Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[N:10]=2)=[CH:5][CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH3:28][N:25]1[C:26]2[CH:27]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=4)=[N:10][C:11]3=[O:15])[CH:20]=[CH:21][C:22]=2[C:23]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29][C:24]1=2
Reactant: O=c1nc(-c2ccc(C(F)(F)F)nc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)nc4=O)cc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 135 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
A suspension of 4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2(1H)-one (69 mg, 0.29 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (120 mg, 0.32 mmol), 8-hydroxyquinoline (8.4 mg, 0.058 mmol) and Cs2CO3 (110 mg, 0.35 mmol) in DMSO (5.0 mL) was degassed under reduced pressure for 30 min. CuI (66.7 mg, 0.35 mmol) was then added to the above solution, and the reaction mixture was degassed under reduced pressure for 5 min. The suspension was then stirred at 135° C. under nitrogen overnight. The suspension was cooled and diluted with ethyl acetate. The resulting mixture was washed with aqueous LiCl (5%), ammonium hydroxide (2×), and brine. The organic extract was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by preparative TLC (hexanes/ethyl acetate 1:1 then DCM/MeOH 96:4). The desired band was collected and extracted with dichloromethane. The resulting solution was treated with charcoal, filtered through a pad of celite, and concentrated under reduced pressure to give the title compound (36 mg, 20%) as a yellow foam: 1H NMR (500 MHz, CDCl3) δ 9.36 (s, 1H), 8.76 (d, J=7.0 Hz, 1H), 8.99 (d, J=6.5 Hz, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.58-7.56 (m, 1H), 7.38-7.37 (m, 1H), 7.09-7.08 (m, 1H), 6.93 (d, J=7.0 Hz, 1H), 3.80-3.68 (m, 4H), 3.68 (s, 3H), 3.09-2.99 (m, 4H), 1.49 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)=[CH:11][CH:10]=1
Reactant: Brc1cncnc1
Reactant: OB(O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc(-c2cncnc2)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 81.7 %

Procedure:
5-Bromopyrimidine (954 mg, 6 mmol) and 1.0 g (5.0 mmol) of 4-bromophenylboronic acid were dissolved in 20 ml of N,N-dimethylformamide and 5 ml of water. Tetrakistriphenylphosphine palladium (590 mg, 0.5 mmol) and 830 mg (7.5 mmol) of sodium carbonate were added to the solution, and the mixture was stirred at 80° C. for 2.5 hr. Ethyl acetate (60 ml) and 8.5 ml of water were added to the reaction solution. The mixture was filtered through Celite. The filtrate as an organic layer was washed five times with 30 ml of water. The organic layer was dried over anhydrous sodium sulfate and was filtered. The solvent was then removed by distillation, and the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give 960 mg (yield 82%) of the title compound.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1.O>CN(C=O)C.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:20]1[CH:21]=[CH:22][CH:23]=[C:19]1/[CH:18]=[C:11]1\[C:12](=[O:17])[NH:13][C:14]2[C:10]\1=[CH:9][C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:16][CH:15]=2
Reactant: C#C[Si](C)(C)C
Reactant: O=C1Nc2ccc(Br)cc2/C1=C/c1ccc[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Temperature: 70 °C

Procedure:
(Trimethylsilyl)acetylene (1.36 g,13.8 mmol) (Aldrich) and (Z)-5-bromo-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (2.0 g, 6.9 mmol) (Starting Material 7) were dissolved in 30 mL DMF and 40 mL triethylamine. The solution was degassed for 30 minutes by bubbling argon through the solution. At this time CuI (130 mg, 0.68 mmol) (Aldrich) and (Ph3P)2PdCl2 (400 mg, 0.57 mmol) (Aldrich) were added, and the reaction was heated, under argon, at 70° C. for 22 hours. Water (20 mL) was then added and the precipitate was filtered off and dried. The product was purified via flash column chromatography (SiO2, 230-400 mesh) with 1% MeOH/CHCl3 to give (Z)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-5-(trimethylsilyl)ethynyl-2H-indol-2-one as a yellow powder. (Yield 1.07 g, 51%).
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Si:30]([O:37][CH2:38][CH2:39][S:40][C:41]1[N:42]=[CH:43][N:44]2[CH:48]=[CH:47][S:46][C:45]=12)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].[Cl-].[NH4+]>C1COCC1>[Si:30]([O:37][CH2:38][CH2:39][S:40][C:41]1[N:42]=[CH:43][N:44]2[CH:48]=[C:47]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])[S:46][C:45]=12)([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:32])[CH3:31]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)[Si](C)(C)OCCSc1ncn2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCO[Si](C)(C)C(C)(C)C)c2s1
Reaction time: 1 h

Procedure:
Tri-n-butylstannyl chloride (1.79 ml) and 13.2 ml of a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution were added to a solution of 1.734 g of 7-(2-t-butyldimethylsilyloxyethyl)thioimidazo[5,1-b]thiazole in 60 ml of THF at −40° C. under an argon atmosphere, and the mixture was stirred at that temperature for one hr. An aqueous ammonium chloride solution was added to the reaction solution. The mixture was extracted with ethyl acetate, followed by washing with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to prepare 2.784 g of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:21](O)([CH3:24])([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1.Cl>CN(C=O)C.O>[S:1]1[CH:5]=[C:4]([C:6]([O:8][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:7])[N:3]=[CH:2]1
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cscn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cscn1
Temperature: 60 °C
Yield: 47 %

Procedure:
To a solution of thiazole-4-carboxylic acid 7.1 (1 g, 7.2 mmol) and carbonyldiimidazole (6.3 g, 38.7 mmol) in commercial dry DMF (50 mL) under N2 was stirred at 50° C. for 20 min. Tert-butanol (8.6 g, 116.0 mmol) and DBU (5.8 mL, 38.7 mmol) were then successively added at once and the reaction was warmed at 60° C. for 48 h. The RM was then allowed to cool down to RT and the pH was adjusted to 4 with a solution of HCl (2M, ˜80 mL). The mixture was diluted with water (250 mL) and extracted with Et2O (3×100 mL). The combined org. layers were washed with brine (250 mL), dried over MgSO4, concentrated and purified on silica gel using DCM to afford title product as yellowish oil (47%). Yield: 3.37 g (47%). LCMS: P=98%, rt=3.65 nm, m/z=186.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[OH-].[K+]>CCO.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a mixture of ethyl 1-((4-fluorophenyl)carbamoyl)cyclopropane-carboxylate (8.9 g, 35.4 mmol) in EtOH/THF (50/50 mL, Guangdong Guanghua Chem. Co. Ltd.) was added KOH (3.98 g, 70.8 mmol, Guangdong Guanghua Chem. Co. Ltd.) aqueous solution dropwise via a syringe. The reaction was stirred at RT overnight under N2. The mixture was concentrated in vacuo. The residue was then acidified to pH 2 with 5 N HCl and extracted with EtOAc (150 mL×4), the combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was recrystallized in EtOAc/n-hexane (1:40 v/v) to give the title compound as a white solid (7.66 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:34])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[C:28]4[CH2:29][CH2:30][CH2:31][CH2:32][C:27]=4[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:34])[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[C:28]4[CH2:29][CH2:30][CH2:31][CH2:32][C:27]=4[S:26][C:24]=3[N:25]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c4c(sc3n2)CCCC4)cc1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(Cl)c(Cl)c3)c3c4c(sc3n2)CCCC4)cc1

Procedure:
The reaction procedure as above wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester
Reaction SMILES: [CH3:1][C:2]([N:6]([CH3:11])[CH:7]1[CH2:10][O:9][CH2:8]1)([CH3:5])[CH:3]=O.[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([C@@H:36]3[CH2:41][CH2:40][CH2:39][N:38]([C:42](=[O:46])[CH2:43][C:44]#[N:45])[CH2:37]3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:24][C:23]=3[F:35])[C:14]=12.N1CCCC1.[Si](Cl)(C)(C)C>>[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([C@@H:36]3[CH2:41][CH2:40][CH2:39][N:38]([C:42]([C:43](=[CH:3][C:2]([CH3:1])([N:6]([CH3:11])[CH:7]4[CH2:10][O:9][CH2:8]4)[CH3:5])[C:44]#[N:45])=[O:46])[CH2:37]3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:24][C:23]=3[F:35])[C:14]=12
Reactant: CN(C1COC1)C(C)(C)C=O
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Agent: C[Si](C)(C)Cl
Solvent: C1CCNC1
Product: CN(C1COC1)C(C)(C)C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
The mixture of 2-methyl-2-[methyl(oxetan-3-yl)amino]propanal (66.69 mg, 0.42 mmol), 3-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-3-oxo-propanenitrile (100 mg, 0.2100 mmol) and pyrrolidine (0.1 mL, 1.27 mmol) was stirred at room temperature for 10 min. The reaction mixture was cooled to 0° C., followed by addition of TMS-Cl (0.11 mL, 0.85 mmol). The ice bath was removed and the reaction mixture was stirred for another 1 hour at room temperature, checking process by TLC and LC-MS. The solvent was removed and the resultant residue purified by column chromatography (MeOH, CH2Cl2, MeOH gradient from 0 to 10% to get 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[methyl(oxetan-3-yl)amino]pent-2-enenitrile (118.5 mg) as a white powder. LC-MS (ES, m/z): 612 [M+H]
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:18]=[CH:19][N:20]([C@@H:36]3[O:42][C@H:41]([CH2:43][OH:44])[C@@H:39]([OH:40])[C@H:37]3[OH:38])[C:21]=2[NH:22][C:23]([NH:25]C(OCC2C=CC=CC=2)=O)=[O:24])=[O:16])C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C1COCC1.C(O)C.[Pd]>[NH2:25][C:23]([NH:22][C:21]1[N:20]([C@@H:36]2[O:42][C@H:41]([CH2:43][OH:44])[C@@H:39]([OH:40])[C@H:37]2[OH:38])[CH:19]=[N:18][C:17]=1[C:15]([OH:16])=[O:14])=[O:24]
Reactant: O=C(NC(=O)OCc1ccccc1)Nc1c(C(=O)OC(c2ccccc2)c2ccccc2)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCO
Product: NC(=O)Nc1c(C(=O)O)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 2 h

Procedure:
5-[[[[(phenylmethoxy)carbonyl]amino]carbonyl]amino]-1-(β-D-ribofuranosyl)-1H-imidazole-4-carboxylic acid diphenylmethyl ester (1.76 g, 2.9 mmol) was dissolved in the mixture of DMF (50 mL), THF (20 mL) and ethanol (30 mL) and mixed with 10% palladium on charcoal. The mixture was hydrogenated at 50 psig pressure for 2 h. The catalyst was removed by filtration through Celite, and washed extensively with DMF and ethanol. Combined washing and filtrate was concentrated under reduced pressure to dryness. Residue was dissolved in 30% aqueous ethanol and filtered through a C18-Sep-Pak to remove the last traces of catalyst. This eluate was concentrated to dryness and partitioned between water (100 mL) and ether (2×100 mL). The aqueous layer was concentrated to dryness, redissolved in water and evaporated again and pumped under high vacuum to give 5-[[(amino)carbonyl]amino]-1-(β-D-ribofuranosyl)-1H-imidazole-4-carboxylic acid as a colorless glass: yield 0.64 g (73%); IR (KBr) 3340, 1692 cm -1 ; NMR (Me2SO-d6) δ3.72-3.53 (m, 2), 3.84 (d, 1, J=4.3 Hz), 4.05 (s, 1), 4.14 (s, 1), 5.05 (s, 1), 5.11 (s, 1), 5.34 (s, 1), 5.50 (d, 1, J=4.3 Hz), 6.28 (s, 2), 7.92 (s, 1), 8.07 (s, 1); UV max (H2O) 215 nm (ε5800).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+].[I-].[K+].O>CS(C)=O>[CH2:2]([C:7]1([CH2:7][CH2:6][CH2:14][CH3:13])[C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:1][CH2:4][CH3:5]
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(C(C)=O)cc21
Temperature: 15 °C
Reaction time: 2 h
Yield: 181.3 %

Procedure:
15.9 g of 2-acetylfluorene (11) (76.4 mmol), 18.9 g of potassium hydroxide (0.27 mol, purity: 80%), and 1.26 g of potassium iodide (7.6 mmol) were dissolved in 350 ml of anhydrous dimethylsulfoxide under nitrogen atmosphere, and a reaction temperature was maintained at 15° C. Then, 33 ml of n-bromobutane (0.3 mol) was slowly added thereto for 2 hours, followed by stirring at 15° C. for 1 hour. Thereafter 200 ml of distilled water was added to the reaction mixture and stirred for about 30 minutes, a product was extracted with 300 ml of dichloromethane, and the extracted organic layer was washed with 100 ml of distilled water three times. Then, the recovered organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure. The obtained product was purified using a silica gel column chromatography (developing solvent: dichloromethane:n-hexane=15:1), thereby obtaining 22.2 g of 1-(9,9-di-n-butylfluorene-2-yl)-ethanone (12) (90.8%) as a light yellow liquid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:5]=[CH:6][C:7](O)=[O:8].C(OC(=O)C(C)(C)C)(=O)C(C)(C)C.[H][H]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC(P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:5]=[CH:6][CH:7]=[O:8]
Reactant: COc1ccc(C=CC(=O)O)cc1O
Reactant: [H][H]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Product: COc1ccc(C=CC=O)cc1O
Temperature: 80 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
Palladium acetate (58 mg, 0.257 mmol), tri(p-tolyl) phosphine (157 mg, 0.515 mmol), 3-hydroxy-4-methoxycinnamic acid (5.00 g, 25.7 mmol) and pivalic acid anhydride (14.4 g, 77.2 mmol) were added thereto, and thereafter the mixture was bubbled with nitrogen gas for 30 minutes to substitute nitrogen gas completely for the gas in the system of reaction, whereby the system was filled with nitrogen gas. Next, hydrogen gas was added thereinto to substitute hydrogen gas for the gas in the system, and then the mixture was stirred under hydrogen pressure of 3.4 MPa at 80° C. for 24 hours for reaction. Thus obtained reaction solution was concentrated under reduced pressure to remove tetrahydrofuran by vaporization. The remaining residue was subjected to a purification process with a silica gel column chromatography (eluting solvent: toluene/ethyl acetate=4/1) to obtain 3-hydroxy-4-methoxycinnamaldehyde (2.26 g, 12.7 mmol, yield: 49%).
Reaction SMILES: [C:1]1(I)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[CH2:9].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:1]1(/[CH:9]=[CH:8]/[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Ic1ccccc1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C(=C/c1ccncc1)\c1ccccc1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
A mixture of phenyl iodide (100 ml, 0.89mol), 4-vinylpyridine (115 ml, 1.07 mol), palladium acetate (2.4 g, 0.01 mol), tri-o-tolylphosphine (6.08 g, 0.02 mol) and triethylamine (150 ml, 1.07 mol) was refluxed for 3 hours. The reaction was cooled to room temperature, the resulting solid dissolved in dichloromethane (2 l) and washed with saturated aqueous sodium carbonate solution (2 l). The aqueous phase was further extracted with dichloromethane (3×1.5 l) and the combined organic phases dried (MgSO4) and evaporated. The resulting solid was washed with ethyl acetate (1.5 l), filtered and dried in vacuo to give (E)-4-(2-phenylethenyl)pyridine (90 g, 56%); δH (CDCl3) 7.01 (1H, d, J 16.3 Hz, ArCH=CH), 7.25-7.41 (6H, m, PhH, ArCH=CH), 7.53 (2H, d, J 5.3 Hz, 3-H, 5-H), and 8.58 (2H, d, J 5.2 Hz, 2-H, 6-H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][C:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]1=[O:43]>ClCCl.C(OCC)C>[O:43]=[C:27]1[C:28]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][CH2:30][N:26]1[CH2:25][CH:24]=[O:23]
Reactant: O=C1N(CCO)CCC1(c1ccccc1)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of Dess-Martin periodinane (8.03 g, 18.92 mmol) in dichloromethane (100 mL) was added a solution of the product from Example 67A (4.84 g, 17.20 mmol) in dichloromethane (50 mL) at room temperature. After 30 minutes at room temperature, the reaction is diluted with diethyl ether, filtered and concentrated. Chromatography eluting with a gradient of 50% to 100% ethyl acetate/hexanes using a SF25-40 g (Analogix®, Burlington, Wis.) column gave the title compound. MS (DCI+) m/z 280.1 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[OH-].[Na+].CO.Cl>C1COCC1>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[CH:7]=[N:6][C:5]([C:3]([OH:4])=[O:2])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.7 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (40 mg, 0.13 mmol), 2M NaOH (2 mL), MeOH (2 mL) and THF (1 mL) was stirred at r.t. for 4 h. 1 M HCl was added until pH was about 2, and the resulting mixture was cooled in an ice bath for 30 min. The precipitate formed was collected by filtration and dried under high vacuum to afford 23 mg of the title compound as a yellow solid. MS: (+) m/z 297.00 (M+1).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.C(OC1C=C(C=C(OC(=O)C)C=1OC(=O)C)C(O)=O)(=O)C.C(OC(=O)C)(=O)C.C(Cl)(=O)C.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+].S(Cl)(Cl)=O.P(Cl)(Cl)Cl.C(OC1C=C(C=C(OC(=O)C)C=1OC(=O)C)C(Cl)=O)(=O)C.C([O-])(=O)C.[Na+].Cl.C([N:90](CC)CC)C>CO.C(O)C.N1C=CC=CC=1>[C:1]([NH2:90])(=[O:12])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Agent: CC(=O)Oc1cc(C(=O)Cl)cc(OC(C)=O)c1OC(C)=O
Agent: CC(=O)Oc1cc(C(=O)O)cc(OC(C)=O)c1OC(C)=O
Agent: CC(=O)[O-]
Solvent: ClP(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: NC(=O)c1cc(O)c(O)c(O)c1

Procedure:
Namely, gallic acid is converted into 3,4,5-triacetoxybenzoic acid by reacting with acetic anhydride or acetic acid chloride in the presence of a base such as NaOH (J. Chem. Soc., 2495 (1931)), Na2CO3, pyridine or so on and, further, converted into the corresponding acid chloride by reacting with thionyl chloride or phosphorus trichloride. The thus-obtained 3,4,5-triacetoxybenzoic acid chloride was made to react with an appropriate amine in the presence of a base such as pyridine, triethylamine or the like. Thereafter, the reaction product is treated with sodium acetate, sodium hydroxide or hydrochloric acid in methanol or ethanol to produce an intended gallic acid amide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][N:16]2[N:19]=[C:20]([NH2:33])[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[C:15]2[N:14]=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:33][C:20]2[C:21]([C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:26][CH:27]=3)=[C:15]3[N:14]=[C:13]([CH3:12])[CH:18]=[CH:17][N:16]3[N:19]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: Cc1ccn2nc(N)c(-c3ccc(OC(F)(F)F)cc3)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccn2nc(NC(=O)Cc3ccc(F)cc3)c(-c3ccc(OC(F)(F)F)cc3)c2n1
Reaction time: 40 h

Procedure:
4-Fluorophenylacetic acid (32 mg, 0.21 mmol) was added to a stirring solution of the product from Example 168A (20 mg, 0.065 mmol) in DMF (0.5 mL) and pyridine (0.5 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (43 mg, 0.22 mmol) was added and stirring was continued at room temperature for 40 h. The reaction mixture was quenched by addition of MeOH (1 mL) and HOAc (0.1 mL) and stirred for 40 minutes. The solution was concentrated under vacuum, and the residue was purified by HPLC (30×100 mm XBridge column eluted with aqueous 0.1 M (NH4)2CO3-MeOH, 60:40-0:100 over 15 min) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.56 (s, 3H), 3.65 (s, 2H), 7.03 (d, J=7.1 Hz, 1H), 7.15 (t, J=8.8 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 7.29-7.40 (m, 2H), 7.76 (d, J=8.8 Hz, 2H), 8.94 (d, J=7.1 Hz, 1H), 10.42 (s, 1H); MS (DCI/NH3) m/z 445 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:47]1[C:52](=[O:53])[CH2:51][CH2:50][C:48]1=[O:49])=[N+](C)C)C>>[O:49]=[C:48]1[CH2:50][CH2:51][C:52](=[O:53])[N:47]1[O:30][C:29](=[O:31])[C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:33][CH:32]=1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)O)cc1
Agent: F[B-](F)(F)F
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)ON2C(=O)CCC2=O)cc1

Procedure:
4-(15-tert-Butoxycarbonylpentadecanoylamino)-benzoic acid (29 mg, 0.063 mmol) was converted to the succinimidyl ester using TSTU similar to described above.