Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7]I.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][C:15]([CH3:19])=[N:16]2)=[C:12]([Cl:20])[N:11]=1.O>C1COCC1>[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[C:15]([CH3:19])[N:16]2[CH3:7])=[C:12]([Cl:20])[N:11]=1
Reactant: CI
Reactant: Cc1nc2nc(Cl)nc(Cl)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(Cl)nc(Cl)nc2n1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Potassium carbonate (442 mg) and methyl iodide (0.17 mL) were added to a solution of 2,6-dichloro-8-methyl-7H-purine (500 mg) in THF (5 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 hours. After the reaction mixture was ice-cooled, water was added thereto, extraction thereof was performed using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=9:1 to 8:2), whereby 2,6-dichloro-8,9-dimethyl-9H-purine (310 mg) was obtained as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCBr)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
1,2-Dibromoethane (30 mL, 0.35 moles) was added to a mixture of 4-hydroxy-1-naphthaldehyde (6 g, 35 mmoles) and potassium carbonate (24 g, 175 mmoles) in DMF (110 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3×300 mL). The combined organic phases were washed with saturated sodium chloride (300 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:1) to afford 8.5 g (88%) of 4-(2-bromoethoxy)-1-naphthaldehyde as a solid. M.p.: 83-84° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:19][CH:20]1[CH2:22][NH:21]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([C:16]([N:21]3[CH2:22][CH:20]3[CH3:19])=[O:18])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(C(=O)O)o2)c(C)[nH]c1=O
Reactant: CC1CN1
Product: CCc1cc(-c2ccc(C(=O)N3CC3C)o2)c(C)[nH]c1=O
Yield: 81 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-carboxylic acid and 2-methylaziridine to give the title compound (81% yield). LC/MS: RT 2.02 min; m/e 287 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH:15]=O>>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(F)c(Br)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-bromo-4-fluorobenzaldehyde in an analogous manner to that described in Example 1 gave 9-(3-bromo-4-fluorophenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from absolute ethanol gave a pale yellow crystalline solid of melting point 260° C. (decomposition).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.Cl.[CH2:19]([NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[C:25]([CH3:35])[CH:24]=1)[CH3:20].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH2:19]([NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:33][CH2:34]2)=[C:25]([CH3:35])[CH:24]=1)[CH3:20]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(C)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(C)c1
Temperature: 90 °C
Yield: 35.4 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.429 mmol), N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide hydrochloride (133 mg, 0.469 mmol), (cyanomethyl)trimethylphosphonium iodide (167 mg, 0.686 mmol) and N,N-diisopropylethylamine (374 μl, 2.143 mmol) were suspended in Propiononitrile (Volume: 1287 μl) and heated in a closed vial at 90° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature and purified using HPLC (NH4HCO3 buffered, 20-70% ACN in water). The fractions were concentrated in vacuo and the resulting solid was slurried with hot MeCN (5 mL), cooled to ambient temperature, filtered off, washed with water (2 mL) and dried in vacuum to afford (S)—N-ethyl-3-methyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (70.3 mg, 0.152 mmol, 35.4% yield) as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.20 Hz, 3H) 1.33-1.57 (m, 3H) 1.64 (d, J=12.13 Hz, 1H) 1.85 (d, J=11.37 Hz, 1H) 2.04 (d, J=12.13 Hz, 1H) 2.26 (s, 3H) 2.52-2.70 (m, 5H) 2.87 (br. s., 4H) 3.19-3.29 (m, 2H) 3.37-3.43 (m, 2H) 3.84 (dd, J=11.49, 2.65 Hz, 1H) 4.50 (d, J=12.88 Hz, 1H) 6.98 (d, J=1.52 Hz, 1H) 7.01 (d, J=8.34 Hz, 1H) 7.62 (d, J=8.59 Hz, 1H) 7.65 (dd, J=9.35, 1.26 Hz, 2H) 8.26 (t, J=5.43 Hz, 1H) 10.49 (s, 1H); [M+H] calc'd for C26H34N6O2, 463; found, 463.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:22])[CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCCN1CCOCC1
Reactant: N#Cc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Yield: 56.7 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-6-cyano-7-hydroxyquinoline (1 95 mg, 0.6 mmol), 4-(3-chloropropyl)morpholine (124 mg, 0.76 mol), (J. Amer. Chem. Soc. 1945, 67, 736), potassium carbonate (172 mg, 1.2 mmol) and DMF (5 ml) was heated at 100° C. for 6 hours. The mixture was cooled to ambient temperature, and was partitioned between water and methylene chloride. The organic layer was dried (MgSO4), insoluble materials were removed by filtration and silica (2 g) was added to the filtrate. The solvent was removed by evaporation and the powder obtained was purified by flash chromatography eluting with methylene chloride/methanol/ammonia (100/2/0.5 increasing to 100/20/1). Removal of the volatiles by evaporation gave an oil which was triturated with ether, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-cyano-7-(3-morpholinopropoxy)quinoline (150 mg, 55%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][O:15]3)[CH:11]=[C:10]([C:17]([NH:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(O)C>[OH:15][CH:14]([C:12]1[CH:11]=[C:10]([C:17]([NH:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:18])[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=1)[CH2:16][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C3CO3)c2)cc1
Reactant: C1COCCN1
Solvent: CCO
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(O)CN3CCOCC3)c2)cc1
Temperature: 50 °C

Procedure:
Into a 20 mL reaction vessel were combined 4′-methyl-N-((6-methylpyridin-3-yl)methyl)-5-(oxiran-2-yl)biphenyl-3-carboxamide (15 mg, 0.042 mmol), ethanol (2 mL), and morpholine (13 mg, 0.15 mmol). The mixture was heated at 50° C. overnight. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford the title product.
Reaction SMILES: [C:1]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=O)[CH3:11])[CH2:3][CH:2]=1.C(N(CC)CC)C.Cl.[O:21]([NH2:23])[CH3:22]>CO>[CH3:22][O:21][N:23]=[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]1[CH2:3][CH:2]=1)[CH3:11]
Reactant: CC(=O)CCCCCCC1=CC1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=C(C)CCCCCCC1=CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.4 %

Procedure:
To a solution of 0.15 g (0.9 mmol) of 8-cycloprop-1-enyl-octan-2-one in 10 mL of methanol cooled in an ice bath was added 0.30 g (3 mmol1) of triethylamine and 0.83 g of a 30-35% aqueous solution of methoxylamine hydrochloride (3 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 1.5 hours. Water and ether were added. The phases were separated and the aqueous phase was washed with ether. The combined ether phases were washed with dilute aqueous hydrochloride acid, water (2×), and brine, then dried over magnesium sulfate, filtered and stripped. Column chromatography gave 50 mg of 8-cycloprop-1-enyl-octan-2-one O-methyl oxime (Compound 47) as a 30% solution in ether. The ratio of oxime isomers was 3:1.
Reaction SMILES: [C:1]([S:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].C([O:20][C:21](=[O:29])[CH2:22][NH:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)(C)(C)C.[I-].[Na+].Cl[Si](C)(C)C>C(Cl)Cl.C(#N)C>[C:1]([S:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:23]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:22][C:21]([OH:29])=[O:20])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Reactant: COc1cccc(C(=O)O)c1SC(C)=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cccc(C(=O)N(CC(=O)O)C2CCCC2)c1SC(C)=O
Reaction time: 8 h

Procedure:
N,N1 -Dicyclohexylcarbodiimide (10.3 g, 50 mmol) in methylene chloride (80 ml) was added to 2-acetylthio-3-methoxybenzoic acid (11.3 g, 50 mmol) and N-cyclopentylglycine t-butyl ester (10.0 g, 50 mmol) in methylene chloride (300 ml) at 0°-5° C. Overnight stirring was followed by filtration and washing of the filtrate with dilute hydrochloric acid, sodium bicarbonate solution and brine. Drying and concentration gave a gum which was dissolved in acetonitrile (65 ml), combined with sodium iodide (11.2 g, 75 mmol) and heated to 40°-50° C. Chlorotrimethylsilane (8.1 g, 75 mmol) was introduced and the mixture was heated for 30 minutes, then quenched with water. The organic phase was washed with water, aqueous sodium thiosulfate and brine then concentrated. Aqueous sodium bicarbonate was added to the residue and the resulting solution was washed with methylene chloride and ether, then acidified and extracted with ethyl acetate. The organic portion was dried and concentrated and the residue passed through a silica gel column to provide the amorphous product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Mg]Br.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18](=[O:21])[CH2:19][CH3:20])[CH:15]=[CH:16][CH:17]=1.[Cl-].[NH4+].Cl>C1COCC1.O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])([OH:21])[CH2:19][CH3:20])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccccc1[Mg]Br
Reactant: CCC(=O)c1cccc(OC)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)(c1cccc(OC)c1)c1ccccc1C
Reaction time: 8 h
Yield: 438.6 %

Procedure:
To a solution of 2-methylphenyl magnesium bromide (prepared from 4.9 g magnesium turnings and 24 ml of 2-bromotoluene) in dry THF (300 ml) was added dropwise a solution of 3'-methoxypropiophenone (25.9 g, 0.16 mol) in dry THF (200 ml). When addition was complete the mixture was heated at reflux temperature for 2 h. Water (250 ml) was added followed by a saturated ammonium chloride solution (250 ml) and the mixture was left overnight. A 4 N hydrochloric acid solution was added until a clear solution was obtained and the phases was separated. The organic phase was dried over magnesium sulphate and the solvent evaporated in vacuo. The residue was submitted to flash chromatography on silica gel (690 g) using a gradient of n-heptane in ethyl acetate to give 28.2 g (55%) of 1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propanol. A mixture of 1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propanol (26.2 g, 0.10 mol), isopropanol (300 ml) and a 6 N solution of sulphuric acid (150 ml) was stirred at room temperature for 2 h. The reaction mixture was neutralised with a 4 N sodium hydroxide solution and extracted with ethyl acetate (2×200 ml). The combined organic phases was dried over magnesium sulphate and the solvent was evaporated in vacuo. The residue was submitted to flash chromatography on silica gel (800 g) using n-heptane as eluent to give 18.4 g (76%) of 1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propene.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]([CH:11]1[CH:17]([OH:18])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[N+:9]=[N-:10]>C(Cl)Cl>[N:8]([CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH:17]1[OH:18])=[N+:9]=[N-:10]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(N=[N+]=[N-])CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NC1CCNCCC1O
Temperature: 35 °C
Yield: 96.6 %

Procedure:
Trifluoroacetic acid (20 mL) was added to a solution of tert-butyl 4-azido-5-hydroxyazepane-1-carboxylate (7.43 g, 29.0 mmol) in DCM (70 mL) and the mixture heated behind a blast shield at 35° C. for 4 hr. The solvents were removed under reduced pressure and the residue re-dissolved in MeOH and passed through an SCX column, washing with DCM and MeOH and eluting with 3-10% 7 N ammonia in MeOH/DCM to give 5-azidoazepan-4-ol as a yellow oil (4.38 g, 28.0 mmol) which was dissolved in dry DMSO (100 mL). 5-Chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (5.20 g, 32.2 mmol) and potassium fluoride (6.51 g, 112 mmol) were added. The mixture was heated at 70° C. for 16 hr, allowed to cool to room temperature, poured into water (1000 mL) and extracted into EtOAc (4×250 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol as a yellow gum (7.27 g, 77% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 3.94-3.66 (m, 4H), 3.65 (td, J=9.7, 3.8 Hz, 1H), 3.44-3.18 (m, 4H), 2.50 (d, J=2.8 Hz, 1H), 2.24-2.12 (m, 2H), 2.02-1.89 (m, 2H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:23]([Sn](CCCC)(CCCC)CCCC)[CH:24]=[CH2:25]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([C:19]1[CH:20]=[C:15]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:16]=[N:17][C:18]=1[Cl:22])[CH:24]=[CH2:23]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1cc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Yield: 110.3 %

Procedure:
3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromo-6-chloropyridine (2.0 g, 5.14 mmol) in toluene (15 mL) was added tetrakis(triphenylphosphine)palladium (15 mg) and allyltributyltin (3.2 mL, 10.2 mmol). The mixture was stirred and refluxed for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to afford an oil (2.0 g, 100%): 1H NMR (CDCl3, 300 MHz) δ 1.24-1.40 (m, 2H), 1.46 (s, 9H), 1.62 (m, 1H), 1.88 (m, 1H), 2.02 (m, 1H), 3.38 (m, 1H), 3.45 (d, 2H, J=7.0 Hz), 3.90 (m, 1H), 4.16 (m, 2H), 5.10-5.20 (m, 2H), 5.94 (m, 1H), 7.14 (m, 1H), 7.96 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/e 352 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-phenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 69% overall yield. FDMS m/e=366(M+of free base). α[D]589 =-10.45(c=0.61, methanol).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.CCCCCC>CCOCC>[F:14][C:7]([F:6])([F:13])[C:8]([NH:5][CH2:4][CH2:3][NH:2][CH3:1])=[O:10]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CNCCN
Solvent: CCOCC
Solvent: CCCCCC
Product: CNCCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
N-Methyl ethylenediamine (15 g, 202.3 mmol) was added dropwise to a stirred solution of ethyl trifluoroacetate (28.7 g, 204.34 mmol) in dry Et2O (50 mL) at 0° C. The resulting solution was stirred at room temperature for 2 hours. Hexane (75 mL) was added and the solution was left at −20° C. for 16 hours to produce a white precipitate which was removed by filtration, washed with Et2O (100 mL) and dried in vacuo for 3 hours to afford the title compound (29.4 g, 85%). 1H NMR (300 MHz, CDCl3) δ 3.42 (t, J=5.8 Hz, 2H), 2.80 (t, J=5.9 Hz, 2H), 2.43 (s, 3H); mass spectrum (API-TIS) 171 (M+H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9](/[CH:12]=[C:13](\[CH3:30])/[CH2:14][CH2:15]/[CH:16]=[C:17](\[CH3:29])/[CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:28])/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[N:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31](C/C(/C)=C/CC/C(/C)=C/CC(Cl)=O)/C=C(/CCC=C(C)C)\C>>[CH3:30]/[C:13](/[CH2:14][CH2:15]/[CH:16]=[C:17](\[CH3:29])/[CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:28])/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:12]\[C:9]1[O:8][C:7]([C:1]2[CH:2]=[CH:3][C:4]([CH3:31])=[CH:5][CH:6]=2)=[N:11][N:10]=1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC(=O)Cl
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/c1nnc(-c2ccccc2)o1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/c1nnc(-c2ccc(C)cc2)o1
Yield: 16 %

Procedure:
Similar to the preparation of 29a, the reaction of 25 with 28b afforded the desired compound 29b (20.8 mg, 16%) as oil. TLC Rf: 0.42 (20% EtOAc/petroleum ether); 1H NMR (400 MHz, CDCl3): δ 7.92 (d, 2H), 7.29 (d, 2H) 5.11-5.09 (m, 3H), 4.98 (d, 2H), 3.65 (s, 2H), 2.42 (s, 3H), 2.18-2.16 (m, 4H), 2.07-2.04 (m, 4H), 1.99-1.96 (m, 4H), 1.67 (s, 3H), 1.60 (s, 3H), 1.59 (s, 3H), 1.58 (s, 3H). LCMS: MS (m/z): 419.40 (M+H); ret. time: 8.32 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=1Br.C(N(CC)CC)C.[CH:21]#[C:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=1[C:21]#[C:22][CH2:23][CH2:24][CH3:25]
Reactant: C#CCCC
Reactant: COC(=O)c1ccc(C=O)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC#Cc1cc(C=O)ccc1C(=O)OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a room temperature solution of 2-Bromo-4-formyl-benzoic acid methyl ester (500 mg, 2.05 mmol) in degassed DMF (5 mL) are added triethylamine (2.0 mL, 14.35 mmol), dichlorobis(triphenylphosphine)palladium (II) (144 mg, 0.205 mmol, 10 mol %), copper (I) iodide (20 mg, 0.103 mmol, 5 mol %), and 1-Pentyne (406 μL, 4.10 mmol). The reaction mixture is heated to 80° C. in a sealed tube. After 2 h, the reaction is concentrated and the residue is chromatographed (0% to 10% EtOAc/Hex) to yield the title compound (279 mg, 59%). 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 8.02-7.98 (m, 2H), 7.80 (dd, 1H, J=7.9, 1.8 Hz), 3.95 (s, 3H), 2.48 (t, 2H, J=7.0 Hz), 1.73-1.63 (m, 2H), 1.09 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:15])=[O:4].Br[CH:17]([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7]([CH:17]([CH3:19])[CH3:18])[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1c(C)[nH]c2cc(Cl)ccc12
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(C)n(C(C)C)c2cc(Cl)ccc12
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A mixture of 6-chloro-2-methyl-1H-indole-3-carboxylic acid methyl ester (300 mg, 1.34 mmol), 2-bromopropane (1.75 mL, 18.6 mmol), potassium carbonate (743 mg, 5.37 mmol) and DMF (3.5 mL) is heated to 100° C. for 14 h. The mixture is diluted with water and extracted with ether. The ether layers are washed with water and brine and dried over MgSO4. The residue is purified via flash chromatography eluting with 80% CH2Cl2-heptane to give the title compound (217 mg, 61%) as a white solid. ES/MS m/e 266.0 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)(Cl)Cl.[N+:16]([O-])([OH:18])=[O:17]>O>[N+:16]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)([O-:18])=[O:17]
Reactant: c1ccc2ccccc2c1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc2ccccc12
Yield: 74 %

Procedure:
Naphthalene (13.62 g), Zn2+ montmorillonite (0.25 g) and CCl4 were stirred in 50 ml two-necked round-bottomed flask equipped with Dean-Stark apparatus. Fuming nitric acid (5 ml) was added dropwise into the reaction mixture. The reaction mixture was heated to reflux where upon the required amount of liberated water is collected in the Dean-Stark apparatus which usually takes 1 hr. Later on, the catalyst was filtered and the organic layer is concentrated to obtain 1-nitronaphthalene.