Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[NH2:14][CH2:15][CH2:16][CH2:17][NH2:18]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:14][CH2:15][CH2:16][CH2:17][NH2:18]
Reactant: NCCCN
Reactant: Brc1ccccn1
Solvent: c1ccncc1
Product: NCCCNc1ccccn1
Yield: 50.1 %

Procedure:
A mixture of 2-bromopyridine (12.3 mL, 126.7 mmol) and pyridine (13 mL, 161 mmol) in 1,3-diaminopropane (53.5 mL, 640 mmol) was refluxed under nitrogen for 18 hours. The reaction mixture was evaporated under reduced pressure and cooled, and the resulting residue was treated with THF (150 mL) to yield a white precipitate. The precipitate was filtered and washed with additional THF (100 mL). Evaporation of the filtrate afforded an orange oil, which was distilled in vacuo to give N-(2-pyridinyl)-1,3-propanediamine (9.6 g, 50%) as a colorless oil: bp 128-132° C. (2 mmHg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)CCC>C1(C)C=CC=CC=1>[Br:8][C:4]1[CH:3]=[C:2]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Brc1cccc(Br)c1
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccco2)c1
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
1,3-Dibromobenzene (1.0 g) was dissolved in toluene (20 ml), the solution was added with tri-n-butyl-(2-furyl)tin 1.59 g) and tetrakistriphenylphosphine palladium (0.25 g), and the mixture was stirred for 30 minutes under reflux by heating. The reaction mixture was concentrated under reduced pressure, and then the residue was dissolved in hexane. The solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in diethyl ether, the solution was added with cesium fluoride (1.01 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added with a mixed solvent of hexane:ethyl acetate=10:1, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane alone) to obtain the title compound (0.59 g).
Reaction SMILES: Br[CH2:2]/[C:3](/[F:15])=[C:4](/[CH3:14])\[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH:16]1([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:23]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:2]/[C:3](/[F:15])=[C:4](/[CH3:14])\[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:26][CH:25]=2)=[O:31])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C/C(CNC(=O)OC(C)(C)C)=C(\F)CBr
Reactant: O=C(NC1CCCCC1)c1ccc(O)cc1
Product: C/C(CNC(=O)OC(C)(C)C)=C(\F)COc1ccc(C(=O)NC2CCCCC2)cc1

Procedure:
This compound was synthesized from tert-butyl [(2E)-4-bromo-3-fluoro-2-methylbut-2-en-1-yl]carbamate and N-cyclohexyl-4-hydroxybenzamide following procedure F and was obtained as a colorless solid; 1H-NMR (400 MHz, CDCl3): δppm: 1.15-1.27 (3H, m), 1.37-1.48 (2H, m), 1.43 (9H, s), 1.62-1.67 (1H, m), 1.72-1.77 (2H, m), 1.76 (3H, d, J 4.0 Hz), 2.00-2.04 (2H, m), 3.77 (2H, d, J 5.7 Hz), 3.95 (1H, m), 4.61 (1H, br s), 4.75 (2H, d, J 21.4 Hz), 5.85 (1H, br s), 6.95 (2H, d, J 9.0 Hz), 7.72 (2H, d, J 9.0 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].N1C=CC=CC=1>C(O)C>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=[N:26][OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
A mixture of 2,4-dibenzyloxybenzaldehyde (2 g), hydroxylamine hydrochloride (0.45 g) and pyridine (0.53 mL) in ethanol (20 mL) is heated at reflux for 1 hour. The solvent is then removed in vacuo, the residue dissolved in ethyl acetate and the solution washed with 1 N hydrochloric acid then with brine. Removal of the solvent in vacuo gives a beige coloured solid which crystallises from a mixture of ether and petroleum ether to give 2,4-dibenzyloxybenzaldehyde oxime in the form of a white solid, m.p., 130° C. [Elemental analysis:- C,76.1; H,5.75; N,4.28%. Calculated:- C,75.7; H,5.74; N,4.20%].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[NH:19]1[C:27]2[C:22](=[C:23]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C@H:12]1[CH2:17][CH2:16][C@@H:15]([N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]4[C:22]=3[CH:21]=[CH:20][NH:19]4)[CH2:29][CH2:30]2)[CH2:14][CH2:13]1
Reactant: COc1ccc2[nH]cc(C3CCC(=O)CC3)c2c1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc2[nH]cc([C@H]3CC[C@@H](N4CCN(c5cccc6[nH]ccc56)CC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
A solution of 4-(5-methoxy-1H-indol-3-yl)-cyclohexanone (1.2 g, 5 mmol), 1-(indol-4-yl)piperazine (1 g, 5 mmol), sodium triacetoxyborohydride (1.47 g, 6.2 mmol) and acetic acid (0.28 ml, 4 mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×60 ml) and washed with brine (3×60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (2.5% methanol-ethyl acetate) afforded 1.18 g (55%) of product as a white solid: mp 105-108° C.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][C@H:27]([OH:29])[C@@H:26]([OH:30])[C@H:25]([OH:31])[C@H:24]1[CH2:32][OH:33]>CN(C=O)C>[S:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH:27]([OH:29])[CH:26]([OH:30])[C@H:25]([OH:31])[CH:24]2[CH2:32][OH:33])=[O:11])[S:2]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Reactant: OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCC[C@@H]1CCSS1)OCCCN1CC(O)C(O)[C@H](O)C1CO
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-[(3R)-1,2-dithiolan-3-yl]pentanoic acid 6 (500 mg, 2.42 mmol) in DMF (5 mL) was added K2CO3 (1.4 g, 9.69 mmol) at room temperature and the mixture was stirred for 30 min. Then a solution of hydrochloride salt of (2R,3R,4R,5S)-1-(3-chloropropyl)-2-(hydroxymethyl)piperidine-3,4,5-triol 5 (581 mg, 2.1 mmol) in DMF (5 mL) was added to the reaction mixture and the mixture was heated at 60° C. for 16 h. The reaction mixture was then filtered through a celite pad, washed with DCM (100 mL). The filtrate was concentrate under reduced pressure to get crude which was purified by column chromatography using 100-200 mesh silica gel and eluting with 6% methanol in DCM to afford 3-[(3R)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl]propyl 5-[(3R)-1,2-dithiolan-3-yl]pentanoate, compound 7 (300 mg, 30%) as brown oil.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=34)=[N:8][CH:9]=2)[N:4]1[C@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C=O)C>[C:29]([N:25]1[CH2:26][CH2:27][CH2:28][C@H:23]([N:4]2[C:3](=[O:2])[NH:11][C:10]3[C:5]2=[N:6][C:7]([C:12]2[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=24)=[N:8][CH:9]=3)[CH2:24]1)(=[O:31])[CH3:30]
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n([C@H]5CCCNC5)c4n3)c2c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)N1CCC[C@H](n2c(=O)[nH]c3cnc(-c4cnn5ccc(C#N)cc45)nc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
To a solution of the compound obtained in example 6 (31 mg, 0.063 mmol) in anhydrous DMF (3 mL), acetic anhydride (0.007 mL, 0.08 mmol) and anhydrous TEA (0.02 mL, 0,127 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off. It was quenched with saturated NaHCO3 aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were dried over anhydrous Mg2SO4, filtered and concentrated. The crude residue was flash chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 14.5 mg of the desired compound (57% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][O:16][CH3:17])[CH:6]=[CH:7][C:8](O)=O.[NH2:18][C:19]1[C:20](=[O:33])[N:21]([CH2:30][CH2:31][CH3:32])[C:22](=[O:29])[N:23]([CH2:26][CH2:27][CH3:28])[C:24]=1[NH2:25].[OH-].[Na+].Cl>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][O:16][CH3:17])/[CH:6]=[CH:7]/[C:8]1[NH:18][C:19]2[C:20](=[O:33])[N:21]([CH2:30][CH2:31][CH3:32])[C:22](=[O:29])[N:23]([CH2:26][CH2:27][CH3:28])[C:24]=2[N:25]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COCOc1ccc(C=CC(=O)O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OCOC)c(OC)c3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
3-Methoxy-4-methoxymethoxy cinnamic acid (4.63 g, 19.4 mmol) and 3-(3-diethylaminopropyl)-1-ethylcarbodiimido hydrochloride (5.08 g) were added to a mixed solution of 4.00 g (17.7 mmol) of 5,6-diamino-1,3-dipropyluracil [J. Med. Chem., 28, 487 (1985)] in 50 ml of dioxane/25 ml of water. The solution was stirred at room temperature for 1 hour while adjusting to pH 5.5. The reaction mixture was cooled to room temperature, then 1.59 g of sodium hydroxide and 2N sodium hydroxide solution (50 ml) were added thereto. The mixture was heated under reflux for 1 hour, followed by cooling. The mixture was neutralized by adding 2N hydrochloric acid and the resulting precipitate was collected by filtration. The obtained crude product was recrystallized from dioxane/water to give 5.06 g (67% yield) of Compound c as pale yellow crystals.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C=O.[Cl:21][CH2:22]Cl>[Cl-].[Cl-].[Zn+2]>[Cl:21][CH2:22][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:1])([F:17])[F:18])[CH2:6][CH2:7]2)=[CH:12][CH:13]=1
Reactant: ClCCl
Reactant: O=C(N1CCC(c2ccccc2)CC1)C(F)(F)F
Agent: C=O
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C(N1CCC(c2ccc(CCl)cc2)CC1)C(F)(F)F
Temperature: 25 °C

Procedure:
A suspension of the product of step i) (18 g), paraformaldehyde (14 g) and zinc dichloride (14 g) in dichloromethane (700 mL) was stirred at room temperature. Hydrogen chloride gas was bubbled through the reaction for 30 minutes. The reaction was stirred at room temperature under a blanket of nitrogen for a further 18 hours. Water (150 mL) was added and the phases separated. The organic phase was dried using magnesium sulfate and concentrated in vacuo to give a green oil which was purified (SiO2 eluting with 30% i-hexane in dichloromethane) to give the sub-title compound (12 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]=3[C:4]3[C:12]2=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=3)=[CH:26][CH:25]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(=O)CCC3
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2Cc2ccc(F)cc2)CCCC1=O
Reaction time: 0.33 h
Yield: 66.3 %

Procedure:
6-Methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.5457 g, 0.027 mol) is added to a slurry of pentane-washed NaH (0.1369 g, 0.0034 mol) in DMF (3 mL) and after stirring for 20 min, p-fluorobenzyl bromide (0.42 mL, 0.0034 mol) is added, followed by additional DMF (2 mL). After the slurry had stirred for 2.5 h, it is partitioned between water and ethyl acetate. The combined organic layers are washed with water, dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (200 mL) using dichloromethane (100%) to give 0.6929 g (82%) of the title compound. An aliquot is recrystallized from ethyl acetate/heptane; mp 209.5-210° C.; MS (ESI+) for C20H18FNO m/z 308.2 (M+H)+; IR (drift) 2939, 1629, 1510, 1467, 1449, 1413, 1362, 1225, 1219, 1190, 1158, 1107, 1094, 832, 797 cm−1; 1H NMR (CDCl3) δ2.23, 2.47, 2.59, 2.85, 5.27, 6.99, 7.05, 7.12, 8.11. Anal. Calcd for C20H18FNO: C, 78.15; H, 5.90; N, 4.56. Found: C, 77.64; H, 5.87; N, 4.44.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH3:28][C:29]([CH3:37])([CH2:33][N:34]([CH3:36])[CH3:35])[C:30](Cl)=[O:31]>CC(C)=O>[CH3:28][C:29]([CH3:37])([CH2:33][N:34]([CH3:36])[CH3:35])[C:30]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16](=[O:17])(=[O:18])[NH2:19])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1)=[O:31]
Reactant: CN(C)CC(C)(C)C(=O)Cl
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(O)cc2)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(C)CC(C)(C)C(=O)Oc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Reaction time: 72 h

Procedure:
A solution of 5-[(4-hydroxyphenyl)sulfonyl]thiophene-2-sulfonamide (3.19 g. 0.01 mole) in acetone (60 ml) at -10° was treated with triethylamine (1.11 g, 0.011 mole). Then 2,2-dimethyl-3-dimethylaminopropionyl chloride hydrochloride (2.20 g, 0.011 mole) was added portionwise, during 15 minutes at -10°. The cooling bath was removed and stirring was continued. After 72 hours at room temperature, the reaction mixture was heated on a steam bath for 4 hours. The reaction mixture was cooled and treated with triethylamine (1.11 g, 0.011 mole) and heated on a steam bath for 1 hour.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:14][C:15](=[O:20])[O:16][CH:17]([CH3:19])[CH3:18])[CH:7]=[C:8]([CH2:11][O:12][CH3:13])[C:9]=1[OH:10].Cl[CH2:22][C:23]#[N:24]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([NH:14][C:15](=[O:20])[O:16][CH:17]([CH3:18])[CH3:19])[CH:7]=[C:8]([CH2:11][O:12][CH3:13])[C:9]=1[O:10][CH2:22][C:23]#[N:24]
Reactant: N#CCCl
Reactant: COCc1cc(NC(=O)OC(C)C)cc(Cl)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(NC(=O)OC(C)C)cc(Cl)c1OCC#N
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
3-Chloro-4-hydroxy-5-methoxymethylaniline (52.8 g) and N,N-diethylaniline (42.0 g) were dissolved in ethyl acetate (300 ml). To the resultant solution was dropwise added isopropyl chloroformate (34.6 g) in 15 minutes under ice-cooling. After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice-water. The organic layer was washed with dilute aqueous hydrochloric acid and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using tolouene and ethyl acetate as the eluent to give isopropyl N-(3-chloro-4-hydroxy-5-methoxymethylphenyl)carbamate (65.6 g). Sodium hydride (9.60 g, 60% dispersion in mineral oil) was added to dimethylformamide (240 ml). To the resultant mixture was added isopropyl N-(3-chloro-4-hydroxy-5-methoxymethylphenyl)carbamate (65.6 g) under 5° C. The resulting solution was stirred for 30 minutes at a temperature of 20° C. and, to this solution was added chloroacetonitrile (19.0 g) in 5 minutes. The mixture was heated at 90° C. for 10 minutes and poured into ice-water and extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene and ethyl acetate as the eluent to give isopropyl N-(3-chloro-4-cyanomethoxy- 5-methoxymethylphenyl)carbamate (67.5 g) in a yield of 76.8%. M.P., 58.5°-60.5° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][OH:27])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>O1CCCC1>[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][O:27][S:34]([C:31]3[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=3)(=[O:36])=[O:35])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CO)no1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
A suspension of sodium hydride 60% suspension in mineral oil (1.52 g, 38.00 mmol) in anhydrous tetrahydrofuran (30 ml) was cooled to 0° C. and treated with a solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 85) (13.40 g, 38.00 mmol) in anhydrous tetrahydrofuran (120 ml) and stirred under a nitrogen atmosphere for 30 minutes. p-Toluene sulphonyl chloride (7.25 g, 38.00 mmol) was added portionwise and the mixture was allowed to warm to room temperature over 18 hours. The solvent was removed under reduced pressure The residue was dissolved in ethyl acetate and washed with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with dichloromethane to afford the title compound (10.75 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:22](=[O:23])[C:21]4=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]4[C:19]3=[O:28])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>[Pd].O>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:22](=[O:23])[C:21]4=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]4[C:19]3=[O:28])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CN(CCCCN1C(=O)c3ccccc3C1=O)CC2
Reaction time: 144 h
Yield: 103.3 %

Procedure:
A mixture of 5% palladium on carbon paste (3.44 g), 7-nitro-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (19.15 g, 0.05 mol), ethanol (791 ml) and water (69 ml) was hydrogenated at 50 psi and 30° C. for 6 days. The reaction mixture was then filtered through Kieselguhr and evaporated in vacuo to give the title compound as an oil (18.04 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[OH-].[Na+].Cl[C:15]([F:20])([F:19])C([O-])=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH:15]([F:20])[F:19])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(O)cc(Br)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)cc(OC(F)F)c1
Temperature: 55 °C
Yield: 4.2 %

Procedure:
To a solution of 3-bromo-5-nitrophenol (3.1 g, 14.4 mmol) and powdered sodium hydroxide (0.63 g, 15.8 mmol) in DMF (14 mL), sodium chlorodifluoroacetate (4.4 g, 28.7 mmol) was added in five portions every 0.5 hour to the warmed reaction mixture at to 55° C. The reaction was maintained at to 55° C. for 1 day and then allowed to cool to room temperature. The reaction mixture was partitioned between EtOAc and water, the layers separated, and the aqueous portion was extracted (2×25 mL) EtOAc and the combined organic layers were washed with aqueous 1.0 M NaOH solution (3×25 mL), water (3×25 mL) and brine (50 mL). The organic layer was dried (MgSO4), and concentrated. The resulting residue was purified by flash chromatography (SiO2, 0-50% EtOAc in hexanes) to afford 1-bromo-3-(difluoromethoxy)-5-nitrobenzene (160 mg, 0.6 mmol). 1H NMR (400 MHz, CDCl3) δ 6.61 (t, J=71.6 Hz, 1H) 7.65 (s, 1H) 7.96 (s, 1H) 8.21-8.31 (m, 1H).
Reaction SMILES: [P:1](=[O:53])([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])([O:45][CH3:46])[O:2][CH:3]([CH2:22][O:23]C(C1C=CC(OC)=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:4][O:5][CH2:6][CH2:7][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][CH3:21]>CO.C(Cl)(Cl)Cl>[P:1](=[O:53])([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])([O:45][CH3:46])[O:2][CH:3]([CH2:22][OH:23])[CH2:4][O:5][CH2:6][CH2:7][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][CH3:21]
Reactant: CCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1)OP(=O)(OC)OCCCCC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCCCCCCCCCOCC(CO)OP(=O)(OC)OCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 152 %

Procedure:
A solution of 10 g of phosphoric acid, 2-(hexadecyloxy)-1-[[(4-methoxyphenyl)-diphenylmethoxy]methyl]ethyl methyl pentyl ester in 100 ml of methyl alcohol and 50 ml of chloroform is brought to a boil, the heat removed and 5 g of Amberlite®-15 resin carefully added. The reaction is stirred at ambient temperature for 2 hours, filtered to remove the resin and the cake washed well with 2:1 methyl alcohol:chloroform. The solvent is removed to give 9.7 g of a thick syrup. The product is chromatographed using dry column silica gel with 1:1 ethyl acetate:hexanes. Product fractions are combined and the solvents evaporated to give 1.38 g of a less polar isomer oily product and 1.46 g of a more polar isomer oily product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2cccc(Cl)c2)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(3-chlorophenyl)-boronic acid (CAN 63503-60-6) as starting materials; LC-MS (UV peak area/ESI) 100%, 408.0719 (M+H)+.