Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[C:8](=[N:10]/[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])/[CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH3:20][Al](C)C.[OH-].[K+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[C:12]([CH3:19])=[CH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])([CH3:20])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: C[Al](C)C
Reactant: C/C(=N\c1c(C)cc(C)cc1C)c1cccc(Br)n1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(NC(C)(C)c2cccc(Br)n2)c(C)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
In argon atmosphere, to a solution of 5.59 g (17.61 mmol) of N-[(1E)-1-(6-bromopyridin-2-yl)ethylidene]-2,4,6-trimethylaniline in 140 ml of dry toluene cooled to 0° C., a solution of 2.53 g (35.2 mmol) AlMe3 in 20 ml of dry toluene was added dropwise for 10 min. This mixture was slowly warmed to room temperature, stirred for 25 min at 40° C., cooled to 0° C., and then 140 ml of 5% KOH was added dropwise for 1 h. The aqueous layer was separated, the organic layer was washed with 100 ml of water, then 100 ml of brine, dried over Na2SO4, and then evaporated to dryness. The crude product was purified by flash chromatography on silica gel 60 (40-63 um, eluent: dichloromethane-ethyl acetate=20:1, vol.). Yield 2.80 g (47%) of yellow crystalline solid. Anal. calc. for C17H21BrN2: C, 61.27; H, 6.35; N, 8.41. Found: C, 61.14; H, 6.26; N, 8.31. 1H NMR (CDCl3): δ 7.63 (dd, J=8.0 Hz, J=0.6 Hz, 1H, 5-H in pyridine), 7.49 (t, J=7.6 Hz, 1H, 4-H in pyridine), 7.32 (dd, J=8.0 Hz, J=0.6 Hz, 1H, 3-H in pyridine), 6.78 (s, 2H, 3, 5-H in mesityl), 3.65 (br.s, 1H, NH), 2.21 (s, 3H, 4-Me in mesityl), 2.01 (s, 6H, 2, 6-Me in mesityl), 1.46 (s, 6H, CMe2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10]O.P(Br)(Br)[Br:13].O>C(OCC)C>[Br:13][CH2:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: BrP(Br)Br
Reactant: OCCCc1ccccc1F
Solvent: CCOCC
Solvent: O
Product: Fc1ccccc1CCCBr

Procedure:
Compound 22-1 (8.68 g) was dissolved in diethyl ether (100 ml), phosphorus tribromide (6.35 ml) was added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hr. To the reaction mixture was slowly added water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (5.00 g) as a yellow oil.
Reaction SMILES: [C-:1]#[N:2].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[C:16]([CH2:21]Cl)[CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1>>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:21][C:1]#[N:2])[C:15]=3[CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: Fc1ccc(-c2nccc3c(CCl)cccc23)cc1
Reactant: [C-]#N
Agent: [Na+]
Product: N#CCc1cccc2c(-c3ccc(F)cc3)nccc12

Procedure:
Sodium cyanide and 1-(4-fluorophenyl)-5-chloromethylisoquinoline were reacted in the same way as in step (b) in Example 2 to afford 1-(4-flurophenyl)isoquinoline-5-acetonitrile having a melting point of 136° to 136.5° C.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C.O>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:10]=1
Reactant: Brc1cccc(Br)n1
Reactant: Sc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: Brc1cccc(Sc2ccccc2)n1
Reaction time: 8 h

Procedure:
To sodium hydride, 0.91 g, (22.3 mmol) (washed with hexane) is added, under nitrogen, 8 ml of tetrahydrofuran. The suspension is then cooled in an ice bath. Thiophenol (2.32 g, 21.1 mmol) in 8 ml of tetrahydrofuran is added dropwise over 30 minutes, after which 4 ml of hexamethylphosphorictriamide is added. The solution is added dropwise over 15 hr to 5 g (21.1 mmol) 2,6-dibromopyridine in 8 ml tetrahydrofuran and 2 ml hexamethylphosphorictriamide at 24°. The reaction mixture is stirred overnight under nitrogen. After addition of 2 ml hexamethylphosphorictriamide, the solution is refluxed for 3 days, then diluted with water and extracted with ether, washed with 5% sodium hydroxide (2×), water (3×) and brine, dried over magnesium sulfate and concentrated. The residue is finally washed with 100 ml cold (ice bath) hexane to give 2-bromo-6-phenylthiopyridine, m.p. 47°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:26]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:28]([C:38]([O:40]C)=[O:39])[CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[OH-].[Na+]>C1COCC1.O>[C:34]([O:33][C:31]([N:29]1[CH2:30][C@@H:26]([C:4]2[CH:5]=[CH:6][C:7]([C:8]3[S:9][C:10]4[C:15]([N:16]=3)=[CH:14][CH:13]=[C:12]([C:17]3([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH2:19][CH2:18]3)[N:11]=4)=[C:2]([F:1])[CH:3]=2)[CH2:27][C@H:28]1[C:38]([OH:40])=[O:39])=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: COC(=O)[C@@H]1C[C@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (2S,4R)-1-tert-butyl 2-methyl 4-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)pyrrolidine-1,2-dicarboxylate (0.100 g, 0.17 mmol) in 2 mL THF was added sodium hydroxide (0.70 mL, 0.70 mmol). The yellow cloudy reaction mixture was diluted with 0.7 mL water, and stirred rapidly at ambient temperature. After 6 h, the reaction mixture was quenched with ice and 5 N HCl until slightly acidic. The aq. Layer was extracted with DCM and the combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give (2S,4R)-1-(tert-butoxycarbonyl)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo-[5,4-b]pyridine-2-yl)phenyl)pyrrolidine-2-carboxylic acid as a white solid. MS (ESI) m/z: Calculated: 559.2; Observed: 559.7 (M++1).
Reaction SMILES: Cl[C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH:7]=[O:8].[Na+].[C:10]1([S:16]([O-:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([S:16]([C:2]2[S:6][CH:5]=[N:4][C:3]=2[CH:7]=[O:8])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ncsc1Cl
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: O=Cc1ncsc1S(=O)(=O)c1ccccc1

Procedure:
The title compound was prepared by the method of Preparation 5a using 5-chlorothiazole-4-carbaldehyde and phenylsulfinic acid sodium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([O:24]C)=[O:23])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:16])[F:17])[C:11](=[O:20])[N:10]([CH2:21][C:22]([OH:24])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The enantiomerically pure compound of Example 6A (1.6 g, 4.21 mmol) was dissolved in 77 ml of methanol, and 17 ml of a 1M solution of lithium hydroxide in water were added. The mixture was stirred at RT for 1 h and then concentrated on a rotary evaporator. The residue was diluted with 100 ml of water and acidified to pH 1-2 with 1 N hydrochloric acid. The precipitated product was filtered off, washed successively with water and cyclohexane and sucked dry. Further drying under high vacuum gave 1.1 g (71% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[N:31]([C:35](=O)[C:36]([F:39])([F:38])[F:37])[C@H:30]([CH3:41])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.B.CSC>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[N:31]([CH2:35][C:36]([F:37])([F:38])[F:39])[C@H:30]([CH3:41])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1C(=O)C(F)(F)F
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1CC(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a solution of compound 316 (100 mg, 0.17 mmol) in tetrahydrofuran (5 mL) was added a solution of borane/dimethylsulfane (10 mol/L, 2 mL) dropwise at 0° C. After the addition was completed, the reaction mixture was stirred at that temperature for 30 min and then allowed to warm to 50° C. After stirred for another 1 hour the reaction mixture was quenched by adding 15 mL of methanol and 5 mL of 1 M HCl aqueous solution slowly. The mixture was stirred at room temperature for 2 hours before concentration to the residue. The mixture was treated with dichloromethane and water. The organic layer was concentrated to dryness and the crude was purified by pre-TLC (Hexanes/EtOAc=1:1) to afford 60 mg of 351. (Yield: 61%) 1H NMR (CDCl3, 400 MHz): δ8.02 (s, 1H), 7.51-7.46 (m, 1H), 7.09-6.97 (m, 4H), 6.45 (d, J=8.8 Hz, 1H), 4.18 (t, J=4.8 Hz, 2H), 3.84-3.80 (m, 2H), 3.27 (q, J=9.6 Hz, 2H), 3.07 (t, J=4.8 Hz, 2H), 2.84 (d, J=6.8 Hz, 2H), 2.57-2.51 (m, 2H), 1.22-1.34 (d, J=6.0 Hz, 6H). LC-MS (ESI): m/z=577 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1/[CH:13]=[CH:14]/[C:15]1[CH:33]=[CH:32][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][C:28]([O:30]C)=[O:29])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][C:28]([OH:30])=[O:29])=[CH:32][CH:33]=1
Reactant: COC(=O)Cc1ccccc1OCc1ccc(/C=C/c2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1/C=C/c1ccc(COc2ccccc2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.8 %

Procedure:
To a mixture of methyl 2-[2-[4-[(E)-2-(5-methyl-2-phenyl-4-oxazolyl)ethenyl]benzyloxy]phenyl]acetate (0.44 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added a 1N aqueous sodium hydroxide solution (2 mL) and the mixture was stirred at room temperature for 15 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the, mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.31 g, 72%) of 2-[2-[4-[(E)-2-(5-methyl-2-phenyl-4-oxazolyl)ethenyl]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 189-190° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:37][C:38]2[CH:43]=[CH:42][C:41]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:40][CH:39]=2)=CC=1)([O-])=O>>[N:44]1([C:41]2[CH:40]=[CH:39][C:38]([NH:37][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)=[O:7])=[CH:43][CH:42]=2)[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C(Nc1ccc(N2CCOCC2)cc1)N1CCC(c2ncnc3cc(F)ccc23)CC1

Procedure:
Prepared essentially as described in Example 67 using 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester and (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride, which was prepared as described in Example 66a. 1H NMR (CDCl3) δ 9.23 (s, 1H), 9.21 (dd, J=9.35 Hz and 5.85 Hz, 1H), 7.69 (dd, J=9.48 and 2.52 Hz, 1H), 7.44 (m, 1H), 7.27 (d, J=8.95 Hz, 2H), 6.89 (d, J=8.95 Hz, 2H), 6.29 (s, 1H), 4.27 (m, 2H), 3.86 (t, J=4.74 Hz, 4H), 3.73 (m, 1H), 3.17 (m, 2H), 3.11 (t, J=4.78 Hz, 4H), 2.15 (m, 2H), 1.99 (m, 2H). Calcd for C24H27FN5O2 (MH+) 436.2, found 436.1.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C(OC1N=NC(C#CC(C)C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C([O:51][C:52]1[N:53]=[N:54][C:55]([C:66]([C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([C:74]([F:77])([F:76])[F:75])[CH:69]=2)=[CH2:67])=[CH:56][C:57]=1[O:58]CC1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[OH:58][C:57]1[C:52](=[O:51])[NH:53][N:54]=[C:55]([CH:66]([C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([C:74]([F:76])([F:75])[F:77])[CH:69]=2)[CH3:67])[CH:56]=1
Reactant: C=C(c1cccc(C(F)(F)F)c1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: CC(C)C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(c1cccc(C(F)(F)F)c1)c1cc(O)c(=O)[nH]n1

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(3-methylbut-1-ynyl)pyridazine (Intermediate 43) except that the solvent mixture used for the hydrogenation was made up of ethyl acetate and tetrahydrofuran and the product was recrystallised from heptane and MTBE.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:3]=12.[H-].C([Al+]CC(C)C)C(C)C.Cl>C(Cl)Cl>[I:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2sc3c(c2c1I)CCCC3
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: Cc1nc2sc3c(c2c(I)c1CO)CCCC3
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.9 %

Procedure:
To a solution of ethyl (4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-yl)carboxylate (Preparation 5, 260.2 g, 0.65 Mol) in CH2Cl2 (2.0 L) was added 25% (w/w) diisobutyl aluminium hydride (2.0 L, 1.97 Mol) at 5° C. over 1.5 hours under argon. The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The resulting mixture was diluted with dichloromethane (1.0 L), cooled to 0° C. and 2 M hydrochloric acid (200 mL) was added very carefully. 6M hydrochloric acid was then added until the pH of the aqueous was measured at pH 2. The resulting mixture was stirred vigorously for 1 hour. The precipitate was collected by filtration and the filter-cake was washed with dichloromethane (300 mL) and water (300 mL). The solids were suspended in dichloromethane (250 mL) and 1 M sodium hydroxide solution (400 mL) and stirred vigorously until the solids were free flowing. The solids were collected by filtration, washing the filter-cake with water (200 mL). The filter-cake was concentrated from propan-2-ol (500 mL), methanol (500 mL) and dichloromethane (500 mL) sequentially under reduced pressure to give the title compound as a cream coloured solid (212.3 g, 91%).
Reaction SMILES: Br[C:2]1[C:3]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+]>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[C:3]([O:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:4][C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[N:6][CH:7]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(Oc2nc(-c3cccnc3)ncc2Br)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(Oc2nc(-c3cccnc3)ncc2N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 95 °C
Yield: 80.1 %

Procedure:
To a dry Schlenk tube was added a mixture of Compound 20d (100 mg; 0.28 mmol), piperazine-1-carboxylic acid tert-butyl ester (52 mg; 0.56 mmol), Cs2CO3 (227 mg; 0.70 mmol), (Diphenylphosphino)ferrocene (54 mg; 0.10 mmol), and Tris(dibenzylideneacetone)dipalladium(0) (25.6 mg; 0.028 mmol). Sealed the tube with a teflon-lined septum, evacuated, and refilled with argon. Added dioxane (0.3 mL; reaction conc. >0.75M) to the mixture via syringe. The mixture was heated at 95° C. for 3 h. Diluted the resulted mixture with EtOAc, washed with saturated NH4Cl(aq) and H2O. The organic phase was washed sequentially with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 20e (104 mg; 80% yield). 1H-NMR (400 MHz, CDCl3): δ 9.28 (d, 1H), 8.58 (dd, 1H), 8.35 (dt, 1H), 8.22 (s, 1H), 7.29 (td, 1H), 7.14 (dd, 2H), 6.98 (dd, 2H), 3.87 (s, 3H), 3.66 (t, 4H), 3.25 (t, 4H), 1.56 (s, 9H); MS: m/z 464.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[CH:13]=2)[N:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>CO>[C:22]([O:21][C:19]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCCN1CCN(C(=O)OC(C)(C)C)c2ccc(C(=O)OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1CCN(C(=O)OC(C)(C)C)c2ccc(C(=O)O)cc21
Temperature: 40 °C
Reaction time: 12 h
Yield: 79.1 %

Procedure:
To a stirred solution of 1-tert-butyl 6-methyl 4-butyl-3,4-dihydroquinoxaline-1,6(2H)-dicarboxylate (158 mg) in methanol (1.4 mL) was added 1 M potassium hydroxide (1.4 mL). The mixture was stirred at 40° C. for 12 h and then concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified to pH 4 with 1 N hydrochloric acid and extracted with chloroform (4×100 mL). The combined organic extracts were dried (sodium sulfate), filtered, and concentrated under reduced pressure to give 120 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.55, 7.40, 7.37, 3.79, 3.38, 3.34, 1.60, 1.53, 1.39, 0.97.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:21])[N:6]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20]
Reactant: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (686 mg) was dissolved in DMF (5 mL), and tert-butyl bromoacetate (473 mg) was added. Potassium carbonate (352 mg) was further added, and the mixture was stirred at room temperature overnight. After water was added carefully to the reaction solution, ethyl acetate (200 mL) was added, followed by extraction. The resulting organic layer was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=2:1) afforded white crystals. The resulting fraction was recrystallized from IPE to obtain 679 mg of white powders.
Reaction SMILES: [Cl-].[CH:2]([N+](=C)C(C)C)(C)C.[Cl:10][C:11]1[C:16]([F:17])=[C:15]([CH3:18])[N:14]=[CH:13][N:12]=1>C(#N)C>[Cl:10][C:11]1[C:16]([F:17])=[C:15]([CH:18]=[CH2:2])[N:14]=[CH:13][N:12]=1
Reactant: Cc1ncnc(Cl)c1F
Reactant: C=[N+](C(C)C)C(C)C
Agent: [Cl-]
Solvent: CC#N
Product: C=Cc1ncnc(Cl)c1F
Temperature: 25 °C

Procedure:
To a solution of N-isopropyl-N-methylenepropan-2-aminium chloride (13.3 g, 88.7 mmol) in acetonitrile (55 mL) was added 4-chloro-5-fluoro-6-methylpyrimidine (10.0 g, 68.2 mmol). The reaction flask was flushed with argon and the mixture was heated at reflux for 24 hours with stirring, then cooled to room temperature. Water (130 mL) was added and the mixture was extracted with dichloromethane (140 mL). The organic phase was washed with 10% aqueous KHSO4 (400 mL) and dried over Na2SO4. The solution was filtered and evaporated in vacuo at 300 millibar pressure and 35° C. tert-Butylcatechol (30 mg, 0.2 wt %, based on the mass of the crude material) was added. Residual solvent was removed under vacuum at 50° C. and the crude product was then distilled at 5 millibar pressure and 50° C. (oil bath). tert-Butylcatechol (0.1 wt %) was added to the distilled 4-chloro-5-fluoro-6-vinyl pyrimidine (7.9 g, 73%) which was obtained as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl.O>[CH3:34][S:35]([O:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[C:15](=[O:26])[NH:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:13][CH:12]=2)=[CH:23][CH:22]=1)(=[O:37])=[O:36]
Reactant: O=C(/C=C/c1ccc(CO)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCc1ccc(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 2.3 g (6.3 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-hydroxymethylphenyl)acrylamide in 200 mL of dichloromethane is combined with 1.94 mL (13.9 mmol) of triethylamine and then with 0.54 mL (6.92 mmol) of methanesulfonic acid chloride. The reaction mixture is stirred for 18 hours at ambient temperature, diluted with water, and extracted several times with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered through silica gel and the filtrate is evaporated down. Yield: 1.85 g (67% of theory); C23H20ClN04S (M=441.93); calc.: molecular ion peak (M+H)+: 442/444 (Cl); found: molecular ion peak (M+H)+: 442/444 (Cl); Rf value: 0.73 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).