Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][O:15][CH3:16])[N:11]([CH2:17][C:18]([N:20]2[C:28]3[CH:27]=[C:26]([C:29]4[CH2:33][CH2:32][CH2:31][CH:30]=4)[N:25]=[CH:24][C:23]=3[C:22]([CH3:35])([CH3:34])[CH2:21]2)=[O:19])[CH2:10][C@H:9]1[CH3:36])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][O:15][CH3:16])[N:11]([CH2:17][C:18]([N:20]2[C:28]3[CH:27]=[C:26]([CH:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)[N:25]=[CH:24][C:23]=3[C:22]([CH3:35])([CH3:34])[CH2:21]2)=[O:19])[CH2:10][C@H:9]1[CH3:36])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2cnc(C3=CCCC3)cc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2cnc(C3CCCC3)cc21
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a solution of (2R,5R)-4-[2-(6-cyclopent-1-enyl-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl)-2-oxo-ethyl]-5-methoxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (see Table 1) (60 mg, 0.12 mmol) in THF (5 mL) and MeOH (5 mL) was added palladium on carbon (10%, 10 mg) and the mixture was hydrogenated for 2 h. The catalyst was filtered and the filtrate evaporated to afford the title compound (52 mg, 87%) as a white solid. MS [M+H]+=501.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S([Cl:21])(C1C=CC(C)=CC=1)(=O)=O>N1C=CC=CC=1>[C:1]1([C:7]#[C:8][CH2:9][Cl:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC#Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: ClCC#Cc1ccccc1
Temperature: 0 °C
Yield: 63 %

Procedure:
1-Phenyl-1-propyn-3-ol (5 g), 5.1 g of tosyl chloride and 20 ml of pyridine were stirred at room temperature for 1 hour. The reaction mixture was poured into 100 ml of ice water and extracted with ethyl acetate. The oil layer was washed with 1 N hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away. The residue was purified by silica gel column chromatography (ethyl acetate:hexane 1:5) to give 2.54 g of 3-phenyl-2-propynyl chloride as a pale yellow, oily substance.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH2:28][C:29]#[C:30][CH3:31])[C@H:3]([O:21]C1CCCCO1)/[CH:4]=[CH:5]/[C@@H:6]1[C@@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:20])[CH2:8][CH2:7]1>C(O)(=O)C.O.C1COCC1>[CH3:1][C:2]([CH3:32])([CH2:28][C:29]#[C:30][CH3:31])[C@H:3]([OH:21])/[CH:4]=[CH:5]/[C@@H:6]1[C@@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:20])[CH2:8][CH2:7]1
Reactant: CC#CCC(C)(C)[C@@H](/C=C/[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)O)OC1CCCCO1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC#CCC(C)(C)[C@H](O)/C=C/[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)O

Procedure:
280 mg. of (13E)-(15R)-16,16-dimethyl-9-oxo-15-(tetrahydropyran-2-yloxy)-13-prosten-18-ynoic acid is agitated for 17 hours at 23° with 8 ml. of a mixture of glacial acetic acid/water/THF (65/35/10), evaporated under vacuum, and the residue purified by column chromatography on silica gel. With methylene chloride/5% methanol, 185 mg. of the title compound is obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:15]O>>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Reactant: CO
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1C

Procedure:
reacting 5-bromo-2-methyl-3-nitrobenzoic acid with methanol to form methyl 5-bromo-2-methyl-3-nitrobenzoate;
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]([Sn](CCCC)(CCCC)CCCC)[CH:9]=[CH:10][CH:11]=1)([O:3][CH2:4][CH3:5])=[O:2].FC(F)(F)S(O[C:31]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=[O:34])(=O)=O.[Li+].[Cl-].[F-].[K+]>CN(C=O)C.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.C(Cl)Cl.CCCCCC.CCOCC>[CH3:40][O:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:32]([CH:33]=[O:34])[C:31]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:7]=1
Reactant: COc1cccc(C=O)c1OS(=O)(=O)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C(=O)OCC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(-c2c(C=O)cccc2OC)c1
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 94.1 %

Procedure:
Stannane 3a (4.25 g., 9.68 mmol, 1.5 equiv.) and triflate 2 (1.80 g., 6.44 mmol, 1 equiv.) are suspended in 17 mL of DMF. Bis(triphenylphosphine)palladium dichloride (0.68 g., 0.969 mmol, 0.15 equiv.) and LiCl (0.82 g., 19.3 mmol, 3 equiv.) are added and the mixture is heated to 150° C. After 45 min., more bis(triphenylphospine)palladium dichloride (0.2 g., 0.285 mmol, 0.04 equiv.), more LiCl (0.4 g., 9.42 mmol, 1.46 equiv.), and more stannane 3a (0.8 g., 1.82 mmol, 0.28 equiv.) is added, and heating is continued for 2 hours. (The reaction generally turns from yellow-brown to black when complete.) The mixture is allowed to cool to room temperature, and 15 mL of aqueous saturated KF and 10 mL of ether are added. The mixture is stirred for 30 min., and then filtered through celite to remove the tin salts. The filter cake is washed with EtOAc and ether, and the combined filtrates are washed with water, followed by 3% aqueous ammonia solution and then brine. The organic phase is dried (MgSO4) and then concentrated in vacuo. Chromatography on silica gel using 25%, 50% then 75% methylene chloride/hexane affords 2-methoxy-3'-carboethoxy-[1,1'-biphenyl]-6-carboxaldehyde (4a) (1.72 g., 6.06 mmol, 94%) as a slightly yellow oil which crystallizes on standing: mp=67°-69° C.; UVmax (CHCl3) 242 nm (ε=15819), 324 nm (ε=3953); 1H NMR (300 MHz, CDCl3) δ9.70 (s, 1H, CHO), 8.09 (ddd, J=2, 2, 7 Hz, 1H, ArH), 7.99 (s, 1H, ArH), 7.62 (dd, J=2, 8 Hz, 1H, ArH), 7.49 (m, 3H, ArH), 7.19 (dd, J=2, 8 Hz, 1H, ArH), 4.37 (q, J=7 Hz, 2H, CO2CH2), 3.76 (s, 3H, OCH3), 1.34 (t, J=7 Hz, 3H, CO2CH2CH3); 13C NMR (75 MHz, CDCl3 ) δ191.93 (C=O), 166.31 (C=O), 156.98, 135.27, 133.73, 133.57, 131.92, 130.42, 129.17, 129.09, 128.09,119.30, 115.95, 61.14, 56.06, 14.32; IR (film) 2980, 2940, 2838, 1718, 1694, 1468, 1294, 1260, 1234, 1110, 794 cm- 1 ; MS (DCI) m/e 285 (MH+), 239 (M--C2H5O). Anal. Calcd for C17H16O4.0.25 H2O: C, 70.69; H, 5.76. Found: C, 70.64; H, 5.59.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH:9]([CH3:28])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:30](B1C2CCCC1CCC2)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.O1CCOCC1>[C:1]([O:5][C:6](=[O:29])[N:7]([CH:9]([CH3:28])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:15]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C(=O)Nc1ccc(Br)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CC(C(=O)Nc1ccc(Cc2ccccc2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-bromo-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate C2a (50 mg, 0.11 mmol), 9-benzyl-9-borabicyclo[3.3.1]-nonane (283 μl, 0.14 mmol) Cs2CO3 (71 mg, 0.22 mmol), 1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (8.0 mg, 0.01 mmol) and dioxane (0.6 ml) is stirred under argon atmosphere for 45 minutes at 70° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 26 mg (51%). HPLC-MS: M+H=470; tR=1.97 min (*Method—4).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][C:8]1=[CH2:9].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[CH2:9]=[C:8]([CH2:10][C:11](=[O:12])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:7]([OH:14])=[O:13]
Reactant: c1ccccc1
Reactant: C=C1CC(=O)OC1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: C=C(CC(=O)c1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
To a stirred slurry of benzene (4.50 mL, 50.3 mmol) and itaconic anhydride (5.64 g, 50.3 mmol) in 1,2-dichloroethane at room temperature under argon, was added aluminum chloride (13.42 g, 100.7 mmol) in portions over 30 min A dark green solution formed as the temperature rose to 27° C. before subsiding. After 4 h, the now brown solution was poured rapidly into a stirred mixture of ice (200 g) and concentrated hydrochloric acid (15 mL). The resulting beige solids were filtered and air-dried to give the title compound (4.69 gm, 49%). MS [M+H]+: found 191.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]CS([O-])(=O)=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25](=[O:38])[C@@H:26]([O:35][CH2:36][CH3:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[CH3:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OC(NC1C=CC(CCCS([O-])(=O)=O)=CC=1)=O)(C)(C)C>[CH2:22]([O:24][C:25](=[O:38])[C@@H:26]([O:35][CH2:36][CH3:37])[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:14][CH:13]=2)=[CH:32][CH:33]=1)[CH3:23]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCS(=O)(=O)[O-])cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC
Yield: 99648.8 %

Procedure:
2-[4-(tert-Butoxycarbonylamino)phenyl]ethylmethanesulfonate (52.9 g; 0.168 mmole), (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (40 g; 0.168 mmole) and potassium carbonate (69.5 g; 0.503 mmole) were mixed in acetonitrile (1200 ml) and refluxed overnight. Another portion of 2-[4-(tert-butoxycarbonylamino)phenyl]-ethylmethanesulfonate (2.5 g; 7.9 mmole) was added. The reaction mixture was refluxed for 8 more hours then filtered. Evaporation of the filtrate gave 76.6 g 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: ClC1C=CC(CCCN2C(=O)C(CN3CCN(C)CC3)=CC(C3C=CC4OCCC=4C=3)=N2)=CC=1.[C:35]([C:38]1[C:39](=[O:61])[N:40]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[Cl:60])[N:41]=[C:42]([C:44]2[CH:45]=[CH:46][C:47]3[O:51][CH2:50][CH2:49][C:48]=3[CH:52]=2)[CH:43]=1)(O)=[O:36]>>[Cl:60][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=1[CH2:53][N:40]1[C:39](=[O:61])[C:38]([CH2:35][OH:36])=[CH:43][C:42]([C:44]2[CH:45]=[CH:46][C:47]3[O:51][CH2:50][CH2:49][C:48]=3[CH:52]=2)=[N:41]1
Reactant: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccccc2Cl)c1=O
Agent: CN1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(CCCc3ccc(Cl)cc3)c2=O)CC1
Product: O=c1c(CO)cc(-c2ccc3c(c2)CCO3)nn1Cc1ccccc1Cl

Procedure:
The general procedure of Example 1 (4) was repeated by use of 4-carboxy-2-(2-chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one, to thereby yield the title compound as pale yellow needle-like crystal (yield: 42.8%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](N)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)[CH3:2].N([O-])=[O:12].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O.O>[CH2:1]([C:3]1[C:4](=[O:12])[NH:5][C:6]([CH3:9])=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=N[O-]
Reactant: CCc1ccc(C)nc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
A solution of 3-ethyl-6-methyl(pyridin-2-yl)amine (also see Reimlinger, H. et al. Chem. Ber., 109, 118-124 (1976); Sawyer, J. R. H.; Wibberley, D. G. J. Chem. Soc (Perkin 1), 113801143 (1973); Childs, R. F.; Johnson, A. W. Chem. Ind. (London), 542 (1964)) (41.2 g, 0.4 mol) in sulfuric acid (817 mL) is chilled in an ice bath. To this solution is added a solution of sodium nitrite (23.81 g, 0.345 mol) in H2O (200 mL). The resulting mixture is stirred at ambient temperature for 20 hr. The mixture is brought to pH 9.0 by addition of 3N sodium hydroxide (370 mL) and extracted with ethyl acetate (9×200 mL). The combined organic extract is washed with brine (300 mL), dried, filtered and concentrated. The residue is crystallized from heptane (300 mL) to afford 3-ethyl-6-methyl-1H-pyridin-2-one (also disclosed by Mistryukov, E. A. et al. Izv. Akad. Nauk SSR 512-519 (1964); Chem. Abstr. 64, 90713) (35.78 g, 87% yield) as a white, crystalline solid. The resulting product exhibited characteristic 1H NMR spectrum consistent with that reported in the literature.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24]([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:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1.C(N(CC)CC)C.[C:50](OC(=O)C)(=[O:52])[CH3:51]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:12][N:13]([C:50](=[O:52])[CH3:51])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1CNCC(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1CN(CC(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Reaction time: 4 h
Yield: 87 %

Procedure:
To a stirring solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane (0.404 mole) in anhydrous tetrahydrofuran (1.2 liters) under a nitrogen atmosphere at 0° C. was added triethylamine (66.5 ml, 0.477 mole) and acetic anhydride (45.0 ml, 0.477 mole). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2×) and brine (2×), dried over anhydrous sodium sulfate, filtered, and concentrated to a solid on a rotary evaporator. The resulting solid was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and eluted with a 1:1 mixture of ethyl acetate and hexanes. The product was then crystallized from an ethyl acetate/hexanes mixture. The resulting product of 3-(1H-indol-3-yl)-1-(N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane was crystallized and isolated over three crops giving 208.97 grams (87% yield) of analytically pure material.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1.Cl>CN(C=O)C.N1CCCCC1.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.[Cu]I>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[O:12][C:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[CH:22][C:2]=2[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccc(O)c(I)c1
Reactant: C#Cc1ccc(OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2oc(-c3ccc(OC)cc3)cc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
A mixture of Methyl 3-Iodo-4-hydroxybenzoate (0.7 g, 2.5 mmol), 4-Methoxyphenylacetylene (0.33 g, 2.5 mmol), Pd(Cl)2(PPh3)2 (0.05 g) and CuI (0.03 g) in DMF/Piperidine (20 ml) was heated at 60° C. After 2 hr, the reaction was cooled and poured into 2N HCl. The aqueous layer was extracted with EtOAc and then separated, dried, concentrated to give a solid. The solid was triturated with MeOH, filtered to give 142 (0.5 g, 71%): Mp=157-159° C.; 1H NMR (CDCl3) δ 8.28 (d, 1 H, J=1.3 Hz), 7.97 (dd, 1 H, J=8.5 Hz, 1.7 Hz), 7.82-7.79 (m, 2 H), 7.51 (d, 1 H, 8.5 Hz), 6.99 (d, 2 H, J=8.3 Hz), 6.93 (d, 1 H, J=0.9 Hz), 3.94 (s, 3 H), 3.87 (s, 3 H); MS 283 (M+H)+
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][N:11]=1.[C:17](=[O:19])=[O:18]>C1COCC1>[Cl:9][C:10]1[N:11]=[CH:12][CH:13]=[C:14]([Cl:16])[C:15]=1[C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1c(Cl)ccnc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Lithium diisopropylamide (2M in heptane/THF/benzene, 16.7 mL) was treated dropwise with 2,4-dichloropyridine (5 g, 33.8 mmol) at −78° C. in THF (25 mL). The mixture was stirred at −78° C. for 2 hours, treated with excess dry ice, allowed to warm up to room temperature, and partitioned between diethyl ether and an equal volume of 10% aqueous KOH. The basic extract was neutralized with 10% HCl and extracted with diethyl ether. The ethereal extract was dried (Na2SO4), filtered, and the filtrate wasconcentrated under reduced pressure to provide 9.5 g (70% yield) of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.32 (s, 1H), 7.74 (d, J=5.42 Hz,1H), 8.47 (d, J=5.42 Hz,1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[OH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[CH3:24][O:23][C:13]1[CH:12]=[C:11]([NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([O:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[N:3]=2)[CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: Oc1cccnc1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(Oc2cccnc2)n1

Procedure:
The title compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 3-hydroxypyridine in analogy to example 3. It was purified by column chromatography on Si—NH2 gel (Isolute) using ethyl acetate as eluent to give the title compound as a yellowish solid in 21% yield.
Reaction SMILES: Cl.CO.[OH:4][C:5]1[CH:15]=[CH:14][C:8]2[C:9](=[O:13])[CH:10]=[CH:11][O:12][C:7]=2[CH:6]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:22]=O)[CH3:17]>O>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:22]=[C:10]2[C:9](=[O:13])[C:8]3[CH:14]=[CH:15][C:5]([OH:4])=[CH:6][C:7]=3[O:12][CH2:11]2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH3:17]
Reactant: O=c1ccoc2cc(O)ccc12
Reactant: CCOc1cc(C=O)ccc1OC
Agent: Cl
Solvent: O
Solvent: CO
Product: CCOc1cc(C=C2COc3cc(O)ccc3C2=O)ccc1OC
Reaction time: 22.5 h
Yield: 20.6 %

Procedure:
After a saturated hydrogen chloride-methanol solution 15 ml was added to 7-hydroxy-4(4H)-benzopyranone 1.0 g and 3-ethoxy-4-methoxybenzaldehyde 1.30 g, the mixture was srtirred for 22.5 hours, water 100 ml was added, and the precipitated crystals were filtered. The crystals were added to methanol 30 ml of 55° C., and the mixture was filtered. The resulting crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.415 g.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-])=O)[C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>C(O)C.O>[NH2:18][C:9]1[C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=[C:13]2[C:8]=1[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: COc1cc2c(c([N+](=O)[O-])c1OC)c(=O)c(C(=O)O)cn2C1CC1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: COc1cc2c(c(N)c1OC)c(=O)c(C(=O)O)cn2C1CC1
Yield: 97.7 %

Procedure:
Under N2, 1-cyclopropyl-6,7-dimethoxy-5-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (10 g, 29.9 mmol) was treated with sodium sulfide nonahydrate (71.9 g, 299 mmol) in a mixture of Ethanol (100 mL) and Water (100 mL) for 2 h at 100° C. LCMS showed completion of reaction. After cooling down, the mixture was poured into cold water and the solution was adjusted to pH 2. The yellow precipitate was collected by filtration, washed with water and dried to afford 5-amino-1-cyclopropyl-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (8.9 g, 29.2 mmol, 98% yield) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]([CH3:19])([CH3:18])[CH2:7][CH2:6][C:5]2([CH3:21])[CH3:20].C([Li])(C)(C)C.[C:27](=[O:29])=[O:28].Cl>O1CCCC1.CCCCC>[CH2:12]([C:11]1[C:2]([C:27]([OH:29])=[O:28])=[CH:3][C:4]2[C:5]([CH3:20])([CH3:21])[CH2:6][CH2:7][C:8]([CH3:19])([CH3:18])[C:9]=2[CH:10]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: O=C=O
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCc1cc2c(cc1C(=O)O)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
15 g of 6-bromo-7-hexyl-1,1,4,4-tetramethyl-1, 2,3,4-tetrahydro-naphthalene were dissolved in 180 ml of tetrahydrofuran and treated dropwise at -78° C. with 64.5 ml of a 1.5 molar solution of tert.butyl-lithium in pentane. After stirring at -78° C. for 1 hour, a carbon dioxide stream was conducted vigorously into the reaction vessel for 2 hours. Subsequently, the reaction mixture was acidified by the addition of 190 ml of 2N hydrochloric acid, extracted several times with ethyl acetate, washed with water, dried over sodium sulfate and evaporated. The oily crude product was filtered over silica gel (eluent hexane, then hexane/ethyl acetate=4:1) and recrystallized from hexane. There were obtained 7.6 g of 3-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-carboxylic acid in colorless crystals, m.p. 98°-99° C.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[C:6]([C:12](=[O:15])[NH:13][CH3:14])=[C:7](B(O)O)[O:8][C:4]=2[CH:3]=1.C1C(=O)N([I:26])C(=O)C1>CC#N>[NH2:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[C:6]([C:12]([NH:13][CH3:14])=[O:15])=[C:7]([I:26])[O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CNC(=O)c1c(B(O)O)oc2cc(N)c(Br)cc12
Solvent: CC#N
Product: CNC(=O)c1c(I)oc2cc(N)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of (6-amino-5-bromo-3-(methylcarbamoyl)benzofuran-2-yl)boronic acid (2 g, 6.4 mmol) in MeCN (20 mL) was added NIS (1.44 g, 6.4 mmol) at 0° C., and then the mixture was stirred at 25° C. overnight. After concentrated in vacuum, the residue was purified by column chromatography (DCM:EtOAc=10:1) to give to give pure 6-amino-5-bromo-2-iodo-N-methylbenzofuran-3-carboxamide (2 g, yield: 80%). 1H-NMR (CDCl3, 400 MHz) δ 7.84 (s, 1H), 6.80 (s, 1H), 6.45 (s, 1H), 2.92 (s, 3H). MS (M+H)+: 395/397.