Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)S(O[C:18]1[O:36][CH2:35][C@:21]2([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[F:44])[N:22]=[C:23]([NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:24][CH2:25][C@@H:20]2[CH:19]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:18]2[O:36][CH2:35][C@:21]3([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=4[F:44])[N:22]=[C:23]([NH:26][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[S:24][CH2:25][C@@H:20]3[CH:19]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)COC(OS(=O)(=O)C(F)(F)F)=C[C@H]2CS1)c1ccccc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C2=C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccc(F)cc3F)CO2)cc1
Temperature: 65 °C
Reaction time: 17 h

Procedure:
(4-Cyanophenyl)boronic acid (55 mg, 0.37 mmol, 2.0 equiv) was added to a solution of (4aR,8aS)-2-(benzoylamino)-8a-(2,4-difluorophenyl)-4,4a,8,8a-tetrahydropyrano[3,4-d][1,3]thiazin-6-yl trifluoromethanesulfonate (P4) (100 mg, 0.19 mmol, 1.0 equiv) in tetrahydrofuran (1.5 mL). An aqueous 2 M solution of cesium carbonate (0.47 mL, 0.935 mmol, 5.0 equiv) and dichlorobis(triphenylphosphine)palladium(II) (6.4 mg, 9 μmol, 0.05 equiv) were added. The reaction was de-gassed and stirred at 65° C. for 17 hours. The reaction mixture was partitioned between water (10 mL) and ethyl acetate (20 mL) and the organic layer separated. The extraction was repeated twice and the combined organics were washed with saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 50% ethyl acetate in heptane) afforded the product as a white solid. Yield: 64 mg, 70%. LCMS m/z 488.3 [M+H+].
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Br[C:61]1[N:66]=[CH:65][CH:64]=[CH:63][N:62]=1.CC1(C)C(C)(C)OB([C:75]2[CH:80]=[CH:79][C:78]([OH:81])=[CH:77][CH:76]=2)O1>>[N:62]1[CH:63]=[CH:64][CH:65]=[N:66][C:61]=1[C:75]1[CH:80]=[CH:79][C:78]([OH:81])=[CH:77][CH:76]=1
Reactant: Brc1ncccn1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: Oc1ccc(-c2ncccn2)cc1

Procedure:
Compound 81A was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with 2-bromopyrimidine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 9.92 (s, 1H), 8.80 (d, J=4.6 Hz, 2H), 8.22-8.26 (m, 2H), 7.31 (t, J=4.6 Hz, 1H), 6.89-6.89 (m, 2H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[C:11]1([C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:17])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: OC(Cc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a suspension of Mg (1.7 g, 0.07 mol) in dry ether (25 mL) was added a solution of benzyl bromide (10 mL, 1.5 equ.) in dry ether (25 mL) drop-wise and allowed to stir at RT for 1 h. By the time all magnesium was dissolved and the reaction mixture was cooled to 0° C. To this was added a solution of benzophenone (10 g, 0.05 mol) in dry ether (25 mL) and allowed to stir at RT for 5 h. The progress of the reaction was followed by TLC and when it was ready the reaction mixture was quenched with saturated NH4Cl solution, extracted with ether (100 mL), washed with brine, dried and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (10% ethyl acetate in pet. ether) to give the title compound (9.6 g, 65%) as a white solid. TLC: Pet. ether/EtOAc, 9:1, Rf=0.4
Reaction SMILES: C(S)C.[H-].[Na+].[CH2:6]([O:8][C:9](=[O:30])[C:10]1[CH:15]=[C:14]([F:16])[C:13](SCC)=[N:12][C:11]=1[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)C.C([O:33]C(=O)C1C=C(F)C(SCC)=NC=1Cl)C.C(OC(=O)C1C=C(F)C=NC=1NCC1C=CC(OC)=CC=1)C.ClC(OC(Cl)=O)(Cl)Cl>[Ni].C(O)C>[F:16][C:14]1[CH:13]=[N:12][C:11]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:6](=[O:33])[O:8][C:9](=[O:30])[C:10]=2[CH:15]=1
Reactant: CCOC(=O)c1cc(F)c(SCC)nc1NCc1ccc(OC)cc1
Reactant: CCOC(=O)c1cc(F)c(SCC)nc1Cl
Agent: [Ni]
Agent: CCOC(=O)c1cc(F)cnc1NCc1ccc(OC)cc1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCS
Solvent: CCO
Product: COc1ccc(Cn2c(=O)oc(=O)c3cc(F)cnc32)cc1

Procedure:
2,6 Dichloro-5-fluoro-nicotinic acid was selected as a starting material to make the compounds of structure (Ia) with fluoro substitution at 6-position of naphthyridine moiety. 2,6 Dichloro-5-fluoro-nicotinic acid was esterified by treating with thionyl chloride followed by refluxing with dry ethanol to yield 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester, depicted by formula 21 in Scheme 10. This ester gave 2-chloro-6-ethylsulfanyl-5-fluoro-nicotinic acid ethyl ester, depicted by formula 22 in Scheme 10, when reacted with ethanethiol and sodium hydride. 6-Ethylsulfanyl-5-fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester, depicted by formula 23 in Scheme 10, was prepared by amination of 2-chloro-6-ethylsulfanyl-5-fluoro-nicotinic acid ethyl ester, which was converted into 5-fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester, depicted by formula 24 in Scheme 10, by refluxing with ethanol and raney nickel. 5-Fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester was then reacted with trichloromethylchloroformate to yield 6-fluoro-1-(4-methoxy-benzyl)-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione, depicted by formula 25 in Scheme 10. The sequence of reactions is shown in Scheme 10.
Reaction SMILES: O.[C@@H:2]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CO>[CH3:22][N:23]([CH:25]=[N:15][C:14]1[C:13]2[N:12]=[CH:11][N:10]([C:19]=2[N:18]=[CH:17][N:16]=1)[C@@H:2]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1)[CH3:24]
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: O
Product: CN(C)C=Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 50 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a stirred solution of 2′-deoxyadenosine monohydrate 54 (1.00 g; 3.71 mmol) in methanol (43 mL), N,N-dimethylformamide dimethyl acetal (2.48 mL; 18.6 mmol) was added. The reaction was stirred at 50° C. for 16 h. After evaporation, CH2Cl2-hexane (1:1) was added. The white solid formed was then filtered, collected and washed by hexane to afford 55 as white solid (1.13 g; 99% yield): 1H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H, CHN(CH3)2), 8.44 (s, 1H, 2-H), 8.43 (s, 1H, 8-H), 6.48 (dd, J=6.2, 7.8 Hz, 1H, 1′-H), 4.59 (m, 1H, 3′-H), 4.07 (m, 1H, 4′-H), 3.86 (dd, J=3.1, 12.2 Hz, 1H, one of 5′-H), 3.76 (dd, J=3.5, 12.2 Hz, 1H, one of 5′-H), 3.25 (s, 3H, one of NCH3), 3.24 (s, 3H, one of NCH3), 2.80-2.88 (ddd, J=5.9, 7.8, 13.5 Hz, 1H, one of 2′-H), 2.40-2.47 (ddd, J=2.8, 6.1, 13.4 Hz, 1H, one of 2′-H); 13C NMR (100 MHz, CD3OD) δ 161.0, 159.9, 152.8, 151.1, 142.8, 127.0, 89.7, 86.9, 72.9, 63.5, 41.5 (N(CH3)2), 35.3; HRMS (FAB+) calcd for C13H19O3N6 (M+H+): 307.1519, found: 307.1511.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][C:17]([C:21]2[S:22][CH:23]=[C:24]([C:26]3[C:27]([O:41][CH:42]4[CH2:45][CH2:44][CH2:43]4)=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]([C:36]([O:38][CH3:39])=[O:37])[C@@H:31]([CH3:40])[CH2:30][CH2:29]4)[N:25]=2)([O:19][CH3:20])[CH2:16]1)=O)(C)(C)C>ClCCl>[CH:42]1([O:41][C:27]2[C:26]([C:24]3[N:25]=[C:21]([C:17]4([O:19][CH3:20])[CH2:18][NH:15][CH2:16]4)[S:22][CH:23]=3)=[CH:35][CH:34]=[C:33]3[C:28]=2[CH2:29][CH2:30][C@H:31]([CH3:40])[N:32]3[C:36]([O:38][CH3:39])=[O:37])[CH2:43][CH2:44][CH2:45]1
Reactant: COC(=O)N1c2ccc(-c3csc(C4(OC)CN(C(=O)OC(C)(C)C)C4)n3)c(OC3CCC3)c2CC[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N1c2ccc(-c3csc(C4(OC)CNC4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-3-methoxyazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.070 g, 0.13 mmol) in dichloromethane (3 mL), and the resulting solution stirred for 2 h at room temperature. The reaction mixture was concentrated under vacuum, and the residue was purified by preparative-HPLC with the following conditions (Waters I): Column, Xbridge C18, 5 um, 19×150 nm; Mobile phase water (0.05% ammonium bicarbonate) and acetonitrile (25% to 65% acetonitrile in 10 min; flow rate: 20 mL/min); Detector, 220&254 nm. This afforded (S)-methyl 5-cyclobutoxy-6-(2-(3-methoxyazetidin-3-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.037 g, 65%) as an off-white solid. 1H NMR (400 MHz, CD3OD) 1.20 (d, J=6.80 Hz, 3H), 1.25-65 (m, 3H), 1.95-2.20 (m, 4H), 2.20-2.31 (m, 1H), 2.45-2.55 (m, 1H), 2.90-3.01 (m, 1H), 3.30 (s, 3H), 3.80 (s, 3H), 3.92-3.98 (m, 2H), 4.10-4.22 (m, 3H), 4.55-4.62 (m, 1H), 7.36 (d, J=8.40 Hz, 1H), 7.82 (d, J=8.40 Hz, 1H), 7.95 (s, 1H). MS (ESI, pos. ion) m/z 444 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([N:16]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)=[O:5])[CH3:2].Cl.C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([N:16]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34](=[NH:41])[NH2:35])=[CH:32][CH:33]=1)=[O:5])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)Cn1c(COc2ccc(C#N)cc2)nc2ccc(N(CCN(C)C)S(C)(=O)=O)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)Cn1c(COc2ccc(C(=N)N)cc2)nc2ccc(N(CCN(C)C)S(C)(=O)=O)cc21

Procedure:
Prepared analogously to Example 1e from 1-ethoxycarbonylmethyl-2-[(4-cyanophenyl)-oxymethyl]-6-[N-(2-dimethylaminoethyl)-methanesulphonylamino]-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O[CH:15]=[C:16]([C:22]([CH3:24])=O)[C:17]([O:19]CC)=[O:18])C>>[CH2:3]([N:10]1[CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:22]([CH3:24])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NNCc1ccccc1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Agent: Cl
Product: Cc1nn(Cc2ccccc2)cc1C(=O)O
Yield: 27.8 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 1 using benzylhydrazine dihydrochloride (8.0 g) and ethyl 2-ethoxymethyleneacetoacetate (7.6 g), the residue was recrystallized from ethyl acetate to give 1-benzyl-3-methylpyrazole-4-carboxylic acid (2.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[F:18][CH:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:21]2[CH2:22][CH2:23][CH2:24][CH:19]([F:18])[CH2:20]2)[CH:3]=1
Reactant: FC1CCCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Cl)cc1N1CCCC(F)C1
Temperature: 40 °C
Yield: 97.8 %

Procedure:
A solution of 4-chloro-2-fluoro-1-nitro-benzene (0.30 g, 1.7 mmol) in toluene (5 mL) was treated with solid Na2CO3 (0.40 g, 3.7 mmol) and 3-fluoropiperidine (0.25 mg, 1.8 mmol) and heated to 40° C. for 6 h. The reaction was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.43 g, 98%) as a bright yellow oil. 1H-NMR (CDCl3; 400 MHz): δ 7.76 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.4 Hz), 6.95 (dd, 1H, J=8.8, 2.4 Hz), 4.86-4.67 (m, 1H), 3.46-3.35 (m, 1H), 3.15-3.06 (m, 2H), 2.99-2.92 (m, 1H), 2.10-1.90 (m, 2H), 1.88-1.69 (m, 2H). LC-MS (ESI, m/z): Calcd. for C11H12ClFN2O2 259.1 (M+H), found 259.1.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:29][C:28]4[C:23](=[N:24][CH:25]=[CH:26][C:27]=4[O:30][C:31]4[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:40][C:41](=[O:49])[CH2:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[S:39])=[CH:33][C:32]=4[F:50])[CH:22]=3)=[CH:17][CH:16]=2)[CH2:10]1)(C(C)(C)C)(C)C>CC#N.CO.Cl>[F:50][C:32]1[CH:33]=[C:34]([NH:37][C:38]([NH:40][C:41](=[O:49])[CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[S:39])[CH:35]=[CH:36][C:31]=1[O:30][C:27]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:22]=[C:21]([C:18]3[CH:17]=[CH:16][C:15]([CH2:14][N:11]4[CH2:12][CH2:13][C@H:9]([OH:8])[CH2:10]4)=[CH:20][CH:19]=3)[S:29][C:28]=12
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=S)NC(=O)Cc6ccccc6)cc5F)c4s3)cc2)C1
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CC[C@H](O)C5)cc4)sc23)c(F)c1
Reaction time: 2 h
Yield: 8.7 %

Procedure:
To a solution of 103 (34 mg, 0.047 mmol) in CH3CN/MeOH (0.5 mL/2.0 mL), concentrated HCl (8 drops) was added and the reaction was allowed to stir 2 h. The solvents were removed under reduced pressure and the resultant solid was triturated with diethyl ether followed by purification by Gilson HPLC preparative system, column Aquasil C18 (25% MeOH in water to 100% MeOH), to afford title compound 104 (2.5 mg, 9% yield), as a white solid. 1H NMR (DMSO) δ (ppm): 11.82 (1H, s), 8.51 (1H, d, J=5.28 Hz), 8.23 (1H, s), 8.02-7.98 (2H, m), 7.82 (2H, d, J=7.83 Hz), 7.52 (2H, br), 7.41 (2H, d, J=7.83 Hz), 7.33-7.25 (5H, m), 6.64 (1H, d, J=5.09 Hz), 4.20 (1H, br), 3.83 (2H, s), 3.38 (2H, s), 2.34-2.32 (2H, m), 2.03-1.96 (2H, m), 1.56 (2H, br). MS (m/z) 613.3 (M+H).
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC#N)C(=O)COC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)=[CH:52][C:53]4[N:58]([CH2:59][C:60]#[N:61])[C:57](=[O:62])[CH:56]([CH3:63])[O:55][C:54]=4[N:64]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1)(C)(C)C>>[NH2:39][C:40]1([C:44]2[CH:45]=[CH:46][C:47]([C:50]3[C:51]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)=[CH:52][C:53]4[N:58]([CH2:59][C:60]#[N:61])[C:57](=[O:62])[CH:56]([CH3:63])[O:55][C:54]=4[N:64]=3)=[CH:48][CH:49]=2)[CH2:41][CH2:42][CH2:43]1
Reactant: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(CC#N)C1=O
Agent: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Product: CC1Oc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc2N(CC#N)C1=O
Yield: 98.2 %

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, tert-butyl(1-(4-(1-(cyanomethyl)-3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (25 mg, 0.048 mmol) was reacted to afford the title compound (20 mg). 1H NMR (500 MHz, CH3OD) 7.71 (s, 1H), 7.45 (d, 2H), 7.39 (d, 2H), 7.32 (m, 3H), 7.26 (m, 2H), 5.14 (s, 2H), 5.10 (q, 1H), 2.74-2.80 (m, 2H), 2.55-2.61 (m, 2H), 2.22-2.26 (m, 1H), 1.96-1.99 (m, 1H), 1.71 (d, 3H). LCMS (Method D): RT=0.81 min, M+H+=425.2.
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:16])[C:11]([O:13]CC)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>CO>[CH2:1]([NH:9][C:10](=[O:16])[C:11]([OH:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCNC(=O)C(=O)O
Reaction time: 1 h

Procedure:
To a solution of ethyl N-(n-octyl)oxamate (5 g., 0.022 mole) in methanol (50 ml.) is added slowly NaOH solution (20 ml. of 1 N NaOH diluted with 25 ml. of H2O). After standing for one hour, the mixture is evaporated until the residue is mainly solid. 6 N HCl solution (75 ml.) is added. After stirring for 1 hour the solids are removed by filtration and dried. The yield of N-(n-octyl)oxamic is 3.85 g. (m.p. 89°-93° C.).
Reaction SMILES: CO[C:3]1[C:8]([C:9]([C:11](=[C:17](SC)SC)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])=[CH:7][N:6]=[C:5]([S:22][CH3:23])[N:4]=1.[NH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([NH:29][CH3:30])=[O:28]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12]([C:11]1[C:9](=[O:10])[C:8]2[CH:7]=[N:6][C:5]([S:22][CH3:23])=[N:4][C:3]=2[N:24]2[C:17]=1[N:29]([CH3:30])[C:27](=[O:28])[C:26]1[CH:31]=[CH:32][CH:33]=[CH:34][C:25]2=1)=[O:13])[CH3:16]
Reactant: CNC(=O)c1ccccc1N
Reactant: CCOC(=O)C(C(=O)c1cnc(SC)nc1OC)=C(SC)SC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(=O)c2cnc(SC)nc2n2c3ccccc3c(=O)n(C)c12
Temperature: 140 °C
Yield: 3.7 %

Procedure:
A solution of ethyl 2-(4-methoxy-2-(methylthio)pyrimidine-5-carbonyl)-3,3-bis(methylthio)acrylate (775 mg, 2.069 mmol) and 2-amino-N-methylbenzamide (475 mg, 3.163 mmol) in toluene (5 mL) was heated over stream of nitrogen allowing toluene to evaporate and continued heating as neat at 140° C. for over night. Cooled to rt and precipitate formed from DCM (10 mL) was filtered off. The solvent of mother liquor was removed under reduced pressure and repeated the precipitation process with Et2O (10 mL). Trituration in methanol (10 mL) afforded the desired product as a yellow solid (30 mg, 4 %). MS (m/z): 397 (MH+). 1H NMR (CDCl3) δ: 9.37 (s, 1H), 8.37 (d, 1H), 8.26 (dd, 1H), 7.70 (m, 1H), 7.49 (m, 1H), 4.46 (q, 2H), 3.61 (s, 3H), 2.60 (s, 3H), 1.43 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O>C(O)C.[Pd]>[O:10]([C:9]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH2:1])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1cnccc1Oc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnccc1Oc1ccccc1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a slurry of 10% Pd/C in 5 ml of absolute ethanol was added 3-nitro-4-phenoxypyridine (7.5 g) in 245 ml of ethanol. This mixture was shaken on a Parr apparatus for two hours. The mixture was filtered and the filtrate concentrated to yield an oil (6.4 g) which was eluted with ethyl acetate on a silica gel column in HPLC. The desired fractions were concentrated to yield an oil (4.5 g). This material was distilled using a Kugelrohr apparatus to yield an oil (1.8 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([C:19]([F:22])([F:21])[F:20])=[CH:12][N:11]=1.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:5][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([C:19]([F:20])([F:21])[F:22])=[CH:12][N:11]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)COc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.1 %

Procedure:
In a 10 ml flask, hydroxy-acetic acid methyl ester (0.4 ml, 0.53 mmol) was dissolved in tetrahydrofuran (1.5 ml), and then sodium hydride (23 mg, 0.57 mmol) was added thereto. After 40 minutes, 2-chloro-3-nitro-5-trifluoromethyl-pyridine (100 mg, 0.44 mmol) was added and then stirred for 2 hours at room temperature. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of n-hexane:ethyl acetate=9:1. The fractions containing the product were collected and evaporated to obtain white solid (84 mg, 68%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](/[C:15](/[CH3:40])=[CH:16]/[C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[C:24]2[CH2:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=2[O:38][CH3:39])=[CH:19][CH:18]=1)=[O:14])(C)(C)C>C(Cl)Cl>[C:13](/[C:15](/[CH3:40])=[CH:16]/[C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[C:24]2[CH2:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=2[O:38][CH3:39])=[CH:19][CH:18]=1)([OH:14])=[O:12]
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(/C=C(\C)C(=O)OC(C)(C)C)cc23)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(Cc2cccc3ccc(/C=C(\C)C(=O)O)cc23)c(OC)c1
Reaction time: 4 h
Yield: 78.8 %

Procedure:
Trifluoroacetic acid (25 ml) was added to a 0° C. solution of methyl E-4-[7-[2-(t-butoxycarbonyl)prop-1-enyl]naphth-1-ylmethyl]-3-methoxybenzoate (6.43 g) in methylene chloride (50 ml). After stirring for 4 hours, the solvent was evaporated without heating. The residue was triturated with ether and the colorless solid filtered. The filtrate was concentrated and hexane was added to give another crop of product as a pale yellow solid. The two crops were combined and dried to give methyl E-4-[7-(2-carboxyprop-1-enyl)naphth-1-ylmethyl]-3-methoxybenzoate (4.43 g, 94%); mp 187.0°-187.5° C.; MS(EI), m/e=390(M+.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-])=O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(Cc2ccccc2[N+](=O)[O-])CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(Cc2ccccc2N)CCN(C(=O)OC(C)(C)C)CC1
Yield: 86.8 %

Procedure:
A mixture of 4-(2-nitro-benzyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.61 g, 4.102 mmol) and 10% palladium on charcoal (0.10 g) in ethanol (190 mL) was hydrogenated at 50 psi overnight. The resultant mixture was filtered through a plug of celite, and the filtrate concentrated under vacuum to provide the desired product (1.29 g, 99%) as colorless oil. Mass spec.: 363.45 (MH)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[CH2:23][O:22][B:21]([OH:24])[C:20]=2[CH:25]=1)(=[O:14])=[O:13])#[N:2]>CO.CS(C)=O.[Ni]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([S:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]3[CH2:23][O:22][B:21]([OH:24])[C:20]=3[CH:25]=2)(=[O:13])=[O:14])=[C:3]([C:1]#[N:2])[CH:8]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Agent: [Ni]
Solvent: CO
Solvent: CS(C)=O
Product: N#Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
To a solution of 2-cyano-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-nitrobenzenesulfonamide (400 mg, 1.1 mmol) in MeOH/DMSO (40 ml/1 ml) was added Raney Ni (100 mg) under nitrogen, then the solution was stirred under hydrogen atmosphere at room temperature for 2 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by prep. HPLC (column: YMC AQ 150×30.0 mm, 5 u; liquid phase: [A-H2O+0.075% TFA; B-MeCN+0.075% TFA] B %: 18%-48%, 10 min) to give the title compound (100 mg, 27.62%) as a yellow solid. 1H NMR: DMSO 400 MHz δ10.25 (s, 1H), 9.21 (s, 1H), 7.60 (d, J=9.6 Hz, 1H), 7.43 (s, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.17 (d, J=9.2 Hz, 1H), 6.92 (s, 1H), 6.77 (d, J=10.4 Hz, 1H), 6.44 (brs, 2H), 4.89 (s, 2H). ESI-MS m/z 330 (M+H, positive); HPLC purity: 97.31% (MaxPlot 190-370 nm), 99.89% (220 nm).