Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH3:10][C:11]1[N:12]=[C:13]([C:22](OCC)=[O:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.CCO>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@@H:2]([NH:1][C:22]([C:13]1[S:14][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([CH3:10])[N:12]=1)=[O:23])[CH2:3]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: CCOC(=O)c1nc(C)c(-c2ccccc2)s1
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc(C(=O)N[C@H]2CN3CCC2CC3)sc1-c1ccccc1
Reaction time: 48 h
Yield: 55 %

Procedure:
The freebase of (R)-3-aminoquinuclidine (1.0 g, 5.02 mmol, 2.26 eq) dissolved in THF (˜5 mL) is added to a solution of the product from Step 89c (0.55 g, 2.22 mmol, 1 eq) in 10 mL EtOH. The mixture is heated under reflux. After 48 h, the mixture is cooled and concentrated in vacuo. The residue is purified by silica gel chromatography using a Biotage Flash 40S column (90:9:1 CHCl3/MeOH/NH4OH) to provide N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-methyl-5-phenyl-1,3-thiazole-2-carboxamide (0.40 g, 55%) as a yellow oil. The p-toluenesulfonic acid salt of the product is made and recrystallized from IPA/ether to give the product as light yellow solid. MS (ESI) for C18H21N3OS m/z 328.2 (M+H)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:50])[CH2:18][C:17]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]3[O:48][CH3:49])[CH:21]=[CH:22][C:16]=2[O:15]1>O>[CH3:50][C:14]1([CH3:13])[CH2:18][C:17]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:3][C:4](=[O:7])[O:5][N:44]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]3[O:48][CH3:49])[CH:21]=[CH:22][C:16]=2[O:15]1
Reactant: CCCc1nc(OC)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(OC)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
A mixture of hydroxylammonium chloride (4.33 g), sodium hydrogen carbonate (6.16 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methoxy-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.85 g) was added, and the mixture was stirred at 90° C. for 5 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.48 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.74 g, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:16]([C:18](O)=[O:19])[CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:45][CH:46]1[CH:51]2[CH2:52][CH2:53][N:48]([CH2:49][CH2:50]2)[CH2:47]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[N:48]12[CH2:53][CH2:52][CH:51]([CH2:50][CH2:49]1)[CH:46]([NH:45][C:18]([C:16]1[CH:17]=[C:2]([Br:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=4)=[N:6][C:5]=13)=[O:19])[CH2:47]2
Reactant: Cc1ccc(-c2nc3c(C(=O)O)cc(Br)cc3o2)cc1
Reactant: NC1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cc(Br)cc3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.4 %

Procedure:
A mixture of 6-bromo-2-p-tolylbenzoxazole-4-carboxylic acid (85 mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg, 0.31 mmol), 1-hydroxybenzotriazole (60 mg, 0.31 mmol) and 3-aminoquinuclidine dihydrochloride (61 mg, 0.31 mmol) in DMF (5 mL) was stirred 10 min at room temperature, then triethylamine (0.12 mL, 1.02 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×25 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-2-p-tolylbenzoxazole-4-carboxamide (60 mg, 54%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.48 (d, J=7.3 Hz, 1H), 8.30 (d, J=1.8 Hz, 1H), 8.10 (d, J=8.3 Hz, 2H), 7.85 (d, J=1.8 Hz, 1H), 7.37 (d, J=8.0 Hz, 2H), 4.35-4.25 (m, 1H), 3.60-3.45 (m, 1H), 3.15-3.00 (m, 2H), 2.95-2.82 (m, 2H),
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:15][NH:16][O:17][CH3:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([N:16]([O:17][CH3:18])[CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCc1ccc(Cl)c(Cl)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CON(C)C(=O)CCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
To a solution of 3-(3,4-dichlorophenyl)propanoic acid (0.50 g, 2.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.27 g, 2.7 mmol) in DCM (5 mL) was added EDCI (0.57 g, 3.0 mmol), HOBt (0.35 g, 2.3 mmol) and TEA (0.39 mL, 2.8 mmol). The reaction mixture was stirred at rt for 18 h, concentrated and the residue was purified by ISCO chromatography (EtOAc/Hexanes 0-100% over 20 min, column 40 g, flow rate 40 mL/min) to give Intermediate 15A (569 mg, 2.17 mmol, 95.0% yield) as a clear oil. HPLC/MS (Method R) RT=1.76 min, [M+1]+ 262.1.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:14][N:15]2[C:22]([NH2:23])=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:9][CH2:8][CH2:7][CH2:6]1>C(O)(=O)C>[NH2:23][C:22]1[N:15]([CH2:14][C:13]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:11]([O:10][CH:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)[CH:12]=2)[C:16](=[O:17])[NH:18][C:19](=[O:20])[C:21]=1[N:1]=[O:3]
Reactant: COc1ccc(Cn2c(N)cc(=O)[nH]c2=O)cc1OC1CCCC1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(N)c(N=O)c(=O)[nH]c2=O)cc1OC1CCCC1
Temperature: 25 °C

Procedure:
15.81 nil of 4N sodium nitrite solution was added dropwise at 65°-70° C. over 8 minutes to a solution of 20.53 g of 1-(3-cyclopentyloxy-4-methoxy-benzyl) 6-amino uracil in 300 ml of acetic acid. After 30 minutes the suspension was cooled to room temperature and the solid collected and washed with water to give the title compound (19.36 g) as pink crystals. The filtrate was evaporated to dryness, the residue suspended in 100 ml of water and the solid collected to give 1.98 g as a second crop.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]([CH3:20])([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([NH2:19])=[S:18])[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:22][I:23]>C(#N)C>[IH:23].[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]([CH3:9])([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[NH:19])[S:18][CH3:22])[CH:11]=1)[CH3:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(NC(N)=S)c1
Solvent: CC#N
Product: CSC(=N)Nc1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1
Product: I
Yield: 54 %

Procedure:
To a mixture of the compound (164 mg) obtained in Example 3 and acetonitrile (15 ml) was added methyl iodide (0.1 ml) and the reaction mixture was heated under reflux for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, chloroform methanol=95:5) to give 130 mg of the titled compound (yield, 54%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.Cl.[F:20][C:21]1([F:25])[CH2:24][NH:23][CH2:22]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[F:20][C:21]1([F:25])[CH2:24][N:23]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)=[CH:17][CH:16]=2)=[O:15])[CH2:22]1
Reactant: FC1(F)CNC1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(c2ccc(C(=O)N3CC(F)(F)C3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 57 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (490 mg, 2.0 mmol), 3,3-difluoroazetidine hydrochloride (260 mg, 2.00 mmol), DIPEA (0.686 mL, 3.93 mmol) and HATU (900 mg, 2.4 mmol) in DMF (4 mL) was stirred at room temperature for 3 days. The reaction mixture was diluted with EtOAc, the organic portion washed successively with water and brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 0-100% EtOAc/hexane) to give Compound B166a (360 mg, 57% yield) as a white solid. HPLC: RT=1.9 min (LCMS Method Q). MS (ES): m/z=324.0 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.87 (s, 2H), 7.62 (d, J=8.1 Hz, 2H), 4.53 (t, J=12.0 Hz, 4H), 1.36 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([NH:23]C(=O)OC(C)(C)C)=[CH:22][C:16]=3[S:15](=[O:32])(=[O:31])[N:14]=2)[C:3]1=[O:33].C(N(CC)CC)C.[C:46]([O:49]C(=O)C)(=O)[CH3:47].[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:1][C:46](=[O:49])[CH3:47])([CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])[C:3](=[O:33])[C:4]=1[C:13]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([NH:23][S:54]([CH3:53])(=[O:56])=[O:55])=[CH:22][C:16]=2[S:15](=[O:32])(=[O:31])[N:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CCC1(N)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 18C (30 mg, 0.05 mmol) in dichloromethane (150 μL) was added triethylamine (150 μL, 0.11 mmol) and acetic anhydride (6 μL, 0.06 mmol) and the mixture stirred at room temperature for 16 hours. Solvent was removed in vacuo and the crude residue was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) and the mixture was stirred at room temperature for 2 hours. Solvent was removed in vacuo and the crude residue was dissolved in dichloromethane (0.5 mL) and triethylamine (150 μL, 0.11 mmol) was added followed by methanesulfonyl chloride (10 μL, 0.11 mmol). The mixture was stirred at room temperature for 1.5 hours and the solvent was removed in vacuo and the crude residue was dissolved in ethyl acetate (0.5 mL) and 1N NaOH (0.5 mL) and the solution stirred at room temperature for 16 hours. 1N HCl was added dropwise until acidic pH, then the mixture was extracted with ethyl acetate (3×5 mL) and the organic extracts were combined and dried (MgSO4). The drying agent was filtered off and the solvent was removed in vacuo to give a crude residue which was purified by column chromatography on silica gel (5% methanol/chloroform) to give the title compound as a colorless solid. MS (ESI) m/z 561 (M+H+). 1H NMR (d6-DMSO) δ 10.03 (s, 1H), 8.04, 8.02 (d, 1H), 7.55-7.25 (m, 6H), 3.07, 3.06 (d, 3H), 2.01-1.59 (m, 2H), 1.82 (s, 3H), 1.31-1.08 (m, 2H), 1.01-0.84 (m, 1H), 0.71-0.62 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])=[CH:28][CH:29]=1)([O-:20])=[O:19]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)nc23)CC1
Yield: 35.6 %

Procedure:
Beginning with 0.100 gm (0.43 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.103 gm (0.56 mMol) 4-nitrobenzoyl chloride, 0.058 gm (36%) of the title compound was recovered as a crystalline solid by the procedure described in Example 4.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](OS(C(F)(F)F)(=O)=O)=[C:9]([Cl:21])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:51]([OH:53])[CH3:52].C(N(CC)CC)C.CN(C)[CH:63]=[O:64]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCC.O>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:63]([O:53][CH2:51][CH3:52])=[O:64])=[C:9]([Cl:21])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: O=S(=O)(Oc1ccc(-c2ccccc2)cc1Cl)C(F)(F)F
Reactant: CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(-c2ccccc2)cc1Cl
Temperature: 85 °C
Reaction time: 6 h

Procedure:
To a solution of 4-phenyl-2-chloro-1-trifluoromethylsulfonyloxybenzene (35 g) in dimethylformamide (300 ml) are added palladium acetate (1.17 g), 1,3-bis(diphenylphosphino)propane (4.29 g), ethanol (91.5 ml) and triethylamine (29.0 ml) under carbon monooxide atmosphere, and the mixture is heated with stirring at 80-90° C. for 6 hours. To the reaction solution is added water, and further added a small amount of n-hexane. The mixture is extracted with ethyl acetate, and the ethyl acetate layer is washed with water, dried, and the residue is purified by silica gel column chromatography (solvent; n-hexane→ethyl acetate:n-hexane=1:100) to give ethyl 4-phenyl-2-chlorobenzoate (20.9 g) as colorless oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C:6](=[CH2:8])[CH2:5][C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[Si:15]([O:1][CH2:2][C@@H:3]1[CH2:7][C:6](=[CH2:8])[CH2:5][C@H:4]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.4 %

Procedure:
To a solution of (+−)-trans-1-hydroxymethyl-4-methylene-2-phenylcyclopentane from Step B (2.5 g, 13.3 mmol) in methylene chloride (50 mL) was added t-butyldimethylsilyl chloride (3.0 g, 20 mmol) and DIPEA (4.7 mL, 27 mmol). The reaction was stirred at rt for 16 h, poured into dilute aq. HCl and extracted twice with ether. The organic layers were washed with brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC (5% ethyl acetate in hexanes) to afford the title product (4.2 g) as a oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[CH2:10][C:9]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[C:6]([C:19]3[N:20]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=C(NC)C=4)[C:5]=2[CH2:4][CH2:3]1.[CH2:39]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])C.C(Cl)(=[O:48])C.O>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:38])[CH2:10][C:9]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[C:6]([C:19]3[N:20]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:42]([N:41]([CH3:39])[C:44](=[O:48])[CH3:45])[CH:43]=4)[C:5]=2[CH2:4][CH2:3]1
Reactant: CNc1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)N(C)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Reaction time: 2 h

Procedure:
Under an argon atmosphere, to a solution of N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylamine (100 mg, 0.18 mmol) and triethylamine (75 μl, 0.54 mmol) in chloroform (1.5 ml) was added acetyl chloride (19 μl, 0.27 mmol) at room temperature, and the mixture was stirred for 2 hr. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylacetamide. A solution of the obtained N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylacetamide in N,N-dimethylformamide (1.4 ml) was added to tetrabutylammonium fluoride (1.8 ml, 1.8 mmol) concentrated in advance under reduced pressure. Ethylenediamine (0.7 ml) was added, and the mixture was stirred with heating at 90° C. for 24 hr. After cooling, water and ethyl acetate were added, and the organic layer was separated. Then, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography to give the title compound (26 mg, yield 42%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2([CH3:26])[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C.O>ClCCl>[O:30]=[C:28]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3([CH3:26])[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20]3)[CH2:11][CH2:10]2)[C@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]2[NH:1]1
Reactant: CCOC(=O)N1CCC(C)(N2CCC(N[C@H]3CCCC[C@@H]3N)CC2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.1 %

Procedure:
A solution of ethyl 4-[4-[[(1S,2S)-2-aminocyclohexyl]amino]-1-piperidyl]-4-methyl-piperidine-1-carboxylate (87 mg, 0.24 mmol) in dichloromethane (5 mL) was added with triphosgene (0.1 mmol) at 0° C. followed by with diisopropylethyl amine (0.5 mmol) and stirred at room temperature for 12 h. Water (2 mL) was added followed by dichloromethane (20 mL), the phases were separated and the aqueous phase was extracted with dichloromethane (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified with preparative LC/MS (high pH) to give the title compound as white solid 24 mg (25%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.96 (s, 3H), 1.22 (t, J=7.08 Hz, 3H), 1.31-1.49 (m, 6H), 1.55-1.63 (m, 1H), 1.66-1.87 (m, 7H), 1.91-1.99 (m, 2H), 2.08-2.22 (m, 2H), 2.24-2.31 (m, 1H), 2.89-3.10 (m, 4H), 3.33-3.43 (m, 2H), 3.45-3.53 (m, 2H), 3.54-3.63 (m, 1H), 4.08 (q, J=7.08 Hz, 2H). MS (M+1): 393.3.
Reaction SMILES: [C:1]([N:5]1[CH2:31][CH2:30][CH2:29][C:8]2[C:9](Br)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1.C([O-])([O-])=O.[K+].[K+]>C(COC)OC.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>[C:1]([N:5]1[CH2:31][CH2:30][CH2:29][C:8]2[C:9]([C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1-c1cccnc1)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Reactant: OB(O)c1cccnc1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cccnc3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Temperature: 90 °C
Yield: 69.1 %

Procedure:
A mixture of 45 mg of 13d, 20 mg of pyridine-3-boronic acid, 30 mg of K2CO3 and 10 mg of Pd(PPh3)4 in 2 ml of degassed dimethoxyethane was heated at 90° C., for 16 hr. The reaction mixture was cooled, diluted with water and the product was extracted with ethyl acetate. The extract was washed once with 2N KOH and once with water, dried and concentrated. The residue was purified by chromatography over silica gel, using a gradient of toluene/acetone as eluent. The isolated product was triturated with diethyl ether, to provide 31 mg of 13e as white, crystalline material; Mp 310-312° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:13][I:14]>C1COCC1>[I-:14].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]2[CH:12]=[CH:11][N:10]([CH3:13])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-n2ccnc2)cc1
Reactant: CI
Solvent: C1CCOC1
Product: Cn1cc[n+](-c2ccc(Cl)cc2)c1
Product: [I-]
Reaction time: 20 h

Procedure:
1-(4-Chlorophenyl)imidazole (0.37 g, 2.07 mmol) is dissolved in THF (5 ml) and subsequently admixed with methyl iodide (1.47 g, 10.4 mmol) and allowed to stand for 20 hours. The precipitate formed is subsequently filtered off and washed with ethanol and with petroleum ether and subsequently dried under reduced pressure. This gives 0.46 g of 1-(4-chlorophenyl)-3-methylimidazolium iodide.