Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([N:5]([CH2:15][C:16]1([C:29]([O:31][CH3:32])=[O:30])[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[F:34][C:2]([F:1])([F:33])[C:3]([N:5]([CH2:15][C:16]1([C:29]([O:31][CH3:32])=[O:30])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl) acetamido)methyl)piperidine-1,4-dicarboxylate (150 mg, 0.310 mmol) in dichloromethane (DCM) (2 mL) was added TFA (0.5 mL, 6.49 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was concentrated and the residue was treated with saturated NaHCO3 aqueous solution, extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated to give 110 mg of product as oil. MS: (M+H)+=385.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.37-1.67 (m, 4H), 2.11-2.32 (m, 2H), 2.42 (ddd, J=10.17, 6.51, 3.54 Hz, 1H), 2.57 (m, J=12.60, 12.60, 5.87, 2.78 Hz, 2H), 2.90-3.07 (m, 2H), 3.17 (dt, J=7.45, 3.60 Hz, 1H), 3.52-3.58 (m, 3H), 3.70-3.84 (m, 2H), 7.10 (d, J=7.07 Hz, 2H), 7.19-7.26 (m, 1H), 7.28-7.35 (m, 2H).
Reaction SMILES: Br[O-].[Na+].BrBr.[C:6]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:15]=2)[CH:10]=1)(=[O:8])C.S(S([O-])=O)([O-])(=O)=[O:25].[Na+].[Na+]>O.O1CCOCC1>[CH2:22]([S:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:6]([OH:8])=[O:25])[CH:18]=[CH:17]2)(=[O:21])=[O:20])[CH3:23]
Reactant: CCS(=O)(=O)c1ccc2cc(C(C)=O)ccc2c1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc2cc(C(=O)O)ccc2c1
Temperature: 5 °C
Yield: 94.3 %

Procedure:
There is prepared in a first stage a solution of sodium hypobromite by adding, at 0° C., 3 cm3 of bromine to a stirred solution containing 7.5 g of soda in 35 cm3 of water. Then, there is slowly introduced a suspension of 1 g of 2-acetyl-6-ethylsulfonyl naphthalene dispersed in 20 cm3 of dioxan in a fashion to maintain the temperature of the reaction mixture lower than 5° C. At the end of the addition, this temperature is again maintained for 1 hour and then there are slowly added at ambient temperature 15 g of sodium metabisulfite dissolved in 150 cm3 of water. On acidifying the mixture with HCl, the anticipated acid precipitates. It is filtered, washed thoroughly with water and dried. 0.95 g of 6-ethylsulfonyl-2-naphthalene carboxylic acid in the form of a white powder whose melting point is 241° C. is obtained.
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:9][C:8]=2[CH:18]=1)(=O)C.ClC1C=CC=[C:22]([C:26]([O:28]O)=[O:27])C=1>ClCCl>[C:26]([O:28][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:9][C:8]=2[CH:18]=1)(=[O:27])[CH3:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C1COc2ccc(C(C)=O)cc2O1
Solvent: ClCCl
Product: CCOC(=O)C1COc2ccc(OC(C)=O)cc2O1

Procedure:
4 g (16 mmol) of the ester obtained in Step C are dissolved in 60 ml of anhydrous dichloromethane; 6.1 g (35.4 mmol) of meta-chloroperbenzoic acid are then added to the medium. After 18 hours of reflux under an inert atmosphere, the mixture is cooled and then hydrolysed with ice-cold water. The aqueous phase is extracted with dichloromethane; the organic phase is then washed several times with a saturated solution of sodium hydrogen carbonate. After drying over magnesium sulphate and evaporation of the solvent in vacuo, the residue obtained is purified on a silica column (eluant: AcOEt/PE: 30/70) to yield the title ester in the form of a syrup.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([NH:17][CH3:18])=[O:16])[CH:10]=2)=[CH:4][CH:3]=1.[I-:19].[K+].C(ON=O)(C)(C)C>C(I)I.CCOC(C)=O>[I:19][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([NH:17][CH3:18])=[O:16])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CNC(=O)c1cc(Oc2ccc(N)nc2)ccn1
Agent: CC(C)(C)ON=O
Agent: [K+]
Solvent: ICI
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(Oc2ccc(I)nc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
A mixture of 4-((6-aminopyridin-3-yl)oxy)-N-methylpicolinamide (0.4 g, 1.64 mmol) and potassium iodide (1.36 g, 8.19 mmol) in methylene iodide (5.46 mL) was treated dropwise with t-butylnitrite (1.95 mL, 16.4 mmol). The mixture was stirred overnight at RT, diluted with EtOAc (75 mL), and washed with 10% sodium carbonate (50 mL), 10% thiosulfate (50 mL), and brine (50 mL). The organics were dried over sodium sulfate, evaporated to dryness and purified by silica gel chromatography ((EtOAc/Hex) to afford 4-((6-iodopyridin-3-yl)oxy)-N-methylpicolinamide (0.214 g, 36.8%). 1H NMR (400 MHz, DMSO-d6): δ 8.78 (br d, J=5.6 Hz, 1H), 8.54 (d, J=5.6 Hz, 1H), 8.40 (d, J=3.0 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.50 (dd, J=8.6, 3.1 Hz, 1H), 7.45 (d, J=2.6 Hz, 1H), 7.23 (dd, J=5.6, 2.7 Hz, 1H), 2.78 (d, J=4.9 Hz, 3H); MS (ESI) m/z: 356.0 (M+H+).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[OH:10])=[N+:2]=[N-:3].N1C=CC=CC=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18]>C(Cl)Cl>[N:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[O:10][S:26]([C:23]1[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=1)(=[O:27])=[O:28])=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=N[C@@H]1CCCC[C@H]1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: [N-]=[N+]=N[C@@H]1CCCC[C@H]1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.8 %

Procedure:
A solution of (±)-trans-2-azidocyclohexan-1-ol (11.3 g, 80.0 mmol) (Zhang, Z. da; Scheffold, R. Helv. Chim. Acta 1993, 76, 2602] in CH2Cl2 (110 mL) at 0° C. was treated successively with pyridine (14.2 mL, 176 mmol) and 4-nitro-benzenesulfonyl chloride (35.6 g, 160 mmol), allowed to warm to room temperature slowly, stirred for 4 d, and partitioned between CH2Cl2 and 1 N HCl. The aqueous phase was extracted with CH2Cl2 and the extracts were washed with saturated NaHCO3, dried and concentrated. Chromatography of the residue with 10:1–1:1 hexanes:EtOAc gave the product (19 g, 72%) as a cream solid: 1H NMR δ 1.19–1.39 (m, 3H), 1.53–1.82 (m, 3H), 2.00–2.10 (m, 1H), 2.26 (m, 1H), 3.36 (m, 1H), 4.35 (ddd, J=4.7, 9.2, 10.8 Hz, 1H), 8.17 (m, 2H), 8.41 (m, 2H).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:20]([OH:30])[CH2:21][C@@H:22]([CH:27]([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[CH3:38][O:39][C:40]1[CH:59]=[CH:58][C:43]([CH2:44][C@H:45]([CH2:49][C:50]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[O:51])C(O)=O)=[CH:42][CH:41]=1>>[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:44][C@H:45]([CH2:49][C:50]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[O:51])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[C@@H:20]([OH:30])[CH2:21][C@@H:22]([CH:27]([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:7])=[CH:58][CH:59]=1
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)C
Reactant: COc1ccc(C[C@H](CC(=O)N2CCOCC2)C(=O)O)cc1
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccc(OC)cc1)C(C)C
Yield: 69.8 %

Procedure:
The procedure described in Example 1(b) was repeated, but using 200 mg (0.37 mmole) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-isopropyl-N-methylhexanamide [prepared as described in Example 1(a)] and 137 mg (0.45 mmole) of 2(R)-(4-methoxybenzyl)-3-(morpholinocarbonyl)propionic acid, to afford 188 mg (yield 70%) of the title compound as white crystals, melting at 128°-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].Br[CH2:37][CH:38]([CH3:40])[CH3:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:37][CH:38]([CH3:40])[CH3:39])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: CC(C)CBr
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: COc1ccc(CC2c3c(OC)ccc(OCC(C)C)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with 1-bromo-2-methyl-propane
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:25][CH3:26])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C(S)CC.C(O)(=O)C>CN(C=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:25][CH3:26])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(Cc3cccc(OC)c3)nc(=O)c1-2
Agent: CCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3cccc(O)c3)nc(=O)c1-2
Temperature: 130 °C
Yield: 61.8 %

Procedure:
To a solution of 1-cyclopentyl-3-ethyl-6-(3-methoxyphenyl methyl)pyrazolo[3,4-d]pyrimidin-4-one (4.49 g, 13 mmol) in DMF (123 mL) was added 97% NaH (1.26 g), followed 20 minutes later by propanethiol (2.96 g, 39 mmol). The reaction mixture was heated at 130° C. overnight, cooled to room temperature and then ice water, followed by acetic acid were added. A precipitate formed which was collected by filtration, recrystallized from ether and dried at 110° C. and 2 mm Hg to afford 2.72 g of 1-cyclopentyl-3-ethyl-6-(3-hydroxyphenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 195-197° C.
Reaction SMILES: C(OC(=O)[N:7]=[C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=2[N:9]1[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[O:36])[CH:30]=1)(C)(C)C.Cl>CO>[Br:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:12]1[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=2[N:9]([CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[O:36])[C:8]1=[NH:7]
Reactant: CC(C)(C)OC(=O)N=c1n(CCCOc2cccc(C(=O)NS(C)(=O)=O)c2)c2ccccc2n1Cc1cccc(Br)c1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)NC(=O)c1cccc(OCCCn2c(=N)n(Cc3cccc(Br)c3)c3ccccc32)c1
Yield: 34.6 %

Procedure:
To [1-(3-bromo-benzyl)-3-[3-(3-methanesulfonylaminocarbonyl-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-ylidene]-carbamic acid tert-butyl ester (90 mg, 0.14 mmol) at rt was added HCl in MeOH (5 ml). The reaction was stirred until the consumption of the starting material was observed by TLC. After this time, the mixture was concentrated under reduced pressure and purified by chromatography on basic alumina eluting with 10% MeOH/chloroform to provide N-(3-{3-[3-(3-bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoyl)-methanesulfonamide (27 mg, 35%). HPLC-MS 557, 559 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:9]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH3:9][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cn1cnc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a mixture of 4-nitro-1H-imidazole (2.0 g, 17.7 mmol) and K2CO3 (3.67 g, 26.5 mmol) in acetonitrile (20 mL) was added iodomethane (1.3 mL, 3.0 g, 21.2 mmol) dropwise while stirring at room temperature. The resulting mixture was stirred at 60° C. overnight. It was then evaporated under reduced pressure and the residue was diluted with water (20 mL). The mixture was extracted with dichloromethane (2×20 mL). The combined extract was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 268a as a yellow solid (1.8 g, 82%). MS-ESI: [M+H]+ 128.1. 1H NMR (500 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.82 (s, 1H), 3.76 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[O:11][CH2:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:12]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1cccc2c1OCC=C2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cccc2c1OCCC2

Procedure:
The compound obtained in Step B (1 g:6.84 mmol) dissolved in glacial acetic acid (10 ml) is poured into the reactor of a Paar apparatus. 10% palladium on carbon (10% by weight; 100 mg), acting as catalyst, is added. The whole is then subjected to a hydrogen pressure of 45 psi for 12 hours at room temperature. After filtration, the solvent is removed under reduced pressure and then extraction is carried out with dichloromethane. The recovered organic phase, dried over magnesium sulphate, is purified after concentration over a silica column eluted with pure dichloromethane. The title product is obtained pure in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1)[NH2:5].[O:22]=[C:23]1[N:27]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][N:24]1[C:34](Cl)=[O:35].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([N:24]2[CH2:25][CH2:26][N:27]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:23]2=[O:22])=[O:35])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)cc3Cl)ccn2)cn1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Solvent: O
Solvent: ClCCl
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)cc3Cl)ccn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A 0° C. mixture of 3-chloro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (0.150 g, 0.499 mmol) and TEA (0.1 mL, 0.716 mmol) in DCM (5 mL) was treated with a solution of Example B2 (0.164 g, 0.705 mmol) in DCM (1.5 mL), warmed to RT and stirred for 1 h. The mixture was treated with water, stirred for 10 min, the layers separated and the organic layer dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(3-chloro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (176 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 10.57 (s, 1 H), 8.34 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 7.96 (s, 1 H), 7.92 (d, J=2.6 Hz, 1 H), 7.46 (dd, J=8.8, 2.6 Hz, 1H), 7.32 (d, J=8.8 Hz, 1 H), 7.19 (d, J=2.4 Hz, 1 H), 6.55 (dd, J=5.7, 2.5 Hz, 1 H), 3.94-3.76 (m, 8 H), 3.46 (t, J=8.2 Hz, 2 H), 3.37 (t, J=11.7 Hz, 2 H), 1.76-1.66 (m, 2 H), 1.59 (d, J=12.4 Hz, 2H); MS (ESI) m/z: 497.2 (M+H+).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[O:27])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:34])[C:8]2=[O:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:37][CH2:38][F:39]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:14]([Cl:34])=[CH:15][C:16]([C:20]4[CH:21]=[CH:22][C:23]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH2:37][CH2:38][F:39])[CH2:32][CH2:33]5)=[O:27])=[CH:24][CH:25]=4)=[CH:17][C:18]=3[Cl:19])[C:8]2=[O:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: FCCBr
Reactant: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCN(CCF)CC1
Temperature: 55 °C
Yield: 64.5 %

Procedure:
Treat a solution of 1-cyclohexyl-3-[3,5-dichloro-4′-(piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-pyrrolidin-2-one (0.67 g, 1.30 mmol) in dimethylformamide (7 mL) with 1-bromo-2-fluoroethane (0.99 g, 7.80 mmol) and heat to 55° C. for 16 hours under a nitrogen atmosphere. Cool the reaction, dilute with ethyl acetate and wash with saturated aqueous sodium bicarbonate then water. Dry the organic layer with sodium sulfate and purify the crude product by silica gel chromatography using a gradient of 0 to 10% methanol in dichloromethane to afford 0.47 g (64%) of the title compound in its racemic form. Separate into the enantiomers by chiral HPLC (Chiralpak AD 8×33 cm column, isocratic 90:10 3 A ethanol:acetonitrile with 0.2% dimethylethylamine, 400 mL/min, 300 nM UV) to afford 286 mg of Isomer 1 (>99% ee) and 283 mg of Isomer 2 (98.9% ee): MS (m/z): 560. Check the purity of each isomer using chiral HPLC (Chiralpak AD-H 4.6×150 mm column, isocratic 90:10 3A ethanol:acetonitrile with 0.2% dimethylethylamine, 0.6 mL/min, 270 nM).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[O:20]([CH2:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[CH2:27][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)COc1ccccc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)COc1ccccc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and phenoxyacetyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenoxyacetamide as an off white powder, m.p. 61.5° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ8.19 (s, 1H), 8.12 (t, J=6.0 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.62 (dd, J=8.4, 1.2 Hz, 1H), 7.44 (dt, J=7.5, 1.2 Hz, 1H), 7.29-7.21 (m, 3H), 6.96-6.88 (m, 3H), 6.62 (s, 2H), 4.60 (t, J=7.2 Hz, 2H), 4.42 (s, 2H), 3.16 (q, J=6.9 Hz, 2H), 1.83 (quintet, J=7.2 Hz, 2H), 1.47 (quintet, J=7.2 Hz, 2H); IR (KBr) 3311, 3180, 2937, 1664, 1618, 1583, 1527, 1493, 1480, 1396, 1244, 755 cm−1; MS (EI) m/e 389.1844 (389.1852 calcd for C22H23N5O2).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)([C:17]([OH:19])=O)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)([C:17]([NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:19])[CH2:13][CH2:12]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)N
Reactant: O=C(OCc1ccccc1)N1CCC(C(=O)O)(C2CCCCC2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)C1(C2CCCCC2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
4-Cyclohexyl-1,4-piperidinedicarboxylic acid 1-(phenylmethyl) ester (8-4) (2.50 g, 7.24 mmol) was dissolved in 36 mL of methylene chloride and cooled at 0° C. in an ice-water bath. Oxalyl chloride (2.0 M solution in CH2Cl2, 3.98 mL, 7.96 mmol) was then added dropwise followed by the addition of 1-2 drops of DMF. This mixture was stirred at 0° C. for 2 h and then concentrated with toluene. The residue was dissolved in 36 mL of methylene chloride and cooled at 0° C. in an ice-water bath. tert-Butylamine (2.28 mL, 21.7 mmol) was then added dropwise, and the reaction mixture was stirred at 0° C. for 2 h, warmed to room temperature, and stirred at room temperature overnight. The resulting mixture was diluted with methylene chloride, washed with brine, dried over MgSO4, filtered, and concentrated to give 2.92 g of title compound 8-5 as a solid. LCMS (ESI): m/z 401 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[C:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl.C(OCC)C.C(O)(=O)C>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][CH:26]([N:9]2[CH2:10][CH2:11][CH:6]([O:5][C:4]3[CH:12]=[CH:13][C:14]([Cl:15])=[C:2]([Cl:1])[CH:3]=3)[CH2:7][CH2:8]2)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1

Procedure:
4-(3,4-Dichlorophenoxy)piperidine (1.5 g) was dissolved in 1,2-dichloroethane (21 ml). 1-Boc-4-piperidone was added (1.21 g) followed by NaBH(OAc)3 (1.81 g) and acetic acid (0.37 g). After 18 hours at room temperature aqueous NaOH (1M) solution and diethyl ether were added. The product was extracted with diethyl ether, the combined organic extracts dried with MgSO4 and concentrated. Purification by silica chromatography (dichloromethane:methanol 92:8) gave the sub-title product (1.97 g).
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.C([Mg]Br)C.Cl[CH2:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO.[Cu]Br>[CH2:12]([C:13]1[CH:26]=[CH:25][C:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:5]#[CH:6]
Reactant: ClCc1ccc(COc2ccccn2)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]Br
Agent: CC[Mg]Br
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Product: C#CCc1ccc(COc2ccccn2)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a solution of trimethylsilyl acetylene (496 μL, 3.51 mmol) in tetrahydrofuran (15 mL) was added ethyl magnesium bromide (3 M diethyl ether solution, 1.09 mL, 3.28 mmol) under nitrogen atmosphere at room temperature, which was stirred for 30 minutes at 65° C. The reaction solution was cooled to room temperature, and copper (I) bromide (168 mg, 1.17 mmol) and 2-(4-chloromethyl-benzyloxy)-pyridine (548 mg, 2.34 mmol) manufactured in Manufacturing Example 30-1-1 were added thereto and stirred for 15 hours and 10 minutes at 65° C. The reaction solution was partitioned into saturated aqueous ammonium chloride solution and ethyl acetate at room temperature. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. To a solution of the resulting residue in methanol (5 mL) and tetrahydrofuran (10 mL) was added potassium carbonate (647 mg, 4.68 mmol), which was stirred for 3 hours and 25 minutes at room temperature. The reaction solution was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=20:1) to obtain a mixture of the title compound and 2-(4-chloromethyl-benzyloxy)-pyridine (448 mg, target purity 20%, 17%).