Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:60][CH2:61][C:62]1[CH:73]=[CH:72][C:65]2[B:66]([OH:71])[O:67][C:68]([CH3:70])([CH3:69])[C:64]=2[CH:63]=1.Cl>C(#N)C.CC(=O)OCC>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:24]([F:26])([F:27])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:60][CH2:61][C:62]4[CH:73]=[CH:72][C:65]5[B:66]([OH:71])[O:67][C:68]([CH3:70])([CH3:69])[C:64]=5[CH:63]=4)=[O:20])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC1(C)OB(O)c2ccc(CN)cc21
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)C(C)(C)OB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
To a solution of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (300 mg, 0.72 mmol) in acetonitrile (5 ml) at 0° C. was added Et3N (291.1 mg, 2.88 mmol), HATU (546.76 mg, 1.44 mmol) and 5-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (194.2 mg, 0.86 mmol). The reaction mixture was stirred overnight at rt. The mixture was poured into 1N HCl solution and extracted with EA (20 ml×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE:EA (1:1 with 2 drops of HOAc) and prep-HPLC to give the final title compound (80 mg, yield 18.8%) as white solid: 1H NMR (300 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.95 (m, 1H), 7.81-7.82 (m, 1H), 7.62-7.64 (m, 5H), 7.49-7.60 (m, 1H), 7.29-7.46 (m, 2H) 4.50-4.52 (d, J=6.0 Hz, 2H), 4.33-4.36 (m, J=9 Hz, 2H), 2.42 (s, 3H), 1.20 (s, 6H); HPLC purity: 97.1% at 214 nm and 98.3% at 254 nm; MS: 591 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)(=[O:4])=[O:3].[NH2:15][C@@H:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=[CH:21][CH:22]=2)[CH2:17]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][C@H:16]([NH:15][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:7]=2)[CH2:25][CH2:24]3)[CH2:27][CH2:28]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: CS(=O)(=O)Oc1cccc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2cccc(OS(C)(=O)=O)c2)CC3)CC1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
A suspension of 3-methanesulfonyloxybenzoic acid (0.20 g, 0.90 mmol; described in: Looker, J. H.; Hayes, C. H.; Thatcher, D. N. J. Am. Chem. Soc. 1957, 79, 741-4) in thionyl chloride (5 mL) was heated at 40° C. for 45 min (the solution became homogeneous). The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (120 mg, 0.50 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.48 mmol) and triethylamine (100 μL, 0.72 mmol) in methylene chloride (20 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 87 mg (41%) of the title compound as white crystals: mp 159-160° C.; [α]21D -27° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 443 (21, M+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([CH3:30])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4ccc(Cl)cc4Cl)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C)cc(-c3ccc(Cl)cc3Cl)c2O1

Procedure:
The title compound was prepared (0.029 g, 14%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,4-dichlorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.26 g, 0.56 mmol) and methylamine (0.174 g, 5.6 mmol). mp 169-171° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]([OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[CH2:13]([N:15]=C=O)[CH3:14].C([O:20]CC)C>C(N(CC)CC)C>[OH:11][C:7]1[CH:6]=[C:5]([C@@H:4]([OH:12])[CH2:3][NH:2][C:1](=[O:20])[NH:15][CH2:13][CH3:14])[CH:10]=[CH:9][CH:8]=1
Reactant: CNC[C@H](O)c1cccc(O)c1
Reactant: CCN=C=O
Reactant: CCOCC
Solvent: CCN(CC)CC
Product: CCNC(=O)NC[C@H](O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a suspension of R-phenylephrine (10.0 g, 59.8 mmol) in diethyl ether (200 ml) with triethylamine (4 drops) is added ethyl isocyanate (4.25 g, 59.8 mmol) in diethyl ether (50 ml). The reaction is allowed to stir overnight at room temperature. A white suspension forms which is decanted from the precipitated gum, filtered and dried giving 3.0 g (21% yield) of product, m.p. 102°-105° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=O)[CH2:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1>O1CCCC1>[ClH:18].[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: COCCNC(=O)CC1(c2ccc(Cl)cc2)CCC1
Solvent: C1CCOC1
Product: COCCNCCC1(c2ccc(Cl)cc2)CCC1
Product: Cl

Procedure:
Borane-methyl sulphide complex (3.4 ml) was added dropwise to a solution of the acetamide (1.6 g) prepared as described above in dry tetrahydrofuran (30 ml). The mixture was heated under reflux for seven hours and then half the solvent removed by evaporation. A mixture of concentrated hydrochloric acid (5 ml) and water (5 ml) was added dropwise with ice-cooling. Water was added and the aqueous layer washed with ether, cooled in ice, basified with 16N sodium hydroxide solution and extracted with ether. The ether extract was washed, dried and the ether removed by evaporation. Hydrogen chloride gas was passed into a solution of a sample of the residue in ether to give N-(2-methoxyethyl)-2-[1-(4-chlorophenyl)cyclobutyl]ethylamine hydrochloride (m.p. 113°-115° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][N:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH:16]=3)[NH:11][C:10]2=[O:29])[CH:2]=1.[H-].[Na+].[C:32](Cl)(=[O:34])[CH3:33]>CN(C)C=O>[C:32]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:19]([F:28])([C:24]([F:25])([F:26])[F:27])[C:20]([F:22])([F:21])[F:23])=[CH:14][CH:13]=2)[CH2:18][N:9]([N:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:10]1=[O:29])(=[O:34])[CH3:33]
Reactant: O=C1Nc2ccc(C(F)(C(F)(F)F)C(F)(F)F)cc2CN1N=Cc1cccnc1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)N(N=Cc2cccnc2)Cc2cc(C(F)(C(F)(F)F)C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
In 10 ml of dimethylformamide was dissolved 0.84 g (2.0 mmol) of 3-(3-pyridylmethylideneamino)-3,4-dihydro-6-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2(1H)-quinazolinone, and to the resulting solution was added 0.09 g (2.3 mmol) of sodium hydride (purity: 62.4%). The reaction was carried out at room temperature for 30 minutes, after which 0.19 g (2.4 mmol) of acetyl chloride was added and the reaction was carried out for 4 hours. After completion of the reaction, the reaction solution was poured into ice water and the desired compound was extracted with ethyl acetate (20 ml×3). The extract solution was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. The crude product thus obtained was purified by silica gel column chromatography (ethyl acetate−methanol 10:1) to obtain 0.51 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:34]=[CH:33][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:18][C:17]=3[C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:34]=[CH:33][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:35][CH:36]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2cccs2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2cccs2)c1
Reaction time: 3 h
Yield: 37.4 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(thiophen-2-yl)phenyl)acetate (20 mg, 0.038 mmol) was diluted with dioxane (500 μL) followed by the addition of NaOH (0.052 ml, 0.26 mmol) and 200 μL of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(thiophen-2-yl)phenyl)acetic acid (7 mg, 37% yield) as a white solid. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.69 (s, 1H), 7.64 (d, 2H), 7.45 (d, 1H), 7.30 (d, 2H), 7.22 (d, 1H), 7.15 (d, 2H), 6.98-7.05 (m, 2H), 6.90 (d, 2H), 3.65 (m, 4H), 2.90 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([NH2:7])=[O:6].C1(C)C=CC=CC=1.C(Cl)(=O)[C:22](Cl)=[O:23].Cl>O>[CH3:13][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([N:7]=[C:22]=[O:23])=[O:6]
Reactant: COc1cccc(OC)c1C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C(=O)N=C=O
Temperature: 60 °C

Procedure:
A 167 g. portion of 2,6-dimethoxybenzamide was slurried in 2 l. of toluene under a nitrogen atmosphere. To this solution was added 145 g. of oxalyl chloride over a one hour period. The solution was heated to 60° C. and maintained at this temperature overnight. HCl was allowed to escape while attempting to prevent water from condensing and going into the reaction mixture. Nitrogen was bubbled subsurface through a gas inlet tube while heating the reaction mixture at reflux (about 110° C.) for 11/2 hours. As stirring continued, the mixture was allowed to come to about 30° C. The solution was filtered through infusorial earth while maintaining a nitrogen atmosphere and the solvent was removed in vacuo. Yield 185 g. (97%). The oil was then stored under nitrogen.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>C1COCC1>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCC(O)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 73.4 %

Procedure:
n-Pentyl magnesium bromide (2.0 M in THF, 27 mL, 54 mmol) was added to a solution of 4-bromobenzaldehyde (5.0 g, 27 mmol) in THF (20 mL) at 0° C. under nitrogen. After 1 h, the reaction was quenched with 3 N HCl and extracted with Et2O (3×120 mL). Combined extracts were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (5% EtOAc/Hex) afforded 5.1 g (74%) of 1-(4-bromophenyl)-hexan-1-ol.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(OC[CH:10]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:11][C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([Br:21])=[CH:20][C:14]=2[CH:13]=1)(=O)=O.[C:30](OCC)(=O)C.C1(C)C=CC=CC=1>CS(C)=O>[Br:21][C:19]1[CH:18]=[CH:17][C:15]2[S:16][C:12]([CH:11]([CH3:30])[CH:10]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[C:1]#[N:2])=[CH:13][C:14]=2[CH:20]=1
Reactant: CCOC(C)=O
Reactant: [C-]#N
Reactant: COc1ccc(C(COS(C)(=O)=O)Cc2cc3cc(Br)ccc3s2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COc1ccc(C(C#N)C(C)c2cc3cc(Br)ccc3s2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1H-NMR (CDCl3) δ: 3.78 (3H, s), 3.9-4.5 (3H, m), 3.70 (3H, s), 4.3 (2H, m), 6.70-7.80 (8H, m) e) 1.2 g of sodium cyanide was dissolved in 30 ml of dimethyl sulfoxide at a temperature of 90° C. To this was gradually added 18.5 g of 3-(5-bromobenzo[b]thien-2-yl)-2-(4-methoxyphenyl)propyl methanesulfonate, followed by stirring at 80° C. for 1 hour. The resulting reaction solution was mixed with an ethyl acetate/toluene mixture, washed with water, and then dried to distill off the solvent. Crystals thus precipitated were washed with ethanol and dried to obtain 5 g of 3-(5-bromobenzo[b]thien-2-yl)-2-(4-methoxyphenyl)butyronitrile. The same compound was also obtained with a yield of 2 g, by concentrating the ethanol solution resulting from the washing of crystals and subjecting the concentrate to silica gel column chromatography using chloroform as an elution solvent.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:22])[N:6]=1)[CH2:3][CH3:4].Cl[C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[NH:30][CH:31]=[CH:32][C:25]=12.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[NH:30]1[C:26]2=[N:27][CH:28]=[CH:29][C:24]([NH:1][C@H:2]([C:5]3[N:14]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:13](=[O:21])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[F:22])[N:6]=3)[CH2:3][CH3:4])=[C:25]2[CH:32]=[CH:31]1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC[C@H](Nc1ccnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (27 mg, 0.091 mmol, 1.0 equiv) in t-BuOH (0.5 mL) at 23° C. is added 4-chloro-1H-pyrrolo[2,3-b]pyridine (21 mg, 0.14 mmol, 1.5 equiv) and diisopropylethylamine (63 μL, 0.36 mmol, 4.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture is concentrated in vacuo and the residue is purified by preparative TLC eluting with CH2Cl2/MeOH to afford the title compound (Compound 5A).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([O:14]C)=[O:13])=[C:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4](=[O:16])[C:3]=1[F:17].[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4](=[O:16])[C:3]=1[F:17]
Reactant: COC(=O)c1c(Cl)c(F)c(=O)n2c1CCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(Cl)c(F)c(=O)n2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 8-chloro-7-fluoro-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxylate (7c, 600 mg, 2.43 mmol) was dissolved in THF (10 ml) and MeOH (5 ml). 1N NaOH (5 ml) was added and the solution stirred at RT overnight. The solution was acidified with 4N HCl then extracted into DCM and the aqueous washed ×3 with DCM. The organic portions were evaporated to give the title compound which was used without further purification (426 mg, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61-1.79 (m, 4H) 2.83 (t, J=6.06 Hz, 2H) 3.94 (t, J=6.32 Hz, 2H) 13.75 (br. s., 1H) [M+H] calc'd for C10H9ClFNO3, 246. found, 246.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O)(C)C.S(=O)(O)[O-].[Na+].[NH2:20][C:21]1[CH:22]=[C:23]([C:34]([C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[C:45]([NH2:56])[CH:44]=2)([C:39]([F:42])([F:41])[F:40])[C:35]([F:38])([F:37])[F:36])[CH:24]=[CH:25][C:26]=1[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O.C(O)C>[F:36][C:35]([F:37])([F:38])[C:34]([C:23]1[CH:24]=[CH:25][C:26]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:10]([C:9]3[CH:12]=[CH:13][CH:14]=[C:7]([C:6]#[CH:5])[CH:8]=3)=[N:20][C:21]=2[CH:22]=1)([C:43]1[CH:48]=[CH:47][C:46]2[N:49]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:10]([C:9]3[CH:12]=[CH:13][CH:14]=[C:7]([C:6]#[CH:5])[CH:8]=3)=[N:56][C:45]=2[CH:44]=1)[C:39]([F:40])([F:41])[F:42]
Reactant: C[Si](C)(C)C#Cc1cccc(C=O)c1
Reactant: Nc1cc(C(c2ccc(Nc3ccccc3)c(N)c2)(C(F)(F)F)C(F)(F)F)ccc1Nc1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C#Cc1cccc(-c2nc3cc(C(c4ccc5c(c4)nc(-c4cccc(C#C)c4)n5-c4ccccc4)(C(F)(F)F)C(F)(F)F)ccc3n2-c2ccccc2)c1

Procedure:
The exact procedure described above (high dilution and dropwise addition) was repeated for 26.0 g of the aldehyde (VI), 110 g of sodium bisulfite, 30.0 g of the tetramine (V) in a total volume of 4.5 L of 1:5 water-ethanol. At the end, the powdery end product (VIII) was fractionated by Soxhlet extraction into an ether-insoluble portion (high oligomers) and an ether-soluble portion (20.0 g, 46.9%). The latter material, when tested on the Kofler hot bench at 250° C., showed a gel time of about 3 minutes.
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]([O:6][C@@H:7]2[C@@H:15]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C@H:14]([CH3:24])[O:13][C:12](=[O:25])[C@@H:11]([NH:26][C:27](=[O:37])[C:28]3[C:33]([OH:34])=[C:32]([O:35][CH3:36])[CH:31]=[CH:30][N:29]=3)[CH2:10][O:9][CH2:8]2)=[CH:4][CH:3]=1.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:40]([O:34][C:33]1[C:28]([C:27](=[O:37])[NH:26][C@H:11]2[CH2:10][O:9][CH2:8][C@H:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:39][CH:38]=3)[C@@H:15]([O:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C@H:14]([CH3:24])[O:13][C:12]2=[O:25])=[N:29][CH:30]=[CH:31][C:32]=1[O:35][CH3:36])(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: COc1ccnc(C(=O)N[C@H]2COC[C@H](Oc3ccc(F)cc3)[C@@H](Oc3ccc(F)cc3)[C@H](C)OC2=O)c1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](Oc3ccc(F)cc3)[C@@H](Oc3ccc(F)cc3)[C@H](C)OC2=O)c1OC(C)=O
Temperature: 40 °C
Reaction time: 14 h
Yield: 80.1 %

Procedure:
To a solution of N-((3S,7S,8S,9S)-7,8-bis(4-fluorophenoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (54 mg, 0.099 mmol) in DCM (0.5 mL) was added TEA (0.028 mL, 0.198 mmol), DMAP (6.1 mg, 0.050 mmol), and acetyl chloride (0.011 ml, 0.149 mmol). The reaction was warmed to 40° C. for and stirred for 14 h. The reaction was then concentrated and the crude residue purified by flash chromatography (SiO2, EtOAc/Hexanes) to give the title compound as a white foam (46.5 mg, 80%): IR (thin film) 3372, 2939, 1765, 1676 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J=8.2 Hz, 1H), 8.37 (d, J=5.4 Hz, 1H), 7.03 (d, J=5.5 Hz, 1H), 6.98-6.86 (m, 6H), 6.74-6.61 (m, 2H), 5.33-5.24 (m, 1H), 5.14 (m, 1H), 4.36 (t, J=9.2 Hz, 1H), 4.30-4.22 (m, 1H), 4.10-3.99 (m, 2H), 3.92 (s, 3H), 3.92-3.87 (m, 1H), 3.79 (dd, J=11.2, 7.3 Hz, 1H), 2.40 (s, 3H), 1.48 (d, J=6.4 Hz, 3H); HRMS-FAB (m/z) [M+H]+ calcd for C29H28F2N2O9, 587.1836; found, 587.1838.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:17][CH2:18][N:19]([CH2:21][CH2:22]Cl)[CH3:20]>CN(C=O)C>[CH3:20][N:19]1[CH2:21][CH2:22][N:1]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH2:17][CH2:18]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1ncc(C=O)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ncc(C=O)s2)CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
In a 25 ml flask are added 0.5 g of 2-aminothiazole-5-carboxaldehyde, 1.35 g of K2CO3 in 5 ml of DMF. After dissolution, 0.901 g of 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride are added. The mixture is left at room temperature for 1 h then heated to 90° C. for 5 h. Next, the mixture is evaporated, dissolved in 100 ml of water, and the aqueous phase is extracted three times with ethyl acetate. The organic phases are combined, washed with sodium chloride saturated solution, dried over sodium sulfate, filtered, and evaporated to yield 420 mg (50%) of 2-(4-methylpiperazin-1-yl)thiazole-5-carboxaldehyde.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24](O)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C[CH2:28][N:29]=[C:30]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:50][C:51]1([OH:66])[CH2:55][CH2:54][N:53]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59](CNC)[CH:58]=2)[CH2:52]1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:29]([CH2:30][C:60]3[CH:59]=[CH:58][C:57]([CH2:56][N:53]4[CH2:54][CH2:55][C:51]([OH:66])([CH3:50])[CH2:52]4)=[CH:62][CH:61]=3)[CH3:28])=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CCN=C=NCCCN(C)C
Reactant: CNCc1cccc(CN2CCC(C)(O)C2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N(C)Cc3ccc(CN4CCC(C)(O)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (35 mg, 0.09 mmol), EDCI (24 mg, 0.12 mmol), HOBt (18 mg, 0.14 mmol) DIPEA (0.032 mL, 0.18 mmol) and 3-methyl-1-{3-[(methylamino)methyl]benzyl}pyrrolidin-3-ol dihydrochloride (30 mg, 0.10 mmol) in DCM (5 mL). The resulting residue was purified by FCC eluting with 5% MeOH in DCM to afford the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([C:11]([Br:14])=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[CH3:18][Si](C=[N+]=[N-])(C)C.C(OCC)C>CO.O1CCCC1>[C:1]([NH:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([C:11]([Br:14])=[CH:12][CH:13]=1)[C:8]([O:10][CH3:18])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Br)c(C(=O)O)c1[N+](=O)[O-]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1c(Br)ccc(NC(C)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 66.4 %

Procedure:
To a mixed solution of 3-(acetylamino)-6-bromo-2-nitrobenzoic acid (2.00 g, 6.60 mmol) in methanol (20 mL) and tetrahydrofuran (5 mL) was added 2M trimethylsilyldiazomethane/diethyl ether solution (10.6 mL, 21.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 5 days. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=25/75→60/40) to give the title compound (1.39 g, yield 66%).