Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[S:5](=[O:15])(=[O:14])[N:4]([CH3:16])[C:3]=1[C:17]([O:19]C)=O.[NH2:21][C:22]1[S:23][C:24]([CH3:27])=[CH:25][N:26]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[S:5](=[O:14])(=[O:15])[N:4]([CH3:16])[C:3]=1[C:17]([NH:21][C:22]1[S:23][C:24]([CH3:27])=[CH:25][N:26]=1)=[O:19]
Reactant: Cc1cnc(N)s1
Reactant: COC(=O)C1=C(O)c2cc(OC)ccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: COc1ccc2c(c1)C(O)=C(C(=O)Nc1ncc(C)s1)N(C)S2(=O)=O
Yield: 89.4 %

Procedure:
5.2 gm (0.017 mol) of methyl 4-hydroxy-6-methoxy-2-methyl-2H-1,2-benzothiazine-3-caboxylate-1,1-dioxide and 2.2 gm (0.019 mol) of 2-amino-5-methyl-thiazole were refluxed in 200 ml of xylene for 24 hours. After cooling, the precipitated crystals were filtered off and recrystallized from tetrahydrofuran. 5.8 gm (89% of theory) of 4-hydroxy-6-methoxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-caboxamide-1,1-dioxide were obtained.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:16][N:15]4[C:24]([C:27]#[N:28])=[CH:25][N:26]=[C:14]4[N:13]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[OH:29]O>CS(C)=O.CC(=O)OCC>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:16][N:15]4[C:24]([C:27]([NH2:28])=[O:29])=[CH:25][N:26]=[C:14]4[N:13]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: N#Cc1cnc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn12
Reactant: OO
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: NC(=O)c1cnc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn12
Temperature: 60 °C

Procedure:
To a suspension of compound 4-10 (40 mg 0.11 mmol.) and K2 CO3 (30 mg, 0.22 mmol) in DMSO (1.0 mL) was added 0.1 mL of H2O2(30% aq.) and the mixture was heated at 60° C. for 3 h. After cooling, the mixture was diluted with 20 mL of EA, the combined organic phase was washed with sat.NaHSO3 (aq) and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.HPLC to give 19 mg of 4-11.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][NH2:23])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]1[CH:29]([CH2:30][C:31](O)=[O:32])[CH2:28][CH2:27][O:26][CH2:25]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][NH:23][C:31](=[O:32])[CH2:30][CH:29]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CC1CCOCC1
Reactant: CC(C)(C)n1ncc(-c2nc(CN)cs2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(CNC(=O)CC3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using the compound obtained in step 2 and tetrahydropyranyl-4-acetic acid and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)[CH3:4].[CH3:9][O:10][C:11]1([O:23][CH3:24])[CH2:15][CH2:14][CH:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1.IC(C)C>C1COCC1.CCOCC>[CH:3]([C:13]1([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15][C:11]([O:23][CH3:24])([O:10][CH3:9])[CH2:12]1)([CH3:4])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: COC1(OC)CCC(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Solvent: CCOCC
Solvent: CC(C)I
Solvent: C1CCOC1
Product: COC1(OC)CCC(C(=O)OC(C)(C)C)(C(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a cooled (−78° C.) solution of LDA (1.5 M in cyclohexane, 41 mL, 61 mmol) in THF (150 mL) was added dropwise over 10 min tert-butyl 3,3-dimethoxycyclopentanecarboxylate (9.37 g, 40.7 mmol) in 25 mL of THF. The resulting mixture was stirred at −78° C. for 30 min, then was treated dropwise with 2-iodopropane (16.3 mL, 163 mmol). After stirring for an additional 10 min, the reaction mixture was permitted to warm to room temperature. After stirring overnight, the reaction mixture was diluted with ether and washed with brine. The ethereal layer was dried over anhydrous MgSO4, filtered, and concentrated. After storing the crude product under vacuum overnight, it was purified by MPLC (silica, 20% ethyl acetate/hexane) to give 8.32 g of tert-butyl 1-isopropyl-3,3-dimethoxycyclopentanecarboxylate (75%). 1H NMR (500 MHz, CDCl3) δ 3.21 (s, 3H), 3.18 (s, 3H), 2.56 (app d, J=14 Hz, 1H), 2.26 (m, 1H), 1.78-1.89 (m, 3
Reaction SMILES: Br[C:2]1[C:15]([F:16])=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=2)=[C:4]([O:17][CH3:18])[CH:3]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+].[CH:28](B1OC(C)(C)C(C)(C)O1)=[CH2:29]>O.C(#N)C>[F:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:14]=[C:15]([F:16])[C:2]([CH:28]=[CH2:29])=[CH:3][C:4]=2[O:17][CH3:18])[N:8]=1
Reactant: COc1cc(Br)c(F)cc1Oc1cccc(F)n1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: C=Cc1cc(OC)c(Oc2cccc(F)n2)cc1F
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To 2-(4-bromo-5-fluoro-2-methoxyphenoxy)-6-fluoropyridine (227 mg, 0.71 mmol) were added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (58.9 mg, 0.07 mmol) and potassium carbonate (597 mg, 4.26 mmol). To the mixture were added acetonitrile (4 mL), water (1.3 mL) and vinyl boronic acid pinacol ester (180 μL, 1.07 mmol). The reaction was flushed with argon, and left to stir for 3 days at 60° C. The reaction mixture was then filtered on celite, rinsed with dichloromethane and concentrated. After purification by preparative TLC (cyclohexane/ethyl acetate: 70/30), the title product was isolated as an orange oil (166 mg, 89%).
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.[NH:24](C(OCC1C=CC=CC=1)=O)[C@H:25]([C:32]([NH:34][C@H:35]([C:39](O)=[O:40])[CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:26][C:27]1[N:31]=[CH:30][NH:29][CH:28]=1>>[NH2:24][C@@H:25]([CH2:26][C:27]1[N:31]=[CH:30][NH:29][CH:28]=1)[C:32]([NH:34][C@@H:35]([CH:36]([CH3:38])[CH3:37])[C:39]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:40])=[O:33]
Reactant: CC(C)[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Product: CC(C)[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
The title compound was prepared substantially following the procedures as set forth in Method B, Example 12, and employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-His-Val-OH as the starting materials, which yielded the title compound as a white powder. 1H NMR (CD3OD, 300 MHz): δ 8.47 (s, 1H), 7.25 (s, 1H), 4.25 (t, 1H), 4.10 (d, 1H), 4.0 (m, 1H), 3.6-3.5 (dd, 1H), 3.10-3.00 (m, 2H), 2.09-2.02 (m, 1H), 1.95-1.86 (m, 2H), 1.80-1.54 (m, 8H), 1.41-1.02 (m, 3H), 1.0-0.95 (m, 9H). 31P NMR (CD3OD, 300 MHz): δ 42.66. LCMS m/z: [M+H]+=472.
Reaction SMILES: [Cl:1]/[C:2](=[C:7](\[Cl:12])/[C:8](OC)=[O:9])/[C:3](OC)=[O:4].[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>O>[F:13][C:14]1[CH:20]=[CH:19][C:17]([N:18]2[C:3](=[O:4])[C:2]([Cl:1])=[C:7]([Cl:12])[C:8]2=[O:9])=[CH:16][CH:15]=1
Reactant: COC(=O)/C(Cl)=C(/Cl)C(=O)OC
Reactant: Nc1ccc(F)cc1
Solvent: O
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1ccc(F)cc1
Yield: 97.3 %

Procedure:
15g (0.07 mol) of dimethyl 2,3-dichloromaleate was added to 100 ml of water. To the resulting solution 6.7g (0.06 mol) of 4-fluoroaniline was added dropwise over a period of 5 min. at reflux temperatures under agitation. The mixture was then allowed to react for 2 hours at reflux temperatures. Upon cooling the reaction mixture, precipitated crystal was separated by filtration to obtain 15.2g of N-(4-fluorophenyl)-2,3-dichloromaleimide melting at 240°-242° C (not corrected) at a yield of 97.3%. An analysis by gas chromatography showed the product had a purity of 94.1%.
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:9][O:8][C:7](=[O:10])[CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:17][CH:18]([N:26]1[C@H:29]([SH:30])[C@H:28]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]1=[O:42])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CC(C)=O.C(OCC)(=O)C>[OH:17][CH:18]([N:26]1[C@H:29]([S:30][CH2:2][C:3]([CH:5]2[CH2:9][O:8][C:7](=[O:10])[CH2:6]2)=[O:4])[C@H:28]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:27]1=[O:42])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)C(O)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1S
Reactant: O=C1CC(C(=O)CCl)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(O)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SCC(=O)C1COC(=O)C1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
(RS)-4-Chloroacetyltetrahydrofuran-2-one (2.060 g, 12.6 mmol), followed by potassium carbonate (0.690 g, 5 mmol) were added to crude t-butyl (2RS)-2-hydroxy-[(3R,4R)-4-mercapto-3-phenoxyacetamidoazetidin-2-on-1-yl]acetate (3.866 g) (prepared as described in Example 1c) in acetone (10 ml). The reaction was stirred 1 h. then diluted with ethyl acetate, washed with water (x2) and brine, dried, concentrated and flash chromatographed on silica gel eluting with 50,60,75,90% ethyl acetate in hexane to provide the title compound as a foam (3.458 g, 68%), νmax (CH2Cl2) 3380, 1780, 1680, 1235, 1150 cm-1 ; [Mass spectrum: +ve ion (thioglycerol) MH+ (509)].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:11]C(=O)C2C=CC=CC=2)=[S:10])[CH:5]=[C:4]([Br:20])[N:3]=1.[OH-].[Na+].CCOC(C)=O.CCCCCC>C1COCC1.CO.O>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[C:4]([Br:20])[N:3]=1
Reactant: O=C(NC(=S)Nc1cc(Br)nc(Br)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=S)Nc1cc(Br)nc(Br)c1
Temperature: 70 °C
Yield: 82.8 %

Procedure:
To a solution of N-(2,6-dibromopyridin-4-ylcarbamothioyl)benzamide (14.50 g, 34.93 mmol) in a mixture of THF (600 mL) and MeOH (200 mL) was added a solution of NaOH (7.0 g, 174.65 mmol) dissolved in 200 mL of water. The mixture was heated to 70° C. for 16-22 h. After reaction, the solvent wad distilled under reduced pressure, water added and extracted with EtOAc (3×500 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue thus obtained was treated with 20% EtOAc-hexane and finally filtered to obtain the desired product as an off-white solid (9.0 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:7](/[C:8](/O)=[CH:9]\[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20].[N:30]1([C:36](=[S:38])[NH2:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[C:7]([C:8]2[N:37]=[C:36]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[S:38][C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20]
Reactant: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Reactant: NC(=S)N1CCOCC1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Yield: 48 %

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step A using N-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (4.05 g, 8.83 mmol) and 4-morpholinecarbothioamide (1.29 g, 8.83 mmol), the title compound was obtained as a bright yellow solid (2.61 g; 48% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 8.29 (d, J=5.5 Hz, 1H), 7.64-7.74 (m, 1H), 7.46-7.56 (m, 2H), 7.39 (dd, J=7.1, 1.7 Hz, 1H), 7.23 (t, J=9.1 Hz, 2H), 6.19 (d, J=5.5 Hz, 1H), 3.71 (t, J=4.6 Hz, 4H), 3.54 (t, J=4.3 Hz, 4H).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)=[C:8]([CH3:21])[CH:7]=1.[CH3:22]O>>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:22])=[O:19])=[CH:16][CH:17]=2)=[C:8]([CH3:21])[CH:7]=1
Reactant: CO
Reactant: Cc1cc(N)ccc1-c1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc(N)cc2C)cc1
Yield: 89 %

Procedure:
Thionyl chloride (10 ml) was added dropwise and cautiously to methanol (200 ml) with stirring. 4'-Amino-2'-methylbiphenyl-4-carboxylic acid (D1) (8.44 g, 37 mmol) was added, and the mixture was then stirred at reflux for 3 h. Solvent was then removed in vacuo to yield the title compound (9.16 g, 89%) as the hydrochloride salt.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][C:4]([NH2:8])=[C:3]([OH:9])[CH:2]=1.Cl.Cl.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22](O)=O.[OH-].[Na+]>>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22]1[O:9][C:3]2[CH:2]=[CH:1][C:6]([NH2:7])=[CH:5][C:4]=2[N:8]=1
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: Nc1ccc(O)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2oc(-c3ccc4ccccc4c3)nc2c1
Temperature: 180 °C
Reaction time: 3.5 h
Yield: 74.9 %

Procedure:
80 μmol of 2,4-diaminophenol.2HCl and 80 μmol of naphthalene-2-carboxylic acid were dissolved in 100 mg of PPA, and then, the mixed solution was stirred at a temperature of 180° C. for 3 to 4 hours. After completion of the reaction, the reaction solution was cooled, neutralized with 10% NaOH, and filtered by using distilled water for recrystallization in a slow manner, thereby obtaining 15.6 mg of 2-(naphthalene-2-yl)benzo[d]oxazole-5-amine (Derivative #3) (yield: 75%).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[C:9]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=3[CH:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].[O:21]=[S:22]1(=[O:39])[CH2:26][CH2:25][CH:24]([CH2:27]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[O:21]=[S:22]1(=[O:39])[CH2:26][CH2:25][CH:24]([CH2:27][O:20][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[CH:13]=[CH:12][N:11]3[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH2:1][CH2:2][CH3:3])[N:10]=2)[CH2:23]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCS(=O)(=O)C2)cc1
Reactant: CCCSc1nccc(-n2ccc3c(O)cccc32)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCCSc1nccc(-n2ccc3c(OCC4CCS(=O)(=O)C4)cccc32)n1
Temperature: 70 °C
Reaction time: 60 h
Yield: 129.7 %

Procedure:
1-(2-Propylsulfanyl-pyrimidin-4-yl)-1H-indol-4-ol (1.56 g) and toluene-4-sulfonic acid 1,1-dioxo-tetrahydro-1lambda*6*-thiophen-3-ylmethyl ester (2.37 g) were added to NMP (20 mL), followed by cesium carbonate (5.08 g). The mixture was stirred at 70° C. for 60 hours, after which solvent was removed by distillation. The residue was diluted with 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to give 2.96 g of 4-(1,1-dioxo-tetrahydro-1lambda*6*-thiophen-3-ylmethoxy)-1-(2-propylsulfanyl-pyrimidin-4-yl)-1H-indole.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]([N:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CC(C)([O-])C.[Na+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C1(C)C=CC=CC=1>[C:13]([O:12][C:10]([N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1cccnc1I
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccnc1N1CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 65 °C

Procedure:
Toluene (1.5 mL) was added to a mixture of 2-iodo-3-methoxypyridine (350 mg, 1.49 mmol), BOC-homopiperazine (0.410 mL, 2.09 mL), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (26 mg, 0.07 mmol), and trisdibenzylideneacetone dipalladium (20 mg, 0.02 mmol). To this suspension was added sodium t-butoxide (201 mg, 2.09 mmol) and the mixture was heated to 65° C. for 15 h. The mixture was filtered through celite, and the filter cake was washed with EtOAc. The resulting solution was washed with H2O, then brine, and dried over MgSO4. After removal of the solvent, the residue was purified on silica to give 335 mg of the title compound as a dark oil. MS (ES) m/z 308 (M+H+).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:21][CH:20]([CH2:22][OH:23])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:21][CH:20]([CH:22]=[O:23])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(C=O)C1
Temperature: -78 °C

Procedure:
To 40 mL dry DCM was added 2.19 mL (30.8 mmol) DMSO. The solution was cooled to −78° C. under nitrogen and 1.95 mL (23.1 mmol) oxalyl chloride was added dropwise. A solution of 2.88 g (15.4 mmol) 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester in 20 mL dry DCM was added quickly via syringe followed by 10.5 mL (77 mmol) triethylamine. The mixture was allowed to warm to room temperature and then quenched by extraction with 1 M HCl (2×50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give the product which was used in the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.O.Cl.Cl.[O:11]=[C:12]1[N:21]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:20][CH2:19][C:18]2[N:17]=[C:16]([CH2:28][CH2:29][CH3:30])[C:15]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:14][C:13]1=2.[CH:36]1([C:39]2[C:44]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)=[C:43]([F:52])[C:42]([O:53][CH2:54][CH3:55])=[C:41]([CH:56]=O)[CH:40]=2)[CH2:38][CH2:37]1.[Na]>C1COCC1>[CH:36]1([C:39]2[C:44]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)=[C:43]([F:52])[C:42]([O:53][CH2:54][CH3:55])=[C:41]([CH2:56][N:25]3[CH2:24][CH2:23][CH:22]([N:21]4[CH2:20][CH2:19][C:18]5[N:17]=[C:16]([CH2:28][CH2:29][CH3:30])[C:15]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:14][C:13]=5[C:12]4=[O:11])[CH2:27][CH2:26]3)[CH:40]=2)[CH2:38][CH2:37]1
Reactant: CCOc1c(C=O)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Reactant: CCCc1nc2c(cc1C(=O)OCC)C(=O)N(C1CCNCC1)CC2
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1nc2c(cc1C(=O)OCC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OCC)CC1)CC2
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
Triethylamine (3.26 g) was added to a mixture of ethyl 5-oxo-6-(piperidin-4-yl)-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate dihydrochloride monohydrate (5.92 g) and 6-cyclopropyl-3-ethoxy-2,4′-difluorobiphenyl-4-carbaldehyde (5.35 g) in THF (100 mL) at room temperature. The mixture was stirred at the same temperature under nitrogen atmosphere for 10 minutes. Sodium triacetoxyhydroborate (6.82 g) was added to the reaction mixture at room temperature. The mixture was stirred at the same temperature under nitrogen atmosphere for 16 hours. The mixture was quenched with saturated sodium hydrogen carbonate aqueous solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate then NH silica gel, hexane/ethyl acetate) to give the title compound (7.98 g)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:20][C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cnc1Cl
Reactant: Oc1ccc(F)cc1
Product: COC(=O)c1cc(Br)cnc1Oc1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 56 from methyl 5-bromo-2-chloronicotinate (J. Org. Chem. 1989, 54, 3618–3624) and 4-fluorophenol: 1H-NMR (CDCl3) δ 8.37 (1H, d, J=2.5 Hz), 8.27 (1H, d, J=2.5 Hz), 7.10 (2H, d, J=6.2 Hz), 3.95 (3H, s); MS (ESI) m/z 326 (M+H)+.
Reaction SMILES: C(OC([O:11][CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[CH:25]=[C:24]([F:26])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@H:15]([O:27][C:28](=[O:40])[CH2:29][NH:30][C:31](=[O:39])[CH:32]([CH2:36][CH2:37][CH3:38])[CH2:33][CH2:34][CH3:35])[C@@H:14]1[O:41][C:42](=[O:54])[CH2:43][NH:44][C:45](=[O:53])[CH:46]([CH2:50][CH2:51][CH3:52])[CH2:47][CH2:48][CH3:49])=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH2:33]([CH:32]([CH2:36][CH2:37][CH3:38])[C:31]([NH:30][CH2:29][C:28]([O:27][C@@H:15]1[C@H:14]([O:41][C:42](=[O:54])[CH2:43][NH:44][C:45](=[O:53])[CH:46]([CH2:50][CH2:51][CH3:52])[CH2:47][CH2:48][CH3:49])[C@@H:13]([CH2:12][OH:11])[O:17][C@H:16]1[N:18]1[CH:25]=[C:24]([F:26])[C:22](=[O:23])[NH:21][C:19]1=[O:20])=[O:40])=[O:39])[CH2:34][CH3:35]
Reactant: CCCC(CCC)C(=O)NCC(=O)O[C@@H]1[C@H](OC(=O)CNC(=O)C(CCC)CCC)[C@@H](COC(=O)OCc2ccccc2)O[C@H]1n1cc(F)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: CCCC(CCC)C(=O)NCC(=O)O[C@@H]1[C@H](OC(=O)CNC(=O)C(CCC)CCC)[C@@H](CO)O[C@H]1n1cc(F)c(=O)[nH]c1=O
Reaction time: 0.83 h
Yield: 70.5 %

Procedure:
After dissolving 0.62 g of 5'-O-benzyloxycarbonyl-2',3'-bis-O-[N-(2-n-propyl-n-pentanoyl)glycyl]-5-fluorouridine in 25 ml of ethanol, 0.2 g of 5% palladium carbon was added to the solution and the mixture was stirred under hydrogen stream, at room temperature and atmospheric pressure for 50 minutes. After the catalyst was filtered off, the residue obtained by condensing the reaction mixture under reduced pressure was applied to silica gel column chromatography to give 0.36 g (Yield: 68%) of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:44]=[CH:43][CH:42]=[CH:41][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][C:28]=2[C:37]([O:39]C)=[O:38])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].CO.O>C1COCC1>[CH2:1]([C:5]1[O:6][C:7]2[CH:44]=[CH:43][CH:42]=[CH:41][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]=2[C:37]([OH:39])=[O:38])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OCc4ccc(C(=O)OC)cc4C(=O)OC)ccc3c2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OCc4ccc(C(=O)O)cc4C(=O)O)ccc3c2)o1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A mixture of dimethyl 4-[({6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)methyl]isophthalate (155.1 mg, 0.263 mmol), prepared in the previous step, and 1 N NaOH (1.55 mL, 1.55 mmol) in 100 mL of THF, plus 100 mL of methanol, plus 10 mL of water was refluxed under nitrogen for 24 h. By LC/MS starting material remained. An additional 1.55 mL (1.55 mmol) of 1 N NaOH was added and the reaction refluxed for an additional 24 h. After cooling to room temperature the reaction was filtered and then acidified by the addition of 4 mL of 1 N HCl. The reaction was concentrated under reduced pressure to remove most of the THF and methanol. The solid present was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (122.7 mg, 83%) as a white solid, mp 285-287° C. Elemental Analysis for C34H27NO7. 0.11 H2O Calc'd: C, 72.46; H, 4.87; N, 2.49. Found: C, 71.71; H, 4.92; N, 2.35.