Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([O:12]C)=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+]>CO.O>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1cnc2cn[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.7 %

Procedure:
To a solution of methyl 1H-pyrazolo[4,3-b]pyridine-6-carboxylate (3.52 g, 20 mmol) in methanol (250 mL) and water (190 mL) at 0° C. was added aqueous sodium hydroxide (2M, 64 mL, 128 mmol), dropwise. The suspension was then allowed to warm to ambient temperature and stirred for 18 hours. The methanol was then removed in vacuo and the aqueous mixture extracted with ethyl acetate (250 mL). The aqueous layer was acidified (to pH 5-6) with 2 N aqueous hydrochloric acid (70 mL). The cream solid which had precipitated out was then filtered off and dried in a desiccator to yield the title compound (0.675 g, 21%). 1HNMR (400 MHz, DMSO-d6, δ): 8.97 (s, 1H), 8.45 (s, 1H), 8.39 (s, 1H).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14][CH2:13]3)[N:4]=[CH:3]1.[Cl:21][C:22]1[S:26][C:25]([CH:27]=O)=[CH:24][CH:23]=1>[OH-].[K+].CCO>[ClH:21].[Cl:21][C:22]1[S:26][C:25]([CH:27]=[C:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][CH:19]=[C:10]([O:9][CH2:8][CH2:7][C:5]4[N:4]=[CH:3][NH:2][CH:6]=4)[CH:11]=3)[C:16]2=[O:20])=[CH:24][CH:23]=1
Reactant: O=C1CCCc2cc(OCCc3c[nH]cn3)ccc21
Reactant: O=Cc1ccc(Cl)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccc(Cl)s2)CCc2cc(OCCc3c[nH]cn3)ccc21
Yield: 114.3 %

Procedure:
According to the method of Example 34, 6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one, monohydrochloride (0.313 g, 1.07 mmol) was reacted with 5-chloro-2-thiophene carboxaldehyde (0.165 g, 1.13 mmol) in 5 mL of 4% KOH in EtOH overnight to afford 0.272 g (60%) of the title compound as a dull yellow powder, mp dec. >210° C.: CI-MS m/e 385, 387 (M+ -Cl).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1.[O:26]=[CH:27][C:28]1[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[C:30](O)[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:34][O:33][C:32]1[CH:35]=[CH:36][C:28]([CH:27]=[O:26])=[CH:29][C:30]=1[O:23][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([F:24])([F:25])[F:13])=[CH:20][CH:19]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: OCCc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1OCCc1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 72.3 %

Procedure:
Under an argon atmosphere, stirring and cooling with ice, diethyl azodicarboxylate (40% toluene solution, 3.80 mL, 8.38 mmol) was added dropwise to a solution of 2-[4-(tri-fluoromethyl)phenyl]ethanol (1.59 g, 8.36 mmol), isovanillin (1.28 g, 8.41 mmol) and triphenylphosphine (2.20 g, 8.39 mmol) in anhydrous tetrahydrofuran (50 mL). After completion of the dropwise addition, the mixture was stirred for 1 hour under cooling with ice, and then allowed to stand overnight at room temperature. The reaction mixture was concentrated and the residue was purified by silica gel column chro-matography (eluent: n-hexane:ethyl acetate=6:1 v/v) to afford 1.96 g (72%) of the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C1C=NC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.[CH3:68][C:69]1[S:70][C:71]([CH2:74][N:75]2[C:80]3[CH:81]=[C:82]([C:84]4[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=4)[S:83][C:79]=3[C:78](=[O:90])[N:77]([CH:91]3[CH2:96][CH2:95][NH:94][CH2:93][CH2:92]3)[C:76]2=[O:97])=[CH:72][N:73]=1>CCN(C(C)C)C(C)C>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:94]4[CH2:95][CH2:96][CH:91]([N:77]5[C:78](=[O:90])[C:79]6[S:83][C:82]([C:84]7[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=7)=[CH:81][C:80]=6[N:75]([CH2:74][C:71]6[S:70][C:69]([CH3:68])=[N:73][CH:72]=6)[C:76]5=[O:97])[CH2:92][CH2:93]4)=[O:22])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: Cc1ncc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)s1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5cnc(C)s5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (199 mg; compound C10), TOTU (213 mg) and HOAT (102 mg) in DIPEA (259 mg) is stirred for 50 min at RT. Subsequently, 1-[(2-methyl-1,3-thiazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione trifluoroacetate (276 mg; compound B44) is added and the reaction mixture is stirred for additional 60 min at RT. The solvent is removed under reduced pressure and to the resulting residue DCM (15 ml) and saturated aqueous sodium bicarbonate solution (3 ml) are added. The organic phase is separated and the aqueous phase is extracted with DCM (10 ml). The combined organic phases are applied to a phase separator, dried over magnesium sulfate and the solvent is removed under reduced pressure to give the crude title compound. The residue is first purified by flash chromatography [amino phase silica gel, eluation gradient: cyclohexane/EtOAc, 100/0 to 0/100 (v/v)]. After a second purification step applying preparative TLC [20×20 cm TLC plates with 0.5 mm thickness, eluent: EtOAc/triethylamine, 97/3 (v/v)] the title compound is obtained as a solid.
Reaction SMILES: [CH2:1]1[C:10](=[O:11])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C(N(CC)CC)C.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:19][Si:20]([CH3:22])([CH3:21])[O:11][C:10]1[CH2:1][CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:9]=1
Reactant: O=C1CCc2ccccc2C1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OC1=Cc2ccccc2CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Charge an oven dried, nitrogen flushed 100-mL round bottomed flask equipped with a stirring bar with β-tetralone (4.977 grams, 0.0340 moles), triethylamine (6.970 grams, 0.0689 moles), 4-dimethylamino pyridine (0.219 grams,0.0018 moles), trimethylsilyl chloride (7.704 grams, 0.0709 moles) and 30 mL methylene chloride. Stir at RT for 20 hours, filter, wash the solid with 1×20 mL methylene chloride, wash the combined organic layers with 1×5 mL saturated sodium bicarbonate solution, 1×5 mL water, dry over magnesium sulfate, concentrate on a Buchi rotavapor and distill (96°-99° C., 1 Torr) to yield the product as a viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:19]([NH:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:21])[CH3:20]>CO>[C:19]([NH:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][CH:25]([CH3:26])[CH3:27])(=[O:21])[CH3:20].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Agent: CC(=O)N[C@@H](CC(C)C)C(=O)O
Solvent: CO
Product: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 mL). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30° C. to a constant weight, yielding 49.6 g (90% recovery) of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine-N-acetyl-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4@pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm×4.6 mm, 0.5 mL/min., @240 nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(C)=O)[N:3]=1.[O:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1.O>CN1CCCC1=O>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:28][CH:25]2[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)[N:3]=1
Reactant: NC1CCOCC1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(S(C)=O)nc1N
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCOCC2)nc1N

Procedure:
A solution of (4-amino-2-methanesulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (235 mg, 0.73 mmol, Example 157) and tetrahydro-pyran-4-ylamine (Combi-Blocks) (260 mg, 2.3 mmol) in N-methylpyrrolidinone (15 ml) was heated for 30 minutes at 100° C. The solution was cooled, poured into water and extracted into ethyl acetate (2×). The combined organic extracts were washed with 5% sodium bicarbonate and saturated sodium chloride. The solution was dried (Na2SO4) and solvent was removed under vacuum to give a crude solid. Purification was by silica gel chromatography to give [4-amino-2-(tetrahydro-pyran-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid. HRMS, observed: 346.1445; Calcd for M+: 346.1441.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:20]2[CH:19]=[CH:18][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc2ccccc2c1
Reactant: COC(=O)[C@@H]1C[C@@H](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: COC(=O)[C@@H]1C[C@H](Oc2ccc3ccccc3c2)CN1C(=O)OC(C)(C)C

Procedure:
To a stirred mixture of methyl (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarboxylate (4.22 g, 17.2 mmol, 2-naphthol (2.73 g, 18.9 mmol) and PPh3 (4.96 g, 18.9 mmol) in THF (80 ml) was added DIAD (3.72 ml, 18.9 mmol) at room temperature under an atmosphere of nitrogen. After stirring over night, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel [600, CHCl3/EtOAc (10/1)], to give methyl (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylate (5.37 g), which was used to the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]([CH3:15])[C:8]2=[N:7]1)[C:3]#[N:4].[O:18]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:16][C:12]1[CH:13]=[C:14]([CH3:15])[C:8]2[C:9]([CH:11]=1)=[N:10][N:6]([CH2:5][C:2]([NH:1][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:33][CH:32]=1)([C:3]#[N:4])[CH3:17])[N:7]=2
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: Cc1cc(Cl)cc2nn(CC(C)(N)C#N)nc12
Product: Cc1cc(Cl)cc2nn(CC(C)(C#N)NC(=O)c3ccc(Oc4ccccc4)cc3)nc12

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-4-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile (60 mg, described in Example 27) and 4-phenoxybenzoyl chloride (0.067 mL), the title compound was isolated as a white solid (90 mg, 84%). MS (ES): M/Z [M+H]=446. NMR: (400 MHz, DMSO-d6): 1.73 (s, 3H), 2.47 (s, 3H), 5.38 (d, J=13.3 Hz, 1H), 5.45 (d, J=13.3 Hz, 1H), 7.08 (t, J=8.25 Hz, 4H), 7.23 (t, 1H), 7.28 (s, 1H), 7.45 (t, 2H), 7.84 (d, J=8.79 Hz, 2H), 7.91 (m, 1H) and 8.68 (s, 1H).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.O[N:25]1[C:29](=[O:30])[CH2:28][CH2:27][C:26]1=[O:31].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)C>O1CCCC1>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([O:13][N:25]1[C:29](=[O:30])[CH2:28][CH2:27][C:26]1=[O:31])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 18 h

Procedure:
1.04 Grams of Z-Tyr-OH was dissolved in 30 ml of tetrahydrofuran, to this solution 0.38 g of N-hydroxysuccinimide was added, then the reaction mixture was ice-cooled, 0.68 g of dicyclohexylcarbodiimide was added under ice-cooled condition, and the whole mixture was stirred at 4° C. for 18 hours. The precipitate formed was removed by suction filtration, the filtrate was subjected to distillation under a reduced pressure, to the residue obtained was added ethyl ether and petroleum ether and was decanted, then dried to obtain the desired product.
Reaction SMILES: Br[CH2:2][C:3]([CH2:26][CH3:27])=[CH:4][CH2:5][C:6]1[C:14]([O:15]CC[Si](C)(C)C)=[C:13]2[C:9]([CH2:10][O:11][C:12]2=[O:22])=[C:8]([CH3:23])[C:7]=1[O:24][CH3:25].C[O:29][P:30]([O:33]C)[O:31]C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>>[CH2:26]([C:3](=[CH:4][CH2:5][C:6]1[C:14]([OH:15])=[C:13]2[C:9](=[C:8]([CH3:23])[C:7]=1[O:24][CH3:25])[CH2:10][O:11][C:12]2=[O:22])[CH2:2][P:30](=[O:29])([OH:33])[OH:31])[CH3:27]
Reactant: CCC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CBr
Reactant: COP(OC)OC
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Product: CCC(=CCc1c(O)c2c(c(C)c1OC)COC2=O)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.2 %

Procedure:
A solution of 6-(3-bromomethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (230 mg, 0.5 mmol) in trimethylphosphite (1.5 mL, 12.75 mmol) was heated to 100° C. for 4 hours. The reaction was worked up by removal of excess trimethylphosphite under reduced pressure. The residue was dissolved in acetonitrile (1 mL) and TMSBr (646 μL, 5.0 mmol) and 2,6-lutidine (580 μL, 5.0 mmol) were added at 0° C. The reaction solution was allowed to warm to room temperature and stirred for 4 hours. The reaction was cooled to 0° C. and quenched with addition of MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 77 mg (58%) of the product. 1H NMR (300 MHz, CD3OD) δ 1.08 (t, 3H), 2.16 (s, 3H), 2.43 (m, 2H), 2.48 (d, 2H, J=22 Hz), 3.46 (t, 2H, J=6 Hz), 3.79 (s, 3H), 5.25 (s, 2H), 5.38 (q, 1H, J=7 Hz) ppm.; 31P (121.4 MHz, CD3OD) δ 25.65 ppm.; MS (m/z) 355 [M−H]−, 357 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:20]=2)[N:15]=1.C(#N)C>O>[O:24]([C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([NH:13][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([N:2]([CH3:1])[CH3:12])[CH:4]=3)=[N:15]2)=[CH:20][CH:19]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Reactant: CN(C)c1cccc(C(=O)O)c1
Solvent: CC#N
Solvent: O
Product: CN(C)c1cccc(C(=O)Nc2ccc3ccc(Oc4ccccc4)nc3n2)c1
Temperature: 4 °C
Yield: 83.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-dimethylaminobenzoic acid (23.1 g), N,N'-carbonyldiimidazole (22.7 g) and 2-amino-7-phenoxy-1,8-naphthyridine (23.7 g). The product produced by precipitation in water (44 g; m.p. approximately 90° C.) is dissolved in boiling acetonitrile (1000 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×50 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-3-dimethylaminobenzamide (32 g) is produced (m.p. 120° C.).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH2:18][NH:19][S:20]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][C:31](Cl)=[O:32])[CH:26]=[CH:27][CH:28]=3)(=[O:22])=[O:21])=[CH:17][C:12]=2[O:11][CH2:10]1>O1CCCC1>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH2:18][NH:19][S:20]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][C:31]([NH:2][OH:3])=[O:32])[CH:26]=[CH:27][CH:28]=3)(=[O:22])=[O:21])=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCc2ccc3c(c2)OCO3)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(S(=O)(=O)NCc2ccc3c(c2)OCO3)c1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.37 g, 5.40 mmol) in tetrahydrofuran (6 ml) a saturated NaHCO3 solution (4.5 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-{3-[(benzo[1,3]dioxol-5-ylmethyl)-sulfamoyl]-phenyl}-acryloyl chloride (0.41 g) in tetrahydrofuran (4 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate and washed with diethyl ether affording the title compound (0.14 g, 35%). M.p. 163° C. 1H NMR (DMSO-d6, HMDSO) δ: 3.92 (2H, d, J=6.4 Hz); 5.92 (2H, s); 6.49 (1H, d, J=16.0 Hz); 6.67 (3H, s); 7.34-7.89 (5H, m); 8.12 (1H, t, J=6.4 Hz); 9.07 (1H, br s); 10.78 (1H, br s). HPLC analysis on Symmetry C8 column: impurities 3.5% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 30:70; sample concentration 0.25 mg/ml; flow rate 1.2 ml/min; detector UV 254 nm). Anal. Calcd for C17H16N2O6S, %: C, 54.25; H, 4.28; N, 7.44. Found, %: C, 54.19; H, 4.20; N, 7.33.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])=[O:11].[NH2:24][C@@H:25]([CH3:44])[CH2:26][O:27][C:28]1[CH:43]=[CH:42][C:31]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[CH:30][CH:29]=1.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([NH:24][C@@H:25]([CH3:44])[CH2:26][O:27][C:28]2[CH:43]=[CH:42][C:31]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:33])=[CH:30][CH:29]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])=[O:11]
Reactant: C[C@H](N)COc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Br
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(CC(=O)N[C@@H](C)COc2ccc(C(=O)OCc3ccccc3)cc2)ccc1NC(=O)Nc1ccccc1Br
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-bromophenyl)ureido]phenylacetic acid (480 mg, 1.27 mmol), benzyl (S)-4-(2-amino-1-propoxy)benzoate (361 mg, 1.27 mmol), EDC(hydrochloride) (364 mg, 1.90 mmol), HOBt (256 mg, 1.89 mmol), and 4-DMAP (31 mg, 0.25 mmol) in DMF (8 mL) was stirred at room temp. overnight. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3 to 5% MeOH in CHCl3 as eluent to give 476 mg (58%) benzyl (S)-4-[2-[3-methoxy-4-[N′-(2-bromophenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as a brown solid. 1H-NMR (CDCl3) δ 1.25–1.28 (m, 3 H), 3.51 (s, 2 H), 3.74 (s, 3 H), 3.95–3.97 (m, 2 H), 4.36–4.39 (m, 1 H), 5.33 (s, 2 H), 6.75–6.94 (m, 5 H), 7.26–7.70 (m, 8 H), 7.99–8.26 (m, 5 H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C[N:16]1C[CH2:19][CH2:18][C:17]1=O.C(N)CC>O>[CH2:17]([NH:16][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH2:18][CH3:19]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CN1CCCC1=O
Solvent: CCCN
Solvent: O
Product: CCCNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5.23 g of 4-fluoro-3-nitro-benzo trifluoride and 25 ml of N-methylpyrrolidone was added 3.69 g of n-propylamine under ice cool, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into water, and the deposited solid was collected by filtration. This solid was washed with water, then, dried under reduced pressure to obtain 2.78 g of N-propyl-2-nitro-4-trifluoromethylaniline.