Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Cl:25][CH2:26][CH2:27][CH2:28][CH:29]([CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:30]([OH:32])=O.[C:39]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])(=[O:42])[NH:40][NH2:41]>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:25][CH2:26][CH2:27][CH2:28][CH:29]([CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:30]([NH:41][NH:40][C:39]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:32]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)C(CCCCl)C1CCCCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NNC(=O)C(CCCCl)C1CCCCC1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 36 %

Procedure:
IPEA (0.68 ml) and BOPCl (496 mg) were added to a solution of 5-chloro-2-cyclohexyl-valeric acid (285 mg) and tert-butyl carbazate (215 mg) in methylene chloride (2.5 ml), and the reaction solution was stirred at room temperature for 5.5 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was sequentially washed with 1 N hydrochloric acid, water, a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 156 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[C:6]([O:9][CH3:10])=[CH:5][N:4]([C:11]2[C:21]([F:22])=[CH:20][C:14]3[O:15][C:16]([F:19])([F:18])[O:17][C:13]=3[CH:12]=2)[N:3]=1.[C:23]1([N:29]2[C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=[N:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(O)=O.[Na+]>[CH3:10][O:9][C:6]1[C:7](=[O:8])[C:2]([C:33]2[N:29]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:30]=[CH:31][CH:32]=2)=[N:3][N:4]([C:11]2[C:21]([F:22])=[CH:20][C:14]3[O:15][C:16]([F:19])([F:18])[O:17][C:13]=3[CH:12]=2)[CH:5]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Reactant: COc1cn(-c2cc3c(cc2F)OC(F)(F)O3)nc(Br)c1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cn(-c2cc3c(cc2F)OC(F)(F)O3)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 60.2 %

Procedure:
A mixture of 3-bromo-5-methoxy-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)pyridazin-4(1H)-one (145 mg, 0.383 mmol), 1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (155 mg, 0.575 mmol), K2CO3 (106 mg, 0.766 mmol) and PdCl2{P(t-Bu)2(Ph-p-NMe2)}2 (13.6 mg, 0.0192 mmol) in toluene (1.9 mL) and water (0.19 mL) was heated to reflux for 18 h under Ar. The mixture was diluted with NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with AcOEt/hexane to yield the title compound (102 mg, 60% yield) as a pale yellow solid: mp 200-202° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.76 (3H, s), 6.97 (1H, d, J=1.9 Hz), 7.27-7.47 (6H, m), 7.79 (1H, d, J=1.9 Hz), 7.86 (1H, d, J=9.4 Hz), 8.48 (1H, d, J=1.9 Hz). Anal. Calcd for C21H13F3N4O4: C, 57.02; H, 2.96; N, 12.67. Found: C, 56.94; H, 3.01; N, 12.59.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:37]=[CH:36][C:21]([O:22][CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][N:25]3C(OC(C)(C)C)=O)=[CH:20][CH:19]=2)=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:12]1([C:9]([CH2:10][CH3:11])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[C:18]2[CH:37]=[CH:36][C:21]([O:22][CH2:23][C@@H:24]3[CH2:28][CH2:27][CH2:26][NH:25]3)=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCC2CCCN2C(=O)OC(C)(C)C)cc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OC[C@@H]2CCCN2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.7 %

Procedure:
To a stirred solution of tert-butyl 2-((4-(1-(4-hydroxyphenyl)-2-phenylbut-1-enyl)phenoxy)methyl)pyrrolidine-1-carboxylate (400 mg, 1.0 eq) in 20 mL CH2Cl2 was added 1 mL TFA dropwise at 0° C. The reaction was stirred at rt for 3 h, then quenched with sat. NaHCO3, and extracted with CH2Cl2. The extract was dried, concentrated and purified by column chromatography to give the desired product (210 mg, 68% yield, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.07-7.17 (m, 6H), 7.05 (d, J=8.4 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 6.68 (d, J=8.4 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 6.44 (d, J=8.4 Hz, 1H), 3.96-4.00 (m, 0.5H), 3.89-3.93 (m, 0.5H), 3.82-3.85 (m, 0.5H), 3.73-3.77 (m, 0.5H), 3.53-3.59 (m, 0.5H), 3.43-3.49 (m, 0.5H), 2.90-3.11 (m, 2H), 2.44-2.51 (m, 2H), 1.77-1.99 (m, 3H), 1.52-1.66 (m, 1H), 0.92 (t, J=7.2 Hz, 3H); m/z=400[M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:36])[NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:36])[NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[CH:20][C:21]=1[C:22]([F:25])([F:23])[F:24])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-{[5-(3-hydroxy-benzylcarbamoyl)-3-trifluoromethyl-thiophene-2-carbonyl]-amino}-propionic acid methyl ester (0.19 g, 0.34 mmol) in DCM (6 mL) was added TFA (3.0 mL). The mixture was stirred at room temperature 1 h and evaporated. Isolate 0.23 g of crude product which was used without further purification.
Reaction SMILES: C([O:5]O)(C)(C)C.[C:7]([O:11][C:12]([NH:14][C@H:15]([C@@H:23]([OH:27])[CH2:24][CH:25]=[CH2:26])[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([NH:14][C@H:15]([C@@H:23]([OH:27])[C@@H:24]([OH:5])[CH:25]=[CH2:26])[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13])([CH3:9])([CH3:8])[CH3:10]
Reactant: CC(C)(C)OO
Reactant: C=CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Product: C=C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C

Procedure:
An allylic oxidation using stoichiometric SeO2 and t-butyl hydroperoxide (Umbriet, M. A. and Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526) was performed on the resultant product of Example 50 to give the desired product after silica gel chromatography.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1>C1C=CC=CC=1>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:1][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: OCc1cccnc1
Solvent: c1ccccc1
Product: O=C(OCc1cccnc1)c1ccc(F)cc1
Temperature: 20 °C
Yield: 67.7 %

Procedure:
10.5 g. of 3-hydroxymethyl-pyridine are dissolved in 60 ml. of anhydrous benzene. The solution is stirred at 20° C. and 7.6 g. of 4-fluorobenzoic acid chloride dissolved in 60 ml. of benzene are added dropwise thereto. The reaction mixture is refluxed for 30 minutes and then cooled to 20° C. The precipitated 3-hydroxymethyl-pyridine hydrochloride is filtered off. The filtrate is extracted with 250 ml. of 5% aqueous hydrochloric acid. The separated aqueous acidic layer is washed with 50 ml. of diethyl ether and then adjusted to pH=9 with 20% aqueous sodium carbonate solution. The basified solution is extracted three times with 50 ml. each of diethyl ether, the combined ether extracts are dried with anhydrous sodium sulfate, filtered and the filtrate is evaporated. The evaporation residue is dissolved in 80 ml. of a 1:1 mixture of isopropanol and ether and etheric hydrogen chloride solution is added to adjust the pH-value to 2. The precipitated acid addition salt is separated by filtration and recrystallized from a mixture of equal values of acetone and ethanol. 8.5 g. of 3-[ (4-fluorobenzoyl)-oxymethyl]-pyridine (67.7% of theoretical yield) are obtained; m.p.: 142°-143° C.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[P:5]([OH:8])([OH:7])[OH:6].P(Cl)(Cl)Cl>O1CCOCC1>[CH3:2][C:1]([P:5]([OH:8])([OH:7])=[O:6])([P:5]([OH:8])([OH:7])=[O:6])[OH:4]
Reactant: OP(O)O
Reactant: CC(=O)O
Solvent: C1COCCO1
Solvent: ClP(Cl)Cl
Product: CC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 92.5 °C
Yield: 5.2 %

Procedure:
Acetic acid (50 g), phosphorous acid (240 gm) and 1,4-dioxane (1000 mL) was taken in a four necked round bottom flask fitted with an addition funnel, mechanical stirrer, condenser and thermometer pocket and allowed to stir at 90-95° C. Phosphorus trichloride (400 gm) was then added to the reaction mixture and allowed to heat at 90-95° C. The reaction mixture was cooled and distilled water (500 ml) was added to it. The reaction mixture was further heated to 90-95° C. It was then cooled and acetonitrile (1000 mL) was added to it. The solution was further cooled to 0-5° C. and stirred for 4-5 hrs. The precipitated solid was filtered, washed with acetonitrile and dried in vacuum oven to give 9 gm of product.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([NH2:14])[CH3:13])=[C:10]([F:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Br[C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([Br:23])[N:22]=1.CCN(C(C)C)C(C)C>C(#N)C>[Br:23][C:21]1[N:22]=[C:17]([NH:14][CH:12]([C:11]2[C:2]([F:1])=[C:3]3[C:8](=[CH:9][C:10]=2[F:15])[N:7]=[CH:6][CH:5]=[CH:4]3)[CH3:13])[C:18]([NH2:24])=[N:19][CH:20]=1
Reactant: CC(N)c1c(F)cc2ncccc2c1F
Reactant: Nc1ncc(Br)nc1Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1nc(Br)cnc1N)c1c(F)cc2ncccc2c1F
Temperature: 180 °C
Yield: 35.2 %

Procedure:
A mixture of 1-(5,7-difluoroquinolin-6-yl)ethanamine (800 mg, 3.8 mmol), 3,5-dibromopyrazin-2-amine (972.0 mg, 3.8 mmol) and DIPEA (2.0 g, 15.4 mmol) in acetonitrile (50 mL) was heated with microwave irradiation at 180° C. for 45 min. The reaction mixture was concentrated under reduced pressure, diluted with water, extracted with DCM three times. The combined organic layers were separated and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (DCM/MeOH) to give the title compound as a yellow solid (508 mg, 35%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.95 (d, 1H), 8.46 (dd, 1H), 7.63 (d, 1H), 7.60 (dd, 1H), 7.11 (s, 1H), 7.08 (dd, 1H), 6.36 (bs, 2H), 5.45 (m, 1H), 1.70 (d, 3H). LCMS (method A): [MH]+=380/382, tR=5.03 min.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CCCCCC>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccccc1
Solvent: CCCCCC
Product: CN(C)C=CC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 50.0 g of acetophenone and 150 ml of N,N-dimethylformamide dimethyl acetal was stirred and heated at reflux for 8 hours. The mixture was allowed to cool to room temperature, then the solvent was removed in vacuo to give a crystalline residue. The residue was treated with 400 ml of hexane then filtered. The material on the filter was washed with hexane to give 47.8 g of the desired product as yellow crystals, mp 88°-91° C.
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[CH2:8]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14](F)[CH:13]=1)[CH3:9]>C(#N)C>[CH2:8]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([NH:3][CH3:1])[CH:13]=1)[CH3:9]
Reactant: CCNC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCN(CC)CC
Solvent: CC#N
Product: CCNC(=O)c1ccc([N+](=O)[O-])c(NC)c1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
Methylamine•monohydrochloride (1.23 g) and triethylamine (2.5 ml) were added to a solution of N-ethyl-3-fluoro-4-nitrobenzamide (1.92 g) in acetonitrile (40 ml), followed by stirring at 50° C. for 15 hours. The reaction solution was concentrated under reduced pressure and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain N-ethyl-3-(methylamino)-4-nitrobenzamide (1.99 g) as a yellow orange solid.
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:10][CH2:11][N:12]2[CH2:17][CH:16]3[CH2:18][CH2:19][CH:13]2[CH2:14][CH2:15]3)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C>[C:20]1([C:7]([C:8]2[NH:28][N:27]=[N:26][N:9]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH:16]3[CH2:15][CH2:14][CH:13]2[CH2:19][CH2:18]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N#CC(CCN1CC2CCC1CC2)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(C(CCN2CC3CCC2CC3)(c2ccccc2)c2nnn[nH]2)cc1

Procedure:
Thus 2,2-diphenyl-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile described in U.S. Pat. No. 3,318,869 is reacted with sodium azide in DMF to provide 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-tetrazole. This tetrazole is reacted with ethyl chloroglyoxylate in pyridine at -6° C to provide ethyl [1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1,3,4-oxadiazole-2-carboxylate hydrochloride. This ester is hydrolysed in aqueous potassium hydroxide to provide 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1,3,4-oxadiazole-2-carboxylic acid. Heating this acid for 15 minutes in an oil bath at 130°-140° provides 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1,3,4-oxadiazole. The hydrochloride salt melts at 233°-234.5° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52][CH2:51][NH:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:50]3[CH2:51][CH2:52][C:53]5[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=5)[CH2:49]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: c1ccc2c(c1)CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]c(C(=O)N3CCc4ccccc4C3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 3,4-dihydro-1H-isoquinoline (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([NH2:20])=[CH:18][CH:17]=[C:16]([CH3:21])[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@@H:6]([N:13]1[C:14]2=[N:15][C:16]([CH3:21])=[CH:17][CH:18]=[C:19]2[NH:20][C:28]1=[O:29])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C[C@@H](Nc1nc(C)ccc1N)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of (R)-3-(3-amino-6-methyl-pyridin-2-ylamino)-3-phenyl-propionic acid ethyl ester (390 mg, 1.30 mmol) in THF (10 mL) was added CDI (317 mg, 1.95 mmol). The reaction mixture was stirred at room temperature for 2 hours and then heated to 60° C. for another 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 250 mg (59%) of the title compound as a light brown foamy residue. LCMS, M++1, m/z: 326.43
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1>O.C(O)C>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccnc3)c2cc1OC
Temperature: 70 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
N,N-Dimethylformamide (1 ml), ethanol (0.5 ml), and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 3-pyridylboronic acid (44 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 3 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (33 mg, yield 75%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([NH2:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[O:14][CH3:15])[CH3:2].[C:17](OCC)(=[O:19])C.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([N:11]=[C:17]=[O:19])=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[O:14][CH3:15])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOc1c(Cl)cc(N)cc1NC(=O)OC
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOc1c(Cl)cc(N=C=O)cc1NC(=O)OC
Temperature: 25 °C

Procedure:
Methyl N-(2-ethoxy-3-chloro-5-aminophenyl)carbamate (2.67 g) in toluene (20 ml) was dropwise added to an ethyl acetate solution containing 10 g of phosgene at 10° to 20° C. The resultant mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give methyl N-(2-ethoxy-3-chloro-5-isocyanatophenyl)carbamate. The thus obtained crude substance was added to a toluene solution (50 ml) containing triethylamine (1.0 g) and 3-buten-2-ol (0.79 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give 1-methyl-2-propenyl N-(3-chloro-4-ethoxy-5-methoxycarbonylaminophenyl)carbamate (Compound No. 3) (3.57 g) in a yield of 95.6 %. nD25.0 1.5383.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])=[O:10]
Reactant: COc1ccc(OC)cc1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccc(OC)c(C(=O)c2ccccc2OC)c1
Temperature: 200 °C

Procedure:
A mixture of o-anisoyl chloride (25.8 g, 0.15 mmol) and 1,4-dimethoxybenzene (37.2 g, 0.27 mol) was heated for 20 hours at 200° C., under N2. Distillation led to recovered 1,4-dimethoxybenzene (18.7 g), b.p. 232° C. (8 mm) followed by the title product, shown below, (25.4 g, 63%), b.p. 232° C. (7 mm) which was suitable for carrying forward to the next step. ##STR3##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:39])=[C:14]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:15](=[O:33])[N:16]3[CH2:19][CH2:20][N:21]([CH3:32])[C:22]([O:24]CC3C=CC=CC=3)=O)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH:40](N(C(C)C)CC)(C)C.C(OC(=O)C)(=O)C>C(Cl)Cl.[Pd]>[C:22]([N:21]([CH3:32])[CH2:20][CH2:19][N:16]1[C:17]2[C:12](=[N:11][CH:10]=[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:18]=2)[C:13]([OH:39])=[C:14]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:15]1=[O:33])(=[O:24])[CH3:40]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(=O)OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(C)=O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[2-(methyl {[(phenylmethyl)oxy]carbonyl}amino)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.023 g, 0.043 mmol) in CH2Cl2 (1.5 mL) was combined with diisopropylethylamine (0.0038 mL, 0.22 mmol), acetic anhydride (0.021 mL, 0.22 mmol) and Pd/C (0.012 g, 10% w/w). The resulting suspension was flushed with nitrogen and evacuated several times the charged with hydrogen under a balloon and stirred at ambient temperature overnight. The reaction mixture was filtered, washed with CH2Cl2, and concentrated in vacuo. The residue was dissolved in CH2Cl2, washed with 1N NaHSO4, and brine, concentrated the organics to afford the title compound as an oil: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J=6.59 Hz, 3 H), 1.86 (s, 3 H), 2.94 (s, 3 H), 3.50 (t, J=6.86 Hz, 2 H), 4.18 (s, 2 H), 4.28 (q, J=6.83 Hz, 4 H), 7.12 (t, J=8.69 Hz, 2 H), 7.35-7.40 (m, 2 H), 8.02 (d, J=6.40 Hz, 1 H), 8.47 (s, 1 H); ES+ MS: 442 (M+H+).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.C(N(CC)CC)C.[CH3:20][C:21]([C:23]1[C:28]([NH2:29])=[CH:27][C:26]2[O:30][CH2:31][O:32][C:25]=2[CH:24]=1)=[O:22]>C1(C)C=CC=CC=1>[C:21]([C:23]1[C:28]([NH:29][C:6]([C:4]2[C:3]3[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=3[O:1][CH:5]=2)=[O:7])=[CH:27][C:26]2[O:30][CH2:31][O:32][C:25]=2[CH:24]=1)(=[O:22])[CH3:20]
Reactant: CC(=O)c1cc2c(cc1N)OCO2
Reactant: O=C(Cl)c1coc2ccccc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2c(cc1NC(=O)c1coc3ccccc13)OCO2
Temperature: 20 °C
Reaction time: 24 h

Procedure:
Into solutions of 154 (5.0 mmol) in 200 mL of dry toluene were added triethylamine (4 mL) and 2-amino-4,5-methylenedioxy acetophenone (148) (5 mmol). The mixtures were stirred at 20±2° C. for 24 h and then evaporated. The residues were washed with acetone and EtOH and then recrystallized from acetone or EtOH to form 155. Obtained as a pale-yellow solid; mp 144-145° C.; ESI-MS (Positive mode): m/z 324 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): δ 2.63 (3H, s), 6.19 (2H, s), 7.41-7.50 (21-1, m), 7.68 (1H, s), 7.75 (1H, dd, J=1.6, 6.8 Hz), 8.15 (1H, dd, J=2.0, 8.8 Hz), 8.27 (1H, s), 8.71 (1H, s), 12.63 (1H, s); IR (KBr): 1635, 1677 (C═O) cm−1.