Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:6]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([Cl:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[ClH:37].[ClH:1].[CH3:3][O:4][C:5]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:6]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[CH2:10][CH2:9]1
Reactant: COc1ccc(CN2CCNCC2)c(OC)c1OC
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: COc1ccc(CN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1OC
Yield: 22.1 %

Procedure:
2.4 g (7.1 millimoles) of 2,3,4-trimethoxybenzylpiperazine dihydrochloride, 1.8 g (7.5 millimoles) of bis(4-fluorophenyl)methyl chloride [see J. Chem. Soc. Perkin II, 1051 (1977)] and 5.0 ml (36 millimoles) of triethylamine were heated under reflux for 9 hours in 80 ml of xylene. The reaction mixture was allowed to cool to room temprature, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. A mixture of 2 ml of conc. hydrochloric acid and 20 ml of ethanol was added to the resulting oily product, and the mixture was concentrated under reduced pressure. Ether was added, and the precipitated crystals were collected by filtration. Recrystallization of the crystals from ethanol-ether gave 0.85 g of 1-(2,3,4-trimethoxybenzyl)-4-[bis(4-fluorophenyl)methyl]piperazine dihydrochloride. The product showed the same property values as the compound obtained in Example 4.
Reaction SMILES: C(O)C.[C:4]([C:7]1[C:8]([OH:18])=[CH:9][C:10]([CH3:17])=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:12]=1)(=O)[CH3:5].[Cl-].[OH:20][NH3+:21].C([O-])(=O)C.[Na+]>O>[OH:18][C:8]1[C:7]([C:4](=[N:21][OH:20])[CH3:5])=[CH:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[C:10]([CH3:17])[CH:9]=1
Reactant: CC(=O)Nc1cc(C(C)=O)c(O)cc1C
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1cc(C(C)=NO)c(O)cc1C
Yield: 86 %

Procedure:
To an ethanol (560 ml)-water (180 ml) mixed solvent were added the compound (35.46 g, 171.1 mmol) obtained in step B, hydroxylammonium chloride (19.41 g, 279.3 mmol) and sodium acetate (22.83 g, 278.3 mmol), and the mixture was heated under reflux for 70 min. The reaction mixture was cooled, water (500 ml) was added, and the solution was concentrated under reduced pressure (about 300 ml) to allow precipitation of a solid. Water (500 ml) was added hereto again, and the precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (32.7 g, yield 86%) as a colorless solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: COC(=O)CCc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)CCc1ccc(C(=O)c2ccc(O)cc2)cc1
Temperature: 0 °C
Yield: 95.5 %

Procedure:
A mixture of methyl 3-(4-{[4-(methyloxy)phenyl]carbonyl}phenyl)propanoate (167) (0.45 g, 1.51 mmol) and AlCl3 (0.82 g, 6.03 mmol) were refluxed in benzene (20 mL) for 1 h and then cooled to 0° C. in an ice bath. Water (15 mL) was added slowly, and the mixture was extracted with ether (2×50 mL). The combined ethereal extract was washed with water, brine, and dried over Na2SO4. Concentration gave light brown oil, which was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 45% EtOAc:hexanes to afford 0.41 g (96%) of the title compound 168 as colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.68 (t, J=7.7 Hz, 2H), 3.03 (t, J=7.7 Hz, 2H), 3.68 (s, 3H), 5.44 (s, 1H), 6.89 (d, J=8.7 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 7.69 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H). LCMS (ESI): m/z 285 (M+H)+, m/z 283 (M−H)−.
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].CO[C:11](=[O:40])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:22][O:23][C:24]=2[C:25](C)(C)[O:26][SiH2]C(C)(C)C)=[N:14][CH:13]=1.C(OCC)(=O)C>CCCCCC.O1CCOCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[OH:26][CH2:25][C:24]1[O:23][N:22]=[C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:20]=1[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:8][CH:5]([CH3:7])[CH3:6])=[O:40])=[CH:13][N:14]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(C)(C)O[SiH2]C(C)(C)C)nc1
Reactant: CC(C)N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Al](C)C
Agent: [F-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccccc3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
Trimethylaluminum (4.4 mL of a 2M solution in hexane, 8.8 mmol) was slowly added to a solution of isopropylamine (0.76 mL, 8.9 mmol) in dioxane (7.5 mL) and stirred at room temperature for 1 h. Then a solution of 6-[5-(tert-butyl-dimethyl-silanyloxymethyl)-3-phenyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.0 g, 2.2 mmol) in dioxane (7.5 mL) was added dropwise. The mixture was stirred at 90° C. for 2 h. After cooling to room temperature and extractive workup (ethyl acetate/aqueous saturated Seignette salt solution) the organic phase was dried (Na2SO4) and filtered over a silica pad. The solvent was evaporated to furnish an intermediate which was dissolved in a tetrabutylammonium fluoride solution (2 mL of a 1M in THF). After 1 h the reaction mixture was extractively worked up (ethyl acetate/aqueous saturated citric acid). The organic phase was dried over sodium sulfate, filtred and concentrated and then purified by HPLC (Chiralpak AD, heptane/ethanol) to afford the title compound as a colorless oil (0.15 g, 18%). MS: m/e=368.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH:11]1(Br)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[CH:11]1([O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[OH:1])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: BrC1CCCC1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC2CCCC2)c(O)c1
Temperature: 77.5 °C
Reaction time: 1 h

Procedure:
A suspension of 3,4-dihydroxy benzaldehyde (50.0 g, 0.3623 mol), cyclopentyl bromide (135 g, 0.9058 mol) and potassium carbonate (50.0 g, 0.3623 mol) in N,N-dimethylformamide (500 mL) was stirred at about 75-80° C. for about 1.0 hr. 4×12.5 g potassium carbonate was then added after every 1.0 hr. The reaction mixture was cooled to ambient temperature and filtered to remove inorganic materials. The residue obtained after concentration of the filtrate was diluted with toluene (250 mL), and extracted with 5-10% aqueous sodium hydroxide solution (6×50 mL). The combined aqueous layer was acidified to pH about 3 to 5 by 5N aqueous hydrochloric acid solution. The solid which separated was filtered, washed with water and dried to give 4-cyclopentyloxy-3-hydroxy benzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:33]([NH:35][C:36]2[CH:37]=[C:38]([S:54]([OH:57])(=[O:56])=[O:55])[CH:39]=[C:40]3[C:45]=2[C:44]([S:46]([OH:49])(=[O:48])=[O:47])=[CH:43][C:42]([S:50]([OH:53])(=[O:52])=[O:51])=[CH:41]3)=[O:34])[CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([S:29]([OH:32])(=[O:31])=[O:30])[CH:14]=[C:15]3[C:20]=2[C:19]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:18][C:17]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:16]3)=[O:9])[CH:7]=1.[F:58][S:59]([C:62]1[CH:63]=[C:64]([N:68]=[C:69]=[O:70])[CH:65]=[CH:66][CH:67]=1)(=[O:61])=[O:60]>O>[F:58][S:59]([C:62]1[CH:63]=[C:64]([NH:68][C:69](=[O:70])[NH:1][C:2]2[CH:3]=[C:4]([C:33]([NH:35][C:36]3[CH:37]=[C:38]([S:54]([OH:57])(=[O:56])=[O:55])[CH:39]=[C:40]4[C:45]=3[C:44]([S:46]([OH:49])(=[O:47])=[O:48])=[CH:43][C:42]([S:50]([OH:53])(=[O:52])=[O:51])=[CH:41]4)=[O:34])[CH:5]=[C:6]([C:8]([NH:10][C:11]3[CH:12]=[C:13]([S:29]([OH:32])(=[O:30])=[O:31])[CH:14]=[C:15]4[C:20]=3[C:19]([S:21]([OH:24])(=[O:22])=[O:23])=[CH:18][C:17]([S:25]([OH:28])(=[O:26])=[O:27])=[CH:16]4)=[O:9])[CH:7]=2)[CH:65]=[CH:66][CH:67]=1)(=[O:61])=[O:60]
Reactant: O=C=Nc1cccc(S(=O)(=O)F)c1
Reactant: Nc1cc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)cc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c1
Solvent: O
Product: O=C(Nc1cc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)cc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c1)Nc1cccc(S(=O)(=O)F)c1
Temperature: 95 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 3.0 g of 8,8'-[(5-amino-m-phenylene)bis(carbonylimino)]di-1,3,6-naphthalenetrisulfonic acid, hexasodium salt in 45 ml of water is added 3.0 g of m-fluorosulfonylphenylisocyanate. Stirring is continued for 6 hours at room temperature, the resulting mixture is heated to about 95° C and is filtered through diatomaceous earth. The filter pad is washed with 40 ml of hot water and the filtrate is diluted with 500 ml of anhydrous ethanol while heating in a steam bath. The solution is filtered after standing at room temperature for 72 hours and the precipitate is washed with absolute ethanol followed by ether to give 8,8'-{{5-{3-[m-(fluorosulfonyl)phenyl]ureido}-1,3-phenylene}bis(carbonylimino)}di-1,3,6-naphthalenetrisulfonic acid, hexasodium salt.
Reaction SMILES: [CH3:1][C@:2]([C:11]([NH:13][CH2:14][C:15]([O:17]CC)=O)=[O:12])([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:3]>C(O)(CC)C.C1(C)C=CC=CC=1>[CH2:4]([C@@:2]1([CH3:1])[NH:3][C:15](=[O:17])[CH2:14][NH:13][C:11]1=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)CNC(=O)[C@](C)(N)Cc1ccccc1
Solvent: CCC(C)O
Solvent: Cc1ccccc1
Product: C[C@]1(Cc2ccccc2)NC(=O)CNC1=O
Reaction time: 21 h
Yield: 97.4 %

Procedure:
A solution of (α-methyl-(R)-phenylalanyl)glycine, ethyl ester (0.63 g, 2.4 mmol) in sec-butanol (14 ml) and toluene (7 ml) was stirred at reflux. After 21 h, the solvent was removed in vacuo and the residue azeotroped with toluene (3×) to afford the product (0.51 g, 100% yield) as a white solid. MS (ESI) 219 (M+H). This was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[O:20][C:19]3[CH:18]=[C:17]([OH:21])[CH:16]=[C:15]([OH:22])[C:14]=3[C:12](=[O:13])[CH:11]=2)=[CH:7][C:8]=1[OH:9].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C)C=O.CN(P(N(C)C)(N(C)C)=O)C>[CH2:25]([C:16]1[C:17]([O:21][CH2:12][CH:11]=[CH2:10])=[CH:18][C:19]2[O:20][C:10]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH2:4][CH:3]=[CH2:8])[CH:7]=3)=[CH:11][C:12](=[O:13])[C:14]=2[C:15]=1[O:22][CH2:7][CH:6]=[CH2:5])[CH:26]=[CH2:27]
Reactant: C=CCBr
Reactant: COc1ccc(-c2cc(=O)c3c(O)cc(O)cc3o2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: C=CCOc1cc(-c2cc(=O)c3c(OCC=C)c(CC=C)c(OCC=C)cc3o2)ccc1OC
Temperature: 40 °C

Procedure:
12 g of diosmetin in 100 ml of dimethylformamide and 15 ml of HMPA are added very slowly to a suspension of 4.8 g of sodium hydride in 30 ml of dimethylformamide. The mixture is then stirred at 40° C. until the evolution of gas has ceased. 17.25 g of allyl bromide are then added dropwise and the whole is heated at 60° C. for 16 hours, after which the solvents are removed by distillation under reduced pressure. The residue is taken up in dichloromethane and then chromatographed on silica using a 98% dichloromethane/2% methanol mixture as eluant. In that manner a fraction of 7.6 g of compound very fluorescent under 366 nm is recovered. An analytical sample of the title compound is prepared by recrystallisation from isopropanol, m.p.: 107° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([O:13][CH3:14])=[CH:6][C:5]=1[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1>C1COCC1.CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:3][C:4]1[C:5]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:22][CH2:23][N:24]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:25][CH2:26]3)[CH2:17][CH2:16]2)=[CH:6][C:7]([O:13][CH3:14])=[C:8]([CH:9]=1)[NH2:10]
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(C)cc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(C)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
Sodium borohydride (0.30 g, 7.93 mmol) was added in portions to a stirring suspension of 1-{1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (1.09 g, 2.64 mmol) and Nickel(II)chloride hexahydrate (0.19 g, 0.8 mmol) in THF (10 mL) and MeOH (20 mL) at rt. The reaction mixture was allowed to stir at rt for 2 h and then it was concentrated in vacuo. The residue was taken up in DCM and passed through a bed of celite. The resultant filtrate was then concentrated onto silica gel and purified by flash chromatography to afford 5-methyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (0.58 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.55 (s, 1H), 6.43 (s, 1H), 4.30 (s, 2H), 3.70 (s, 3H), 3.05-3.15 (m, 4H), 2.89-2.96 (m, 2H), 2.86 (s, 3H), 2.52-2.65 (m, 6H), 2.26-2.41 (m, 1H), 2.06 (s, 3H), 1.74-1.85 (m, 2H), 1.43-1.63 (m, 2H).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.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>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: OB(O)c1ccccc1
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: CCO
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3)[nH]c2c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 49 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (from Step 3) in DME and EtOH (0.2 M, 3:1, v/v) was added phenyl-boronic acid (1.2 eq.) followed by 2 M aqueous Na2CO3 (8.5 eq,). The mixture was degassed with ultrasound for 30 min, then Pd(PPh3)4 (0.1 eq.) was added and mixture degassed with ultrasound for a further 30 min. The reaction was stirred under nitrogen at 90° C. for 6 h and then cooled to RT. Water was added and the solids filtered off. They were washed with Et2O to give the title compound (49%). The combined mother liquors together with the reaction solvents were washed with water (150 ml) and after phase-cut the organic phase was dried over Na2SO4 and evaporated to dryness. The residual solid was crystallized from boiling CHCl3 to give more title compound (38%, 87% total yield). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.21-1.48 (m, 3H), 1.65-1.80 (m, 5H), 1.90-2.05 (m, 2H), 2.79-2.95 (m, 1H), 3.88 (s, 3H), 7.2-7.34 (m, 1H), 7.40-7.50 (m, 1H), 7.51-7.60 (m, 3H), 7.60 (d, J 7.6, 1H), 7.84 (d, J 7.6, 1H), 8.00 (s, 1H); MS (ES+) m/z 334 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:35])([C:24]2[CH:29]=[CH:28][C:27]([CH2:30]OC(=O)C)=[CH:26][CH:25]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:9])[CH2:3]1>CO.[OH-].[Pd+2].[OH-].[C].[H][H]>[F:36][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:35])([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:8]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[O:9])[CH2:3]1
Reactant: CC(=O)OCc1ccc([C@@](O)(C(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)[C@@H]2CCC(F)(F)C2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc([C@@](O)(C(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)[C@@H]2CCC(F)(F)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a solution of 42 mg of t-butyl 4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-((acetyloxy)methyl)phenyl)-ethanoyloxy)tetrahydropyridine-1(2H)-carboxylate in 1 ml of methanol, 20 mg of palladium hydroxide-carbon catalyst was added, followed by 16 hours' stirring at ambient temperature and pressure in hydrogen atmosphere. The reaction liquid was filtered with Celite and the solvent was distilled off under reduced pressure to provide 37 mg of the title compound.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[N:17]=[CH:16][C:15]2[NH:18]/[C:19](=[N:32]\[C:33](=[O:41])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)/[N:20]([C@@H:21]3[CH2:26][CH2:25][C@H:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]3)[C:14]=2[CH:13]=1)C1C=CC=CC=1.Cl>CCO.[Pd]>[F:40][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=1)[C:33](/[N:32]=[C:19]1/[N:20]([C@@H:21]2[CH2:22][CH2:23][C@H:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:26]2)[C:14]2[CH:13]=[C:12]([O:11][CH2:10][CH2:9][OH:8])[N:17]=[CH:16][C:15]=2[NH:18]/1)=[O:41]
Reactant: CCOC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3cccc(F)c3)[nH]c3cnc(OCCOCc4ccccc4)cc32)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3cccc(F)c3)[nH]c3cnc(OCCO)cc32)CC1
Reaction time: 24 h
Yield: 100.1 %

Procedure:
A round bottom flask under nitrogen was charged with cis-ethyl 4-((E)-6-(2-(benzyloxy)ethoxy)-2-(3-fluorobenzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate (2.5 g, 4.46 mmol), 10% Pd/C (0.712 g, 0.669 mmol), EtOH (8.92 mL), and concentrated HCl (0.372 mL, 4.46 mmol). The reaction mixture was stirred under an atmosphere of hydrogen for 24 hours. The mixture was diluted with EtOH (50 mL) and filtered through Celite® brand filter aid. The cake was washed with DCM (50 mL), EtOH (50 mL), and MeOH (50 mL), and the filtrate was concentrated to dryness. The residue was dissolved in 2% MeOH/DCM (100 mL) and washed with aqueous NaHCO3 (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford cis-ethyl 4-((E)-2-(3-fluorobenzoylimino)-6-(2-hydroxyethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate as a tan solid (2.1 g, 100% yield). MS m/z=471.2 [M+H]. Calc'd for C24H27FN4O5: 470.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11]=O)=[CH:7][N:6]=1)=[O:4].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(C=O)cn1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cnc(CN2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
A mixture of 5-formyl-pyrazine-2-carboxylic acid methyl ester (0.400 g, 2.40 mmol), piperidine (0.204 g, 2.40 mmol), and NaB(OAc)3H (1.40 g, 3.60 mmol) in DCM (10 mL) was stirred for 18 h at rt. The reaction was quenched by the addition of 10% aq. NaOH (10 mL) and the mixture was stirred for 30 min. The mixture was extracted with DCM (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to yield the title compound (0.130 g, 23%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][C:20]=1[O:29]CC1C=CC=CC=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:37])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][C:20]=1[OH:29])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1O
Yield: 87.3 %

Procedure:
3-(4-Acetylamino-2-benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (0.99 g, 1.8 mmol) was dissolved in 50 mL methanol and 20% Pd/C (0.09 g) is added. The reaction was placed under 50 psi of hydrogen for approximately 1 hour. The reaction was filtered and concentrated in vacuo. The crude product was chromatographed with 2:1 ethyl acetate/hexane to yield 3-(4-acetylamino-2-hydroxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester 0.7 g (85%) of an brown solid. MS (APCI) m/z 444.2 (M−1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[F-].[K+]>C1COCC1>[C:2]1([C:16]2[C:17]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Brc1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(-c2cccc3ccccc23)cc1
Yield: 99.8 %

Procedure:
Bromobenzene (82 mg, 0.52 mmol) reacted with 1-naphtylboronic acid (110 mg, 0.64 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (90 mg, 1.55 mmol) in THF (2 ml) at room temperature to give the title compound (106 mg, 99%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 7.99-7.91 (m, 3H), 7.60-7.47 (m, 9H). 13C{1H}-NMR (100 MHz, CDCl3): δ 140.71, 140.21, 133.75, 131.57, 130.05, 128.23, 127.60, 127.21, 126.90, 125.99, 125.74, 125.36. GC/MS(EI): m/z 204 (M+). Anal. Calcd for C16H12: C, 94.08; H, 5.92. Found: C, 93.96; H, 6.11.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=O.[O:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][C:15]=2[NH2:24])[CH2:8][CH2:7]1>ClCCl>[Cl:1][CH2:2][C:3]1[N:13]([CH2:12][CH:9]2[CH2:8][CH2:7][O:6][CH2:11][CH2:10]2)[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cnc2ccccc2c1NCC1CCOCC1
Solvent: ClCCl
Product: ClCc1nc2cnc3ccccc3c2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.5 %

Procedure:
Chloroacetyl chloride (12 mL, 151 mmol) was dissolved in dichloromethane (30 mL) and added via addition funnel, over 20 minutes, to a stirring solution of N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (35.3 g, 137 mmol) in dichloromethane (300 mL). The resulting solution was stirred at ambient temperature under nitrogen for 24 hours at which point the solution was heated to 40° C. for an additional 24 hours. The mixture was cooled to ambient temperature, diluted with dichloromethane (150 mL) and transferred to a separatory funnel. The organic layer was washed with water (2×200 mL) and brine (2×200 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide 38.3 g of 2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline as a light brown solid.