Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[C:12](=[O:32])[N:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:14]3[C:19]([C:20]=2O)=[CH:18][CH:17]=[CH:16][N:15]=3)=O)=[CH:4][CH:3]=1.O.[NH2:34][NH2:35].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:11]3[C:12](=[O:32])[N:13]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=4)[C:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:20]=3[NH:35][N:34]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=C(Cc1ccc(F)cc1)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccc(F)cc3)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-(4-fluorophenylacetyl)-4-hydroxy-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (604 mg, 1.4 mmol) produced in Synthesis Example 34 in DMF (5.5 mL) was added hydrazine monohydrate (purity of 80%, 220 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(4-fluorobenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (536 mg, yield 90%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C@@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][NH:9]1.[Cl:14][C:15]1[N:16]=[N:17][C:18](Cl)=[C:19]([CH3:22])[C:20]=1[CH3:21]>CN(C=O)C>[Cl:14][C:15]1[N:16]=[N:17][C:18]([N:12]2[CH2:11][CH2:10][NH:9][C@H:8]([CH3:7])[CH2:13]2)=[C:19]([CH3:22])[C:20]=1[CH3:21]
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1c(Cl)nnc(Cl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)nnc(N2CCN[C@H](C)C2)c1C
Temperature: 60 °C
Reaction time: 48 h
Yield: 48.8 %

Procedure:
Solid K2CO3 (10 g, 72.4 mmol, 1.8 eq) is added to a solution of (R)-2-methyl-piperazine (4.00 g, 40 mmol, 1 eq) and 3,6-dichloro-4,5-dimethyl-pyridazine (8 g, 45.2 mml, 1.1 eq) in DMF (50 mL), and the resulting solution is stirred at 60° C. for 48 h. The reaction mixture is concentrated to ½ volume under reduced pressure and the minimum water (ca. 15 mL) required to dissolve the solid salts is added, followed by the addition of dichloromethane (100 mL). The organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure, then purified by silica gel column chromatography (2%-20% MeOH/CH2Cl2) to yield the desired compound as a white solid (4.7 g, 49%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)=[O:4].[Cl:18][S:19](O)(=[O:21])=[O:20]>CCOC(C)=O>[F:17][C:2]([F:1])([F:16])[C:3]([NH:5][C:6]1[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]([S:19]([Cl:18])(=[O:21])=[O:20])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(Nc1cccc2cccnc12)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(S(=O)(=O)Cl)c2cccnc12)C(F)(F)F
Temperature: 80 °C
Yield: 31 %

Procedure:
Under N2 at 25° C., 2,2,2-trifluoro-N-(quinolin-8-yl)acetamide (5.0 g, 20.8 mmol) was added to chlorosulfonic acid (15 ml) and then heated at 80° C. for 19 h. The mixture was then poured into ice-water (200 ml), followed by addition of EtOAc (300 ml). The organic layer was passed through a short bed of silica gel followed by EtOAc (700 ml) and then evaporated and triturated with Et2O to give the product as a light tan solid (2.2 g, 31%). 1H NMR (400 MHz, CDCl3) δ 11.02 (s, 1H), 9.19 (dd, J=8.8, 1.4 Hz, 1H), 9.05 (dd, J=4.2, 1.4 Hz, 1H), 8.84 (d, J=8.5 Hz, 1H), 8.48 (d, J=8.5 Hz, 1H), 7.85 (dd, J=8.8, 4.2 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:17](=[O:24])[C:18]3[C:23]([C:15]=2[C:14]2[C:9](=[CH:10][C:11]([OH:25])=[CH:12][CH:13]=2)[N:8]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:3].S(=O)(=O)(O)O.[N+:31]([O-])([OH:33])=[O:32]>>[CH3:3][N:2]([CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:17](=[O:24])[C:18]3[C:23]([C:15]=2[C:14]2[C:9](=[C:10]([N+:31]([O-:33])=[O:32])[C:11]([OH:25])=[CH:12][CH:13]=2)[N:8]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:1]
Reactant: O=[N+]([O-])O
Reactant: CN(C)CCNc1nc2cc(O)ccc2c2c1C(=O)c1ccccc1-2
Agent: O=S(=O)(O)O
Product: CN(C)CCNc1nc2c([N+](=O)[O-])c(O)ccc2c2c1C(=O)c1ccccc1-2
Temperature: 5 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
A mixture of 6-(((dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno[2,1-c]quinoline-7-on obtained in example 3 (100 mg, 0.3 mmol), conc. sulfuric acid (1 ml) and nitric acid (1 ml) was stirred at 5° C. for 2 hours. The reaction mixture was poured into ice water, and a crystal precipitated was collected by filtration. The crystal obtained was purified by silica gel column chromatography (eluent; a lower layer of chloroform:methanol:water=9:3:1(v/v/v)) and crystallized from ethanol-diethylether to give 60 mg (yield: 52.9%) of title compound. The physicochemical properties thereof are shown in table 1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[C:13](O)[CH:12]=2)[CH2:7][N:6]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:4].O=P(Cl)(Cl)[Cl:33]>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[C:13]([Cl:33])[CH:12]=2)[CH2:7][N:6]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)C1CC(Oc2cc(O)nc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C
Product: COC(=O)C1CC(Oc2cc(Cl)nc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Crude 4-(2-hydroxy-7-methoxy-quinolin-4-yloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3.18 g, 7.60 mmol) was dissolved in POCl3 (76 mL) and heated to 40° C. overnight. The reaction mixture was concentrated in vacuo and dissolved in CH2Cl2 (40 mL). 4 N HCl in 1,4-dioxane (40 mL) was added and stirred at r.t. for 1 h. The crude material was partitioned between H2O and CH2Cl2 and pH was adjusted to 11 with NaHCO3 and 1 N NaOH. The aqueous layer was extracted with CH2Cl2 (3×150 mL). The combined organic layer was dried with Na2SO4 and concentrated. The crude product was purified by combi-flash to give 2.05 g of 4-(2-Chloro-7-methoxy-quinolin-4-yloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH:21]=[C:20](B4OC(C)(C)C(C)(C)O4)[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.Br[C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[C:36]#[N:37]>>[CH3:1][N:2]([CH3:32])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH:21]=[C:20]([C:34]4[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=4[C:36]#[N:37])[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)N3CC=C(B4OC(C)(C)C(C)(C)O4)CC3)cc2)C1
Reactant: N#Cc1ccccc1Br
Product: CN(C)C1CCN(c2ccc(NC(=O)N3CC=C(c4ccccc4C#N)CC3)cc2)C1

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 2-bromobenzonitrile by method O-a. This resulted in the product with the molecular weight of 415.54 (C25H29N5O); MS (ESI): 416 (M+H+)
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].[OH:13][C:14]1[CH:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][C:15]=1[CH:16]=O>C(#N)C>[O:25]1[CH2:24][CH2:23][N:22]([C:20]2[CH:19]=[CH:18][C:15]3[CH:16]=[C:2]([C:3]([O:5][CH3:6])=[O:4])[O:13][C:14]=3[CH:21]=2)[CH2:27][CH2:26]1
Reactant: COC(=O)CBr
Reactant: O=Cc1ccc(N2CCOCC2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc2ccc(N3CCOCC3)cc2o1

Procedure:
Methyl bromoacetate (3.0 g) and K2CO3 (3.0 g) were added to a solution of 2-hydroxy-4-morpholinobenzaldehyde (3.5 g) in acetonitrile (100 ml), and after heated reflux for 16 hours, the reaction solution was filtered and the mother liquor was concentrated under reduced pressure. MeOH (100 ml) and concentrated hydrochloric acid (10 ml) were added to the residue, and after reflux for 5 hours, the reaction solution was concentrated under reduced pressure. A saturated NaHCO3 aqueous solution (100 ml) was added to the residue prior to extraction with AcOEt, and the organic layer was dried with MgSO4 and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=5/1) to obtain methyl 6-morpholinobenzofuran-2-carboxylate.
Reaction SMILES: C[O-].[Na+].N#N.[CH:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.C[O:21][C:22](=O)[C:23]([CH3:25])=[CH2:24]>CO>[NH:12]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:22](=[O:21])[C:23]([CH3:25])=[CH2:24])=[CH:15][CH:14]=1)[C:9]1[CH:8]=[CH:7][CH:6]=[CH:11][CH:10]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: C=C(C)C(=O)OC
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: CO
Product: C=C(C)C(=O)Nc1ccc(Nc2ccccc2)cc1
Temperature: 70 °C
Yield: 80.15 %

Procedure:
A one liter flask equipped with an agitator was charged with 90 grams of methanol and 30 grams (0.55 mol) of sodium methoxide while under a slow N2 purge. The mixture was stirred until solution was achieved. 450 milliliters of xylene followed by 92 grams (0.5 mol) of p-aminodiphenylamine and 70.8 (0.71 mol) of methylmethacrylate were added to the flask while agitating. The homogeneous solution was then slowly heated and methanol was removed through a packed column. Methanol forms an azeotrope with methylmethacrylate and thus the distillate contained some methylmethacrylate as well as some xylene. Approximately 120 grams of distillate was removed over a period of two hours, during which the column outlet temperature stayed at 62°-63° C. while the flask temperature rose from 90° C. to 138° C. The column outlet temperature then started climbing, indicating the absence of methanol. The flask was then cooled to 70° C. and the sodium salt was filtered through a Buchner funnel. The salt was first washed with xylene to remove the residual amine and then with hexane. The salt was allowed to air dry and then restirred in one liter of cold water. It was then hydrolyzed with 10 percent sulfuric acid to pH of about 6. The product was filtered and air dried yielding 101 grams of N-(4-anilinophenyl) methacrylamide having a melting point of 102°-103° C. The yield was 80.15 percent.
Reaction SMILES: [CH3:1][O:2][N+:3]([O-])=[C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:5].[B].[H-].[Na+].C[OH:17]>>[CH3:1][O:2][N:3]=[C:4]([C:6]1[CH2:7][N:8]([OH:17])[CH2:9][CH2:10][CH:11]=1)[CH3:5]
Reactant: CO[N+]([O-])=C(C)c1cccnc1
Reactant: CO
Agent: [B]
Agent: [H-]
Agent: [Na+]
Product: CON=C(C)C1=CCCN(O)C1
Temperature: -10 °C

Procedure:
3.5 g of 3-acetyl-pyridine-O-methyl-oxime-N-oxide [J. Heterocyclic Chem. 16 1459, (1979)] is dissolved in 50 cm3 of methanol and cooled to -10° C. 2.4 g of boron and sodium hydride is added, with agitation for 2 hours at ambient temperature followed by evaporation to dryness. The residue is taken up with water and extracted with ethyl acetate. The extracts are dried, evaporated to dryness, and purified by chromatography on silica gel, (eluene: ethyl acetate). 2.85 g of the expected product is obtained. m.p. 94°-96° C., after crystallizing from hexane.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]3[CH:21]([CH3:22])[CH2:20][CH:19](Br)[C:18](=[O:24])[C:16]=3[S:17][C:11]=2[N:10]=[C:9]1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[C:26]=1[Br:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]3[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([OH:24])[C:16]=3[S:17][C:11]=2[N:10]=[C:9]1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[C:26]=1[Br:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2nc3sc4c(c3c(=O)n2Cc2ccccc2)C(C)CC(Br)C4=O)c(Br)c(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(-c2nc3sc4c(O)ccc(C)c4c3c(=O)n2Cc2ccccc2)c(Br)c(OC)c1OC

Procedure:
3-Benzyl-7-bromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-5-methyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione (compound No. 685) (100 mg, 100 mol-%) and NaOH (20 mg, 400 mol-%) in 1.5 ml of ethanol was heated by using microwaves (100° C., 100 s). The solvent was evaporated. EtOAc was added and the reaction mixture was washed with 5% HCl-solution. The product was purified by chromatography using dichloromethane-EtOAc 9.5:0.5 as an eluent.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]([C@H:20]1[C@H:27]2[C@H:23]([CH2:24][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26]2)[CH2:22][CH2:21]1)=[N+]=[N-].C(N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][CH2:11][CH3:13])[C:14](=[O:16])[NH:17][C@H:20]1[C@H:27]2[C@H:23]([CH2:24][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26]2)[CH2:22][CH2:21]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: [N-]=[N+]=N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21

Procedure:
tert-Butyl((S)-1-oxo-1-((3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylamino)pentan-2-yl)carbamate was prepared by substituting N-(tert-butoxycarbonyl)-L-norvaline for N-(tert-butoxycarbonyl)-L-leucine and (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Example 16 Step D for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.58 (d, J=7.2, 1H), 7.91 (d, J=8.3, 1H), 7.42 (d, J=7.3, 2H), 7.36 (t, J=7.4, 2H), 7.27 (t, J=7.2, 1H), 4.64 (dd, J=14.4, 7.7, 1H), 4.45-4.34 (m, 1H), 3.56 (d, J=13.1, 1H), 3.40 (d, J=13.2, 1H), 2.74 (d, J=8.9, 1H), 2.48 (d, J=0.7, 2H), 2.39-2.27 (m, 2H), 2.26-2.19 (m, 1H), 2.14 (dq, J=12.0, 6.0, 1H), 2.07-1.96 (m, 1H), 1.85 (td, J=13.8, 8.2, 2H), 1.65 (td, J=14.3, 7.3, 1H), 1.49 (d, J=8.5, 11H), 1.45-1.33 (m, 1H), 0.81 (t, J=7.3, 3H); MS (ESI+) m/z 416 (M+H)+.
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][C:8](=[O:9])[CH2:7][CH:6]([N:5]1[C:1](=[O:26])[C:2]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:3]2[C:4]1=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Product: COc1ccc(C(CC(=O)NCc2ccccc2)N2C(=O)c3ccccc3C2=O)cc1OC
Yield: 92 %

Procedure:
The procedure of Example 46 is utilized starting with 3-phthalimido-3-(3,4'-dimethoxyphenyl)propionic acid and benzylamine (1.0 equiv) to afford 2.45 g (92%) of 3-phthalimido-3-(3',4'-dimethoxyphenyl)propionic benzylamide as white powder: mp 208.4°-209.8° C.; 1H NMR (DMSO-d6, 250 MHz) δ 8.60 (t, 1 H, J=6 Hz), 7.78-7.92 (m, 4 H), 6.85-7.20 (m, 8 H), 5.73 (t, 1 H, J=8 Hz), 4.10-4.30 (m, 2 H), 3.73 (s, 3 H), 3.72 (s, 3 H), 3.20-3.45 (m, 2 H); 13C NMR (DMSO-d6) δ 169.1, 167.7, 148.5, 148.3, 139.2, 134.5, 131.4, 131.2, 127.9, 126.7, 123.1, 119.5, 111.5, 111.2, 101.9, 55.4, 55.37, 50.6, 41.7, 37.4; Anal. Calcd. for C26H24N2O5. Theoretical: C, 70.26; H, 5.44; N, 6.30. Found: C, 70.12; H, 5.53; N, 6.25.
Reaction SMILES: [C:1]([C:4]1[C:5](I)=[N:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:1]([C:4]1[C:5]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:21])[CH:27]=2)=[N:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCn2nc(I)c(C(N)=O)c2C1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2nc(-c3cccc(Cl)c3)c(C(N)=O)c2C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 79.1 %

Procedure:
To a stirred solution of Intermediate 156C (500 mg, 1.275 mmol) and (3-chlorophenyl)boronic acid (399 mg, 2.55 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added and potassium phosphate tribasic (666 mg, 3.82 mmol). The reaction mixture was purged with nitrogen for 5 min. PdCl2(dppf)-CH2Cl2 (52.1 mg, 0.064 mmol) was added and the reaction mixture was stirred at 80° C. for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude was purified by ISCO (24 g silica column) using 2% methanol in chloroform. Fractions were collected and concentrated to afford Intermediate 156D (380 mg, 79%). MS(ES): m/z 377 [M+H]+; 1H NMR (300 MHz, CDCl3) δ ppm 7.60 (s, 1H), 7.46 (m, 3H), 5.32 (bs, 2H), 4.97 (s, 2H), 4.21 (t, J=5.1 Hz, 2H), 3.94 (t, J=5.7 Hz, 2H), 1.29 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3]([F:18])=[C:4](F)[C:5]([F:16])=[C:6]([C:12]([O:14][CH3:15])=[O:13])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].C1CCN2C(=NCCC2)CC1.Cl.[N+:31]([CH3:34])([O-:33])=[O:32]>>[F:16][C:5]1[C:4]([CH2:34][N+:31]([O-:33])=[O:32])=[C:3]([F:18])[C:2]([F:1])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)OC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1c(F)c(F)c(C[N+](=O)[O-])c(F)c1C(=O)OC
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
200 g of dimethyl tetrafluorophthalate was dissolved in 400 ml of nitromethane (Ishikawa, Suzuki & Tanabe: Nippon Kagaku Kaishi, 1976, 200) and the solution was cooled on an ice-salt bath. At an internal temperature of 15°-20° C., 171 g of 1,8-diazabicyclo[5,4,0]-7-undecene was added dropwise over a period of 30 minutes. After completion of the dropwise addition, the mixture was further stirred at an internal temperature of 10° C. for 30 minutes, then, the mixture was poured into a mixture of 1.5 liters of 1N hydrochloric acid and 1 liter of ice.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7](C(OC(C)(C)C)=O)[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][NH:7][C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON=C1CN[C@H](C(=O)OC)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
A solution was made containing e.g. 1-tert-Butyl 2-methyl (2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate (0.892 g, 3.28 mmol), in anhydrous DCM (28 ml). TFA (20%, 7 mL) was added dropwise. The mixture was stirred at r.t. for 20 min. Solvents were evaporated and the desired product, e.g. methyl (2S,4EZ)-4-(methoxyimino)-2-pyrrolidinecarboxylate (0.564 g, quant.) was isolated as a yellow oil and used without further purification.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:12])[CH2:4]/[CH:5]=[CH:6]/[C:7]([O:9]CC)=[O:8].Cl.CCO>O>[ClH:1].[CH3:2][N:3]([CH3:12])[CH2:4]/[CH:5]=[CH:6]/[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)/C=C/CN(C)C
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN(C)C/C=C/C(=O)O
Temperature: 45 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
(E)-ethyl 4-(dimethylamino)but-2-enoate hydrochloride (20 g, 0.103 mol) was dissolved in water (102 mL) in 250 mL two-neck flask, and then conc. HCl (2.6 mL) was added therein. After refluxing the reaction mixture for 3 hours, the temperature of the reaction mixture was reduced to room temperature. EtOH formed in the reaction was eliminated by distillation under reduced pressure, and then water (34 mL) was added therein. After adding conc. HCl (1.3 mL) therein again, the reaction mixture was refluxed again for 2 hours and water in the reaction mixture was eliminated by distillation under reduced pressure. Re-crystallization was carried out by adding IPA (100 mL) to the solid remained therein. At this time, IPA solution was heated to the temperature of 40 to 50° C., and the solution was stirred for 2 hours at room temperature. After filtering the solid with a filter, the solid was washed with IPA (10 mL). (E)-4-(dimethylamino) but-2-enoic acid hydrochloride of 12 g was obtained with a yield of 70% by drying the collected solid (99.8% Purity by HPLC, Corona Detector).
Reaction SMILES: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[CH3:13][C@H:14]([C:27]([OH:29])=[O:28])[C:15]1[CH:16]=[CH:17][C:18]2[CH:19]=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][C:23]=2[CH:24]=1.[ClH:30].C(OCC)(=O)C.C(OCC)C>ClCCl>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[CH3:13][C@H:14]([C:27]([OH:29])=[O:28])[C:15]1[CH:16]=[CH:17][C:18]2[CH:19]=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][C:23]=2[CH:24]=1.[ClH:30]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(N)O
Temperature: 25 °C

Procedure:
In 1 ml of dichloromethane, 684 mg (1.76 mmol) of the Boc-aminopropanol-naproxen obtained above was dissolved, and 2 ml of 4 M hydrochloric acid/ethyl acetate was added thereto under ice-cooling, followed by stirring under ice-cooling for 20 minutes and at room temperature for 1 hour. After confirming disappearance of Boc-aminopropanol-naproxen by TLC, and diethyl ether was added thereto, followed by decantation three times. Thereafter, the residue was dried under reduced pressure to quantitatively give the titled substance at a yield of 564 mg. The structure was identified by 1H-NMR (CDCl3).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)([CH3:6])[CH2:3][CH:4]=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C1COCC1.[Zn]>[CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)([CH3:6])[CH2:3][CH2:4][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: CC(C)(CC=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(CCN1CCOCC1)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-methyl-3-(4-nitrophenyl)butan-1-one (509 mg, 2.4 mmol) and morpholine (0.21 mL, 2.4 mmol) in THF (30 mL) was added NaBH(OAc)3 (0.73 g, 3.4 mmol). The mixture was stirred at RT overnight and washed with HCl (1M). CH2Cl2 was added and the layers were separated. The aqueous layer was basified to pH 9 using NaOH 1M and extracted with CH2Cl2. The organic layer was dried and evaporated the nitro compound. To a solution of the nitro compound (0.50 g, 1.8 mmol) in THF (40 mL) was added AcOH (1.97 mmol, 34.5 mmol) followed by zinc (9.1 g, 137 mmol). The mixture was stirred for 1 h, filtered on Celite®, diluted with H2O and aqueous NaHCO3, and the THF layer was evaporated. The residue was extracted with EtOAc, dried and evaporated to give the title compound.