Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:6]([Cl:25])=[CH:7][C:8]([NH:18][CH2:19][C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[C:9]([CH:17]=1)[C:10]([O:12][CH2:13][CH2:14][CH2:15][OH:16])=[O:11])(=[O:4])=[O:3].[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1.C1CN2C(=NCCC2)C1.C(#N)C>ClCCl>[NH2:1][S:2]([C:5]1[C:6]([Cl:25])=[CH:7][C:8]([NH:18][CH2:19][C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[C:9]([CH:17]=1)[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:11])(=[O:3])=[O:4]
Reactant: O=C1CCC(=O)O1
Reactant: NS(=O)(=O)c1cc(C(=O)OCCCO)c(NCc2ccco2)cc1Cl
Agent: C1CN=C2CCCN2C1
Solvent: CC#N
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)OCCCOC(=O)CCC(=O)O)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 3-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)propanol (805) (0.060 mole), succinic anhydride (Aldrich) (0.060 mole), DBN (1,5-diazabicyclo[4.3.0]non-5-ene,(Aldrich) (0.060 mole) and dry acetonitrile (50 mL) is stirred at ambient temperature for 10 hours. The reaction mixture is diluted with dichloromethane (200 mL) and extracted with 0.1 N hydrochloric acid solution, washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give to give 4-(3-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)propoxy)(4-oxo)butanoic acid (810).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]4[C:21](=O)[C:22](=[O:27])[C:23]=4[O:24]CC)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[NH4+:30]>C(O)C>[NH2:30][C:21]1[C:22](=[O:27])[C:23](=[O:24])[C:20]=1[NH:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CCOc1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(=O)c1=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(=O)c1=O
Temperature: 25 °C

Procedure:
A mixture of 0.8 g of 3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylamino]-4-ethoxy-cyclobut-3-ene-1,2-dione, 8 mL of ammonium hydroxide, and 8 mL of ethanol was refluxed for 1 hr. The mixture was cooled to room temperature and the solid was collected and washed with ethanol and ether giving 0.65 g of 3-Amino-4-[4-(3-bromo-phenylamino)-quinazolin-6-ylamino]-cyclobut-3-ene-1,2-dione as a yellow powder: mass spectrum (m/e): M+H 412.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Cl:11]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:11][C:7]1[C:2]([OH:1])=[N:3][CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1ccc(O)nc1
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
2-Hydroxy-5-nitropyridine (50 g, 357 mmol) and N-chlorosuccinimide (55 g, 410 mmol) were suspended in anhydrous DMF (150 mL). The suspension was stirred at room temperature for 18 hours. The resulting homogeneous reaction mixture was diluted by the slow addition of water (750 mL), which resulted in a pale yellow precipitate. The solids were isolated via filtration and dried under high vacuum to provide 3-chloro-5-nitro-2-hydroxypyridine (59 g, 95% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7])[CH3:2].[OH-].[K+].[O:20]1CCC[CH2:21]1>>[CH2:16]([N:3]([CH2:1][CH3:2])[C:4](=[O:15])[C:5]([CH2:21][OH:20])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7])[CH3:17]
Reactant: C1CCOC1
Reactant: CCN(CC)C(=O)C(C(=O)O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CCN(CC)C(=O)C(CO)(C(=O)O)c1ccccc1
Reaction time: 5 h

Procedure:
The phenylmalonic acid diethylamide (2.34 g) obtained in Example 1-b) and paraformamide (390 mg) were suspended in tetrahydrofuran (20 ml), and to this suspension was added potassium hydroxide (catalytic amount) at 60° C. The mixture was stirred for 5 hours and concentrated to remove the solvent. The residue was chromatographed on a column of silica gel with ethyl acetate:hexane=1:1 to give the title compound (2.31 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[NH:7][C:6]=2[CH:5]=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:12])([F:13])[F:14])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[CH3:27])[C:6]=2[CH:5]=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)c2nc(C(F)(F)F)[nH]c2c1
Reactant: Cc1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1Cn1c(C(F)(F)F)nc2c(Br)cc([N+](=O)[O-])cc21
Temperature: 90 °C
Reaction time: 6 h
Yield: 56.2 %

Procedure:
Charged a 100 mL round bottom flask containing 4-bromo-6-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (4.3 g, 13.87 mmol) dissolved in N,N-Dimethylformamide (DMF) (30 mL) with 1-(bromomethyl)-3-chloro-2-methylbenzene (3.81 g, 17.34 mmol) then added potassium carbonate (4.79 g, 34.7 mmol). The resulting reaction suspension was stirred for 6 h at 90° C., then cooled to RT, and filtered to remove potassium carbonate. The resulting filtrate was concentrated to a small volume (˜10 mL), and diluted with water. The aqueous suspension was extracted with chloroform (3×), the organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and finally concentrated in vacuo. The crude solid was slurried in hexane to provide 4-bromo-1-(3-chloro-2-methylbenzyl)-6-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (3.5 g, 7.80 mmol, 56.2% yield). The material was carried onto the nitro reduction without further purification. MS (ES+) m/e: 449.0, 450.8 [M+H]+(bromine pattern). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.55 (d, J=2.02 Hz, 1H) 8.08 (d, J=1.77 Hz, 1H) 7.40 (d, J=8.08 Hz, 1H) 7.04 (t, J=7.96 Hz, 1H) 6.23 (d, J=7.83 Hz, 1H) 5.63 (s, 2H) 2.52 (s, 3H)
Reaction SMILES: [C:1]12[C:18](=[O:19])[O:17][C:15](=[O:16])[C:13]3[C:14]1=[C:5]([C:6]1[C:11]([CH:12]=3)=[N:10][CH:9]=[CH:8][CH:7]=1)[CH:4]=[CH:3][CH:2]=2.[N+:20]([O-])([O-:22])=[O:21].[Na+].O>S(=O)(=O)(O)O>[N+:20]([C:3]1[CH:2]=[C:1]2[C:18](=[O:19])[O:17][C:15](=[O:16])[C:13]3=[CH:12][C:11]4[C:6]([C:5]([CH:4]=1)=[C:14]23)=[CH:7][CH:8]=[CH:9][N:10]=4)([O-:22])=[O:21]
Reactant: O=C1OC(=O)c2cc3ncccc3c3cccc1c23
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1OC(=O)c2cc3ncccc3c3cc([N+](=O)[O-])cc1c23
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
As above for example 2, part A, 8-azaphenanthrene-1,10-dicarboxylic anhydride (7.62 g, 30.6 mmol) was nitrated in concentrated sulfuric acid (30 mL) at 110° C. by the addition of sodium nitrate (6.50 g, 76.5 mmol) in five portions over 31 h. The acid solution was poured into water (300 mL), rinsing the residue from the reaction flask with water (4×25 mL). The aqueous suspension was neutralized to about pH 4 with concentrated sodium hydroxide solution and sodium acetate (5 g) was added as a buffer. The precipitated solid was collected on a frit and dried. The crude material was heated at reflux in acetic acid (70 mL) and acetic anhydride (10 mL) for 4 h and the suspension was cooled to room temperature. The brown solid was collected on a frit, washed with acetic acid (20 mL), and dried to give 5.94 g (66%) of the nitro compound: mp >300° C.; 1H NMR (CDCl3, 300 MHz) δ 7.97 (dd, 1H, J=9.0, 4.5 Hz), 9.16 (d, 1H, J=9.0 Hz), 9.33 (d, 1H, J=4.5 Hz), 9.42 (s, 1H), 9.48 (d, 1H, J=1.5 Hz), 9.87 (d, 1H, J=1.5 Hz); MS (CI, CH4) m/e (%) 295 (M+H+, 100), 250 (4), 121 (6), 103 (4), 93 (19).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[N:15][CH:16]=1.Cl>CN(C=O)C>[Br:1][C:2]1[C:3]([OH:9])=[N:4][C:5]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[N:15][CH:16]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(S(N)(=O)=O)nc1
Reactant: Oc1nc(Cl)ncc1Br
Agent: Cl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(Nc2ncc(Br)c(O)n2)cn1
Temperature: 100 °C
Reaction time: 30 h

Procedure:
2.0 g (9.62 mmol) of 5-bromo-2-chloro-4-hydroxypyrimidine and 1.686 g (9.62 mmol) of 5-amino-pyridine-2-sulfonic acid amide are mixed in 50 ml of DMF (p.a.) with 2.88 ml of hydrochloric acid (4 molar in dioxane). It is stirred for 30 hours at 100° C., cooled and concentrated by evaporation. After being taken up in methanol, 1.505 g (45% of theory) of 5-(5-bromo-4-hydroxy-pyrimidin-2-ylamino)-pyridine-2-sulfonic acid amide is crystallized out, which is dried at 50° C. in a vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([S:12][CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[CH:16][N:15]=3)=[N:11][C:6]2=[CH:5][C:4]=1[CH3:23].ClC1C=CC=C(C(OO)=[O:32])C=1.C(=O)(O)[O-].[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([S:12]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[CH:16][N:15]=3)=[O:32])=[N:11][C:6]2=[CH:5][C:4]=1[CH3:23]
Reactant: COc1ccnc(CSc2nc3cc(C)c(OC)nc3[nH]2)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccnc(CS(=O)c2nc3cc(C)c(OC)nc3[nH]2)c1C
Temperature: -30 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
5-Methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)thio)-6-methyl-3H-imidazo[4,5-b]pyridine (784 mg, 2.37 mmol) was dissolved in a mixture of methanol (6 ml) and toluene (54 ml). Metachloroperbenzoic acid (566 mg) in a mixture solution of methanol (3 ml) and toluene (3 ml) were added thereto at −40° C. under nitrogen flow, and the reaction mixture was stirred at −20 to −40° C. for 2 hours. After the reaction was completed, a sodium bicarbonate solution was added, and the organic layer was separated. The aqueous layer was extracted with chloroform (40 ml), combined with the organic layer and dried over sodium sulfate, the solvent was evaporated and the residue was obtained which was then precipitated as a solid from a mixture of chloroform and ether, thereby yielding the title compound (654 mg, 1.89 mmol, 80%) as a purple gray solid.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:40]=[CH:39][C:12]([NH:13][C:14]2[CH:26]=[C:25](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[CH:24]=[CH:23][C:15]=2[C:16]([O:18]C(C)(C)C)=[O:17])=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:14]2[CH:26]=[C:25](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:31][CH:30]=3)[CH:24]=[CH:23][C:15]=2[C:16]([OH:18])=[O:17])=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc(C(F)(F)F)cc2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(/C=C/c2ccc(C(F)(F)F)cc2)cc1Nc1ccc(F)cc1

Procedure:
Trifluoroacetic acid 15 mL solution of the obtained tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(4-trifluoromethylphenyl)vinyl)benzoate was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give 2-(4-fluoroanilino)-4-((E)-2-(4-trifluoromethylphenyl)vinyl)benzoic acid 50 mg of pale yellow solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:27]1[C:36]2[CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:30]=2[CH:29]=[CH:28]1>C(Cl)Cl>[NH:27]1[C:36]2[CH2:35][CH2:34][CH2:33][CH2:32][N:31]([C:10]([CH:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)=[O:12])[C:30]=2[CH:29]=[CH:28]1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: c1cc2c([nH]1)CCCCN2
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)N1CCC(C(=O)N2CCCCc3[nH]ccc32)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
To a mixture of 1-acetyl-piperidine-4-carboxylic acid (822 mg, 4.8 mmol, 1.2 eq.), EDC (920 mg, 1.2 eq.), HOBt (648 mg, 1.2 eq.) in DCM (15 mL) was added TEA (1.3 mL, 2 eq.) and 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine (550 mg, 4 mmol). The mixture was stirred at rt for 2 days. The reaction was diluted with DCM, washed with water, sat. NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 1.1 g of 1-[4-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepine-4-carbonyl)-piperidin-1-yl]-ethanone as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]=[C:11]=[O:12])[CH:5]=1.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][C:26]2[CH:39]=[CH:38][C:29]([C:30]([NH:32][C:33]3[N:34]=[N:35][NH:36][N:37]=3)=[O:31])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>ClC(Cl)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([N:24]([C:21]2[CH:20]=[CH:19][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:23][CH:22]=2)[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30](=[O:31])[NH:32][C:33]3[N:34]=[N:35][NH:36][N:37]=3)=[CH:38][CH:39]=2)=[O:12])[CH:5]=1
Reactant: COC(=O)c1cccc(N=C=O)c1
Reactant: CC(C)(C)c1ccc(NCc2ccc(C(=O)Nc3nn[nH]n3)cc2)cc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(NC(=O)N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)c2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2.50 mmol 3-isocyanatobenzoic acid methyl ester dissolved in 5 mL dichloroethane was added to the above resin 4-[(4-tert-butylphenylamino)methyl]-N-(2H-tetrazol-5-yl)benzamide (500 mg). Shaking the mixture 5 hours at 25° C. followed by filtration and washing of the resin with dichloromethane (2×10 mL), DMF (2×10 mL) and THF (3×10 mL) afforded the resin bound title compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]([SH:9])=[N:7][C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:5]1)([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH2:25]Cl)[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH2:25][S:9][C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)n1nc(-c2ccncc2)nc1S
Reactant: O=C(CCl)Nc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1nc(-c2ccncc2)nc1SCC(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of the thiol TFA salt from Step A (100 mg, 0.30 mmol), N-(3-Chlorophenyl)-2-chloroacetamide (61 mg, 0.30 mmol), and triethylamine (0.145 mL 1.040 mmol) in dichloromethane (2.0 mL) was stirred at room temperature for 6 h. The solvent was removed by evaporation, and the crude product was purified by HPLC to afford the title compound as a colorless solid, 127 mg (85%). MS (ES): 388 (M+H)+
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:11]([O:15][C:16](=[O:29])[N:17]([C:19]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][C:20]=1[N+:26]([O-])=O)[CH3:18])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([O:15][C:16](=[O:29])[N:17]([C:19]1[CH:24]=[C:23]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:22]=[CH:21][C:20]=1[NH2:26])[CH3:18])([CH3:14])([CH3:12])[CH3:13]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)ccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To anhydrous DMF were added benzyl alcohol (2.48 ml) and 55% NaH (1.05 g) and then N-(2-nitro-5-chlorophenyl)-N-methylcarbamic acid t-butyl ester (5.73 g) was added in small portions. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and concentrated. The resulting residue was stirred in a mixture of dioxane (100 ml), water (10 ml), sodium hydrosulfite (20.9 g) and sodium hydrogencarbonate (21.0 g) at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water and the extract was dried over anhydrous sodium sulfate and concentrated. The resulting residue was chromatographed on a silica gel column using ethyl acetate/n-hexane (1/2) as the eluant to afford the title compound (2.29 g). melting point: 86-89° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[N+:9]([C:12]1[CH:13]=[CH:14][C:15]2[NH:20][CH2:19][CH2:18][O:17][C:16]=2[CH:21]=1)([O-])=O.[H-].[Na+]>CN(C=O)C>[CH3:1][N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([NH2:9])[CH:13]=[CH:14][C:15]1=2
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCOc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
Potassium carbonate (800 mg, 6 mmol) and methyl iodide (1.3 g, 9 mmol) were added to a solution of 3,4-dihydro-7-nitro-2H-benzo[b][1,4]oxazine (540 mg, 3 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature overnight. Sodium hydride (100 mg, 95%) and methyl iodide (1.0 g) were added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was suspended in water. A solid precipitated which was filtered and washed with water. The bright yellow solid was then suspended in MeOH (20 mL) and Pd/C (10%) was added. The suspension was stirred under an atmosphere of hydrogen overnight, then filtered through celite and the filtrate concentrated under vacuum to give the product (470 mg) as a purple oil.
Reaction SMILES: [CH2:1]([SH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][SH:11].C(=O)([O-])[O-].[K+].[K+].Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:36])[C:27]([CH3:35])([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH3:28])=[CH:22][CH:21]=1>CC(N(C)C)=O>[SH:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][C:20]1[CH:21]=[CH:22][C:23]([C:26](=[O:36])[C:27]([CH3:28])([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[CH3:35])=[CH:24][CH:25]=1
Reactant: SCCCCCCCCCCS
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C(=O)c1ccc(SCCCCCCCCCCS)cc1)N1CCOCC1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
51.7 g (0.25 mol) of 1,10-decanedithiol are added to a suspension of 13.9 g (0.10 mol) of potassium carbonate in 50 ml of dimethylacetamide. The suspension is heated to 85° C., and a solution of 13.4 g (0.05 mol) of 1-(4-chlorophenyl)-2-methyl-2-morpholin-4-yl-propan-1-one in 25 ml of dimethylacetamide is added dropwise over 5 h. After stirring for 18 h, the solid is filtered off, the filtrate is poured into 30 ml of 2N HCl solution. The formed white precipitate is collected by filtration and then dissolved in methylene chloride and neutralized with 30 ml of 2N NaOH solution. After methylene chloride is distilled off, the residual crystals are further purified by recrystallization from chloroform-ethanol (20:80). The obtained product has a melting point of 87-90° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.28-1.39 (m, 9H), 1.45 (m, 2H),1.31 (s, 6H), 1.64 (q, 4H), 1.69 (m, 2H), 2.52 (q, 2H), 2.56 (m, 4H), 2.99 (m, 2H), 3.71 (m, 4H), 7.26 (d, 2H), 8.49 (d, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:9]=1[NH:17][C:18](=[O:34])[CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[CH:22]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]2[NH:17][C:18](=[O:34])[CH2:19][C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)[CH:22]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1ccc(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)c(NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc2c(c1)N=C(c1cccc(-c3ccncc3)c1)CC(=O)N2

Procedure:
The title compound was prepared from {5-ethoxy-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M145) (193 mg, 0.41 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a brown solid (105 mg, 72%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:28])=[C:4]2[CH2:26][CH2:25][N:24]([CH3:27])[C:5]2=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CN(C)CCN(C)C.[Li]CCCC.COB(OC)OC.[C:49]([O:52]O)(=[O:51])[CH3:50].C(N(CC)CC)C.C(OC(=O)C)(=O)C>C1COCC1.CN(C1C=CN=CC=1)C.O>[C:49]([O:52][C:2]1[C:3]([CH3:28])=[C:4]2[CH2:26][CH2:25][N:24]([CH3:27])[C:5]2=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:51])[CH3:50]
Reactant: CC(=O)OO
Reactant: CCCCCCCCCCCCCCCCc1nc2c(c(C)c1Br)CCN2C
Agent: CN(C)CCN(C)C
Agent: CN(C)c1ccncc1
Agent: COB(OC)OC
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCc1nc2c(c(C)c1OC(C)=O)CCN2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 43.5 mg (0.10 mmol) of 5-bromo-1,4-dimethyl-6-hexadecyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 1 mL of THF was added 14.2 μL (0.10 mmol) of tetramethylethylenediamine (TMEDA) at −20° C. followed by 119 μL (0.19 mmol, 1.6 M in hexanes) of n-BuLi. After 30 min, 23.4 μL (0.21 mmol) of trimethoxy boron was added and the resulting mixture was stirred for another 1 h. To the reaction mixture was added slowly 44.1 μL (0.21 mmol, 32 wt %) of peracetic acid and the solution was then warmed to 0° C. over a period of 30 min. The mixture was diluted by 5 mL of H2O and extracted with three 5-mL portions of EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and the solvent was concentrated under diminished pressure. The resulting oil was dissolved in 2 mL of CH2Cl2 at 0° C., followed by the addition of 79.6 μL (0.57 mmol) of triethylamine, 1.2 mg (0.01 mmol) of DMAP and 27.0 μL (0.29 mmol) of acetic anhydride. The reaction mixture was stirred at room temperature for 1 h and quenched by the addition of 2 mL of sat aq NH4Cl. The solution was then extracted with three 5-mL portions of EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and the solvent was concentrated under diminished pressure. The residue was purified by flash chromatography on a silica gel column (20 1.7 cm). Elution with 100:1 hexanes/ethyl acetate gave 2c as a yellow oil: yield 15.0 mg (37%); silica gel TLC Rf 0.20 (3:7 EtOAt/hexanes); 1H NMR (CDCl3) δ 0.86 (t, 3H, J=6.8 Hz), 1.23-1.28 (m, 28H), 1.60 (quint, 2H, J=7.6 Hz), 1.93 (s, 3H), 2.28 (s, 3H), 2.44 (t, 2H, J=8.0 Hz), 2.82 (t, 2H, J=8.0 Hz), 2.87 (s, 3H) and 3.41 (t, 2H, J=8.0 Hz); 13C NMR (CDCl3) δ 12.9, 14.1, 20.5, 22.7, 24.6, 28.7, 29.4, 29.51, 29.59 29.64, 29.68, 29.68, 29.68, 29.68, 29.68, 29.68, 29.68, 31.9, 32.5, 33.3, 52.8, 120.1, 134.7, 136.5, 149.7, 161.2 and 169.9; mass spectrum, m/z 430.3 (M)+ (theoretical 430.4); mass spectrum (APCI), m/z 431.3637 (M+H)+ (C27H47N2O2 requires 431.3638).
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[CH2:4][NH:3]1.C(N(CC)CC)C.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:21]([N:3]1[CH2:4][C:2]1([CH3:5])[CH3:1])([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)CN1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2-Dimethyl aziridine is dissolved in CH2Cl2 and triethyamine under argon at 0° C. Benzylchloroformate is added and the contents of the flask are stirred at room temperature overnight. The mixture is poured into 10% citric acid and extracted with CHCl3. The organic layer is washed with dilute aqueous NaHCO3 and dried over MgSO4. The solution is evaporated to yield N-Cbz-2,2-dimethylaziridine.