Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13](O)[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.O>CCCCCC>[C:1]([O:12][CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COc1cc(CO)ccc1O
Reactant: CCCCCCCCCC(=O)O
Solvent: O
Solvent: CCCCCC
Product: CCCCCCCCCC(=O)OCc1ccc(O)c(OC)c1
Temperature: 50 °C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
Decanoic acid (2.00 g, 11.61 mmol), vanillyl alcohol (1.74 g, 11.27 mmol), and Novozym 435 (100 mg) were measured and placed in a flask (25 ml). The mixture in the flask free of a plug was heated with stirring in an oil bath at 50° C. for 20 hours. After 2 to 3 hours of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The reaction mixture was returned to room temperature, hexane (50 ml) was added, and Novozym 435 and a small amount of precipitated vanillyl alcohol were removed by filtration. The filtrate was washed with 5% aqueous citric acid solution (25 ml) and saturated brine (25 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give a mixture (3.41 g) of vanillyl decanoate and decanoic acid as a colorless oil. As a result of the analysis, the yield of vanillyl decanoate was 94.1%. The mixture contained 6.0 wt % of decanoic acid relative to vanillyl decanoate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[C:5]([C:12]#[N:13])=[CH:4][C:3]=1[F:14].[N+:15]([C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)([O-:17])=[O:16].C(N=C=NC(C)C)(C)C>C(Cl)Cl>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([O:10][C:9](=[O:11])[CH2:8][C:6]2[C:5]([C:12]#[N:13])=[CH:4][C:3]([F:14])=[C:2]([Cl:1])[N:7]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: N#Cc1cc(F)c(Cl)nc1CC(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: N#Cc1cc(F)c(Cl)nc1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.05 h
Yield: 84.2 %

Procedure:
A homogeneous brown solution of (6-chloro-3-cyano-5-fluoro-pyridin-2-yl)-acetic acid (2.37 g, 11.0 mmol), as prepared in the previous step, 4-nitrophenol (1.84 g, 13.2 mmol), and DCM (11 mL) was stirred under argon at 0° C. while 1,3-diisopropylcarbodiimide (DIC) (1.90 mL, 12.1 mmol) was added dropwise with stirring over 3 min. The ice bath was immediately removed following completion of the DIC addition, and the brown mixture with yellowish precipitate was stirred at rt for 1 h 40 min. The crude reaction was then directly loaded onto a flash silica column and eluted with 96:4 toluene/CH3CN to afford the title compound as a translucent pale yellow oil (3.11 g, 84%). 1H-NMR (300 MHz, CDCl3) δ 8.29 (m, 2H), 7.80 (d, 1H), 7.35 (m, 2H), 4.35 (d, 0.7 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.C(O[B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1)(C)C.O>C1COCC1>[CH3:39][C:34]1([CH3:40])[C:35]([CH3:38])([CH3:37])[O:36][B:32]([C:2]2[C:3]3[C:8]([C:9]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:33]1
Reactant: Cc1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2c3ccccc3c(B3OC(C)(C)C(C)(C)O3)c3ccccc23)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
4.6 g (1 eq, 13.25 mmol) of 9-bromo-10-p-tolyl-anthracene was dissolved in 150 ml of THF in a 500 ml round-bottomed flask in Ar gas condition, and 6.36 ml (1.2 eq, 15.9 mmol) of 2.5M n-BuLi (in hexane) was added to the solution at −78° C. After stirring the solution at −78° C. for 1 hour, 3.52 ml (1.3 eq, 17.23 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added to the solution and stirred at room temperature for 2 hours. Next, 50 ml of water was added to the solution to terminate the reaction, and the organic phase of the solution was extracted using brine and methylene chloride. The extracted organic phase was dried using anhydrous magnesium sulfate and filtered to remove the solvent. The dried organic phase was dissolved in a small amount of toluene and subjected to column chromatography (silica and hexane) to remove impurities. Next, the polarity of the eluent solvent was increased to obtain 3.5 g (67%) of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=1)=[O:5])[CH3:2].Br[CH2:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=1)=[O:33].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:12][SiH2:13][C:14]([CH3:17])([CH3:15])[CH3:16])[N:8]([CH2:31][C:32](=[O:33])[NH:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)n[nH]1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)n(CC(=O)Nc2ccc(Cl)cn2)n1
Reaction time: 3 h

Procedure:
To a solution of 5 g 5-(tert-Butyl-diphenyl-silanyloxymethyl)-2H-pyrazole-3-carboxylic acid ethyl ester in 10 ml DMF 4 g Cs2CO3 and 3 g 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added and the mixture was stirred for 3 h. Then 10 ml of water were added and the mixture was extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Inspection of the TLC and HPLC/MS indicated that a 1:1 mixture of the desired product together with the regioisomeric 5-(tert-Butyl-diphenyl-silanyloxymethyl)-2-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-2H-pyrazole-3-carboxylic acid ethyl ester was present. Purification of this mixture on silica gel eluting with a gradient on n-heptane/ethylacetate yielded the desired product as the faster eluting less polar isomer.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[CH3:44][S:45]([CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:47])=[O:46]>>[CH3:32][O:31][C:28]1[N:27]=[CH:26][C:25]([NH:24][C:17]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:23][C:20]([CH2:21][N:51]3[CH2:52][CH2:53][CH:48]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:49][CH2:50]3)=[CH:19][N:18]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CS(=O)(=O)C1CCNCC1
Product: COc1ccc(Nc2ncc(CN3CCC(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.200 g, 0.346 mmol) and 4-(methylsulfonyl)piperidine (PharmaBlock, Carrboro, N.C.) (0.085 g, 0.519 mmol). 1H NMR (400 MHz, CDCl3) δ 11.67 (s, 1H); 8.71 (d, J=2.15 Hz, 1H); 8.36 (d, J=2.54 Hz, 1H); 8.18 (d, J=2.35 Hz, 1H); 8.11 (dd, J=9.00, 2.74 Hz, 1H); 6.77 (d, J=8.80 Hz, 1H); 5.76 (s, 2H); 3.94 (s, 3H); 3.49 (s, 2H); 3.10 (d, J=11.35 Hz, 2H); 2.80-2.86 (m, 4H); 2.55 (s, 3H); 2.00-2.18 (m, 4H); 1.84-2.00 (m, 3H). m/z (ESI, +ve ion) 484.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([NH2:26])=[CH:23][CH:24]=2)[CH:19]=[N:18]1>O1CCOCC1.CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:26][C:22]4[CH:21]=[C:20]5[C:25](=[CH:24][CH:23]=4)[NH:17][N:18]=[CH:19]5)[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Solvent: C1COCCO1
Solvent: CCCCO
Product: c1cc(Nc2cc(C3CC3)[nH]n2)nc(Nc2ccc3[nH]ncc3c2)n1
Temperature: 100 °C
Yield: 5.3 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.8 5 mmol, 1 equiv.) and 1H-indazol-5-amine (340 mg, 2.55 mmol, 3 equiv.) in 1,4-dioxane (1 ml) and n-BuOH (0.5 ml) was heated to 100° C. The mixture was allowed to react overnight (about 15 hr). The mixture was filtered under reduced pressure to afford title compound N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1H-indazol-5-yl)pyrimidine-2,4-diamine (Compound 13) (44.5 mg, 15.8%) as solid. LC-MS (m/z)=333.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.44 (s, J=17.7 Hz, 2H), 0.82 (t, J=17.7 Hz, 2H), 1.758 (s, 1H), 6.02 (s, 1H), 6.41 (s, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.56 (d, J=9 Hz, 1H), 7.92 (d, J=6.6 Hz, 1H), 8.04 (d, J=9.6 Hz, 2H), 9.71 (s, 1H), 10.38 (s, 1H), 11.77 (s, 1H), 13.05 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])(=[O:20])=[O:19])[CH2:15][C@H:14]3[C:28]([OH:30])=O)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:31][C@@H:32]([CH2:41][CH2:42][CH3:43])[C@H:33]([OH:40])[C:34]([NH:36][CH:37]1[CH2:39][CH2:38]1)=[O:35]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])(=[O:19])=[O:20])[CH2:15][C@H:14]3[C:28]([NH:31][C@@H:32]([CH2:41][CH2:42][CH3:43])[C:33](=[O:40])[C:34]([NH:36][CH:37]3[CH2:39][CH2:38]3)=[O:35])=[O:30])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Br)cc2)CC1
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Br)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-1-[1-(4-bromo-phenyl)-cyclopropanecarbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide in step 1. MS (m/e)=680.1 [M+H+].
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)N)#N.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])[N:18]=2)[CH:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:12]1=[O:38]>>[CH2:10]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])[N:18]=2)[CH:13]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:12]1=[O:38])[C:3]1[CH:4]=[CH:5][CH:7]=[CH:8][CH:9]=1
Reactant: CN1CCN(c2ccnc(Nc3cccc(C#N)c3)n2)C(c2ccccc2)C1=O
Reactant: N#Cc1cccc(N)c1
Product: N#Cc1cccc(Nc2nccc(N3CCN(Cc4ccccc4)C(=O)C3c3ccccc3)n2)c1
Yield: 58 %

Procedure:
Intermediate 5, (0.39 g, 1.03 mmol) and 3-cyanoaniline (0.14 g, 1.17 mmol) were reacted together following the procedure detailed for the compound of Example 2, which gave the title compound as a pale yellow solid (0.28 g, 58%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5]([CH3:8])=[CH:6][CH:7]=1.Cl.CN(C)[CH:16]=[O:17]>[Cu](I)I>[CH3:16][O:17][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(Br)ccc1C
Agent: I[Cu]I
Agent: Cl
Product: COC(=O)c1cc(OC)ccc1C

Procedure:
12.6 g of a 28% sodium methylate methanol solution and 4.2 g of copper iodide were added to 5 g of methyl 4-bromo-toluate dissolved in 20 ml of dimethylformamide and the mixture was refluxed under heating for 2 hours. The reaction mixture was adjusted to about pH 2 by adding 1N-hydrochloric acid thereto and extracted with ethyl acetate. and the organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The residue obtained by removing the solvent was applied to silica gel column chromatography to obtain 2.47 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2>CO.CS(C)=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:20][C@H:19]([OH:18])[CH2:21][O:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)[CH2:14][CH2:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1Cl
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3c(Cl)c(Cl)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6,7-dichloro-3-(piperidin-4-yl)-1H-indole (0.80 g, 3.0 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.58 g, 3.1 mmol). The product was isolated as a white solid. Yield 0.64 g (47%). mp 192-197° C. FDMS m/e=457 (M+ of free base). α[D]589=+6.46 (c=0.99, methanol/dimethylsulfoxide).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:33])([F:32])C1C=C(B(O)O)C=CC=1>>[F:21][C:22]([F:33])([F:32])[C:5]1[CH:6]=[C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:2]=[CH:3][CH:4]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: O=C1NCCc2c(-c3cccc(C(F)(F)F)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 3-trifluoromethylphenylboronic acid (322 mg, 1.70 mmol) were coupled to yield 2-(3-trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 300 mg (80%), as a pale-yellow solid. mp 212.5-213.5° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.08 (m, 2H), 3.40 (m, 2H), 7.27 (app t, 1H, J=7.8 Hz), 7.60 (d, 1H, J=7.8 Hz), 7.71 (d, 1H, J=7.5 Hz), 7.77 (m, 2H), 7.96 (m, 2H), 8.13 (br t, 1H), 11.78 (br s, 1H); MS (FAB, MH+) 331; Anal. (C18H13F3N2O.0.5 H2O) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:19][C:20]([CH3:22])=[O:21]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:19][C:20](=[O:21])[CH3:22])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)C=Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
In a 250 ml single neck flask was charged 12.4 g (100 mmoles,1.0 eq) of 4-fluorobenzaldehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 13.5 g of 4-(4-fluorophenyl)-3-buten-2-one as a faintly yellow oil in 82.3% yield.
Reaction SMILES: O=[C:2]1[C:10]2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]([O:16]C)=[O:15].O.NN.[F:21][C:22]1[C:31]([CH:32]([C:34]2[N:38]3[N:39]=[C:40](C(=O)C)[CH:41]=[CH:42][C:37]3=[N:36][N:35]=2)[CH3:33])=[C:30]([F:46])[CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[N:27]2.Cl>CO>[F:21][C:22]1[C:31]([CH:32]([C:34]2[N:38]3[N:39]=[C:40](/[C:2](=[N:3]/[O:12][CH2:13][C:14]([OH:16])=[O:15])/[CH3:10])[CH:41]=[CH:42][C:37]3=[N:36][N:35]=2)[CH3:33])=[C:30]([F:46])[CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[N:27]2
Reactant: COC(=O)CON1C(=O)c2ccccc2C1=O
Reactant: CC(=O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: C/C(=N\OCC(=O)O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
Methyl 2-(1,3-dioxoisoindolin-2-yloxy)acetate (237 mg, 1.01 mmol) and hydrazine monohydrate (50 mg, 1.0 mmol) were dissolved in methanol (3 mL) and heated at 70° C. for 2 h. After filtration, the solid was washed with EtOAc. The combined solution was concentrated and the residue was diluted with methanol. A solution of NaOH (6 N, 3 mL) was added and the mixture was stirred at 70° C. for 2 h. The solution was concentrated, acidified with 3 N HCl to pH 1 and filtered. The solid was washed with water, and the combined solution was concentrated. The residue was diluted with DCM, then ketone 53.5 (40 mg, 0.113 mmol) and HCl (4 N HCl in dioxane, 0.7 mL) were added. It was stirred at rt for 24 h. After concentration, the residue was purified by prep-HPLC to give 21 mg (34%) of the title compound as white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.90 (s, 1H), 8.97 (d, 1H), 8.45 (d, 1H), 8.26 (d, 1H), 7.70 (d, 1H), 7.60 (d, 1H), 5.27 (q, 1H), 4.76 (s, 2H), 2.03 (d, 3H), 1.94 (s, 3H). LCMS (method B): [MH]+=427, tR=2.259 min. Chiral separation (method L) provided enantiomeric pure compounds example 68-R (tR=7.71 min) and example 68-S (tR=9.99 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([CH3:17])([C:5]1[CH:6]=[CH:7][C:2]([C:20]2[CH:21]=[CH:22][S:18][CH:19]=2)=[CH:3][CH:4]=1)[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: OB(O)c1ccsc1
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2ccsc2)cc1

Procedure:
Prepared in a similar manner to Example 1 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and thiophen-3-ylboronic acid. MS (M+H, 302).
Reaction SMILES: Br[CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:28])[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][NH:21][CH:22]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[CH2:26]([O:25][C:23]([C:19]1[C:18](=[O:28])[C:17]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=2)=[CH:22][N:21]([CH2:2][C:3]([OH:5])=[O:4])[CH:20]=1)=[O:24])[CH3:27]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC(=O)O)cc(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl bromoacetate (341 μl) was added to a suspension of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (400 mg) and cesium carbonate (998 mg) in DMF (8 ml) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted by adding ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and filtered, and the filtrate was then concentrated under reduced pressure. Dichloromethane (15 ml) and TFA (0.59 ml) were added to the residue at room temperature. The reaction mixture was stirred at room temperature for two hours. TFA (1.00 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred overnight. TFA (4.00 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred overnight. Water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate, washed with brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=19:1->17:3 (v/v)] to give 320 mg of the title compound as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]2[C:38]([CH3:40])([CH3:39])[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:41]([OH:43])=[O:42])[CH:35]=3)[NH:30]2)[CH:26]=[CH:27][CH:28]=1>CN(C)C=O>[CH3:39][C:38]1([CH3:40])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:41]([OH:43])=[O:42])[CH:35]=2)[NH:30][CH:29]1[C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:24]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Reactant: O=C(O)c1ccccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)c2ccccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of pyridine-2-carboxylic acid (1.26 g, 10 mmol) and 1,1′-carbonyldiimidazole (2.14 g, 13 mmol) in N,N-dimethylformamide (8 mL) was stirred at 70° C. for 1 h. Then a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2.4 g, 8 mmol) in N,N-dimethylformamide (5 mL) was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-{3-[(pyridine-2-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.85 g, 57%) as a light yellow solid: LC/MS m/e calcd for C24H23N3O3 (M+H)+: 402.47, observed: 402.5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH2:33][OH:34])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[H-].[Na+]>CCOC(C)=O>[C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:11][C:10]=1[CH2:33][O:34][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1COCc1ccccc1
Temperature: -10 °C
Reaction time: 5 h
Yield: 57.8 %

Procedure:
A 100 mL round bottomed flask was charged with 3-[4-(tert-butyldiphenylsilanyloxy)-2-hydroxymethylphenyl]propionic acid tert-butyl ester (1.52 g, 3.10 mmol), anhydrous DMF (15 mL), and then benzyl bromide (1.84 mL, 15.5 mmol) under a nitrogen atmosphere. The solution was cooled to −10° C., and NaH (0.124 g, 3.10 mmol, 60% oil dispersion) was added. The mixture was stirred for 5 h, and was poured into EtOAc (150 mL). The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated to a brown oil. The crude oil was purified using radial chromatography (EtOAc:hexanes 2:98 to 5:95) to give a pale yellow oil (1.04 g, 58%). MS (ES) m/e 598 (M+NH4).