Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10]([O:12][P:13]([O:17]CC)[O:14][CH2:15][CH3:16])[CH3:11].C(Br)C>>[CH3:9][CH2:8][O:7][C:5](/[CH:4]=[CH:3]/[CH2:2][P:13]([O:14][CH2:15][CH3:16])([O:12][CH2:10][CH3:11])=[O:17])=[O:6]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)/C=C/CBr
Solvent: CCBr
Product: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reaction time: 3 h

Procedure:
Ethyl 4-bromocrotonate (7.0 mL) was added to triethylphosphite (9.9 mL) at 120 to 130° C. during 60 minutes periods. After the generation of ethyl bromide ceased, the reaction solution was stirred at the same temperature for 3 hours. After cooling, the resulting reaction solution was concentrated under reduced pressure. Then the residue was purified by distillation at 150 to 210° C. under reduced pressure (17 to 21 hPa) to give triethyl 4-phosphonocrotonate as colorless oil.
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH2:29])[C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N.CO>N1C=CC=CC=1>[C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH:29][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:9]([O:11][Si:12]([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:13])[CH3:14])[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1cnc2c(N)ncnc21
Reactant: O=C(Cl)c1ccccc1
Agent: N
Solvent: CO
Solvent: c1ccncc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1cnc2c(NC(=O)c3ccccc3)ncnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
To a cold (˜0 C, ice/water bath) solution of 50 (2.65 g, 5.7 mmol) in 50 ml of anhydrous pyridine was added dropwise with stirring 1.0 ml (8.6 mmol) of benzoyl chloride (via a syringe). The reaction was allowed to warm up to room temperature, stirred for about 5 hrs until no starting material was found by HPLC analysis, and then treated with 10 ml of 6M NH3/MeOH. After being stirred for about 3 hrs and no more of the bis-benzoylated intermediate found by HPLC, the reaction was concentrated, re-suspended in dichloromethane (˜50 ml) and filtered to remove poorly insoluble benzamide. The filtrate was concentrated, washed with 10% citric acid, saturated NaCl, dried over Na2SO4 and concentrated again. The crude product was crystallized from 50% ethyl acetate/hexane (˜20 ml) to afford 2.4 g (74%) of 51 as white crystals. 1H NMR (DMSO-d6): δ 11.15 (s, 1H), 8.70 (s, 1H), 8.40 (s, 1H), 8.02 (d, J=7.2 Hz, 2H), 7.63 (m, 1H), 7.54 (t, J=7.8 Hz, 2H), 4.33 (m, 1H), 4.21 (m, 1H), 4.04 (m, 1H), 3.58 (m, 2H), 2.38 (m, 1H), 1.19 (d, J=6 Hz, 3H), 0.84 (s, 9H), 0.79 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H), −0.10 (s, 6H).
Reaction SMILES: [OH:1][CH:2]([C:17]1[N:18]=[CH:19][N:20]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:21]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([NH:15][CH3:16])=[O:14])[CH:7]=[CH:6]2.CN(C)C(=O)C.C(OC(C)C)(C)C>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[CH3:16][NH:15][C:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([C:17]3[N:18]=[CH:19][N:20]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:21]=3)=[O:1])[CH:4]=2)[CH:9]=1)=[O:14]
Reactant: CNC(=O)c1ccc2cc(C(O)c3cn(S(=O)(=O)c4ccccc4)cn3)ccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1ccc2cc(C(=O)c3cn(S(=O)(=O)c4ccccc4)cn3)ccc2c1
Temperature: 60 °C
Reaction time: 9.5 h
Yield: 71.4 %

Procedure:
6-(Hydroxy(1-(phenylsulfonyl)-1H-imidazol-4-yl)methyl)-N-methyl-2-naphthamide (8.8 g, 20.88 mmol) and manganese dioxide (16.4 g, 187.9 mmol) were added to N,N-dimethylacetamide (75 mL), and the mixture was stirred at 60° C. for 9.5 hr. The insoluble material was filtered off from the reaction mixture at 60° C., and washed with DMAc (35 mL). The filtrate and washing were combined, and cooled to 40° C., water (53 mL) was added dropwise thereto, and the mixture was stirred at the same temperature for 0.5 hr or more, and then at room temperature for 1 hr or more to give crystals. The obtained crystals were collected by filtration, and washed with water (44 mL) to give wet crystals. The obtained wet crystals were dried under reduced pressure at an outside temperature of 50° C. to give crude crystals (6.3 g). Ethyl acetate (63 mL) was warmed to 40° C., and the crude crystals (6.3 g) were added thereto. The obtained mixture was warmed to 50° C., and stirred for 0.5 hr or more. 13 mL of the solvent was evaporated under reduced pressure to give a residue. The obtained residue was allowed to cool to room temperature, diisopropyl ether (53 mL) was added dropwise thereto at the same temperature, and the mixture was stirred to give crystals. The obtained crystals were collected by filtration, and washed with a mixed solvent (20 mL) of diisopropyl ether/ethyl acetate (1:1, volume ratio) to give wet crystals. The obtained wet crystals were dried under reduced pressure at an outside temperature of 50° C. to give N-methyl-6-[(1-(phenylsulfonyl)-1H-imidazol-4-yl)carbonyl]-2-naphthamide (6.2 g, 14.9 mmol). yield 72%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[CH3:51][O:52][C:53]1[CH:54]=[C:55]([CH:61]=[CH:62][CH:63]=1)[O:56][CH2:57][CH2:58]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:58][CH2:57][O:56][C:55]2[CH:61]=[CH:62][CH:63]=[C:53]([O:52][CH3:51])[CH:54]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: COc1cccc(OCCCO)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(OCCCOC(=O)Nc2cc(C)c(Oc3ccnc4cc(OC)c(OC)cc34)cc2C)c1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (73 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (101 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(3-methoxyphenoxy)-1-propanol (62 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (59 mg, yield 46%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:16]=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[C:14]([C:21]4[O:22][C:23]([NH:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[N:24][N:25]=4)=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C1COCC1.CCN(C(C)C)C(C)C.[S:47](Cl)([CH3:50])(=[O:49])=[O:48]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:16]=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[C:14]([C:21]4[O:22][C:23]([NH:26][CH:27]5[CH2:32][CH2:31][N:30]([S:47]([CH3:50])(=[O:49])=[O:48])[CH2:29][CH2:28]5)=[N:24][N:25]=4)=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(NC2CCNCC2)o1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(NC2CCN(S(C)(=O)=O)CC2)o1
Reaction time: 0.08 h

Procedure:
To a stirred solution of N2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-(piperidin-4-ylamino)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine (Example 131) (30 mg, 0.06 mmol) in DCM (4 mL): THF (4 mL), added DIPEA (0.09 mmol, 1.5 equiv.) and DMAP (0.006 mmol, 0.1 equiv.) and stirred for 5 min. Added mesyl chloride (0.5 mmol, 0.8 equiv.) dropwise at 0° C. Stirred the reaction mixture at 0° C. for 1 h, reaction temperature was brought to room temperature and stirred overnight. The reaction mixture was diluted with DCM. The DCM layer was washed with 10% NaHCO3 solution followed by water. The DCM layer was collected, dried over Na2SO4, filtered and concentrated. The material obtained was purified by prep HPLC to afford the title compound, N2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-((1-(methylsulfonyl)piperidin-4-yl)amino)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine. 1H NMR: 400 MHz, CD3OD: δ 1.34 (d, J=6.40 Hz, 6H), 1.66-1.75 (m, 2H), 2.10-2.14 (m, 2H), 3.027 (s, 3H), 3.30-3.36 (1H, merged with water peak), 3.56-3.60 (m, 1H), 3.78-3.82 (m, 1H), 4.00-4.05 (m, 2H), 6.17 (s, 1H), 7.53-7.57 (m, 1H), 7.98 (d, J=8.80 Hz, 1H), 8.38 (s, 1H), 8.43 (d, J=2.00 Hz, 1H), 9.08 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 1.501 min; LCMS (ES-API), m/z 529.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.771 min; Purity: 99.7%.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:10]=2)[NH:5][CH:4]=1)#[N:2].OO.NC(N)=[O:21].[OH-].[Na+]>CO.O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[NH:5][CH:4]=1)(=[O:21])[NH2:2]
Reactant: CCOC(=O)c1ccc2[nH]cc(C#N)c2c1
Reactant: NC(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)c1c[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A solution of ethyl 3-cyano-1H-indole-5-carboxylate (1.05 g, 4.89 mmol) in methanol (12 mL) was added to a 0° C. solution of urea hydrogen peroxide (4.74 g, 48.9 mmol) and sodium hydroxide (11.7 mL of a 2.5 M solution in water, 29.3 mmol). The mixture was allowed to warm to room temperature and stir overnight. An additional 2 mL of a 2.5 M solution of sodium hydroxide was added and the reaction was left stirring 4 hours. The mixture was concentrated and acidified to pH 2 using 6 M hydrochloric acid. The resulting precipitate was filtered off and dried under vacuum at 60° C. to give the title compound (915 mg, 92%). 1H NMR (400 MHz, DMSO-d6, δ): 12.46 (br. s., 1 H), 11.84 (s, 1 H), 8.85 (s, 1 H), 8.12 (d, J=2.5 Hz, 1 H), 7.75 (dd, J=8.6, 1.6 Hz, 1 H), 7.50-7.63 (m, 1 H), 7.47 (d, J=8.6 Hz, 1 H), 6.88 (br. s., 1 H).
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[Na+].Cl[C:12]1[CH:17]=[C:16]([Cl:18])[N:15]=[C:14]([S:19][CH3:20])[N:13]=1.[NH2:21][C:22]1C=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>C1COCC1>[Cl:18][C:16]1[N:15]=[C:14]([S:19][CH3:20])[N:13]=[C:12]([NH:5][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][N:21]=2)[CH:17]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2cc(Cl)nc(SC)n2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
NaHMDS (65.7 mL, 1M in THF) was added into the solution of 4,6-dichloro-2-(methylthio)pyrimidine (6.4 g) and methyl 4-aminobenzoate (5 g) in THF (200 mL). The reaction was stirred at room temperature for 16 hours, before being quenched by water. The aqueous layer was extracted with EtOAc (3×200 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum to give the crude product, methyl 6-(6-chloro-2-(methylthio)pyrimidin-4-ylamino)nicotinate, which was used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:21][O:20][N:19]([CH3:18])[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 30 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.0 g, 21.8 mmol) in dichloromethane (80 mL) were added N,O-dimethylhydroxylamine hydrochloride (2.55 g, 26.1 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (9.95 g, 26.1 mmol), N-ethyl-N-isopropylpropan-2-amine (8.46 g, 65.42 mmol) and stirred at 30° C. for 16 hours. The reaction was quenched by adding water (100 ml) and extracted with ethyl acetate (200 ml*3). The combined organic layers was washed with brine, dried over sodium sulfate and concentrated under vacuum to give tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate. (5.7 g, yield 97.6%). LRMS (M+H+) m/z: calcd 272.17. found 273.17.
Reaction SMILES: [C:1]([CH:6]1[CH:10](C(OCC)=O)[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:8](=[O:22])[C:7]1=[O:23])([O:3][CH2:4][CH3:5])=[O:2].[CH2:24](OC1C(=O)N(C(C)C)CC=1C(O)=O)[CH3:25]>>[CH:16]1([N:9]2[CH2:10][C:6]([C:1]([OH:3])=[O:2])=[C:7]([O:23][CH2:24][CH3:25])[C:8]2=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1.[C:1]([CH:6]1[CH2:10][N:9]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[C:8](=[O:22])[C:7]1=[O:23])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC1=C(C(=O)O)CN(C(C)C)C1=O
Reactant: CCOC(=O)C1C(=O)C(=O)N(C2CCCCC2)C1C(=O)OCC
Product: CCOC(=O)C1CN(C2CCCCC2)C(=O)C1=O
Product: CCOC1=C(C(=O)O)CN(C2CCCCC2)C1=O

Procedure:
The 1-cyclohexyl derivative 5a was prepared in the current investigation from the enolic 4,5-dicarbethoxy-1-cyclohexyl-2,3-dioxopyrrolidine (1a) by a similar procedure conducted on nearly the same scale (ca. 0.088 mol of 1a used in many experiments). Both the 4,5-dicarbethoxy derivative 1a and the 4,5-dimethoxy derivative (mp 160° C.) have been used as starting materials with similar results. The procedure was identical with that described above for 5b, except that it was not necessary to conduct an evaporation to remove ethanol from the saponification mixture, which was instead filtered and poured into a mixture of 200 mL of ice and 50 mL of ethanol before acidification to precipitate the product. The typical yield of 5a, mp 154°-155° C., from 0.088 mol of starting material was 16 g (72%), a result equivalent to the best obtained from the more complex two-step conversion of 4-carbethoxy-1-cyclohexyl-2,3-dioxopyrrolidine described previously.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[C:7]2SCCCS2)[CH2:5][C:4]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[O:3]1.Cl(O)(=O)(=O)=[O:20].[C:24](=O)(O)[O-:25].[Na+]>CO.Cl[Hg]Cl>[CH3:1][CH:2]1[CH:6]([C:7]([O:25][CH3:24])=[O:20])[CH2:5][C:4]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[O:3]1
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: CC1OC2(CCN(C)CC2)CC1=C1SCCCS1
Reactant: O=C([O-])O
Agent: Cl[Hg]Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CC2(CCN(C)CC2)OC1C

Procedure:
A suspension of 2,8-dimethyl-3-(1,3-dithian-2-ylidene)-1-oxa-8-azaspiro[4.5]decane (2.84 g, 9.95 mmol), HgCl2 (10.8 g, 0.04 mol) and perchloric acid (60%, 5.2 ml) in MeOH/85 ml) was heated at reflux for 2 hours, cooled and decomposed with saturated aqueous sodium bicarbonate solution. The solids were filtered and the filtrate was extracted with methylene chloride. The organic extracts were dried and evaporated. The residue obtained was chromatographed on silica gel and eluted with ammoniated 10-25% MeOH/CH2Cl2 to give the title ester as an oil (1.39 g). A 1 g sample of the oil was converted to the maleate salt in ether. The crude salt was crystallized from methylene chloride/ether to give the maleate salt of the title product (0.48 g), mp 105°-107° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:28])[NH:11][CH:12]=[C:13]([C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)[C:14]=1[F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:28])[N:11]([CH3:29])[CH:12]=[C:13]([C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)[C:14]=1[F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cc(-c2cccc(-c3ccccc3)c2)c(F)c1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(-c2cccc(-c3ccccc3)c2)c(F)c(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 3-(benzyloxy)-5-(biphenyl-3-yl)-4-fluoropyridin-2(1H)-one (24 mg, 0.065 mmol) in DMF (0.8 mL) was added Cs2CO3 (27 mg, 0.084 mmol) followed by a solution of MeI (10 mg, 0.071 mmol) in DMF (0.05 mL). After stirring at room temperature for 1 h the reaction mixture was filtered. Purification by preparative HPLC (10-80% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 22 mg (88%) of 3-(benzyloxy)-5-(biphenyl-3-yl)-4-fluoro-1-methylpyridin-2(1H)-one as a colorless glass. LC/MS (M−141)+ 296.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=[CH:4][C:3]1=2.O[C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCOC(C)=O>CN(C=O)C>[CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([O:19][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC1(C)CC=C(c2cccs2)c2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1

Procedure:
A solution of 5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylic acid (Compound E6, 50.0 mg, 0.177 mmol), ethyl 4-hydroxybenzoate (38.2 mg, 0.230 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44.0 mg, 0.230 mmol), and 4-N,N-dimethylaminopyridine (28.0 mg, 0.230 mmol) in 2.0 mL DMF was stirred overnight at room temperature. EtOAc (50 mL) was added and the solution washed with H2O, 5% HCl, saturated aqueous NaCO3, and saturated aqueous NaCl before being dried over MgSO4. Removal of the sovents under reduced pressure and column chromatography (10% EtOAc-hexanes) of the residual oil afforded the title compound as a colorless solid.
Reaction SMILES: [C:1]1([N:7]2[C:12](=O)C3SC=C(C4C=CC=CC=4)C=3N=C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.[CH:40](OCC)(OCC)OCC.NC1C=CC=C(C)C=1>C(O)(=O)C>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]1[C:24]2[N:23]=[CH:12][N:7]([C:1]3[CH:2]=[C:3]([CH3:40])[CH:4]=[CH:5][CH:6]=3)[C:36](=[O:38])[C:25]=2[S:26][CH:27]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Solvent: CC(=O)O
Solvent: Cc1cccc(N)c1
Product: Cc1cccc(-n2cnc3c(-c4ccccc4F)csc3c2=O)c1
Yield: 65 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (80 mg, 0.3 mmol), triethyl orthoformate (0.79 ml), m-toluidine (63.8 mg, 0.59 mmol), and acetic acid (0.09 ml) were used to give 70 mg (0.21 mmol, 65.0% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[H][H].[CH3:12][O:13][CH2:14][CH2:15]O>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH2:15][CH2:14][O:13][CH3:12]
Reactant: [H][H]
Reactant: Cc1cccc(C)c1N
Reactant: COCCO
Product: COCCNc1c(C)cccc1C
Temperature: 275 °C

Procedure:
In a quartz tube 30 cm in length and 0.5 cm in diameter, which is arranged vertically and surrounded by a heating jacket, 2 ml of this catalyst are activated at 130° C., in the manner described in Example 2, and then heated to 275° C. under hydrogen. At 275° C., 1.21 g of 2,6-dimethylaniline, 1.52 g of 2-methoxyethanol and 0.67 N1 of hydrogen are then passed, per hour, under normal pressure, through the reactor from top to bottom. The mixture which issues from the reactor is condensed and worked up by distillation.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][CH:14]=3)=[CH:11][S:12][C:8]=2[CH:7]=[CH:6][N:5]=1>ClCCl>[NH2:3][C:4]1[C:9]2[C:10]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:17][CH:18]=3)=[CH:11][S:12][C:8]=2[C:7]([Br:1])=[CH:6][N:5]=1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2csc3ccnc(N)c23)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(-c2csc3c(Br)cnc(N)c23)cc1
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
A solution of bromine (0.4 mL, 4.6 mmol) in dichloromethane (5 mL) was added dropwise to a −5° C. solution of Example 76A (1.57 g, 4.6 mmol) in dichloromethane (30 mL). The mixture was stirred at −5° C. to 0° C. for 15 minutes and quenched with 1:1 saturated NaHCO3 and saturated NaHSO3 (10 mL). The organic phase was separated, washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide 1.85 g of the desired product. MS (ESI(+)) m/e 421 (M+H)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:43])[N:20]([CH2:39][CH:40]2[CH2:42][CH2:41]2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:43])[N:20]([CH2:39][CH:40]2[CH2:41][CH2:42]2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(CC2CC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(C)n(CC2CC2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.74 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(cyclopropylmethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.55 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (6 mL). N,N′-carbonyldiimidazole (0.29 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.089 g, 14%).