Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[NH:19][C:18]2[NH:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=1)=[O:10].CCN(CC)CC.C1([O:33][C:34](=O)[NH:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)C=CC=CC=1>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[NH:19][C:14]2[CH2:15][CH2:16][N:17]([C:34]([NH:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[O:33])[CH2:18][C:13]=2[CH:12]=1)=[O:10]
Reactant: Nc1ccccc1NC(=O)c1cc2c([nH]1)NCCC2
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)c1cc2c([nH]1)CCN(C(=O)Nc1cccnc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-aminophenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2]pyridine-2-carboxamide (1.0 eq) in DMF was added Et3N (3.0 eq.) followed by Pyridin-3-yl-carbamic acid phenyl ester (1.0 eq). Reaction was stirred at room temperature for overnight. Reaction mixture was then quenched with water and extracted with ethyl acetate, dried over sodium sulphate and concentrated to dryness. Crude mass was then purified by silica gel column chromatography to afford N2-(2-aminophenyl)-N5-pyridin-3-yl-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-2,5-dicarboxamide.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([F:13])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1>C1COCC1.CCOC(C)=O>[Cl:15][C:16]1[CH:21]=[C:20]([O:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([F:13])([F:14])[F:3])[N:19]=[CH:18][N:17]=1
Reactant: OC(c1ccccc1)C(F)(F)F
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)C(Oc1cc(Cl)ncn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.9 %

Procedure:
NaH (60%, 120 mg, 3.0 mmol) was added to a solution of 2,2,2-trifluoro-1-phenyl-ethanol (350 mg, 2.03 mmol) in 5 ml of THF. The mixture was stirred for 20 minutes at room temperature. 4,6-Dichloro-pyrimidine (300 mg, 2.03 mmol) was added and then the reaction mixture was heated at 70° C. for 1 hour. After cooling, the THF was evaporated to provide a residue, which was dissolved in 15 ml of EtOAc, and then washed with water, and dried over sodium sulfate. The solvent was removed by rotovap to give 550 mg of 4-chloro-6-(2,2,2-trifluoro-1-phenyl-ethoxy)-pyrimidine, yield 95%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].S(=O)(=O)(O)O.[S-:18][C:19]#[N:20].[Na+].C1OCCOCCOCCOCCOC1>ClC1C=CC=CC=1>[CH3:12][C:3]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=1[NH:1][C:19]([NH2:20])=[S:18]
Reactant: COC(=O)c1cccc(N)c1C
Reactant: N#C[S-]
Agent: C1COCCOCCOCCOCCO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COC(=O)c1cccc(NC(N)=S)c1C
Temperature: 100 °C

Procedure:
90.7 g of methyl 3-amino-2-methylbenzoate (0.55 mol) were dissolved in 510 ml of chlorobenzene and, at −5° C., admixed with 14 ml of conc. sulfuric acid and 49 g of sodium thiocyanate (0.6 mol). 2 ml of 15-crown-5 were then added, and the reaction mixture was heated at 100° C. for 13 h. After cooling, the solid was filtered off with.suction, washed with water and dried. Yield: 104.8 g (85%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:13])[CH2:7][CH2:6]1)=[O:20])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of ethyl-N-benzenesulfonyl-isonipecotate (5 g, 0.016 mole) in tetrahydrofuran (1 L) at -78° C. was treated with a solution of Lithium bis (trimethylsilyl)amide in tetrahydrofuran (18.5 mL of a 1M solution). The solution was stirred at -60° for 15 minutes at which time benzyl bromide (3.15 g, 0.016 moles) was added and the reaction warmed to room temperature over 1.5 hours. The reaction was concentrated at reduced pressure to @ one quarter volume and then poured into saturated aqueous sodium bicarbonate (1 L) and extracted with ethyl acetate (2×800 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The residue was chromatographed on silica gel with 30% ethyl acetate/hexane as eluent to give 5.1 g. 1H NMR CDCl3 δ 7.7 (d,=8.5 Hz, 2H), 7.6-7.4 (m, 3H), 7.3-7.2 (m, 3H), 7.1-7.0 (m, 2H), 3.98 (q, J=7 Hz, 2H), 3.65 (m, 2H), 2.78 (s, 2H), 2.35 (dt, J=2.5, 12 Hz, 2H), 2.19 (d, J=12 Hz, 2H), 1.61 (dt, J=4.5, 12 Hz, 2H).
Reaction SMILES: Br[C:2]1[N:3]([C:34]2[N:35]=[CH:36][N:37]=[C:38]([NH2:41])[C:39]=2[N:40]=1)[C@@H:4]1[O:33][C@H:23]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@H:5]1[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH2:42]([O:49][C:50]1[CH:51]=[C:52]([C:56]2[CH:61]=[CH:60][C:59]([CH2:62][NH2:63])=[CH:58][CH:57]=2)[CH:53]=[CH:54][CH:55]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)C(C)C)(C)C>C(O)CC>[CH2:42]([O:49][C:50]1[CH:51]=[C:52]([C:56]2[CH:57]=[CH:58][C:59]([CH2:62][NH:63][C:2]3[N:3]([C:34]4[N:35]=[CH:36][N:37]=[C:38]([NH2:41])[C:39]=4[N:40]=3)[C@@H:4]3[O:33][C@H:23]([CH2:24][O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27])[C@@H:14]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[C@H:5]3[O:6][Si:7]([C:10]([CH3:13])([CH3:11])[CH3:12])([CH3:9])[CH3:8])=[CH:60][CH:61]=2)[CH:53]=[CH:54][CH:55]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(Br)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: NCc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4cccc(OCc5ccccc5)c4)cc3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 62 h
Yield: 83.3 %

Procedure:
A mixture of 8-bromo-2′,3′,5′-tris-O-(tert-butyl-dimethylsilyl)adenosine (0.660 g), 3′-benzyloxybiphenyl-4-ylmethylamine (0.832 g) and N,N-diisopropylethylamine (0.667 mL) in 1-propanol (9.6 mL) was heated under reflux with stirring for 62 hours. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate (35 mL) and 10% aqueous citric acid (10 mL). The organic layer was washed successively with 10% aqueous citric acid (10 mL×2), saturated aqueous sodium hydrogen carbonate (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on aminopropylated silica gel (eluent: hexane/ethyl acetate=2/1) to give the title compound (0.716 g).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1.C1COCC1.CCOCC.O.C(OCC)(=O)C>[N:1]1([CH2:23][C:19]2[O:18][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(Cl)c1ccco1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: c1coc(CN2CCCc3ccccc32)c1
Reaction time: 1 h
Yield: 23 %

Procedure:
To 1.4 g (10.5 millimoles) of 1,2,3,4-tetrahydroquinoline were added 1.2 g (11.9 millimoles) of triethylamine and 10 ml of toluene, and a solution of 1.5 g (11.5 millimoles) of 2-furoyl chloride in 10 ml of toluene was added dropwise to the mixture at room temperature. The mixture was stirred for 1 hour and water and ethyl acetate were added to the mixture, and the organic layer was separated, dried with anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain a brown solid. The solid was dissolved in 20 ml of THF and the solution was added dropwise to a suspension of 0.5 g (13.2 millimoles) of lithium aluminum hydride in 20 ml of THF at room temperature. The mixture was heated and refluxed for 1 hour, and 1 ml of water and ether were added to the mixture. Then, anhydrous magnesium sulfate was added to the mixture, and the mixture was stirred for 30 minutes. The solid was removed by filtration, and the obtained filtrate was concentrated to dryness under reduced pressure to obtain a light-yellow liquid. The obtained liquid was purified by the silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/15) to obtain 0.5 g (the yield was 23%) of intended compound No. 2 in the form of a light-yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[F-].[Cs+].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:35]1[CH:36]=[CH:37][C:38]2[N:39]([C:41]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)=[CH:42][N:43]=2)[CH:40]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[F:50][C:47]1[CH:46]=[CH:45][C:44]([C:41]2[N:39]3[CH:40]=[C:35]([C:12]4[N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[CH:9]=[N:10][CH:11]=4)[CH:36]=[CH:37][C:38]3=[N:43][CH:42]=2)=[CH:49][CH:48]=1
Reactant: Fc1ccc(-n2ccnc2)cc1
Reactant: Fc1ccc(-c2cnc3ccc(Br)cn23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2cnc3ccc(-c4cncn4-c4ccc(F)cc4)cn23)cc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 31.3 %

Procedure:
To a flame-dried reaction flask were added at room temperature and under an argon atmosphere commercially available 1-(4-fluorophenyl)-1H-imidazole (69.6 mg, 429 μmol), palladium(II)acetate (9.64 mg, 42.9 μmol), cesium fluoride (130 mg, 859 μmol), triphenylarsine (26.3 mg, 85.9 μmol) and 6-bromo-3-(4-fluoro-phenyl)-imidazo[1,2-a]pyridine (intermediate E) (125 mg, 429 μmol). Afterwards DMF (2.15 ml) was added successively by syringe at room temperature and under a stream of argon. The resulting mixture was allowed to stir at 140° C. under an argon atmosphere for 24 h. The reaction mixture was cooled to room temperature, water (10 ml) was added and the mixture was extracted with dichloromethane (2×40 ml). The combined organic layers were washed with water (2×20 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/MeOH, 2-8%) and crystallization (dichloromethane/heptane) to yield the title compound as an off-white solid (50 mg, 31%), MS (ISP) m/z=373.4 [(M+H)+], mp 206° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=O.[NH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[NH:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:15][CH:14]=[CH:13][CH:12]=2>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[N:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:17]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=1
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cccnc12
Solvent: c1ccncc1
Product: COCc1nc2cnc3cccnc3c2n1CCNC(=O)OC(C)(C)C

Procedure:
Methoxyacetyl chloride (5.9 g, 54 mmol) was added dropwise to a chilled (ice bath) solution of tert-butyl N-{2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethyl}carbamate (15.0 g, 49.5 mmol, U.S. Pat. No. 6,194,425, Example 87) in anhydrous pyridine (100 mL). The reaction mixture was heated at reflux until analysis by liquid chromatography/mass spectroscopy (LCMS) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethanol (100 mL), combined with potassium carbonate solution (200 mL of 2 M), and heated at reflux for 4 hours. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide 14 g of tert-butyl N-[2-(2-methoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]carbamate.
Reaction SMILES: C1(=O)[N:5]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([C@@H:15]4[O:30][C@H:29]([CH2:31][O:32]C(C5C=CC(C)=CC=5)=O)[C@@H:18]([O:19]C(C5C=CC(C)=CC=5)=O)[C@@:16]4([CH3:42])[OH:17])[C:8]=3[N:9]=[CH:10][N:11]=2)C(=O)C2=CC=CC=C12.C(N)CCC>CO>[NH2:5][C:6]1[C:7]2[CH:14]=[CH:13][N:12]([C@@H:15]3[O:30][C@H:29]([CH2:31][OH:32])[C@@H:18]([OH:19])[C@@:16]3([CH3:42])[OH:17])[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3ccc4c(N5C(=O)c6ccccc6C5=O)ncnc43)[C@](C)(O)[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Solvent: CO
Solvent: CCCCN
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 27 h

Procedure:
To the toluene solution from Step B at ambient temperature were added methanol (25 L) and n-butylamine (3.13 kg, 42.9 mol). The reaction mixture was aged at 64° C. for 24 to 30 h. The mixture was concentrated to about 9 L, and 9 L of methanol was added. The solution was concentrated to 9 L, and the resulting slurry was aged at 60° C. for 60 min. Toluene (13 L) was added over 1.5 h. The slurry was aged at 60° C. for another 2 h and then allowed to cool to ambient temperature. The solid was filtered and the wet cake was washed with 9 L of 20% methanol in toluene then 9 L of 10% methanol in toluene. The solid was suction dried at ambient temperature under nitrogen to give 1.79 kg (94 wt % pure) of the title nucleoside 4-3 as the toluene solvate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9].[NH2:13][NH2:14].C(N(C(C)C)CC)(C)C>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:13][NH2:14])=[CH:6][C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: NN
Reactant: C[Si](C)(C)c1cc(Cl)nnc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)c1cc(NN)nnc1Cl
Temperature: 72.5 °C
Yield: 56.4 %

Procedure:
A round-bottom flask under N2 was charged with 20 (13.6 g, 61.4 mmol) and anhydrous hydrazine (1M in THF, 184 mL, 184 mmol) followed by diisopropylethyl amine (11 mL, 61.4 mmol). The reaction was heated to a gentle reflux (70-75° C., external temperature) monitoring the reaction by LCMS. After 4 days the dark mixture was cooled, silica gel (20 g) was added and the mixture was concentrated. The crude mixture was combined with the crude material from a second reaction (16 mmol) and purified on a silica column (120 g, 0-5% MeOH/dichloromethane) to provide 7.5 g (45%) of 21 as a reddish oil/solid mix. Some trace impurities and residual diisopropylethyl amine remained. The product was used ‘as is’ in the next step.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>CCOCC.O>[CH3:10][C:9]1[O:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]=1[CH2:4][CH2:3][OH:2]
Reactant: COC(=O)Cc1nc(-c2ccccc2)oc1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCO
Yield: 78.7 %

Procedure:
2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)-acetic acid methyl ester (2.3 g, 10 mmol) was dissolved in 16 mL of Et2O, and then added dropwise at 0° C. to a suspension of LiAlH4 (0.38 g, 10 mmol) in Et2O (4 mL). The solution was stirred at room temperature overnight, to which 0.4 mL H2O, 0.4 mL of 15% NaOH solution, and 1.2 mL of H2O, and a spoon of anhydrous MgSO4 were carefully added in turn. The mixture was filtered, and the filtrate was concentrated to give 1.6 g of 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethanol as a light yellow solid with a yield of 80%.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[H+].[C:7]([CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]1[C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])#[N:8]>C(O)(=O)C>[F:1][B-:2]([F:5])([F:4])[F:3].[NH2:8][C:7]1[O:23][C:19]([CH:20]([CH3:21])[CH3:22])=[N+:10]2[CH:11]=[CH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]=12
Reactant: CC(C)C(=O)N1C=Cc2ccccc2C1C#N
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC(=O)O
Product: CC(C)c1oc(N)c2c3ccccc3cc[n+]12
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
An aqueous solution of fluoroboric acid (48% w/v; 33 ml) was added to a stirred solution of 1-cyano-2-isobutyryl-1,2-dihydroisoquinoline (6.78 g; prepared according to the method described by F. D. Popp and A. Soto, J. Chem. Soc., 1963, 1760) in acetic acid (25 ml) at 60° C. The solution was stirred for 15 minutes and then cooled to 5° C. The solid was collected, washed thoroughly with diethyl ether and dried, to give 1-amino-3-isopropyloxazolo[4,3-a]isoquinolinium tetrafluoroborate (8.55 g) in the form of a pale yellow solid, m.p. 181°-183° C. [Elemental analysis: C, 53.0; H, 4.78; N, 8.9%; Calculated: C, 53.5; H, 4.81; N, 8 9%; N.M.R. in CD3CN): 1.44 (6H, d, J=7 Hz), 3.68 (1H, septet, J=7 Hz), 5.90 (2H, broad s), 7.27 (1H, d, J=8 Hz), 7.48-7.72 (4H, m), 7.92 (1H, d, J=8 Hz); Mass spectrum (fast atom bombardment) m/e=227].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
To a solution of 699 mg (3.62 mmol) of the intermediate obtained in Step B in 15 mL of carbon tetrachloride under nitrogen was added 708.3 mg (3.98 mmol, 1.1 eq) of N-bromosuccinimide and 59 mg (0.36 mmol, 0.1 eq) of azobisisobutyronitrile (AIBN). The resulting mixture was heated in the dark for 4 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum to afford 948 mg (96%) of the product as a yellow solid. 1H NMR (200 MHz, CDCl3): 4.51 (s,2H), 7.25-7.80 (m,8H). FAB-MS: calculated for C14H10BrN 272; found 272,274 (M+). 1H NMR indicates the presence of minor amounts of starting material and dibromo derivative.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].O.[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1.CC(C)=O>C1(C)C=CC=CC=1>[CH3:18][C:17]1([CH3:22])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Yield: 190.7 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (150 mg, 0.68 mmol), p-toluenesulfonic acid monohydrate (50 mg) and acetone (10 mL) in toluene (20 mL) was heated to reflux overnight. After removal of the solvent, the residue was purified by column chromatography on silica gel (MeOH: dichloromethane=1:9) to afford the title compound (130 mg, yield 74%) as an orange solid:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH:15]2[CH2:16][C:11]3(Br)[CH2:12][C:13](Br)([CH2:17][CH:9]1[CH2:10]3)[CH2:14]2)(C)(C)C.[OH-:21].[Na+]>O1CCOCC1>[NH2:7][CH:8]1[CH:15]2[CH2:14][C:13](=[CH2:12])[CH2:17][CH:9]1[CH2:10][C:11](=[O:21])[CH2:16]2
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)NC1C2CC3(Br)CC1CC(Br)(C2)C3
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C1CC2CC(=O)CC(C1)C2N
Yield: 163.7 %

Procedure:
(First step: Rohde, J. J. et al. Discovery and Metabolic Stabilization of Potent and Selective 2-Amino-N-(adamant-2-yl) Acetamide 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors. J. Med. Chem. 2007, 50, 149-64). A solution of 25 (125 mg, 0.305 mmol) in dioxane (0.80 mL) was treated with 2N NaOH (0.70 mL, 1.37 mmol) and irradiated under microwaves (μw, Biotage) for 15 min at 180° C. The dioxane was removed in vacuo. The residue was dissolved in DCM, washed with water, dried (Na2SO4), filtered and concentrated in vacuo to afford 82.5 mg of crude 9-amino-7-methylene-bicyclo[3.3.1]nonan-3-one as a yellow oil, that was used for the next step without further purification.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=O.[C:17]([NH:20][C:21]([NH2:23])=[S:22])(=[NH:19])[NH2:18]>C(O)C>[NH:20]([C:21]1[S:22][C:2]([CH3:16])=[C:3]([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)[N:23]=1)[C:17]([NH2:19])=[NH:18]
Reactant: CC(Br)C(=O)c1ccc2c(c1)CCC(=O)N2
Reactant: N=C(N)NC(N)=S
Solvent: CCO
Product: Cc1sc(NC(=N)N)nc1-c1ccc2c(c1)CCC(=O)N2

Procedure:
A mixture of 6-(α-bromopropionyl)-3,4-dihydrocarbostyril (7 g), amidinothiourea (3.1 g) and absolute ethanol (250 ml) is stirred under reflux overnight. The reaction mixture is cooled to ice bath temperature, and the solid filtered, washed with ethanol, dried, and suspended in aqueous sodium hydroxide. The neutralized solid is filtered, washed with water, dried and recrystallized from 50% aqueous DMF affording the desired product, M.P. >250° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([O:27][CH3:26])=[O:37])=[C:13]([F:18])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)c(F)c1
Yield: 70.8 %

Procedure:
N-benzyl-2-(3-fluoro-4-hydroxyphenyl)-N-hexylacetamide (142 mg, 0.414 mmol), 2-bromomethylbenzoic acid methyl ester (99.4 mg, 0.434 mmol) and potassium carbonate anhydrous (86 mg, 0.620 mmol) were mixed in acetonitrile (5 ml). The mixture was heated to reflux overnight and then evaporated to dry. Ethyl acetate and water were added and the two phases were separated. The organic phase was washed with brine and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, MeOH/DCM (0.5:99.5) as eluant gave 144 mg the desired product, yield 71%.
Reaction SMILES: [CH2:1]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH2:9][NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:19]1[CH:24]=[C:23]([C:25]([OH:27])=O)[CH:22]=[CH:21][C:20]=1[C:28]([OH:30])=O>>[CH2:1]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH2:9][NH:10][C:28]([C:20]1[CH:21]=[CH:22][C:23]([C:25]([NH:10][CH2:9][CH2:8][CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:27])=[CH:24][N:19]=1)=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCC(CCN)CCCCCC
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Product: CCCCCCCCC(CCCCCC)CCNC(=O)c1ccc(C(=O)NCCC(CCCCCC)CCCCCCCC)nc1

Procedure:
N,N'-bis(3-hexylundecyl)pyridine-2,5-dicarboxamide was prepared using the method of Example 1 from 3-hexylundecylamine and pyridine 2,5-dicarboxylic acid. The product which was a brown oil was not distilled but was analysed as being 92% of theoretical strength (based on MW 642) by titration of an aliquot in acetic acid with perchloric acid. It was made up as a 0.2M solution in AROMASOL H and tested for extraction of copper in the presence of chloride ion using the method of Examples 6 and 7. The results are given in Table 3. They indicated that this compound is a strong extractant for copper which would be best employed in extracting copper from solutions of relatively low chloride ion concentration and relatively low acidity.