Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[NH:3][C:4]([CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])CO)=O.C(SC[CH:50]([O:53]C)CN)CCCCCCCCCCCCCCC.[C:55]1(=[O:65])[NH:59]C(=O)C2=CC=CC=C12>>[CH3:50][O:53][C:55]([NH:59][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:4][NH2:3])=[O:65]
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)C(=O)NOC
Reactant: O=C1NC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)NC(=O)OC

Procedure:
2-Methoxycarbamoyl-3-octadecylcarbamoyloxypropanol Ve1 is allowed to react and worked up by the same procdure as described in (3). The phthalimide derivative: m.p. 128°-129° C., the amine derivative: 85°-86° C. The summary of the experimental condition and the physical data of the product are listed in Tables 5 and 6.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[N:17]=[C:16]([N:18]4[CH:22]=[C:21]([CH:23]=O)[C:20]([CH3:25])=[N:19]4)[CH:15]=[CH:14][N:13]=3)[CH:9]=2)[N:4]([CH3:26])[C:3]=1[CH3:27].Cl.[O:29]1[CH2:33][C@@H:32]([OH:34])[CH2:31][NH:30]1.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[N:17]=[C:16]([N:18]4[CH:22]=[C:21]([CH2:23][N:30]5[CH2:31][C@H:32]([OH:34])[CH2:33][O:29]5)[C:20]([CH3:25])=[N:19]4)[CH:15]=[CH:14][N:13]=3)[CH:9]=2)[N:4]([CH3:26])[C:3]=1[CH3:27]
Reactant: O[C@H]1CNOC1
Reactant: Cc1nn(-c2ccnc(Nc3ccc4c(c3)c(Cl)c(C)n4C)n2)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nn(-c2ccnc(Nc3ccc4c(c3)c(Cl)c(C)n4C)n2)cc1CN1C[C@H](O)CO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of Intermediate 3 (190 mg, 0.5 mmol), (S)-isoxazolidin-4-ol hydrochloride (95 mg, 0.75 mmol) and triethylamine (0.4 mL) in 10 mL of dichloromethane, was added NaBH(OAc)3 (0.32 g, 1.5 mmol) at room temperature. The reaction was stirred for 12 hour at room temperature and then quenched with 1N—NaOH. It was extracted with ethyl acetate and washed twice with brine. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography (DCM/MeOH) to afford desired Compound No. 31 as a pale yellow solid (159 mg, 70%); MS (ESI) m/z 454 [M+H]+. 1H NMR (300 MHz, CDCl3) δ 8.43 (s, 1H), 8.34 (d, J=5.4 Hz, 1H), 7.89 (s, 1H), 7.68 (s, 1H), 7.14-7.16 (m, 3H), 4.73 (brs, 1H), 4.23 (brs, 1H), 3.92-3.96 (m, 2H), 3.84 (brs, 1H), 3.63 (s, 3H), 3.25 (brs, 1H), 2.73 (brs, 1H), 2.40 (s, 3H), 2.36 (s, 3H
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([NH2:49])[CH2:42][N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OCC)C>CN(C=O)C>[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH:41]([NH:49][C:12]([CH:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:42][N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)CN1CCOCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A solution of 87 mg (0.34 mmol) of (S)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (Example 1, Step B) and 0.131 mL (1.2 mmol) 4-methylmorpholine was stirred at 25° C. for 30 minutes, after which 136 mg (0.36 mmol) 0-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate in 4 mL dry DMF was added. The resulting solution was cooled in an ice-bath and 150 mg (0.34 mmol) 2-(4-benzyloxy-phenyl)-1-morpholin-4-ylmethyl-ethylamine (Example 3, Step D) was added. The resulting solution was warmed to 25° C. and stirred for 30 minutes. The mixture was then poured into 35 mL diethyl ether, and washed sequentially with 25 mL each of 2.5% aqueous HCl solution, brine, saturated aqueous sodium bicarbonate solution, and finally twice with brine. The mixture was then dried over anhydrous sodium sulfate and concentrated at reduced pressure to give an amber oil that was purified by preparative thin-layer chromatography on a 1000 μm silica gel plate with 50:50:1 ethyl acetate:hexane:methanol as eluant to give 46 mg (24%) of the title compound as a pale amber glass.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:16]=[N:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22][C:23]1[C:35](=[O:36])[N:34]([CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:26]2[N:27]=[C:28](S(C)=O)[N:29]=[CH:30][C:25]=2[C:24]=1[CH3:42].C1(=O)OC(=O)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:16]=[N:17][C:18]([NH:21][C:28]3[N:29]=[CH:30][C:25]4[C:24]([CH3:42])=[C:23]([Br:22])[C:35](=[O:36])[N:34]([CH:37]5[CH2:38][CH2:39][CH2:40][CH2:41]5)[C:26]=4[N:27]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(N)nc2)CC1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Agent: O=C1CCC(=O)O1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(C4CCCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Reaction time: 3 h
Yield: 43.4 %

Procedure:
A solution of 4-(6-amino-pyridin-3-yl)-azepane-1-carboxylic acid tert-butyl ester (614 mg, 2.10 mmol) in toluene (10 mL) was refluxed in a Dean-Stark apparatus for 3 h. The heat was removed and when the reflux subsided 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (700 mg, 1.89 mmol) was added. This mixture was refluxed for 12 h under N2. Succinic anhydride (500 mg) was added and the reflux continued for 3 h. The reaction mixture was cooled and dissolved in ethyl acetate (100 ml) and the organic layer was washed with water (100 mL total). The organic layer was dried over magnesium sulfate and the solvents evaporated. The crude product was subjected to chromatography on silica gel and eluted with a chloroform/2-propanol gradient to give 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-azepane-1-carboxylic acid tert-butyl ester as a yellow powder (414 mg, 0.82 mmol). MS (APCI+) 500, 600 (M+1, 100).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([CH3:8])[CH2:4][C:5](O)=[O:6].[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]>>[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:5](=[O:6])[CH2:4][CH:3]([CH3:8])[C:2]([F:10])([F:9])[F:1])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: CC(CC(=O)O)C(F)(F)F
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)CC(C)C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 14, making variations only as required to use 4,4,4-trifluoro-3-methylbutyric acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white flaky solid (63% yield). 1H NMR (300 MHz, CDCl3) δ 8.07, 7.85, 7.00, 3.69-3.98, 3.67, 3.50, 3.00, 2.71, 2.35, 1.70, 1.50, 1.20, 0.95. MS (ES+) m/z 415 (M+1).
Reaction SMILES: Br[C:2]1[C:11]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[C:10]2[C:5]([NH:6][C:7]([CH3:25])([CH3:24])[C:8](=[O:23])[N:9]2[CH3:22])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][C:35]([F:38])([F:37])[F:36])[CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].C(OCC)(=O)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:21])=[C:14]([CH:19]=1)[O:13][CH2:12][C:11]1[C:2]([C:29]2[CH:30]=[CH:31][C:32]([O:34][C:35]([F:37])([F:38])[F:36])=[CH:33][C:28]=2[O:27][CH3:26])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]([CH3:22])[C:8](=[O:23])[C:7]([CH3:25])([CH3:24])[NH:6]2
Reactant: Cc1ccc(F)cc1OCc1c(Br)ccc2c1N(C)C(=O)C(C)(C)N2
Reactant: COc1cc(OC(F)(F)F)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OC(F)(F)F)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
A mixture of 7-bromo-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 8-1, 49.7 mg, 0.122 mmol), 2-methoxy-4-trifluoromethoxyphenylboronic acid (58.1 mg, 0.246 mmol), cessium carbonate (119 mg, 0.36 mmol) and bis(triphenylphosphin)palladium(II)dichloride (12.0 mg, 0.0171 mmol) was suspended in anhydrous N,N-dimethylformamide (0.5 ml) and stirred at 80° C. for 2 hours under argon atmosphere. After cooling down, ethyl acetate (100 mL) and water (100 mL) was added and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (52.7 mg) as a colorless amorphous product. (Yield 58%)
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:13](=[O:14])[C:12](=[O:15])[NH:11][C:10]1=[S:16].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Br:23].Br>CS(C)=O.CCCCCC>[Br:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[C:12](=[O:15])[C:13](=[O:14])[N:9]([CH3:8])[C:10]1=[S:16]
Reactant: CN1C(=O)C(=O)NC1=S
Reactant: BrCCCCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CN1C(=O)C(=O)N(CCCCCBr)C1=S
Temperature: 0 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Triethylamine (84 ml, 0.60 mole) was added dropwise over a period of 6 hours to a stirred solution of 1-methyl-2-thioxo-4,5-imidazolidinedione (88 g, 0.61 mole) and 1,5-dibromopentane (264 g, 1.20 mole) in dimethylsulphoxide (650 ml) at room temperature. The mixture was allowed to stand overnight and then poured into ice water (3 liters) containing concentrated hydrobromic acid (1 ml). The mixture was extracted with chloroform and the extracts were washed with water, dried over magnesium sulphate and evaporated to give an oil which was treated with hexane to give yellow crystals of 1-(5-bromopentyl)-3-methyl-2-thioxo-4,5-imidazolidine-dione (82.3 g), m.p. 48°-50°.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Li+].CC([N-]C(C)C)C.[CH2:19]1[O:21][CH2:20]1>C1COCC1>[Cl:1][C:2]1[C:9]([CH2:19][CH2:20][OH:21])=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C1CO1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(F)c(CCO)c1Cl
Reaction time: 5 h
Yield: 66.2 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (20.0 g, 128.6 mmol) in THF (200 mL) added LDA (28% wt in THF, 71.0 mL, 142.0 mmol) at −78° C. After addition, the mixture was stirred at the same temperature for 5 h, then ethylene oxide (9.7 ml, 194.2 mmol) was added. The reaction mixture was allowed to warm to R. T. gradually and stirred overnight. The reaction was quenched by adding saturated aqueous NH4Cl solution and extracted with EtOAc (400 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by SiO2 column to give 2-chloro-4-fluoro-3-(2-hydroxyethyl)benzonitrile (17.0 g, 66%). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.58 (dd, J=5.5, 8.6 Hz, 1H), 7.10 (t, J=8.6 Hz, 1H), 3.88 (m, 2H), 3.13 (t, J=6.8 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([C:11]([O:13]C)=[O:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.O.[OH-].[Li+].Cl>C1COCC1.O.CO>[CH3:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: COC(=O)C1(C)Cc2ccccc2C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-methyl-2,3-dihydro-1H-indene-2-carboxylate (1.80 g, 9.46 mmol) in THF/water/MeOH (4/1/1 mL respectively) was added lithium hydroxide monohydrate (1.19 g, 28.4 mmol). The reaction mixture stirred at ambient temperature 4 h, acidified to pH 3 with 1 N HCl and extracted with Et2O (2×25 mL). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo affording the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.39 (s, 3H), 2.83 (d, J=15.9 Hz, 2 H), 3.50 (d, J=15.9 Hz, 2 H), 7.12-7.23 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2F)c1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2F)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 120(a) from 7-cyano-1-(2-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, acetic anhydride, and triethyl amine. The title compound, ESI MS (m/z): 382 (M+H)+.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[N+:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N+:16]([O-])=O)([O-])=O>>[CH3:5][O:4][C:1]([NH:7][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:1]([O:4][CH3:5])=[O:6])=[O:6]
Reactant: COC(=O)OC
Reactant: O=[N+]([O-])CCCCCC[N+](=O)[O-]
Product: COC(=O)NCCCCCCNC(=O)OC
Reaction time: 8 h
Yield: 85 %

Procedure:
In a reinforced glass reactor with a capacity of 5 ml 2 ml of dimethyl carbonate and 150 mg of 1,6-dinitrohexane and 100 mg of Au/CeO2 (1 wt % gold relative to cerium) are introduced. The reactor is closed and purged with N2 to remove oxygen from the solution. Then the reactor is charged at 15 bars of hydrogen and immersed in a silicone bath preheated at 90° C. The suspension is magnetically stirred for 8 hrs. After this time, the reactor is discharged at atmospheric pressure, opened and the mixture is filtered. A gas chromatography analysis revealed the presence of 1,6-bis (methoxycarbonylamino) hexane in an 85% yield.
Reaction SMILES: C([Li])CCC.CCCCCC.Cl[CH2:13][CH2:14][I:15].[CH3:16][O:17][C:18]1C=C[C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][CH:23]=1>C1COCC1>[I:15][C:14]1[C:18]([O:17][CH3:16])=[CH:23][N:22]=[C:21]([C:24]([F:27])([F:26])[F:25])[CH:13]=1
Reactant: ClCCI
Reactant: COc1ccc(C(F)(F)F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cnc(C(F)(F)F)cc1I
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 16 %

Procedure:
In an oven-dried flask, 5-methoxy-2-(trifluoromethyl)pyridine was dissolved in THF (20 mL). This mixture was cooled at −78° C., and then 2.5 M n-butyllithium in hexane (2.60 mL, 6.5 mmol) was added. After stirring at this same temperature for 40 minutes, 1-chloro-2-iodoethane (0.60 mL, 6.6 mmol) was added. The reaction was kept at −78° C. for an additional 30 minutes, and then quenched with saturated aqueous ammonium chloride. The mixture was warmed to room temperature, partitioned between ethyl acetate and water, and the organic layer dried with magnesium sulfate and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (0 to 40% ethyl acetate in heptanes) to yield 0.3128 g (16%) of 4-iodo-5-methoxy-2-(trifluoromethyl)pyridine. 1H NMR (400 MHz, DMSO-d6) δ: 8.38 (s, 1H), 8.29 (s, 1H), 4.05 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12](C)[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1>CN(C=O)C.C([O-])([O-])=O.[K+].[K+].CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[NH:12][C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(-c2ccc3ncc4[nH]c(=O)n(-c5cn(C)nc5C)c4c3c2)cn1
Temperature: 105 °C
Reaction time: 1.5 h

Procedure:
A mixture of 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage A.1, 49 mg, 0.137 mmol), 2-methoxypyridine-5-boronic acid (Sigma-Aldrich, Buchs, Switzerland, 26 mg, 0.170 mmol), and PdCl2(PPh3)2 (6 mg, 0.0085 mmol) in DMF (1.2 ml) and 1 M aqueous K2CO3 (0.343 ml) was stirred under argon at 105° C. for 1.5 h. The RM was cooled toll. The mixture was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 60:40). The fractions containing products were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: tR 2.46 min (Method A); M+H=387 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 11.66 (s, br, 1H), 8.72 (s, 1H), 8.33-8.26 (m, 1H), 8.16-8.10 (m, 1H), 8.09-8.01 (m, 1H), 7.91-7.84 (m, 1H), 7.81-7.74 (m, 1H), 7.51-7.43 (m, 1H), 6.98-6.91 (m, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH2:9])[C:3]=1[OH:10].[C:11]([O-])([O-])=O.[K+].[K+].CCO[CH2:20][CH3:21]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH2:9])[C:3]=1[O:10][CH:20]([CH3:21])[CH3:11]
Reactant: C=Cc1cccc(Cl)c1O
Reactant: O=C([O-])[O-]
Reactant: CCOCC
Agent: [K+]
Solvent: CN(C)C=O
Product: C=Cc1cccc(Cl)c1OC(C)C
Temperature: 60 °C
Yield: 82 %

Procedure:
2-chloro-6-vinylphenol (1.55 g, 10 mmol) and 2-iodopropance (1.5 ml, 15 mmol, 1.5 equiv) were dissolved in DMF, followed by adding K2CO3 (3.9 g, 30 mmol) into DMF solution, then heated at 60° C. overnight. etherification was monitored by TLC and HPLC until completed. The mixture was diluted with Et2O (250 mL), and washed with water (2×200 mL). The aqueous layer was extracted twice with Et2O (150 mL), and the combined organic layers were washed with brine, and dried over MgSO4. The product was purified by flash column (Hexanes:Et2O=6:1) to offer 1.69 g of product 4a (Yield: 82%, purity: 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]([OH:20])=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[CH2:21]([NH:23][CH:24]([CH2:26][CH3:27])[CH3:25])[CH3:22]>S(Cl)(Cl)=O>[CH2:21]([N:23]([CH:24]([CH3:25])[CH2:26][CH3:27])[C:18]([C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:17]=1)=[O:20])[CH3:22]
Reactant: O=C(O)c1cc(-c2ccccc2Cl)nc2ccccc12
Reactant: CCNC(C)CC
Solvent: O=S(Cl)Cl
Product: CCC(C)N(CC)C(=O)c1cc(-c2ccccc2Cl)nc2ccccc12

Procedure:
The procedure of Example 3 is followed using 2-(2-chlorophenyl)-quinoline-4-carboxylic acid (2.8 g), thionyl chloride (10 ml) and N-ethylbut-2-ylamine (4 g) as the starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)/[C:21](=[C:22](\[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)/[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: Clc1cccc(I)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3cccc(Cl)c3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-3-iodo-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.01 (s, 1H), 7.93 (d, 1H), 7.50 (d, 1H), 7.26-7.46 (m, 10H), 7.08 (t, 1H), 6.70 (t, 1H), 6.65 (d, 1H), 6.44 (d, 1H), 4.96 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [N:1]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:5][CH:4]([N:7]2[C@@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH:23]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:23]1([C:28]([N:20]2[CH2:21][CH2:22][CH:17]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C@@H:11]5[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]5[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH2:18][CH2:19]2)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1N[C@@H]2CCCC[C@H]2N1C1CCN(C2CCNCC2)CC1
Reactant: O=C(O)C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C1CCCC1)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To the solution of (3aR,7aR)-1-(1,4′-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one, 0.25 mmol) in dry DMF (3 mL) was added cyclopentanecarboxylic acid (34 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (5 mL) and the solvent was removed in vacuo. Dichloromethane (15 mL) was added and washed with saturated NaHCO3 (10 mL) and brine (10 mL) and dried over Na2SO4. The crude product was purified with high pH prep-LCMS to yield (3aR,7aR)-1-[1′-(cyclopentylcarbonyl)-1,4′-bipiperidin-4-yl]octahydro-2H-benzimidazol-2-one (64 mg, 63%) as white powder. 1H NMR (400 MHz, METHANOL-D4): δ ppm 1.25-1.49 (m, 6H), 1.53-1.73 (m, 8H), 1.76-2.03 (m, 9H), 2.18-2.36 (m, 3H), 2.51-2.62 (m, 2H), 2.91-3.11 (m, 6H), 3.56-3.68 (m, 1H), 4.13 (d, J=13.28 Hz, 1H), 4.58 (d, J=13.28 Hz, 1H). MS (M+1): 403.3
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C:26](=[N:30][OH:31])[CH2:25][CH2:24]5)=[C:18]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5]O[CH2:3][CH2:2]1.N1CCCC[CH2:39]1>>[N:1]1([CH2:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C:26](=[N:30][OH:31])[CH2:25][CH2:24]5)=[C:18]([C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)[CH:17]=3)[CH2:14][CH2:15]2)=[O:9])[CH2:6][CH2:5][CH2:39][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C(CN1CCOCC1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Product: O=C(CN1CCCCC1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Yield: 18 %

Procedure:
The title compound (0.03 g, 18%) was prepared from the product of Example 47 Step 1 and piperidine using the method of Example 47 Step 2; MS(ES+) m/e 484 [M+H]+.