Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C.O>[OH:6][CH:7]([C:16]1[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: CC(C)(C)[Si](C)(C)OC(C(=O)c1ccccc1)c1ccncc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)C(O)c1ccncc1
Reaction time: 1 h
Yield: 13 %

Procedure:
To a solution of 2-(tert-butyl-dimethyl-silanyloxy)-1-phenyl-2-pyridin-4-yl-ethanone (0.81 mg, 2.46 mmol) prepared in Step 2 in 5 mL of tetrahydrofuran was added a solution of 1.0 M tetra-n-butyl ammonium fluoride in THF (7.4 mL) and the resulting mixture was stirred for 1 hour. After the reaction was complete, the reaction materials were diluted with 50 mL of ethyl acetate and 50 mL of water to dissolve salts, followed by separation of layers. The obtained organic layer was successively washed twice with 50 mL of a brine solution. The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography, to give 68 mg (yield: 13%) of 2-hydroxy-1-phenyl-2-pyridin-4-yl-ethanone of the following formula.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>ClCCl>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC1CCCN(C(=O)c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of the tert-butyl(piperidin-3-ylmethyl)carbamate (429 mg) in 10 ml dichloromethane was added triethylamine (558 μl) followed by 417 mg of 3-(trifluoromethyl)benzoyl chloride. The mixture was stirred at room temperature for 1 h, and then concentrated in vacuo. The residue was filtered through a plug of silica gel (eluting with ethyl acetate) to provide tert-butyl({1-[3-(trifluoromethyl)benzoyl]piperidin-3-yl}methyl)carbamate (665 mg, 86%). To a solution of this in 10 ml of dichloromethane was added trifluoroacetic acid (10 ml). The mixture was stirred at 60° C. for 1 h, and then concentrated in vacuo. The residue was diluted with 30 ml of ethyl acetate and basified by slow and cautious addition of 30 ml of a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated and extracted once with 30 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound (401 mg, 82%). Mass spectrum (ESI) 287.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1[S:14]([Cl:13])(=[O:16])=[O:15]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: O=S(=O)(O)Cl
Product: COc1cc(OC)c(S(=O)(=O)Cl)c(OC)c1
Reaction time: 2 h

Procedure:
16.8 g (0.1 mole) 1,3,5 -trimethoxybenzene were added in portions to 33 ml chlorosulphonic acid, giving a clear pale-yellow solution. The solution was allowed to stand at about 20° C. for 2 hours and was then poured onto ice. The crystals formed were collected, washed with water, taken up in CHCl3, washed with water, and dried with sodium sulphate. The solvent was removed in vacuum, giving 15 g of the crude title compound. The crude product was dissolved in a minimum of hot CHCl3 and di-isopropylether was added. After cooling, white crystals of title compound (9 g) were collected; m.p. 134°-136° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27][C@@H:26]1[CH2:38][CH2:39][OH:40])=[O:24])([CH3:21])([CH3:20])[CH3:19]>ClCCl>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:27][C@@H:26]1[CH2:38][CH:39]=[O:40])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1CC=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 50249.6 %

Procedure:
Add dichloromethane (3 mL) to a 50 mL dry schlenk flask, followed by oxalyl chloride (0.178 g, 1.4 mmol) and cool the solution to −78° C. and treat with dimethyl sulfoxide (0.171 g, 2.2 mmol) and triethylamine (0.505 g, 5.0 mmol). After 10 min, add a solution of (S)-4-benzyl-2-(2-hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.320 g, 1.0 mmol) in dichloromethane (5 mL) and stir the resulting mixture at −78° C. for 1 hour. Quench the reaction mixture by adding sat. NaHCO3, extract the aqueous solution with CH2Cl2, wash the organic solvent with brine, and dry over Na2SO4. Purification by silica gel chromatography of the crude product using MeOH/CH2Cl2 (5% to 10%) as eluent to give the title compound (160 g, 50%) as a light yellow oil: mass spectrum (Electrospray): m/z=319.2 (M+1); 1H NMR (400 MHz, CDCl3): δ9.74 (t, 1H, J=2.0 Hz), 7.33–7.21 (m, 5H), 4.57 (br, 1H), 3.88 (m, 2H), 33.52–3.40 (m, 21H), 3.15–3.05 (m, 1H), 2.83–2.66 (m, 4H), 2.22–2.18 (m, 1H), 2.03 (dt, 1H, J=3.4, 11.8 Hz), 1.44 (s, 9H).
Reaction SMILES: F[C:2]1[C:3]([CH3:24])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[C:18]4([CH2:22][CH2:21]4)[CH2:17][NH:16][C:15](=[O:23])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>>[CH:25]1([NH:28][C:2]2[C:3]([CH3:24])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[C:18]5([CH2:21][CH2:22]5)[CH2:17][NH:16][C:15](=[O:23])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C3(CC3)CNC4=O)c2nc1F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)C3(CC3)CNC4=O)c2nc1NC1CC1
Temperature: 100 °C
Yield: 62.6 %

Procedure:
Prepared according to Example 131 using 2′-(3-fluoro-2-methyl-5-quinoxalinyl)-5′,6′-dihydrospiro[cyclopropane-1,7′-pyrrolo[3,2-c]pyridin]-4′(1′H)-one (Ex. 77a; 39 mg, 0.12 mmol), cyclopropylamine (Alfa Aesar, Ward Hill, Mass.; 14 mg, 0.25 mmol) and DIPEA (47 mg, 0.36 mmol) and heating at 100° C. for 1 h. Purification by chromatography (silica gel, 0-100% EtOAc in hexanes followed by 0-10% MeOH in DCM) provided 2′-(3-(cyclopropylamino)-2-methyl-5-quinoxalinyl)-5′,6′-dihydrospiro[cyclopropane-1,7′-pyrrolo[3,2-c]pyridin]-4′(1′H)-one (27 mg, 62% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br s, D2O exch.), 7.95 (1H, dd, J=7.53, 1.47 Hz), 7.58 (1H, dd, J=8.02, 1.37 Hz), 7.42 (1H, dd, J=2.35, 0.59 Hz), 7.36 (1H, br s, D2O exch.), 7.34 (1H, t, J=7.82 Hz), 7.02 (1H, br s, D2O exch.), 3.29 (2H, d, J=2.35 Hz), 2.91 (1H, tq, J=6.75, 3.52 Hz), 2.51 (3H, s), 1.06-1.12 (2H, m), 0.97-1.02 (2H, m), 0.90-0.97 (2H, m), 0.66-0.74 (2H, m). m/z (ESI, +ve) 360.2 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:29])[C:14]([O:16][CH2:17][O:18][C:19](ON1C(=O)CCC1=O)=[O:20])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:12][CH:13]([CH3:29])[C:14]([O:16][CH2:17][O:18][C:19]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:20])=[O:15]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(C)C(=O)OCOC(=O)ON1C(=O)CCC1=O
Solvent: O
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Product: CC(C)C(=O)OCOC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]methyl 2-methylpropanoate (518 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 4 (397 mg, 66% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.95 (br. m, 2H), 1.08 (d, J=7.2 Hz, 6H), 1.17-1.39 (br. m, 3H), 1.64-1.73 (br. m, 2H), 1.82-1.91 (br. m, 2H), 2.10 (tt, J=11.8, 3.8 Hz, 1H), 2.55 (hept., J=7.2 Hz, 1H), 2.78-2.88 (br. m, 2H), 5.61 (s, 2H), 7.55 (t, J=5.6 Hz, 1H), 11.98 (br. s, 1H). MS (ESI) m/z 302.09 (M+H)+; 299.99 (M−H)−.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[CH:24]=[CH:23][CH:22]=[N:21]1>>[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: O=Cc1cccc(-n2cccn2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(1H-pyrazol-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.80 min.; [M+H]+: 392.16 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[N+:18]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].CCN(CC)CC.C(OC(C)(C)C)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:8][C@H:7]([O:9][S:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)(=[O:28])=[O:29])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:17]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: CC(C)(C)OC=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2cccc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Temperature: 2.5 °C
Reaction time: 18 h

Procedure:
N-Boc-cis-4-hydroxy proline methyl ester (1.0 eq, 6.0 g) were dissolved in MeCl2 (60.0 ml) and 3-nitrobenzenesulfonyl chloride (1.06 eq; 5.747 g) was added. This clear colorless solution was cooled to 0-5° C. and the Et3N (3.0 eq., 10.19 ml) was carefully added. After 0.5 h a yellowish thin suspension was formed, which was stirred for 18 h at ambient temperature. The mixture turned then into a light brown suspension. LC-MS-analysis revealed that the reaction was complete. The reaction mixture was diluted with additional MeCl2 (100 ml) and extracted in succession with aq. 0.5 N HCl, 10% Na2CO3. The combined org. layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to yield a light brown viscous oil (10.8 g; 102%). MS (ESI): m/z=331.2 [M+H-Boc]+
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=1Cl)(=[O:10])=[O:9])([CH3:3])[CH3:2].[H-].[Na+].[OH2:24]>>[CH:1]([O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=1[OH:24])(=[O:10])=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)OCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CC(C)OCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-(2-isopropoxyethyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.635 g, 4.58 mmol), 60% NaH (0.41 g, 13.74 mmol) and water (0.099 mL, 5.50 mmol) were reacted. The crude product (1.676 g) was carried on to the next step without purification. LC-MS (m/z) 340 (M-H)+.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].[CH3:22][O:23][C:24]([C:26]1[CH:27]=[CH:28][C:29](N)=[C:30]2[C:35]=1[N:34]=[CH:33][CH:32]=[CH:31]2)=[O:25]>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:29]1[CH:28]=[CH:27][C:26]([C:24]([O:23][CH3:22])=[O:25])=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: COC(=O)c1ccc(N)c2cccnc12
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccc(C(=O)OC)c3ncccc23)c1=O
Temperature: 126 °C
Reaction time: 0.75 h
Yield: 2.8 %

Procedure:
A mixture of (160 mg, 0.556 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417), 5-aminoquinoline-8-carboxilic acid methyl ester (226 mg, 1.114 mmol) (Preparation 99) and ethanol (8 mL) was introduced in the microwave oven. The mixture was stirred at 126.0° C. during 45 minutes. The solvent was evaporated and the residue purified by column chromatography (silica gel, dichloromethane/methanol 100:1) and preparative HPLC/MS to yield the title compound (7 mg, 3% yield).
Reaction SMILES: [CH2:1]([N:8](C)[C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([OH:20])=O.[OH-].[Na+].[CH3:23]C1C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH2:1]([N:8]([C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[N:15]([CH3:16])[CH3:23])[CH:18]=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=CO
Reactant: CN[C@@H]1CCCC[C@H]1N(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CN(C)[C@@H]1CCCC[C@H]1N(C=O)Cc1ccccc1

Procedure:
A solution of trans-N-benzyl-N,N'-dimethyl-1,2-cyclohexanediamine (9.29 g.; 0.04 mole) in 40 ml. of formic acid was refluxed 20 hours, added and poured into 200 g. of ice. It was basified with 15% NaOH and extracted well with ether. The extract was washed with H2O, saturated salt solution, dried (MgSO4) and evaporated. The residue (9.7 g.) was converted to the salt with 2 mole of p-TSA in ether. The resulting gum was crystallized from MeOH-ether to give 13.64 g.; of the titled compound, m.p. 201°-202.5°. The analytical sample melted at 202°-203°. uv sh 210 nm (ε 27,850); sh 222 (25,600); sh 227 (12,350); sh 243 (302); sh 248 (375); λ max 254 (472); 258 (556); 261 (562); 268 (399); sh 272 (175). ir N + H 2720, 2560; C=O 1670, 1650; C=C 1600, 1495; SO3 /ether 1225, 1170, 1120, 1030, 1010, 815, 705, 685. nmr in D2O (100 MHz) was in accord. Mass spectrum M+ 260.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>ClCCl>[C:23]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:5][CH2:6]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC1CCN(C(=O)c2ccccc2)CC1)c1ccc(F)cc1
Reaction time: 3.5 h

Procedure:
To a suspension of N-(piperidin-4-yl)-4-fluorobenzamide (0.5 g) in dichloromethane (5 ml) were added pyridine (218 μl), dichloromethane (5 ml) and benzoyl chloride (290 μl) at ambient temperature. After stirring for 3.5 hours, water (5 ml) was poured into the mixture. An organic layer was separated, and washed with water and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel, toluene:ethyl acetate=1:1 to ethyl acetate). After rinse with diisopropyl ether, N-(1-benzoylpiperidin-4-yl)-4-fluorobenzamide (515 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([F:12])[CH:4]=1.CCN(C(C)C)C(C)C.[CH3:22][C@H:23]1[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[F:12][C:5]1[CH:4]=[C:3]([CH2:2][N:27]2[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@@H:23]([CH3:22])[CH2:28]2)[CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1F
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2ccc([N+](=O)[O-])c(F)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.5 %

Procedure:
A solution of 4-(bromomethyl)-2-fluoro-1-nitrobenzene (232 mg, 1 mmol) and Hunig's base (0.192 mL, 1.1 mmol) in DMF (3 mL) was treated with 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (200 mg, 1 mmol) in DMF (3 mL) and stirred at room temperature for 20 minutes. The reaction mixture was concentrated, re-dissolved in DCM and washed with water and brine, then dried and concentrated. The crude product was purified by column chromatography. Elution with EtOAc/pentane yielded the title compound as a colourless gum (327 mg). δH (CDCl3, 400 MHz) 8.03 (1H, m), 7.34 (1H, dd), 7.27 (1H, m), 4.22 (1H, br.s), 3.84 (1H, d), 3.58 (1H, d), 3.47 (1H, d), 3.13 (1H, td), 2.72 (1H, m), 2.54 (1H, m), 2.22 (1H, dd), 2.09 (1H, m), 1.46 (9H, s), 1.26 (3H, d) [values corrected for incorrectly referenced TMS at 0.62 ppm on spectrum].
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].Cl.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[H-].[Na+].O>CN(C=O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=2[C:2](=[O:3])[O:4][C:5]1=[O:12]
Reactant: ClCc1ccccn1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1oc(=O)n(Cc2ccccn2)c2ccccc12
Temperature: 25 °C
Reaction time: 42 h
Yield: 33.8 %

Procedure:
To a solution of isatoic anhydride (25.4 g, 0.156 mol) in DMF (300 mL) were added 2-(chloromethyl)pyridine hydrochloride (28.1 g, 0.171 mol) and sodium hydride (66% in oil, 12.5 g, 0.34 mol) under ice-cooling. The obtained mixture was stirred at room temperature for 42 hr. Water (750 mL) was added to the reaction mixture and the mixture was ice-cooled. The precipitated solid was collected by filtration, and recrystallized from acetone-diisopropyl ether to give the title compound (13.4 g, 34%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)(=O)=O.[C:28]([Si:30]([CH3:33])([CH3:32])[CH3:31])#[CH:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C(N(CC)CC)C.C(OCC)(=O)C.[Cu](I)I>[CH3:31][Si:30]([C:28]#[C:29][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)([CH3:33])[CH3:32]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)cc3cccnc23)c1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc2cccnc2c(-c2cccc([N+](=O)[O-])c2)n1
Reaction time: 2 h

Procedure:
To a solution of 6-trifluoromethylsulfonyloxy-8-(3-nitrophenyl)-1,7-naphthyridine (200 mg, 0.50 mmol; prepared according to example 13) in dimethylformamide (1 ml) and triethylamine (0.5 ml) is added ethynyltrimethylsilane (0.078 ml, 0.56 mmol), bis(dibensylideneacetone)palladium (5.8 mg, 0.020 mmol), triphenylphosphine (5.3 mg, 0.020 mmol) and copper iodide (3.8 mg, 0.020 mmol). The mixture is kept at 60° C. for 2 h. The solution is diluted with ethyl acetate and washed with water. The product is purified by flash column chromatography on silica gel (20:0.2 toluene/acetone) affording 6-trimethylsilylethynyl-8-(3-nitrophenyl)-1,7-naphthyridine. (Mass M+H 348; mp 160-163° C.)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27](OS(C)(=O)=O)[CH3:28])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:34])[CH:10]2[NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:7])[CH2:3][CH2:2]1.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>C1C=CC=CC=1>[CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[CH3:28])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:34])[CH:10]2[NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC1CC1
Solvent: c1ccccc1
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC1CC1)N1CCOCC1
Reaction time: 8 h

Procedure:
To a solution of p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-methanesulfonyloxyethylidene)acetate (1.12 g) in benzene (11 ml) is added morpholine (0.26 ml) under ice cooling, and the mixture is kept at 10° C overnight. The reaction mixture is washed with water, dried, and evaporated under reduced pressure. Purification of the obtained residue (1 g) by chromatograaphy over silica gel (10 g) using a mixture of benzene and ethyl acetate (1:2) gives p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-morpholinoethylidene)acetate (602 mg). Foam. IR: νmaxCHCl3 3430, 1774, 1694br, 1604, 1105, cm-1. NMR: δCDCl3 0.22m5H, 2.27+2.24s3H, 3.43m4H, 3.77m4H, 4.02d(6.4Hz)2H, 4.57s2H, 5.05-5.27m3H, 5.89d(5.4Hz)1H, 4.12-7.65m7H, 8.23d(8.4Hz)2H.
Reaction SMILES: [F:1][C:2]1[C@H:3]([OH:33])[C@@H:4]2[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]2[C:11]=1[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>C(Cl)Cl>[CH3:41][S:42]([O:33][C@@H:3]1[C@H:4]2[C@H:5]([O:6][C:7]([CH3:10])([CH3:9])[O:8]2)[C:11]([CH2:12][O:13][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:2]1[F:1])(=[O:44])=[O:43]
Reactant: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(F)[C@@H]2O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(F)[C@@H]2OS(C)(=O)=O
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
Compound 10 (787 g (corrected), 1 wt), (gross input 1292 g), was dissolved in DCM (7.87 L, 10 vol) and cooled to 0 to 5° C. Triethylamine (368 mL, 0.468 vol, 1.5 eq) was charged followed by MsCl (164 mL, 0.208 vol, 1.3 eq) whilst maintaining the temperature at 0 to 5° C. IPC by 1H NMR analysis after 30 minutes indicated that 94.2% conversion had been achieved. An additional charge of triethylamine (28 mL) and MsCl (16 mL) (2 mol % per 1% conversion remaining) was made. IPC analysis after 30 minutes indicated that the conversion had increased to 97.3%. A second additional charge of triethylamine (13 mL) and MSCl (7.5 mL) was made. After a further 30 minutes IPC by 1H NMR analysis indicated that 100% conversion had been achieved. Water (7.87 L, 10 vol) was charged to the reaction and the mixture warmed to 15 to 25° C. Once the reaction was within the temperature range it was stirred for 10 minutes and the phases separated. The organic phase was returned to the flask, saturated NaHCO3 (7.87 L, 10 vol) charged and the two phases mixed for 10 to 20 minutes, then separated. The organic phase was dried over Na2SO4 (787 g, 1 wt) for 10 minutes, filtered and the filter cake washed with DCM (2×787 mL, 2×1 vol). The combined filtrate and washes were concentrated at up to 30° C. on a rotary evaporator under vacuum to obtain 11 as an orange oil. 1H-NMR (400 MHz, CDCl3) δ 7.7 ppm, d, 4H, TBDPS-F stage 1 by-product, δ 7.25 to 7.5 ppm, 21H. Trityl group and TBDPS-F by-product, δ 5.23 ppm, (d, J=5.8 Hz, 1H) (CH), δ 5.10 ppm, (t, J=7.1 Hz, 1H) (CH), δ 4.77 ppm, (m, J=2.8 Hz, 1H) (CH), δ 4.0 ppm, (d, J=12.6 Hz, 1H), 3.9 ppm, (d, J=12.6 Hz, 1H) (CH2), δ 3.1 ppm, s, 3H, Mesylate, (CH3), δ 1.4 ppm, 6H, Acetonide, (2×CH3), δ 1.1 ppm, 3, 9H, (3×CH3, TBDPSF), Solvents δ 5.8 ppm, s, 2H DCM.