 40 °C

Procedure:
To a 100 L cylindrical vessel with heating coils were charged EtOAc (20 L) and TsOH/H2O (2.304 kg, 12.11 mol), and the mixture was heated to 35-45° C. to dissolve. The acid solution was fed into the isoxazole batch with further distilling, maintaining a constant volume of 25 L. An additional 20 L of EtOAc was distilled to azeotropically dry the mixture. A slurry began to form, and it continued to thicken on addition and concentration. The final KF was 400 ppm water. The batch was heated to 60° C. and allowed to slowly cool to ambient temperature overnight.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Br[C:6]([CH3:11])([CH3:10])[C:7](Br)=[O:8].[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[CH3:19]>C(Cl)Cl>[CH3:10][CH:6]1[CH2:11][C:16]2[C:15](=[CH:14][C:13]([CH3:12])=[C:18]([CH3:19])[CH:17]=2)[C:7]1=[O:8]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Cc1ccccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc2c(cc1C)C(=O)C(C)C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 557 g (4.2 mol) AlCl3 in 500 ml of CH2Cl2 362 g (1.58 mol) of 2-bromo-2-methylpropanoyl bromide was added dropwise with vigorous stirring over 15 min at 0° C. This mixture was stirred for 45 min at this temperature; then, a solution of 167 g (1.58 mol) of o-xylene in 200 ml of CH2Cl2 was added dropwise. The mixture was slowly warmed to ambient temperature, stirred additionally overnight, and then poured onto 2000 cm3 of ice. The organic layer was separated, and the aqueous layer was extracted with 3×500 ml of CH2Cl2. The combined extract was dried over MgSO4 and evaporated to dryness. Fractional distillation gave a yellowish mixture of the title indanones, b.p. 143-148° C./7 mm Hg. This mixture was recrystallized from 800 ml of n-hexane. Crystals of 2,5,6-trimethylindan-1-one precipitated at −30° C. were filtered off, washed with 2×40 ml of cold n-hexane, and dried in vacuum. Yield 57.8 g (21%) of 2,5,6-trimethylindan-1-one.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:33]=1>O1CCCC1.C(OCC)(=O)C>[C:1]1([C:7]2[N:11]([S:38]([C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)(=[O:40])=[O:39])[CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccnc2)c1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
Under an argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (342 mg) was dissolved in absolute tetrahydrofuran (20 mL) and sodium hydride (60% in oil, 240 mg) was added while stirring at room temperature. After stirring at the same temperature for 15 min, 15-crown-5 (1.21 mL) was added, and the mixture was further stirred at the same temperature for 15 min. Pyridin-3-ylsulfonyl chloride hydrochloride (642 mg) was added, and the mixture was further stirred at the same temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give the title compound as a brown solid (yield 470 mg, 75%).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.[ClH:19]>C(Cl)Cl>[ClH:19].[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCN(CC)CCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 8.3 g (71 mmol) of N,N-diethylethylenediamine under nitrogen atmosphere add 6.6 g (47 mmol) of 4-fluoronitrobenzene. Stir the mixture at ambient temperature for 1 day and heat at 45° C. for 4 h. Upon completion of the reaction add 100 mL of CH2Cl2 and 100 mL 1M HCl. Separate the layers and add 50% sodium hydroxide to the aqueous layer until it is basic. Extract the aqueous layer with 2×100 mL CH2Cl2, dry the organics over anhydrous Na2SO4. Remove drying agent by filtration and remove solvent in vacuo. Dissolve the residue in methanolic HCl and remove the solvent in vacuo. Recrystallize the solid from EtOH to afford the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]3[CH:24]=[CH:25][N:26]=[C:16]23)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1>[Pd].CO>[N:26]1[CH:25]=[CH:24][N:17]2[C:18]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:16]=12
Reactant: c1ccc(COc2ccc(-n3c4ncccc4n4ccnc34)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc(-n2c3ncccc3n3ccnc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
A mixture of 9-[4-(benzyloxy)phenyl]-9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridine (2.48 g), 10% palladium on carbon (containing water (50%), 2.48 g), THF (50 mL) and methanol (50 ml) was stirred under a hydrogen atmosphere at room temperature for 1 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/THF) and recrystallized from ethanol to give the title compound (1.38 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[C:15]([C:19]1[O:23][N:22]=[C:21]([OH:24])[CH:20]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:15]([C:19]1[O:23][N:22]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=2)[C:21](=[O:24])[CH:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Reactant: CC(C)(C)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(=O)n(-c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)o1
Temperature: 0 °C
Reaction time: 6 h
Yield: 18.7 %

Procedure:
After mixing 15.0 g of 2-nitro-5-chlorobenzotrifluoride, 11.3 g of 5-t-butyl-3-hydroxyisoxazole, 11.0 g of potassium carbonate, and 80 ml of dimethyl sulfoxide, the reaction was performed for 6 hours at 100° C. After the reaction was over, the reaction mixture was poured into ice-water and then extracted with ethyl acetate. The organic phase formed was recovered and applied to silica gel column chromatography. The main product thus obtained was recrystallized from a mixture of methanol and water to provide 4.1 g of the desired compound with a yield of 18.7%. The melting point thereof was 125° C. to 126° C.
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.[Br-:10].[Na+]>CN(C=O)C>[Br:10][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1
Reactant: CC1(CCl)COC(=O)N1
Reactant: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(CBr)COC(=O)N1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
To a solution of 4-(chloromethyl)-4-methyloxazolidin-2-one (1.49 g, 9.96 mmol) in DMF (100 ml) was added sodium bromide (11.02 g, 107 mmol), and the suspension heated to 80° C. for 6 h. The suspension was concentrated in vacuo and the residue purified by flash chromatography (30% to 60% ethyl acetate in hexanes) to give the title compound as a white solid (1.33 g, 6.86 mmol, 66%). 1H NMR (CDCl3, 400 MHz) δ 1.54 (s, 3H), 3.47 (s, 2H), 4.14 (d, J=9.2 Hz, 1H), 4.35 (d, J=8.8 Hz, 1H), 6.24 (br s, 1H). LRMS (ESI/APCI): 194 [M+H]+.
Reaction SMILES: [C:1]1(=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[C:2]1=O.[CH2:15]([C:18]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:21]([NH2:22])=[C:20]([CH:28]([CH3:30])[CH3:29])[CH:19]=1)[CH:16]=[CH2:17]>C(O)(=O)C>[CH2:15]([C:18]1[CH:19]=[C:20]([CH:28]([CH3:30])[CH3:29])[C:21]([N:22]=[C:1]2[C:11]3[C:12]4[C:7]([CH:8]=[CH:9][CH:10]=3)=[CH:6][CH:5]=[CH:4][C:3]=4[C:2]2=[N:22][C:21]2[C:23]([CH:25]([CH3:26])[CH3:27])=[CH:24][C:18]([CH2:15][CH:16]=[CH2:17])=[CH:19][C:20]=2[CH:28]([CH3:30])[CH3:29])=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:24]=1)[CH:16]=[CH2:17]
Reactant: C=CCc1cc(C(C)C)c(N)c(C(C)C)c1
Reactant: O=C1C(=O)c2cccc3cccc1c23
Solvent: CC(=O)O
Product: C=CCc1cc(C(C)C)c(N=C2C(=Nc3c(C(C)C)cc(CC=C)cc3C(C)C)c3cccc4cccc2c34)c(C(C)C)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 1.00 g of acenaphthoquinone (5.5 mmol) and 4-allyl-2,6-diisopropylaniline (2.49 g, 11.1 mmol) in acetic acid (10 mL) was heated to reflux. After 1 h the mixture was cooled to room temperature, and the solid was filtered. The product was washed with acetic acid (5 mL), hexane (4×10 mL) and dried in vacuum, yielding 2.59 g as a yellow-golden solid (82%). 1H-NMR (400 MHz, CDCl3): δ 7.86 (d, 2H, Ho-Ace-C═N), 7.37 (t, 2H, Hm-Ace-C═N), 7.07 (s, 4H, H—Ar—N═C), 6.65 (d, 2H, Hp-Ace-C═N), 6.15 (m, 2H, CH═C), 5.15 (m, 4H, C═C—H), 3.50 (d, 4H, CH2—C═C), 3.00 (m, 4H, CH(Me)2),1.22 (d,12H, C(CH3)2), 0.96 (d, 12H, C(CH3)2). Anal. Calcd for C42H48N2: C, 86.86; H, 8.32; N, 4.82. Found: C, 87.75; H, 7.35; N, 4.82.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[N+:14]([C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:6][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)([O-:16])=[O:15]
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(CCN2CCCCC2)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a mixture of 0.49 g (2.0 mmol, 1.0 eq.) of 3-nitrophenethyl methanesulfonate (I-24) and 0.55 g (6.0 mmol, 3.0 eq.) of potassium carbonate in 20 mL of acetonitrile was added 0.4 mL (4.0 mmol, 2.0 eq.) of piperidine. The reaction mixture was stirred at reflux for 16 h. The reaction mixture was allowed to cool to room temperature, filtered and the solvent removed in vacuo. The resulting residue was purified by preparative TLC to provide 0.35 g (1.5 mmol, 75%) of 1-(3-nitrophenethyl)piperidine (I-25).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.O.NN.Cl>C(O)COCCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCCCC(=O)c1ccc(Br)cc1
Agent: Cl
Agent: NN
Solvent: OCCOCCO
Solvent: O
Product: CCCCCc1ccc(Br)cc1
Temperature: 200 °C

Procedure:
A mixture of compound 15 (24.87 g, 0.103 mol), hydrazine hydrate (15.45 g, 55% hydrazine content), and diethylene glycol (200 ml), was heated at 130° to 160° C. for 1 hour and water and the excess of hydrazine hydrate were distilled off. The solution was cooled to below 60° C. and potassium hydroxide pellets (17.37 g, 0.309 mol) were added and the solution heated at 200° C. for 2 hours (glc analysis revealed a complete reaction) cooled, and poured into crushed ice (200 g) and hydrochloric acid (200 ml, 6M). The product was extracted into ether (2×200 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was distilled to give a colourless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:16]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N+:4]([O-:16])[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cnc2c(c1)CCC2
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc(Br)cc2c1CCC2
Temperature: 0 °C

Procedure:
A solution of 3-bromo-6,7-dihydro-5H-[1]pyrindine (4 gm) and 3-chloroperoxybenzoic acid (2 equiv.) in CHCl3 was refluxed for 3 hours. An additional equivalent of 3-chloroperoxybenzoic acid was added to the reaction and heating was continued for another hour. The reaction was then cooled to 0° C., filtered, and extracted into CH2Cl2 from 1:1 saturated NaHCO3 /NaHCO3 (using caution), dried over Na2SO4, filtered, and evaporated. The residue was chromatographed on silica gel using 10:1 hexane/ethyl acetate to remove remaining starting material, ethyl acetate to remove 3-chloroperoxybenzoic acid residues, and then 10% MeOH/CH2Cl2 to elute the final compound. The product yield was 2 gm. 1H NMR(CDCl3): d 8.20 (s, 1 H), 7.25 (s, 1 H), 3.10 (m, 4 H), 2.20 (m, 2 H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([OH:20])[C@H:11]([NH:14][C:15](=[O:19])[CH:16]([Cl:18])[Cl:17])[CH2:12][F:13])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:21]([NH2:24])[C:22]#[CH:23]>C(O)(C)(C)C.O>[NH2:24][CH2:21][C:22]1[N:3]=[N:2][N:1]([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]([OH:20])[C@H:11]([NH:14][C:15](=[O:19])[CH:16]([Cl:17])[Cl:18])[CH2:12][F:13])=[CH:6][CH:5]=2)[CH:23]=1
Reactant: [N-]=[N+]=Nc1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: C#CCN
Solvent: CC(C)(C)O
Solvent: O
Product: NCc1cn(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.3 %

Procedure:
To the solution of ((N-[(1S,2R)-2-(4-Azido-phenyl)-1-fluoromethyl-2-hydroxy-ethyl]-2,2-dichloro-acetamide (150 mg, 0.465 mmol) in tert-butylalcohol: water (1:1, 3 mL) is added Na-ascorbate (12 mg, 0.060 mmol), CuSO4.5H2O (3 mg, 0.012 mmol), propargyl amine (26 mg, 0.472 mmol) resulting reaction mixture stirred at room temperature for 16 hours. Solvent is evaporated in vacuo to get the crude material purified by column chromatography eluting in 25-40% methanol in dichloromethane and washed with diethyl ether and dried under vacuum to afford the title compound (25 mg). 1H-NMR (400 MHz, DMSO-d6) δ: 3.84 (s, 2H), 4.23-4.29 (m, 1H), 4.30-4.34 (m, 0.5H), 4.42-4.46 (m, 0.5H), 4.58-4.61 (m, 0.5H), 4.69-4.73 (m, 0.5H), 4.93 (bs, 1H), 6.07 (d, 1H, J=4.28 Hz), 6.49 (s, 1H), 7.54 (d, 2H, J=8.48 Hz), 7.81 (d, 2H, J=8.52 Hz), 8.57 (s, 1H), 8.61 (d, 1H, J=5.6 Hz). LC-MS (m/z): [M+H]=376.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([NH:18][CH2:19][C@H:20]3[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:40][CH2:41][CH2:42][OH:43].O>CN(C=O)C>[OH:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([NH:18][CH2:19][C@H:20]3[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(-c3ccc(O)cc3)cc3nccnc23)C1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(-c3ccc(OCCCO)cc3)cc3nccnc23)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-tert-butyl 2-((7-(4-hydroxyphenyl)pyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate (115 mg, 0.26 mmol) in DMF (5 mL) was added Cs2CO3 (128 mg, 0.39 mmol) and 3-bromopropan-1-ol (55 mg, 0.39 mmol). The reaction was stirred at 80° C. for 0.5 hours. TLC and LC-Ms showed the reaction had completed and the reaction was poured into water, extracted with EA, washed with water and brine, dried and concentrated, purified on TLC (CH2Cl2:MeOH=30:1) to give yellow solid. MS (m/z): 496 (M+H)+
Reaction SMILES: [Li+].C[CH:3]([N-:5][CH:6]([CH3:8])[CH3:7])[CH3:4].COC(C#N)=O.[CH2:15]1[CH2:19]OC[CH2:16]1>>[NH:5]1[C:6]2[C:7](=[CH:16][CH:15]=[CH:19][CH:8]=2)[CH:4]=[CH:3]1
Reactant: CC(C)[N-]C(C)C
Reactant: C1CCOC1
Agent: COC(=O)C#N
Agent: [Li+]
Product: c1ccc2[nH]ccc2c1
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 1 (473 mg, 1.40 mmol) in THF (6.5 mL) at −78° C. was added dropwise a 1.8 M solution of LDA in THF (1.71 mL, 3.08 mmol) and the reaction stirred for 1 hour, then methylcyanoformate (0.244 mL, 3.08 mmol) added dropwise and the reaction was stirred for 1 hour. The reaction was quenched by the addition of satd NH4Cl (10 mL), the layers separated, and the aqueous extracted with Et2O (3×10 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on silica gel gradiently eluted with 20 to 30% EtOAc/hexanes to give 2 (153 mg, 28% yield) as an off-white solid. Rt=1.83 min using Phenomenex 30×4.6 5u column with flow rate of 5 mL/min over 2 min gradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%. [M+H]=396.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:23]3[C:19](=[CH:20][CH:21]=[N:22]3)[N:18]=[C:17]3[C:13]=2[CH2:14][O:15][CH2:16]3)=[CH:8][CH:7]=1.[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>>[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:23]3[C:19](=[CH:20][CH:21]=[N:22]3)[N:18]=[C:17]3[C:13]=2[CH2:14][O:15][CH2:16]3)=[CH:8][CH:7]=1
Reactant: CC1CCCN1
Reactant: ClCCCOc1ccc(-c2c3c(nc4ccnn24)COC3)cc1
Product: CC1CCCN1CCCOc1ccc(-c2c3c(nc4ccnn24)COC3)cc1

Procedure:
Using the method described for the preparation of 10-{4-[3-(2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[t]indene, the reaction of 8-[4-(3-Chloro-propoxy)-phenyl]-5H,7H-6-oxa-1,4,8a-triaza-s-indacene and 2-methyl-pyrrolidine provided compound.