Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]([C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)#[CH:17].C(N(CC)CC)C>CN(C=O)C.[Cu](I)(I)I>[C:10]1([CH:9]=[CH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[C:17]#[C:16][C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:20][CH:19]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1cnccc1C=Cc1ccccc1
Reactant: C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: I[Cu](I)I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(C#Cc2cnccc2C=Cc2ccccc2)cc1
Temperature: 95 °C
Yield: 32.5 %

Procedure:
3-Bromo-4-(2-phenylethenyl)pyridine (0.74 g, 2.9 mmol) was dissolved in DMF (1.4 ml). The solution was treated with tert-butyl 4-ethynylbenzoate (0.93 g, 4.6 mmol), copper (III) iodide (0.023 g, 0.21 mmol) and triethylamine (0.64 g, 6.3 mmol). The reaction mixture was degassed by bubbling through argon and the catalyst, bistriphenyl phosphinepalladium dichloride (0.03 g, 0.043 mmol), was added. The reaction was heated to 90-100° C. for 3 hours and then partitioned between ethyl acetate and water. The organic layer was washed with water (3×), dried (MgSO4) and evaporated. The residue was purified by chromatography (eluting with ethylacetate/hexane) to give tert-butyl 4-[2-(4-(2-phenylethenyl)-3-pyridyl)ethynyl]benzoate as a dark oil (0.36 g, 33%).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[CH:10][CH:9]=2)[CH2:4]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][N:2]([CH3:21])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: CN(C)[C@H]1CCN(c2ccc(C(=O)OC(C)(C)C)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)[C@H]1CCN(c2ccc(C(=O)O)cc2)C1

Procedure:
A solution of tert-butyl ester 98 (0.595 g, 2.05 mmol) in 1:1 trifluoroacetic acid:DCM (6 mL) was stirred at room temperature for 3 h then concentrated to give title compound 99 (used as is in the next reaction). LRMS: 234.14 (calc) 235.1 (obs)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH:20]([OH:22])[CH3:21])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:5][CH:4]=1.C([O:33][C:34](=[O:37])[CH:35]=[CH2:36])(C)(C)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.FC(F)(F)C(O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH:20]([CH3:21])[O:22][CH2:36][CH2:35][C:34]([OH:37])=[O:33])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][CH:8]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCC(C)O)c23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCC(C)OCCC(=O)O)c23)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Put 100 mg (0.27 mmol) (+)-1-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}-propan-2-ol with 170 mg (1.33 mmol) acrylic acid tert.-butyl ester and 18.1 mg (0.053 mmol) tetra-n-butylammonium hydrogensulphate in 2 ml dichloromethane and cool to 0° C. Then add 250 μl 50% sodium hydroxide solution and stir the mixture vigorously at 0° C. for 1 h. Leave to return to RT and continue stirring overnight at RT. Then dilute with dichloromethane and water. Acidify with 10% citric acid solution and separate the phases. Re-extract the aqueous phase once with dichloromethane. Combine the organic phases, wash once with satd. sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. Dissolve the residue thus obtained in 2.5 ml dichloromethane, add 600 μl trifluoroacetic acid and stir for a further 2 h at RT. Then concentrate by evaporation and purify the residue by chromatographing twice on a silica-gel thick-layer plate (solvent: dichloromethane/methanol 9:1). Extract the product zone with dichloromethane/methanol 9:1. After concentrating by evaporation and drying, 38 mg (42.8% of theor.) of the target compound is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].CI.[C:15](=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:15][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1ncc2c([N+](=O)[O-])cccc21
Reaction time: 12 h
Yield: 35.3 %

Procedure:
6.5 g of 4-nitroindazole (Chem. Ber. (1904), 37, 2583), 1.9 ml of methyl iodide and 14.4 g of cesium carbonate in 110 ml of DMF are stirred for 2 hours at 0° C. and then for 12 hours at room temperature. It is added to water and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation. The residue is recrystallized from ethyl acetate/hexane. 2.49 g of 1-methyl-4-nitroindazole is obtained. The latter is hydrogenated in 70 ml of THF with 420 mg of palladium on activated carbon under normal pressure with hydrogen. The batch is filtered through diatomaceous earth and completely concentrated by evaporation. 2.1 g of the title compound is obtained.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.CN(C=O)C.[NH2:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>O>[Si:1]([O:26][C:22]1[CH:21]=[C:20]([NH2:19])[CH:25]=[CH:24][CH:23]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 250 mL, three-neck, round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with tert-butyldimethylsilyl chloride (12.5 g, 82.8 mmol), imidazole (7.64 g, 112 mmol), and anhydrous DMF (60 mL). 3-aminophenol (10.0 g, 91.7 mmol) was added to the resulting solution. After stirring for 12 h at ambient temperature, the reaction mixture was poured into water (300 mL). The resulting suspension was extracted with hexanes (3×300 mL), and the extracts were combined, dried over sodium sulfate, and filtered. Concentration of the filtrate followed by column chromatography gave compound 122 as a light yellow oil. 1H NMR (DMSO-d6) δ (ppm), 6.84 (t, 1H, J=7.9 Hz), 6.16 (d, 1H, J=6.7 Hz), 6.10 (m, 1H), 5.97 (d, 1H, J=9.1 Hz), 4.98 (s, 2H), 0.95 (s, 9H), 0.16 (s, 6H); m/z=224 (M+H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][C@H:25]3[O:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)[C:20]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)=[CH:19][N:18]=2)=[N:14][CH:15]=1)#[N:9]>ClCCl>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([C:20]2[C:21]([NH:23][CH2:24][C@H:25]3[O:30][CH2:29][CH2:28][NH:27][CH2:26]3)=[CH:22][C:17]([NH:16][C:13]3[N:14]=[CH:15][C:10]([C:8]#[N:9])=[N:11][CH:12]=3)=[N:18][CH:19]=2)=[CH:39][CH:40]=1
Reactant: COc1ccc(-c2cnc(Nc3cnc(C#N)cn3)cc2NC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cnc(Nc3cnc(C#N)cn3)cc2NC[C@@H]2CNCCO2)cc1
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
TFA (0.2 mL) was added to a solution of (R)-tert-butyl 2-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)morpholine-4-carboxylate (0.014 g, 0.027 mmol) dissolved in dichloromethane (2 mL) at room temperature. The reaction mixture was stirred for 20 min. Solvent was removed in vacuo and the mixture was purified by ion exchange on SCX-II acidic resin (500 mg), eluting with methanol then 2M ammonia-methanol. The basic fractions were combined and solvent was removed in vacuo. The crude product was purified by preparative thin layer chromatography, eluting with methanol/dichloromethane (1/19), to give the title compound as a yellow solid (0.007 g, 62%).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3]>C1(C)C=CC=CC=1>[F:3][C:2]([F:5])([F:4])[C:1]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])=[O:6]
Reactant: OCC(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(OCC(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After five cycles similar to the one described above, the gas chromatographic analysis showed only 80% conversion to trifluoroethanol and the catalyst was then regenerated in the following manner. The pressure tube containing the catalyst residue (originally 0.03 mmol) was charged with 20 mg (0.25 mmol) of NaBH(OCH3)3, in a dry box. Tetrahydrofuran (3 ml) was distilled into the tube under vacuum and the solution stirred at room temperature for one hour. The solvent and other volatiles were removed in vacuo and the residue evacuated to dryness. The pressure tube was then charged with toluene (3 ml) and 1.1 gram (5.7 mmols) of ester and the hydrogenation was conducted as described in part (a).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([O:12][CH3:13])=[CH:4][C:3]=1[C:14]([CH3:17])([CH3:16])[CH3:15].S(=O)(=O)(O)O.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([O:1][C:2]1[C:3]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[CH:6][C:7]=1[C:8]([CH3:10])([CH3:11])[CH3:9])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Product: COc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
4-Hydroxy-3,5-di-tert-butylanisole (23.6 g) was dissolved in acetic anhydride (150 ml). Following the addition of conc. sulfuric acid (0.5 ml), the mixture was stirred at 70° C. for 2 h. The reaction mixture was concentrated under reduced pressure and a saturated aqueous solution of sodium hydrogen carbonate was added to the concentrate, followed by extraction with ethyl acetate. The extracted layer was dried over anhydrous magnesium acetate and concentrated. The precipitating solid was recrystallized from methanol-water (2:1) to afford 4-acetoxy-3,5-di-tert-butylanisole [24.5 g (yield, 88%)] as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH2:9]O)[CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH2:9][Cl:26])[CH2:3][CH2:2]1
Reactant: OCc1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: FC(F)Oc1ccc(CCl)cc1OCC1CC1

Procedure:
A solution of crude 3-cyclopropylmethoxy-4-difluoromethoxybenzyl alcohol (24.4 g) and pyridine (9.8 mL, 120 mmol) in chloroform (150 mL) under an argon atmosphere was treated with thionyl chloride (8.0 mL, 110 mmol) and the mixture was heated at reflux for 1 h. The solvent was removed, ether was added and the precipitate was removed by filtration. The filtrate was concentrated to a pale yellow oil (26 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]CCC)=[N+:2]=[N-:3].N([CH2:25][CH2:26]N)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7]([C:8]1[CH:9]=[CH:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:26][CH:25]=1)=[O:21])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCN
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=NCCNC(=O)c1ccc(-c2ccccc2)cc1
Yield: 85.1 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.283 g, 1.31 mmol) was reacted with 2-azidoethanamine (0.113 g, 1.31 mmol) and triethylamine (0.264 g, 2.61 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)biphenyl-4-carboxamide (0.297 g, 85%). 1H NMR (300 MHz, CDCl3) δ 7.88 (d, 2H), δ 7.67 (m, 4H), δ 7.44 (m, 3H), δ 6.63 (s, 1H), δ 3.67 (q, 2H), 6 (3.58 (t, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 167.8, 144.8, 140.1, 132.9, 129.2, 128.3, 127.8, 127.5, 127.4, 51.2, 39.7 ppm; HRMS (ESI) calcd for C15H14N4O (M+) 266.1168. Found 266.1162.
Reaction SMILES: [N+](C)([O-])=O.C[C:6]([O:8][CH2:9][C:10]1[CH2:19][S:18][C@@H:13]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:12]2[C:11]=1[C:20]([OH:22])=[O:21])=O.N>[Cl-].[Zn+2].[Cl-].CO.O>[NH2:17][CH:14]1[C:15](=[O:16])[N:12]2[C:11]([C:20]([OH:22])=[O:21])=[C:10]([CH2:9][O:8][CH3:6])[CH2:19][S:18][C@H:13]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CO
Solvent: C[N+](=O)[O-]
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 60 °C

Procedure:
To 10 ml of nitromethane were added 2.72 g of of 7-amino-cephalosporanic acid (hereinafter referred to as "7-ACA"), 9.63 g of zinc chloride and 0.71 g of methanol. The mixture was heated at 60° C. for 90 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture were added 30 ml of water and 10 ml of methanol. Then, the mixture was adjusted to pH 7.8 with aqueous ammonia at a temperature of from -2° C. to 2° C. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings. The resulting mixture was adjusted to pH 3.5 with 36 % hydrochloric acid to thereby form a precipitate. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 20 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.98 g. The yield of the desired product was 40 %.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH:18]C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].O.[OH-].[Na+]>O1CCOCC1.OS(O)(=O)=O>[NH2:18][C@@H:16]1[CH2:17][C@H:15]1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(OCc2ccc(C#N)cc2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(COc2ccc([C@@H]3C[C@H]3N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.6 %

Procedure:
tert-butyl(trans)-2-{4-[(4-cyanobenzyl)oxy]phenyl}cyclopropylcarbamate (0.31 g, 0.85 mmol) was dissolved in a mixture of 1,4-dioxane/H2SO4 (15 mL, 10:1, v/v) and stirred at room temperature for 45 min. The reaction mixture was poured into water (15 mL), basified by addition of 15 mL of aqueous NaOH (10%) and extracted with EtOAc (2×15 mL); the organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the crude residue was purified by column chromatography on silica gel (0%-3% MeOH/CH2Cl2) to afford 0.19 g of 4-({4-[(trans)-2-aminocyclopropyl]phenoxy}methyl)benzonitrile [Rf=0.2 (5% MeOH/CH2Cl2), beige solid, 85% yield].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]3[CH:10]2[CH2:11][NH:12][CH2:13]3)=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:19](O)=[O:20].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:15][C:16]1[CH:17]=[C:18]([C:19]([N:12]2[CH2:13][CH:14]3[CH:10]([CH:9]3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:11]2)=[O:20])[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: COc1ccc(C2C3CNCC32)cc1
Reactant: Cc1ccc(C(=O)O)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C2C3CN(C(=O)c4ccc(C)c(N)c4)CC32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
A mixture of 6-(4-Methoxyphenyl)-3-azabicyclo[3.1.0]hexane (0.124 g, 0.82 mmol), 3-amino-4-methylbenzoic acid (0.155 g, 0.82 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 0.172 g, 0.90 mmol), 1-hydroxybenzotriazole (˜20% H2O, 0.122 g, 0.90 mmol) and diisopropylethylamine (0.71 mL, 4.1 mmol) in DMF (3 mL) was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc (3×). The combined organic extract was dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography with EtOAc in hexane (60%, then 100%) to give the title compound as a white foam (0.15 g, 57% yield).
Reaction SMILES: [CH3:1][C:2]([OH:10])([C:5]([CH3:9])([CH3:8])[CH2:6][CH3:7])[C:3]#[CH:4].N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH3:1][C:2]([OH:10])([C:5]([CH3:9])([CH3:8])[CH2:6][CH3:7])[CH:3]=[CH2:4]
Reactant: C#CC(C)(O)C(C)(C)CC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Product: C=CC(C)(O)C(C)(C)CC
Temperature: 25 °C
Reaction time: 10 h
Yield: 89.7 %

Procedure:
100 g of 3,4,4-trimethylhex-1-yn-3-ol, 3 g of quinoline and 5.4 g of Lindlar catalyst were initially introduced in 100 ml of petroleum ether and the mixture was stirred at 25° C. for 10 hours under a hydrogen atmosphere. The catalyst was then filtered off, the filtrate was concentrated and the residue was analyzed by means of GC. 91 g (90%) of 3,4,4-trimethylhex-1-en-3-ol were obtained. The residue was processed without purification.
Reaction SMILES: CCCCCC.C([Li])CCC.C1COCC1.[CH:17]1[C:25]2[C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][C:21]=2[CH:20]=[CH:19][CH:18]=1.[Br:30]CCBr>O>[Br:30][C:17]1[C:25]2[C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: BrCCBr
Reactant: c1ccc2c(c1)oc1ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Brc1cccc2oc3ccccc3c12
Temperature: 25 °C

Procedure:
Under nitrogen current at −78° C., an n-butyl lithium hexane solution (1.6M, 69 ml) is dropped to a THF solution (175 ml) containing 16.82 g of dibenzofuran, and the temperature of the mixture is raised to room temperature over 80 minutes. The obtained solution is again cooled to −78° C., 19.0 ml of 1,2-dibromoethane is added to the solution, and the temperature of the solution is raised to room temperature over 120 minutes. Water is added to the obtained reaction solution to stop the reaction. Organic layers extracted from the obtained mixture with ethyl acetate are dried with sodium sulfate, and then concentrated with an evaporator to obtain 12.35 g of Compound 16-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cnc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 110.3 %

Procedure:
A mixture consisting of 5-bromo-2-iodopyrimidine (Bridge Organics, 10.0 g, 35.1 mmol), benzene boronic acid (Alfa Aesar, 4.25 g, 35.1 mmol), tetrakis(triphenylphosphine)palladium (Strem, 0.405 g, 0.351 mmol), toluene (150 mL), and a 2 M aqueous sodium carbonate solution (35 mL) was stirred at 115° C. (degrees Celsius) under a nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was partitioned between chloroform (250 mL) and brine (200 mL). The phases were separated and the organic phase was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an orange oil (9.1 g). The crude product was purified by flash silica column chromatography. Elution through a 500-g Analogix® flash silica cartridge with 100% hexanes afforded the title intermediate as a white solid (3.15 g, 38% yield). Rf 0.69 with 9:1 v/v hexanes-ethyl acetate; 1H-NMR (400 MHz; CDCl3) δ 8.83 (s, 2H), 8.44-8.38 (m, 2H), 7.52-7.46 (m, 3H); MS (APCI+) m/z 236.9 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
4-Hydroxybenzoic acid (1.01 g, 7.31 mmol) and 4-aminophenol (1.19 g, 10.9 mmol) were dissolved in 15 mL of dry DMF. To the above solution EDCI (1.40 g, 7.31 mmoL) was added in one portion and the resulting mixture was stirred at rt overnight under nitrogen. The reaction mixture was then partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was separated, washed consecutively with 1 N HCl, water, saturated sodium bicarbonate solution, water, and brine, and dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified by column chromatography using EtOAc in hexane as an eluent (10% to 20%) to give 580 mg (34% yield) of 4-hydroxy-N-(4-hydroxyphenyl)-benzamide. MS (ES) m/z: 230.04 (M+1).
Reaction SMILES: [CH:1]([N:4]1[CH:13]2[CH:8]([CH2:9][CH2:10][C:11]([CH3:14])=[CH:12]2)[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:6][C:5]1=[O:22])([CH3:3])[CH3:2].[S]>C1C2C(CCCC2)CCC1.C1(C)C=CC=CC=1>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:6][C:5]1=[O:22])([CH3:3])[CH3:2]
Reactant: CC1=CC2C(CC1)C(c1ccc(F)cc1)=NC(=O)N2C(C)C
Agent: [S]
Solvent: Cc1ccccc1
Solvent: C1CCC2CCCCC2C1
Product: Cc1ccc2c(-c3ccc(F)cc3)nc(=O)n(C(C)C)c2c1
Reaction time: 1 h

Procedure:
17.4 g 1-isopropyl-4-(4-fluorophenyl)-7-methyl-4a,5,6,8a-tetrahydro-2(1H)-quinazolinone are dissolved under heating in 50 ml decaline and treated portionwise at 140° with 4 g powdered sulphur. On completion of the addition stirring is continued for 1 hour at 160°. The mixture is diluted with toluene and extracted several times with 15% hydrochloric acid. The acidic phase is treated with methylene chloride and neutralized under ice cooling with sodium hydroxide solution. The water phase is extracted with methylene chloride and the combined methylene chloride extracts concentrated in vacuo. The concentrate is chromatographed on silica gel using dichloromethane and methanol as eluant. After recrystallisation from toluene the title compound is obtained, m.p. 174°-176°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:14]I>C1COCC1>[CH3:14][N:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CI
Reactant: CCOC(=O)c1cc(C)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)cn1C
Reaction time: 0.17 h

Procedure:
To a solution of 4-methyl-2-pyrrolecarboxylic acid ethyl ester (100 mg, 0.653 mmol) in THF (2.5 mL), was added NaH (31.3 mg, 0.783 mmol). The mixture was stirred for 10 min and then MeI (0.061 mL, 0.979 mmol) was added dropwise. The resulting mixture was stirred overnight. The reaction was quenched with sat. NH4Cl. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC (1000 μm, hexanes/EtOAc (9:1)) to give ethyl 1,4-dimethyl-1H-pyrrole-2-carboxylate. 1H NMR (500 MHz, CDCl3): δ 6.77 (s, 1H); 6.58 (s, 1H); 4.28 (q, J=7.1 Hz, 2H); 3.88 (s, 3H); 2.08 (s, 3H); 1.35 (t, J=7.1 Hz, 3H).