Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N2CC[O:10]CC2)CCCCC=1.C(N(CC)CC)C.[ClH:20].[C:21]1([CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:27]([Cl:20])(=[O:10])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccccc1
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: Cl
Solvent: CCN(CC)CC
Product: O=C(Cl)c1ccccc1
Yield: 35 %

Procedure:
Compound IV′c is obtained in 35% yield as a yellow powder, according to Example 4, from morpholino-enamine III′ (36.89 g, 0.17 mol, obtained in Example 2), triethylamine (24.25 g, 0.24 mol), benzoyl chloride (33.73 g, 0.24 mol), toluene (260 mL) and 20% aqueous HCl (85 mL).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[CH3:28][S:29]([NH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH2:7]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2cccc(N)c2)C1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2cccc(NS(C)(=O)=O)c2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl [(3R)-1-(3-aminobenzyl)-3-pyrrolidinyl]carbamate (659 mg) in CH2Cl2 (6.6 mL) was added pyridine (274 uL) and methanesulfonyl chloride (193 uL), which was stirred at room temperature for 20 hours. To the resultant was added H2O. The mixture was extracted with 1-butanol. The organic phase was washed brine, dried Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl [(3R)-1-{3-[(methylsulfonyl)amino]benzyl}-3-pyrrolidinyl]carbamate (845 mg) as pale yellow amorphous.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:6][NH:5][N:4]=1)[CH3:2].[H-].[Na+].[CH2:23]([S:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)C>CN(C=O)C>[CH2:1]([C:3]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:5]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([S:25][CH3:23])=[CH:27][CH:28]=2)[N:4]=1)[CH3:2]
Reactant: CCc1n[nH]cc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCSc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccc(SC)cc2)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 3-ethyl-4-(N-t-butoxycarbonylpiperid-4-yl)-1H-pyrazole (0.83 g, 2.97 mmol, from Step B) in 4 mL DMF was cooled to 0° C. and sodium hydride (155 mg, 3.87 mmol, 60% dispersion in mineral oil) was added cautiously. The mixture was warmed to rt and 4-(ethylthio)benzyl chloride (crude material from Step C) in 6 mL DMF was added. The mixture was stirred for 14 h. The mixture was concentrated and the residue was taken up in methylene chloride. The solution was washed with water and sat'd sodium chloride then dried over magnesium sulfate and concentrated. Flash chromatography (40 g silica, 4/1 hexane/EtOAc) afforded the product.
Reaction SMILES: [CH2:1]([N:5]([C:20]1[CH:29]=[CH:28][C:27]2[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=2[CH:21]=1)[C:6](=[O:19])[NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Li+]>CO.C1COCC1.O>[CH2:1]([N:5]([C:20]1[CH:29]=[CH:28][C:27]2[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:32])([CH3:33])[C:22]=2[CH:21]=1)[C:6](=[O:19])[NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C(=O)Nc1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCN(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
A solution of ethyl 4-[3-butyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (11) (131 mg, 0.29 mmole) in 15 mL methanol, 5 mL of THF and 5 mL of water was treated with 62 mg of lithium hydroxide (5 eq.) and stirred at room temperature for eight hours. The mixture was concentrated in vacuo and the residue was acidified with concentrated HCl solution. The mixture was then extracted with three portions of 20 mL of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid which was purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes+drops of acetic acid) to provide 34 mg (28%) of 4-[3-butyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoic acid (5) as a pale yellow solid. MS (EI): (M++1) 423.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[C:15]([OH:21])(=[O:20])[CH2:16]C(O)=O.C([O-])(=O)C.[NH4+:26]>CCO>[NH2:26][CH:6]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=1)[CH2:16][C:15]([OH:21])=[O:20]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: [NH4+]
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: CCO
Product: COc1cc(C(N)CC(=O)O)cc(OC)c1OC
Temperature: 25 °C

Procedure:
3,4,5-Trimethoxy benzaldehyde (10 mmol, 1 eq), malonic acid (1 eq) and ammonium acetate (1.3 eq) are suspended in EtOH and refluxed for 16 h (Tetrahedron, 58 (2002) 7449-7461). Upon cooling to room temperature a white precipitate is formed. The mixture is concentrated in vacuo and the white solid is partitioned between EtOAc and dilute aqueous HCl (pH 2). The aqueous phase is concentrated in vacuo. 3-Amino-3-(3,4,5-trimethoxy-phenyl)propionic acid (crude product) is obtained as a white solid (51% yield); ES-MS (MH+)=239.0 (M-NH2).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH:4]=[C:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.[NH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[SH:26][CH2:27][C:28](O)=[O:29].Cl>C(OCC)(=O)C.O1CCOCC1>[CH3:1][CH:2]([CH3:12])[CH2:3][CH:4]=[C:5]1[CH2:10][CH2:9][C:8]2([S:26][CH2:27][C:28](=[O:29])[N:13]2[CH2:14][CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:7][CH2:6]1
Reactant: CC(C)CC=C1CCC(=O)CC1
Reactant: O=C(O)CS
Reactant: NCCC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)CC=C1CCC2(CC1)SCC(=O)N2CCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
In an atmosphere of nitrogen, 3.32 g of 4-(3-methylbutylidene)-1-cyclohexanone and 5.35 g of benzyl 3-aminopropionate were added to 35 ml of dioxane and stirred at ambient temperature for 30 minutes, after which 2.25 g of mercaptoacetic acid was added and the resulting mixture was stirred under reflux for 3 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography (eluent: hexane:ethyl acetate=6:1) gave 4.36 g of benzyl 3-[8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionate as a light yellow oily product.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[C:34](O)(=[O:37])[CH2:35][OH:36]>>[OH:37][CH2:34][C:35]([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)=[O:36]
Reactant: O=C(O)CO
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)CO)C3)ccc1-2
Yield: 27 %

Procedure:
Following the procedure for 318, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 31 and glycolic acid were reacted. Purification by reverse phase preparative HPLC (Gemini C18 column, gradient 5-98% MeOH in H2O+0.1% HCO2H) gave 397 as a white solid (46 mg, 27%). LCMS: RT=10.33 min, [M+H]+=426. 1H NMR δ (ppm) (DMSO-d6): 8.30 (1 H, d, J=8.20 Hz), 8.05 (1 H, s), 7.20-7.15 (1 H, m), 7.01 (1 H, d, J=1.82 Hz), 5.82-5.72 (1 H, m), 4.88-4.81 (1 H, m), 4.55-4.46 (1 H, m), 4.34-4.29 (2 H, m), 4.30-4.17 (1 H, m), 4.16 (1 H, dd, J=9.24, 5.41 Hz), 3.90 (2 H, d, J=5.77 Hz), 3.89-3.77 (2 H, m), 3.41-3.35 (2 H, m), 1.49 (6 H, d, J=6.59 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cc(F)c(F)cc3F)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2,4,5-trifluorobenzoyl chloride (29 μL, 0.229 mmol) and mixing for 24 h, 46.2 mg (>100%) of the title compound were recovered.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@H:11]1[NH:16][C:15]([CH3:18])([CH3:17])[CH2:14][C:13](=[O:19])[CH2:12]1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O>[Si:1]([O:8][C@H:9]([C@H:11]1[NH:16][C:15]([CH3:18])([CH3:17])[CH2:14][CH:13]([OH:19])[CH2:12]1)[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CC(=O)CC(C)(C)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CC(O)CC(C)(C)N1
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a solution of (S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-one (42 mg, 0.15 mmol) in MeOH (3 mL) was added NaBH4 (5.6 mg, 0.15 mmol) at 0° C. After the mixture was stirred for 1 h, the mixture was diluted with water (5 mL) and extracted with EtOAc (20 mL). The extract was washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by column chromatography (EtOAc/Heptane) gave 32 mg (76%) of (6S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-ol (a 5:1 mixture of diastereomers): 1H NMR (400 MHz, CHLOROFORM-d) δ 4.17-4.27 (m, 1H), 3.71-3.78 (m, 1H), 2.92-3.02 (m, 1H), 1.56-1.67 (m, 2H), 1.30-1.37 (m, 2H), 1.25 (s, 3H), 1.07 (d, J=6.1 Hz, 3H), 1.02 (s, 3H), 0.83 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:53])[CH2:11][CH2:12][NH:13][CH2:14][C@:15]12[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:16]1[C@@H:17]1[C@@:30]([CH3:33])([CH2:31][CH2:32]2)[C@@:29]2([CH3:34])[C@@H:20]([C@:21]3([CH3:46])[C@@H:26]([CH2:27][CH2:28]2)[C:25]([CH3:36])([CH3:35])[C:24]([C:37]2[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=2)=[CH:23][CH2:22]3)[CH2:19][CH2:18]1)=[O:4].[OH-].[Na+].O.Cl>O1CCOCC1.CO>[C:41]([C:40]1[CH:44]=[CH:45][C:37]([C:24]2[C:25]([CH3:36])([CH3:35])[C@H:26]3[C@:21]([CH3:46])([CH2:22][CH:23]=2)[C@@H:20]2[C@:29]([CH3:34])([C@@:30]4([CH3:33])[C@H:17]([CH2:18][CH2:19]2)[C@H:16]2[C@H:47]([C:50]([CH3:52])=[CH2:51])[CH2:48][CH2:49][C@:15]2([CH2:14][NH:13][CH2:12][CH2:11][C:10]([N:6]2[CH2:7][CH2:8][CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])=[O:53])[CH2:32][CH2:31]4)[CH2:28][CH2:27]3)=[CH:38][CH:39]=1)([OH:43])=[O:42]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCC(=O)N3CCC[C@H]3C(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(CNCCC(=O)N3CCC[C@H]3C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 45 h
Yield: 85.2 %

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-((S)-2-(methoxycarbonyl)pyrrolidin-1-yl)-3-oxopropylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (10 mg, 0.014 mmol) in dioxane (1 ml) and methanol (2 ml) was added 1N sodium hydroxide (0.08 ml, 0.08 mmol) and H2O (0.5 ml). The resulting mixture was stirred at rt for 45 h. The reaction mixture was neutralized with 1N HCl and concentrated in vacuo. The residue was purified by prep. HPLC to afford the title compound (8.5 mg, 85%). MS: m/e 713.5 (MH+), 1.68 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.95 (s, 3H) 0.97 (s, 3H) 1.04 (s, 3H) 1.08 (s, 3H) 1.18 (s, 3H) 1.73 (s, 3H) 0.87-1.86 (m, 20H) 1.99-2.10 (m, 4H) 2.15 (dd, J=17.32, 6.53 Hz, 1H) 2.24-2.33 (m, 1H) 2.52 (td, J=9.60, 4.14 Hz, 1H) 2.83-2.92 (m, 3H) 3.24-3.28 (m, 1H) 3.38 (t, J=6.15 Hz, 2H) 3.52-3.68 (m, 2H) 4.48 (dd, J=8.41, 3.39 Hz, 1H) 4.64 (s, 1H) 4.76 (d, J=1.76 Hz, 1H) 5.30 (dd, J=6.15, 1.63 Hz, 1H) 7.21 (d, J=8.53 Hz, 2H) 7.91 (d, J=8.28 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:27]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)c1

Procedure:
Example 31 was prepared from 1-(4-chloro phenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.45–7.42 (m, 1H), 7.33–7.24 (m, 7H), 6.94 (d, 1H, J=7.1 Hz), 6.58–6.52 (m, 1H), 3.26 (q, 2H, J=6.1 Hz), 2.90 (d, 2H, J=10.8 Hz), 2.56–2.40 (m, 4H), 2.29 (t, 2H, J=6.3 Hz), 2.03–1.87 (m, 6H), 1.83–1.76 (m, 4H), 1.60 (dd, 4H, J=6.8, 4.6 Hz), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 510.4 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:6][O:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:3][C:4]#[N:5].[ClH:18].[H][H]>CO.[Pd]>[ClH:18].[OH:1][CH:2]([CH2:6][O:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:10])=[O:9])[CH2:3][CH2:4][NH2:5]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CC#N)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC(O)CCN)cc1

Procedure:
To a solution of (RS)-3-hydroxy-4-(p-toluenesulfonyloxy)butyronitrile (17.0 g) in methanol (120 ml), 10 wt. % Pd on carbon (3.0 g) and conc. hydrochloric acid (30 ml) were added. The mixture was stirred in a hydrogen atmosphere of 4.0 kg/cm2 at room temperature for 20 hours. After filtrating off the catalyst, the mixture was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (Wako Gel C200, an eluent: methanol/acetone (volume ratio of 3/7) to obtain pure (RS)-3-hydroxy-4-(p-toluenesulfonyloxy)butylamine hydrochloride (18.1 g). Yield, 92 %.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[C:12]([O:16][C:17](=[O:37])[NH:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:24]=[C:23]1[CH2:35][Cl:36])([CH3:15])([CH3:14])[CH3:13].[OH-].[NH4+:39].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[C:12]([O:16][C:17](=[O:37])[NH:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[C:26]([NH2:39])[C:25]=2[N:24]=[C:23]1[CH2:35][Cl:36])([CH3:15])([CH3:13])[CH3:14]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloroperoxybenzoic acid (13.3 g of 77% max, 59.4 eq.) was added in portions over a period of 5 minutes to a solution of tert-butyl[3-(2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate (8.9 g, 23.7 mmol) in chloroform (200 mL). The reaction mixture was allowed to stir at ambient temperature overnight. Ammonium hydroxide (50 mL) was added and the reaction mixture was stirred vigorously. Para-toluensulfonyl chloride (5.43 g, 28.5 mmol) was added over a period of 5 minutes. The reaction mixture was stirred at ambient temperature for 2 hours; an additional 1 g of para-toluensulfonyl chloride was added and the reaction mixture was stirred for another hour. The reaction mixture was filtered to remove solids. The filtrate was transferred to a separatory funnel and the layers were separated. The organic layer was washed with 1:1 water:saturated aqueous sodium bicarbonate (2×150 mL). The combined aqueous was extracted with dichloromethane (2×150 mL) and ethyl acetate (1×100 mL). The combined organic extracts were concentrated under reduced pressure to provide 13.6 g of crude product as a brown foam. The foam was dissolved in dichloromethane (20 mL). The solution was divided and loaded onto two FLASH 40+M silica cartridges (90 g). The first cartridge was eluted sequentially with 1 L 1:1 ethyl acetate:hexanes, 5% methanol in 1:1 ethyl acetate:hexanes, and 10% methanol in 1:1 ethyl acetate:hexanes. The second cartridge was eluted sequentially with 1 L 1:1 ethyl acetate:hexanes, 7% methanol in 1:1 ethyl acetate:hexanes, and 7% methanol in 1:1 ethyl acetate:hexanes. The fractions containing product were combined and then concentrated under reduced pressure to provide 4.3 g of tert-butyl[3-(4-amino-2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate as a light yellow foam.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)=[O:11].C(=O)(O)[O-].[Na+]>COCCO.O.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>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:15]1[CH:16]=[CH:17][C:12]([CH:10]=[O:11])=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: OCc1ccccc1Br
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: COCCO
Solvent: O
Product: O=Cc1ccc(-c2ccccc2CO)cc1
Yield: 69.7 %

Procedure:
i)—To a solution of 2-bromo-benzylalcohol (5 g, 26.7 mmol) in 2-methoxyethanol/water (30 ml, 1/1) were added 4-formylphenylboronic acid (6 g, 40.0 mmol) and sodium bicarbonate (4.4 g, 52.4 mmol) under a nitrogen atmosphere. After (Ph3P)4Pd (1.54 g, 1.34 mmol) was added, the reaction mixture was heated under reflux for 17 h. After cooling, the mixture was filtered over dicalite and the residue was washed with water and ethyl acetate. The product was extracted into ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate concentrated under reduced pressure. Column chromatography afforded 2′-hydroxymethyl-biphenyl-4-carbaldehyde (3.95 g).
Reaction SMILES: [NH2:1][C:2]1[C:31]([NH2:32])=[CH:30][C:29]([Cl:33])=[CH:28][C:3]=1[C:4]([O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:5].[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35].C(OCC)C>O1CCCC1>[Cl:33][C:29]1[CH:28]=[C:3]([C:4]([O:6][CH2:7][C:8]2([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[O:5])[C:2]2[NH:1][C:34](=[O:35])[NH:32][C:31]=2[CH:30]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(Cl)cc(N)c2N)(c2ccc(F)cc2)CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(Cl)cc3[nH]c(=O)[nH]c23)(c2ccc(F)cc2)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-((2,3-diamino-5-chlorobenzoyloxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (714 mg, 1.5 mmol) in tetrahydrofuran (10 mL) at 0° C. was added carbonyldiimidazole (242 mg, 1.5 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was treated with a second portion of carbonyldiimidazole (242 mg, 1.5 mmol) and stirred for 1 h at room temperature. The solution was transferred to a microwave vial and heated at 70° C. for 1 h via microwave. The reaction was poured into diethyl ether, washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%→100 ethyl acetate/n-hexane) gave 0.52 g (69%) as a brown solid. 1H-NMR (CDCl3, 500 MHz) δ 9.69 (bs, 1H), 9.05 (bs, 1H), 7.42 (d, J=1.8 Hz, 1H), 7.38 (dd, J=8.6, 5.2 Hz, 2H), 7.19 (d, J=1.5 Hz, 1H), 7.11 (dd, J=8.6, 8.5 Hz, 2H), 4.32 (s, 2H), 3.81 (m, 2H), 3.09 (m, 2H), 2.24 (m, 2H), 1.89 (m, 2H), 1.44 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 164.6, 162.6, 160.6, 157.4, 155.1, 136.5, 131.1, 128.8 (d, J=7.7 Hz), 126.0, 121.1, 115.7 (d, J=21 Hz), 114.7, 111.8, 79.8, 73.1, 40.6, 39.9, 31.8, 28.6. Mass spec.: 525.87 (MNa)+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1>>[CH2:1]([NH:3][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([OH:4])=[CH:6][CH:7]=1)[CH3:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCN
Product: CCNCc1ccc(O)cc1

Procedure:
prepared by reaction of ethylamine with 4-hydroxy-benzaldehyde
Reaction SMILES: C(O[CH2:9][CH3:10])(=O)C(OCC)=O.[O-][CH2:12]C.[K+].[CH3:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20]C(C)=C[C:17]=1[C:26](=[NH:30])OCC>CN(C=O)C.CS(C)=O>[CH3:12][C:10]1[CH:9]=[C:15]2[C:16]([CH:17]=[CH:26][NH:30]2)=[C:21]([N+:22]([O-:24])=[O:23])[CH:20]=1
Reactant: CC[O-]
Reactant: CCOC(=N)c1cc(C)cc([N+](=O)[O-])c1C
Reactant: CCOC(=O)C(=O)OCC
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c2cc[nH]c2c1
Temperature: 40 °C

Procedure:
A solution of 2,5-dimethyl-3-nitroaniline from Step A (1.21 g, 7.26 mmol) and p-toluenesulfonic acid monohydrate (2 mg, 0.011 mmol) in freshly distilled triethyl orthoformate (1.65 mL, 9.92 mmol) was heated at 120° C. for 45 min in a distillation apparatus, and about 0.4 mL of EtOH distilled over. Vacuum distillation of the residual solution yielded ethyl 2,5-dimethyl-3-nitrophenylimidoformate (b.p.=146° C., ca. 2 mm Hg) as a pale yellow solid. To a solution of diethyl oxalate (868 mg, 5.94 mmol) in DMF (2 mL), at 0° C., was added potassium ethoxide (435 mg, 5.17 mmol) and the resulting solution was added to a solution of ethyl 2,5-dimethyl-3-nitrophenylimidoformate (880 mg, 3.96 mmol) in DMSO (3 mL). The reaction mixture was heated at 40° C. for 1 h than quenched with H2O (30 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=177 (M+1).