Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7].CCOCC>C(OC(=O)C)(=O)C>[CH2:5]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][C:14]=1[N+:1]([O-:4])=[O:2])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Fuming nitric acid (0.8 ml) was added over 10 minutes to a stirred solution of 4'-isobutyl-2-biphenylsulphonyl chloride (3.09 g) in acetic anhydride (18 ml) at -20° C. The solution was kept at -20° C. for 1.5 hours and then allowed to warm to ambient temperature. The solution was stirred for 1.5 hours and then added to ice (300 g) with vigorous sextracted with ether 30 minutes and extracted with ether (3×100 ml) while still below 10° C. The ethereal solution was dried (MgSO4) and the solvent was removed by evaporation. The resulting oil was purified by flash chromatography, eluting with ethyl acetate/hexane (1:9 v/v), to give 4'-isobutyl-3'-nitro-2-biphenylsulphonyl chloride (2.01 g); 1H NMR (CDCl3): 0.95 (d,6H), 1.9-2.05 (m,1H), 2.9 (d,2H), 7.35-7.5 (m,2H), 7.6 (d,1H), 7.7 (d,1H), 7.8 (t,1H), 8.0 (s,1H), 8.25 (d,1H); mass spectrum (EI): 353(M+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)C=O)[CH2:2][CH3:3].[C:13]1(P(=CC(OC)=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37]([O:40][CH2:41][CH3:42])(=[O:39])[CH3:38]>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:7][C:6]=1[CH:13]=[CH:38][C:37]([O:40][CH2:41][CH3:42])=[O:39])[CH2:2][CH3:3]
Reactant: CCCOc1cccc(C=O)c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCOc1ccccc1C=CC(=O)OCC

Procedure:
3-Propoxybenzaldehyde (15.47 g) and methyl (triphenylphosphoranylidene)acetate was suspended in toluene (150 ml), and the resulting suspension was heated at reflux for 2 hours. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the precipitated triphenylphosphine oxide was removed and was washed with ether. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to obtain ethyl 2-propoxycinnamate (21.24 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].C=CC.Cl.[CH3:15][CH2:16][CH2:17][CH2:18]C>[Cl-].[Cl-].[Cl-].[Al+3]>[F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])([OH:4])[CH2:15][CH:16]=[CH:17][CH3:18]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: CCCCC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C=CC
Product: CC=CCC(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 70 %

Procedure:
Referring to scheme (1) above, pentane (300 mL) can be placed in a 500 mL three neck flask and chilled below −30° C. To the pentane can be added hexafluoroacetone (59 grams, 0.36 mole), propylene (16.2 grams, 0.38 mole), and anhydrous aluminum trichloride (0.77 g, 0.006 mole) to form a mixture. This mixture can be stirred and the temperature can be allowed to warm to room temperature over a 3 hour period. A 15% (wt/wt) aqueous HCl solution (20 mL) can be added to the mixture, and the mixture can be washed 3 times with H2O. The aqueous layer, after the wash, can be decanted off, and the organic layer (pentane and propylene) can be dried with MgSO4. Remaining pentane and propylene can be flash vaporized off at 60° C. to give 54.4 grams (70% area percent by gas chromatography) of isomeric 1,1-bis(trifluoromethyl)-3-penten-1-ol.
Reaction SMILES: Cl[CH2:2][C:3](CCl)=[O:4].[C:7]([NH2:10])(=[S:9])[CH3:8].[Cl:11][CH2:12][C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1.S(=O)(=O)(O)[OH:20]>[O-2].[O-2].[Mn+4]>[Cl:11][CH2:12][C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1.[CH2:3]([O:4][C:12]([C:13]1[N:14]=[C:15]2[C:18](=[N:10][CH:7]([CH3:8])[S:9]2)[CH:17]=1)=[O:20])[CH3:2]
Reactant: CC(N)=S
Reactant: O=C(CCl)CCl
Reactant: O=S(=O)(O)O
Agent: [Mn+4]
Agent: Cc1nc(CCl)cs1
Agent: [O-2]
Product: CCOC(=O)C1=CC2=NC(C)SC2=N1

Procedure:
According to the description in J. Heterocyclic Chem., 1979, 16, 1563, 4-chloromethyl-2-methylthiazole was synthesized with 1,3-dichloroacetone and thioacetamide as starting materials. The above-obtained 4-chloromethyl-2-methylthiazole was converted to a 4-hydroxymethyl body by dilute sulfuric acid, and then introduced into a 4-formyl body by oxidation of manganese dioxide (yield to this point: 62%). 5-Ethoxycarbonyl-2-methylpyrrolo[3,2-d]thiazole was obtained by making ethyl azidoacetate act on the above product in the presence of sodium ethoxide and further heating in xylene (yield: 31%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](=S)[NH:4][NH2:5].[Cl:8][CH:9]([C:15]([CH3:17])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].C1C=CC=CC=1>C(O)C>[ClH:8].[CH3:1][N:2]([CH3:7])[C:3]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([CH3:17])[NH:5][N:4]=1
Reactant: CN(C)C(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)c1c(N(C)C)n[nH]c1C
Product: Cl
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A stirred slurry of 2.5 g (0.013 mole) of 4,4-dimethyl-3-thiosemicarbazide in 50 mL of absolute ethanol was treated with 2.1 g (0.013 mole) of ethyl 2-chloroacetoacetate added at a rapid rate under nitrogen atmosphere. The reaction mixture turned yellow immediately, cleared, became cloudy and finally became a clear orange solution within 5 minutes. The reaction mixture was stirred at ambient temperature for ~72 hr, heated to reflux, filtered hot, and concentrated in vacuo to give a yellow oil which solidified. Trituration with benzene gave 3 g of tan solid. After 3 recrystallizations from benzene, 1.8 g of fine pale beige crystalline product was obtained, mp 135°-139° C. After drying at 98° C. under reduced pressure for 3 hr, mp 137°-139° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Br:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[Br-:9].[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N+:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: c1ccc(CSc2ccccn2)cc1
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(C[n+]2ccccc2SCc2ccccc2)cc1
Product: [Br-]
Temperature: 100 °C

Procedure:
A mixture of 4-nitrobenzyl bromide (1.08 g) and 2-(benzylthio)pyridine (1.05 g) were heated at 100° C. for 4 hours and cooled. Crystals which formed on trituration with acetone were removed by filtration and dried to give the title compound as a quarter hydrate (1.6 g) mp 160°-2° C. (Found C, 53.8; H, 4.5; N, 6.4%. C19H17BrN2O2S1/4H2O requires C, 54.1; H, 4.2; N, 6.6%).
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:20][CH2:19]3)=[C:14]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[N:13]=2)=[O:11])[C:6](O)=[O:7])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:57][N:58]1[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59]1>CN(C=O)C>[CH:1]1([CH2:4][C@H:5]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:20][CH2:19]3)=[C:14]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[N:13]=2)=[O:11])[C:6](=[O:7])[NH:57][N:58]2[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59]2)[CH2:2][CH2:3]1
Reactant: O=C(N[C@@H](CC1CC1)C(=O)O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NN1CCC(O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](CC1CC1)C(=O)NN1CCC(O)C1)c1ccc(C2CC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-3-cyclopropyl-2-[(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-propionic acid (100 mg, 0.29 mmol) in DMF (3 mL), was added TBTU (103 mg, 0.319 mmol), DIEA (249 μL, 1.45 mmol) and finally 1-amino-3-pyrrolidinol (CAN 887591-10-8, 30 mg, 0.29 mmol). The reaction mixture was stirred for 16 h at room temperature, concentrated in vacuo and purified by flash chromatography (silica gel, 10 g, 0% to 20% methanol in dichloromethane) to give the title compound, an epimeric mixture of products, (90 mg, 72%) as white foam; LC-MS (UV peak area/ESI) 96%, 429.2493 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].O[CH:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:12]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:11])[N:2]1[O:1][CH:14]1[CH2:15][N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N1CC(O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(ON2C(=O)c3ccccc3C2=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-hydroxy-1H-isoindole-1,3(2H)-dione (1.72 g, 10.541 mmol), di-tert-butyl 4-hydroxypyrazolidine-1,2-dicarboxylate 141 (Journal of Antibiotics, 1993, Vol 46, (12), 1866-1882, 1.52 g, 5.27 mmol) and triphenylphosphine (2.76 g, 10.54 mmol) in THF (50 mL) was added DIAD (2.24 mL, 11.59 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue, which was subjected to chromatography to give 142 (1.8 g, 79° A) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16](F)=[C:15]([C:20](O)=[O:21])[CH:14]=1)[C:7](=[O:23])[NH:6][C:5]2=[O:24].FC1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)N[C:31](=O)[NH:30][C:29]2=[O:37].BrCC1C=CC(F)=C(C=1)C(OC)=O.COC(C1C=[C:57](C=CC=1)[CH2:58][N:59]1C2C(=CC=CC=2)C(=O)N[C:60]1=O)=O>>[CH:28]1([C:29]([N:30]2[CH2:31][CH2:60][N:59]([C:20]([C:15]3[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=3)[CH2:12][N:8]3[C:9]4[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=4)[C:5](=[O:24])[NH:6][C:7]3=[O:23])=[O:21])[CH2:58][CH2:57]2)=[O:37])[CH2:27][CH2:35][CH2:34][CH2:33]1
Reactant: COC(=O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Reactant: O=c1[nH]c(=O)c2cc(F)ccc2[nH]1
Reactant: O=C(O)c1cc(Cn2c(=O)[nH]c(=O)c3cc(F)ccc32)ccc1F
Agent: COC(=O)c1cc(CBr)ccc1F
Product: O=C(c1cccc(Cn2c(=O)[nH]c(=O)c3cc(F)ccc32)c1)N1CCN(C(=O)C2CCCC2)CC1

Procedure:
The following compounds were prepared from 6-fluoro-1-(3-carboxy-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione (prepared from 6-fluoroquinazoline-2,4(1H,3H)-dione and methyl 5-(bromomethyl)-2-fluorobenzoate using procedures similar to those of compounds of Examples 1 and 2), and the corresponding substituted piperazine using a procedure similar to those described for the synthesis of compound of Example 3.
Reaction SMILES: S1C=C[N:3]=[C:2]1[C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH:9]=[C:8]([C:17]([OH:19])=[O:18])[CH:7]=1.[CH:20]1C=CC2C(=CC=CC=2O)C=1>>[C:2]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH:9]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[CH:7]=1)#[N:3]
Reactant: Oc1cccc2ccccc12
Reactant: O=C(O)c1cc(-c2nccs2)c2ccc(O)cc2c1
Product: COC(=O)c1cc(C#N)c2ccc(O)cc2c1

Procedure:
Following the procedure described in Naphthol 5, Step 8, but substituting 1-cyano-3-carboxy-6-naphthol from Step 4 for 1-(2-thiazolyl)-3-carboxy-6-naphthol, the title product was obtained as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6](O)[O:7][CH2:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-:13].[Cs+].[Cs+].[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]([CH2:19][C:20]([O:21][CH2:22][CH3:18])=[O:13])[O:7][CH2:8][C:4]=2[CH:3]=1
Reactant: OC1OCc2cc(Cl)ccc21
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)CC1OCc2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
5-Chloro-1,3-dihydro-2-benzofuran-1-ol (2.95 g, 17.3 mmol) was dissolved in THF (60 mL) and cooled to 0° C. Triethyl phosphonoacetate (11.7 g, 52.1 mmol) and caesium carbonate (17 g, 52.1 mmol) were added. After 20 min the cold bath was removed and the reaction mixture allowed to stir at room temperature for 3 h, then quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. Purification by column chromatography, eluting with ethyl acetate/hexane (1:4), yielded the title compound as a colourless oil.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:62]2[N:63]=[C:64]([NH:67]C(OC(C)(C)C)=O)[S:65][CH:66]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([C@@H:41]([N:43](C(OC(C)(C)C)=O)[CH2:44][CH2:45][CH2:46][NH:47]C(OC(C)(C)C)=O)[CH3:42])[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:47][CH2:46][CH2:45][CH2:44][NH:43][C@H:41]([C:39]1[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]3)/[C:62]3[N:63]=[C:64]([NH2:67])[S:65][CH:66]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:32])=[O:33])[N:40]=1)[CH3:42]
Reactant: C[C@@H](c1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: C[C@H](NCCCN)c1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Temperature: 0 °C
Yield: 25.8 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-((S)-1-((tert-butoxycarbonyl)(3-((tert-butoxycarbonyl)amino)propyl)amino)ethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (0.709 mmol), anisole (153 mg, 1.42 mmol), TFA (273 μl, 35.5 mmol) and DCM (7.1 mL). The reaction mixture was cooled to 0° C. and diluted with DCM and ice water. After vigorous stirring the two layers were separated and aqueous layer was purified by reverse phase prepatory HPLC (XSELECT, C18, 5 um 30×100 mm ACN-water with 0.1 formic acid), affording title compound (110 mg, 25%) as a white solid. LCMS: Rt=0.50 min, m/z=601.3 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, D2O) δ 7.87 (s, 1H) 7.04 (s, 1H) 5.61 (d, J=5.6 Hz, 1H) 5.04-4.97 (m, 1H) 4.89 (d, J=5.4 Hz, 2H) 4.69-4.62 (m, 1H) 3.13-3.00 (m, 4H) 2.04 (t, J=4.0 Hz, 2H) 1.68 (d, J=6.9 Hz, 3H) 1.23 (t, J=3.9 Hz, 2H) 1.11-1.02 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[Br:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:34](=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:27]([O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Br:22][CH2:23][C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:34]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: BrCCCOCc1ccccc1
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(O)C1

Procedure:
In an analogous manner to that described in Example 44(e), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate [Example 46(b)] with benzyl 3-bromopropyl ether in the presence of potassium carbonate in butan-2-one there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxy-piperidine-1-carboxylate, alkylation of which with 2-bromomethyl-naphthalene analogously to Example 1(g) gave tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 582 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5](O)[CH:6]=[CH:7][CH:8]=1.[OH-:11].[Na+].[CH2:13](Br)[CH2:14][CH2:15][CH3:16]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([CH2:16][CH2:15][CH2:14][CH2:13][O:11][CH2:4][CH2:3][CH2:8][CH2:7][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:10])[CH3:1])[CH:4]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)c1cccc(O)c1
Reactant: CCCCBr
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)c1cccc(CCCCOCCCCc2cccc(N(C)C)c2)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
54.8 g (0.4 mol) of 3-dimethylaminophenol and 13.58 g (0.04 mol) of tetrabutylammonium hydrogen sulfate are placed in 200 ml of toluene in a 750 ml sulfonating flask having an anchor mixer, thermometer, reflux condenser and dropping funnel and at RT 80 g (1.0 mol) of a 50% aqueous NaOH solution are added dropwise in the course of 30 minutes. The suspension is then stirred for 30 minutes at 80° C. and then at the same temperature 109.6 g (0.8 mol) of butyl bromide are added in the course of 45 minutes. After a subsequent reaction period of 2 hours the mixture is cooled and filtered, and the filtrate is washed once with 70 ml of H2O, dried over MgSO4, filtered and concentrated by evaporation. The crude product is distilled under a high vacuum, yielding 64 g of 3-dimethylaminophenylbutyl ether in the form of a colourless liquid having a boiling point of 94° -96° C. (0.08 mbar) which no longer has an OH band in the IR spectrum and of which the NMR analysis is in agreement with the said structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[CH:24][C:25](I)=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:29]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)[C:30]#[CH:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[CH:24][C:25]([C:31]#[C:30][CH2:29][N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C#CCN1CCCC1
Reactant: COc1ccc(Nc2ncc3c(n2)-c2cc(I)ccc2NC(=O)C3)cc1OC
Product: COc1ccc(Nc2ncc3c(n2)-c2cc(C#CCN4CCCC4)ccc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to Method O, 2-(3,4-dimethoxy-phenylamino)-10-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-26) and 1-(prop-2-ynyl)pyrrolidine were converted to I-31 (29%): HRMS Calcd. for C27H27N5O3: 470.2192, Found 470.2185.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[NH2:14][CH2:15][C@@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:30])=[O:29])=[C:24]([F:31])[CH:23]=2)[CH2:17]1>C(Cl)Cl>[C:1]([NH:14][CH2:15][C@@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:30])=[O:29])=[C:24]([F:31])[CH:23]=2)[CH2:17]1)(=[O:3])[CH3:2]
Reactant: CS(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(S(C)=O)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
Acetic anhydride (0.173 ml, 1.83 mmol) and pyridine (0.296 ml, 3.67 mmol) were added to a solution of 5-(S)-aminomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one (0.100 g, 0.367 mmol) in DCM (3 ml). The reaction mixture was stirred for 4 h at r.t. and then evaporated to dryness under vacuum. The residue was purified by PTLC (10% methanol in DCM) to give product as a white solid (0.115 g, 99%). M.p. 143-5° C. MS (m/z): [M+H]+=315.
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][NH:10][C:4]=2[CH:3]=1.[CH3:13][N:14]([CH2:19][C:20]1[O:21][C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[C:24]=1[CH3:25])[C:15](=[O:18])[CH:16]=[CH2:17].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:13][N:14]([CH2:19][C:20]1[O:21][C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[C:24]=1[CH3:25])[C:15](=[O:18])/[CH:16]=[CH:17]/[C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][NH:10][C:4]=2[CH:3]=1
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Reactant: Brc1cnc2c(c1)NCCCN2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)NCCCN3)oc2ccccc12
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 44.7 %

Procedure:
A solution of 8-bromo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepine (0.15 g, 0.66 mmol), N-methyl-N-((3-methyl benzofuran-2-yl)methyl)acrylamide (0.30 g, 1.32 mmol), (i-Pr)2EtN (0.34 mL, 2.0 mmol) in DMF (7 mL) was de-oxygenated with Ar for 30 min. Pd(OAc)2 (15 mg, 0.066 mmol) and P(o-tol)3 (40 mg, 0.13 mmol) was added and the solution was de-oxygenated for an additional 15 min. The reaction was heated to 100° C. for 18 hrs at which time the reaction was cooled to room temperature and then filtered through a short column of silica washing with EtOAc (20 mL). The filtrate was washed with brine (2×30 mL), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 99:1) gave the title compound (111 mg, 45%) as a yellow powder; 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6, 1H), 7.43 and 7.39 (2×s, 1H), 7.35-7.22 (m, 3H), 7.08 and 6.82 (2×d, J=15, 1H), 6.22 (s, 1H), 5.25 (s, 1H), 4.90 and 4.78 (2×s, 2H), 3.14-2.93 (m, 7H), 2.26 (s, 3H), 1.68 (m, 2H); ESI MS m/z 377 [C22H24N4O2+H]+
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:16](Cl)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].N#N>O.C(Cl)Cl>[C:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCC(=O)Cl
Agent: N#N
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC(=O)Oc1ccc(C=O)cc1
Reaction time: 20 h
Yield: 86.2 %

Procedure:
To a 250 mL dry round bottom flask were added 4-hydroxybenzaldehyde (6.11 g, 50.0 mmol) and anhydrous CH2Cl2 (50 mL). The solution was cooled in an ice-water bath, then pyridine (8.09 mL, 100 mmol) was added. To the resulting solution, octanoyl chloride (10.3 mL, 60 mmol) was added slowly under stirring and N2. The mixture was first stirred at 0° C. for 2 hours, then at room temperature for 20 hours. To the reaction mixture, water (100 mL) was added and the CH2Cl2 layer was separated. The aqueous layer was extracted continually with CH2Cl2 (100 mL×2). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 4-formylphenyl octanoate (10.7 g) as colorless oil. Yield: 86%. 1H NMR (CDCl3, 300 MHz): δ=9.98 (s, 1H), 7.91 (d, J=8.7 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 2.58 (t, J=6.9 Hz, 2H), 1.38-0.86 (m, 13H). 13C NMR (CDCl3, 75.5 MHz): δ=191.0, 171.7, 155.6, 134.0, 131.3, 122.5, 34.5, 31.7, 29.1, 29.0, 24.9, 22.7, 14.2.