Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[Na+].CN[C@@H]1CCCC[C@H]1NC.Br[C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1.CCCCCCCCCCCC>C(OCC)(=O)C.[Cu]I>[I:1][C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1
Reactant: [I-]
Reactant: Cc1cc(C)cc(Br)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCCCCCCC
Product: Cc1cc(C)cc(I)c1
Temperature: 110 °C
Reaction time: 23 h

Procedure:
A Sclenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), sodium iodide (fine powder, dried, 300 mg, 2.00 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.10 mmol, 10 mol %), 5-bromo-m-xylene (136 μL, 1.00 mmol), and solvent (1.0 μL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 23 h. The resulting suspension was allowed to reach room temperature. Ethyl acetate (2 mL) and dodecane (internal GC standard, 230 μL) were added to the reaction mixture. A 50 μL sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC. The results are tabulated below.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:19])[CH2:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:19][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][NH:25]3)[CH2:17][CH3:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC[C@H](N)c1nc2ccccc2n1-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1-c1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of (S)-1-(1-phenyl-1H-benzoimidazol-2-yl)propylamine from Example 12 (100 mg, 0.398 mmol), 6-chloro-9H-purine (65 mg, 0.418 mmol) and DIPEA (0.348 mL, 2.0 mmol) in dioxane (3 mL) was stirred for 24 h at 100° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% MeOH in EtOAc) and then crystallised from acetonitrile affording 119 as a white solid (50 mg, 34%). LCMS: RT 3.23 min [M+H]+ 370.0. 1H NMR (DMSO, 400 MHz): δ 8.21-8.07 (2H, m), 7.86-7.49 (7H, m), 7.28-7.17 (2H, m), 7.08 (1H, d, J=7.68 Hz), 5.42 (1H, br), 2.08-1.90 (2H, m), 0.83 (3H, t, J=7.32 Hz)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[N:27]=[C:26]([CH2:28][CH2:29][CH:30]4[CH2:36][CH2:35][CH2:34][CH2:33][C:32](=O)[NH:31]4)[NH:25][C:22]3=[N:23][CH:24]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[N:27]=[C:26]([CH2:28][CH2:29][CH:30]4[CH2:36][CH2:35][CH2:34][CH2:33][C:32](=[S:47])[NH:31]4)[NH:25][C:22]3=[N:23][CH:24]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(=O)N5)nc4c3)cc2)c(F)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Cc1ccc(NS(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(=S)N5)nc4c3)cc2)c(F)c1
Yield: 57.1 %

Procedure:
The title compound is analogously synthesized as described for 7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione (compound A2) from 180 mg of N-(2-fluoro-4-methyl-phenyl)-4-{2-[2-(7-oxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide (compound B8) and 146 mg of Lawesson's reagent at 100° C. for 3 hours in 20 ml of dioxane. Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-10 vol. % ethanol) affords 106 mg of the title compound as a colorless solid of m.p. 271° C. ESI-MS: 538.2 (MH+). TLC: Rf=0.40 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH2:35]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:35][C:34]3[CH:37]=[CH:38][C:39]([CH3:40])=[C:32]([F:31])[CH:33]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(CBr)cc1F
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1ccc(Cn2ccc3c(-c4ccc5c(c4)CCCO5)c(C(OC(C)(C)C)C(=O)O)c(C)nc32)cc1F

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 3-fluoro-4-methylbenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.42 (m, 1 H), 7.21 (dd, J=1.9, 10.8 Hz, 1 H), 7.14 (t, J=7.7 Hz, 1 H), 7.05 (t, J=3.4 Hz, 1 H), 6.99-6.89 (m, 3 H), 6.28 (dd, J=3.5, 11.5 Hz, 1 H), 5.60-5.56 (m, 1 H), 5.56-5.39 (m, 2 H), 4.28 (t, J=4.5 Hz, 2 H), 2.95-2.80 (m, 2 H), 2.76 (s, 3 H), 2.25 (s, 3 H), 2.09 (d, 2 H), 1.03-0.88 (s, 9 H); LC/MS (m/z) ES+=517.38 (M+1).
Reaction SMILES: [F:1][CH2:2][C:3]([NH2:11])([CH2:6][CH2:7][CH2:8][O:9][CH3:10])[C:4]#[N:5].C(N(CC)CC)C.[C:19](Cl)(=[O:29])[C:20]1[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:22](Cl)=[O:23]>C(Cl)Cl>[F:1][CH2:2][C:3]([N:11]1[C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]2[C:19]1=[O:29])([CH2:6][CH2:7][CH2:8][O:9][CH3:10])[C:4]#[N:5]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: COCCCC(N)(C#N)CF
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a solution of 2-fluoromethyl-2-amino-5-methoxypentanenitrile (1.62 g, 10 mmol) and triethylamine (2.02 g, 20 mmol) in methylene chloride (30 ml), cooled to -20° C., is added phthaloyldichloride (2.03 g, 10 mmol) in methylene chloride (10 ml). The mixture is allowed to warm up to room temperature overnight. After washing with water, 1N HCl, water again, and drying (Na2SO4), the solvent is removed under reduced pressure to give 2.4 g of crude material. This is purified by chromatography on silica (ethyl acetate/petroleum ether 3:7).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][NH:5][CH2:4]1.[CH:7]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]2[N:20]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([C:28](O)=[O:29])[C:26]=3[CH:27]=2)=[O:18])[CH2:12][CH2:11]1)([CH3:9])[CH3:8].ClC1SC(C2ON=C(CN3C4C(=CC(C(O)=O)=CC=4)C=C3C(=O)NC3CCN(C(C)C)CC3)C=2)=CC=1>>[CH:7]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]2[N:20]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[C:21]3[C:26]([CH:27]=2)=[C:25]([C:28]([N:5]2[CH2:6][CH:3]([O:2][CH3:1])[CH2:4]2)=[O:29])[CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:12][CH2:11]1)([CH3:9])[CH3:8]
Reactant: COc1cccc(Cn2c(C(=O)NC3CCN(C(C)C)CC3)cc3c(C(=O)O)cccc32)c1
Reactant: COC1CNC1
Agent: CC(C)N1CCC(NC(=O)c2cc3cc(C(=O)O)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Product: COc1cccc(Cn2c(C(=O)NC3CCN(C(C)C)CC3)cc3c(C(=O)N4CC(OC)C4)cccc32)c1

Procedure:
The title compound was prepared analogously to example 1 with the difference that 3-Methoxy-azetidine and 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1-(3-methoxy-benzyl)-1H-indole-4-carboxylic acid was used instead of Azetidin-3-ol and 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-5-carboxylic acid. MS (ES+): m/e=519.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:10]([CH3:20])[N:11]=[C:12]2[C:17](Cl)=[N:16][C:15]([CH3:19])=[N:14][C:13]=12.[CH2:21]([NH2:24])[CH2:22][NH2:23]>C(#N)C>[NH2:23][CH2:22][CH2:21][NH:24][C:17]1[C:12]2=[N:11][N:10]([CH3:20])[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[C:13]2[N:14]=[C:15]([CH3:19])[N:16]=1
Reactant: NCCN
Reactant: Cc1nc(Cl)c2nn(C)c(-c3c(Cl)cccc3Cl)c2n1
Solvent: CC#N
Product: Cc1nc(NCCN)c2nn(C)c(-c3c(Cl)cccc3Cl)c2n1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-(2,6-dichlorophenyl)-7-chloro-2,5-dimethylpyrazolo[4,3-d]pyrimidine (652 mg, 2.0 mmol) in acetonitrile (50 mL) at 50° C., add ethylene diamine (2.4 g, 40 mmol) in one portion. Maintain the reaction at 50° C. for 2 h, cool to ambient temperature and remove the volatiles by evaporation. Partition the residue between CH2Cl2 (50 mL) and 1N NaOH (50 mL) and extract the aqueous layer with CH2Cl2 (2×30 mL). Wash the combined organic extracts with water (30 mL), brine (30 mL), dry over MgSO4 and evaporate to obtain the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[NH:13][N:12]=[C:11]([O:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([O:24][CH3:25])[N:16]=2)[CH:10]=1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27].Cl>C(OCC)(=O)C>[CH2:26]([NH:28][C:29]([N:13]1[C:9]([CH3:8])=[CH:10][C:11]([O:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([O:24][CH3:25])[N:16]=2)=[N:12]1)=[O:30])[CH3:27]
Reactant: COc1ccc([N+](=O)[O-])c(Oc2cc(C)[nH]n2)n1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2nc(OC)ccc2[N+](=O)[O-])cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
Triethylamine (0.22 g, 2.2 mmol) was added to a solution of 5-methyl-3-(6-methoxy-3-nitropyridin-2-yloxy)pyrazole (0.5 g, 2.0 mmol) in ethyl acetate (10 ml), and the mixture was cooled to 0° C. Ethyl isocyanate (0.16 g, 2.2 mmol) was added, and the mixture was stirred at an ambient temperature for 30 minutes. The mixture was allowed to have room temperature. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/6), to give a yellow viscous substance of N-ethyl-5-methyl-3-(6-methoxy-3-nitropyridin-2-yloxy)pyrazole-1-carboxamide (0.38 g, yield: 59.8%). 1H-NMR (CDCl3, TMS, ppm): δ 1.24 (t, J=7.3 Hz, 3H), 2.65 (d, J=0.8 Hz, 3H), 3.40 (dq, J=1.4 and 7.3 Hz, 2H), 3.84 (s, 3H), 6.02 (q, J=0.8 Hz, 1H), 6.57 (dd, J=3.5 and 8.8 Hz, 1H), 7.05 (br s, 1H), 8.41 (dd, J=3.5 and 8.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[N:24]([CH2:29][CH:30]1[CH2:32][CH2:31]1)[CH2:25][CH:26]1[CH2:28][CH2:27]1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]1[N:9]=[N:10][NH:11][N:12]=1.[H-].[Na+].[CH3:44]I.O>CN(C=O)C>[F:41][C:2]([F:40])([F:1])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[N:24]([CH2:29][CH:30]1[CH2:31][CH2:32]1)[CH2:25][CH:26]1[CH2:28][CH2:27]1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]1[N:9]=[N:10][N:11]([CH3:44])[N:12]=1
Reactant: CI
Reactant: FC(F)(F)c1cc(CN(Cc2cnc3ccccc3c2N(CC2CC2)CC2CC2)c2nn[nH]n2)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cnc3ccccc3c2N(CC2CC2)CC2CC2)n1
Reaction time: 0.33 h
Yield: 35 %

Procedure:
A mixture of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-quinolin-4-yl)-bis-cyclopropylmethyl-amine (300 mg, 0.52 mmol) and sodium hydride (31 mg, 0.78 mmol) were taken in DMF (10 mL) at 0° C. and stirred for 20 min, then methyl iodide (0.067 mL, 1.04 mmol) was added at that temperature and stirred for 1 h. Water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (100 mL×3) and the organic layer was washed with water (75 mL). Drying over sodium sulfate and concentration under vacuum yielded the crude product that was purified by column chromatography using 230-400 mesh silica gel eluting with 5% ethyl acetate in petroleum ether to afford 0.107 gm (yield: 35%) of yellow colored gummy mass.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:18](=[O:28])[NH:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[F:27])=O)(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[F:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=1[NH:19][C:18]([C@@H:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1c(F)cccc1F)[C@H]1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-(2,6-difluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (50 mg, 129 μmol, Eq: 1.00) in CH2Cl2 (6 mL) was added TFA (2 mL) dropwise. The reaction was stirred at RT for 1 h. The mixture was evaporated to provide (S)-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2,6-difluoro-phenyl)-amide trifluoroacetate which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[F:15][C:16]([F:22])([F:21])[CH2:17][CH2:18][CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[O:14]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:19][CH2:18][CH2:17][C:16]([F:22])([F:21])[F:15])=[CH:7][CH:6]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CC(=O)c1ccc(O)cc1
Reactant: OCCCC(F)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CC(=O)c1ccc(OCCCC(F)(F)F)cc1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of methyl 3-(4-hydroxyphenyl)-3-oxopropanoate (7.8 g, 40.2 mmol) and 4,4,4-trifluorobutan-1-ol (5.15 g, 40.2 mmol) in CH2Cl2 (201 mL) at 0° C. was added triphenylphosphine (12.6 g, 48.2 mmol). The mixture was stirred for a few min, and then DIAD (9.37 mL, 48.2 mmol) was added. The reaction was stirred at 0° C. for 30 min, then warmed to rt and stirred for 3 days. The reaction was loaded directly onto a 300 g silica gel column and eluted with EtOAc in hexanes. Fractions containing the product were combined and concentrated to provide Intermediate 14A (9.9 g, 80%) as a colorless solid. 1H NMR (500 MHz, CDCl3) δ 2.03-2.13 (m, 2H), 2.26-2.39 (m, 2H), 3.75 (s, 3H), 3.96 (s, 2H), 4.09 (t, J=6.05 Hz, 2H), 6.92-6.96 (m, 2H), 7.86-7.97 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.Cl.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[OH:32].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]5[OH:32])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 110 °C
Yield: 7.5 %

Procedure:
To a suspension of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.0 g, 3.0 mmol) and (1S,2R)-2-aminocyclohexanol hydrochloride (916 mg, 6 mmol) in anhydrous DMA (12 mL) was added DIEA (1.6 mL, 9.0 mmol). The mixture was heated in a sealed tube at 110° C. for 12 h. The mixture was cooled to rt and additional (1S,2R)-2-aminocyclohexanol hydrochloride (458 mg, 3 mmol) and DIEA (530 μL, 3 mmol) were added. The mixture was further heated in a sealed tube at 120° C. for 12 h. The mixture was cooled to rt and partitioned between EtOAc (200 mL) and 0.5 M aq K2CO3 (100 mL). The organic layer was separated, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 5% MeOH in CH2Cl2, then by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (89 mg, 7%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.41 (s, 1H), 8.06 (dd, J=2.5, 9.5 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.66 (s, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.21 (dd, J=1.3, 8.3 Hz, 1H), 5.47 (s, 2H), 4.67 (m, 1H), 3.90 (m, 1H), 3.84 (m, 1H), 1.64-1.74 (m, 2H), 1.43-1.63 (m, 4H), 1.25-1.34 (m, 2H); LCMS (ESI) m/z 398 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH:17]([F:19])[F:18])[C:10](O)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH:17]([F:19])[F:18])[C:10]([Cl:22])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(OC(F)F)c(OC2CCCC2)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(OC(F)F)c(OC2CCCC2)c1
Temperature: 80 °C

Procedure:
A mixture of 3-cyclopentyloxy-4-difluoromethoxybenzoic acid (0.47 g; that is prepared as described in Reference Example 42) and thionyl chloride (4 mL) in toluene (10 mL) is heated at 80° C. for 2 hours, and then evaporated under reduced pressure, to give 3-cyclopentyloxy-4-difluoromethoxybenzoyl chloride (0.48 g), in the form of a pale yellow low melting solid, which is used without further purification.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH:21](Br)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH:21]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCCN1CCNCC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a mixture of 1-piperazineethanol (11.4 g), potassium carbonate powder (24.3 g) and N,N-dimethylformamide (100 ml) was added dropwise benzhydryl bromide (21.7 g). The mixture was stirred at room temperature for 2 hours, then diluted with water and extracted with ethyl ether. The ethyl ether layer was washed with saturated aquus sodium chloride and dried over sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel chromatography [eluent: hexane-ethyl acetate (2:1)] to give 21.9 g (84.2%) of 4-benzhydryl-1-piperazineethanol as an oil.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:5]([C:7]([OH:9])=O)[N:6]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C:48]([O:52][C:53](=[O:62])[NH:54][CH2:55][C@@H:56]1[CH2:61][CH2:60][CH2:59][CH2:58][NH:57]1)([CH3:51])([CH3:50])[CH3:49]>C(#N)C>[C:48]([O:52][C:53](=[O:62])[NH:54][CH2:55][C@@H:56]1[CH2:61][CH2:60][CH2:59][CH2:58][N:57]1[C:7]([C:5]1[N:6]=[C:2]([Br:1])[S:3][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:9])([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCCN1
Reactant: O=C(O)c1nc(Br)sc1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC[C@@H]1CCCCN1C(=O)c1nc(Br)sc1-c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
2-bromo-5-(4-fluoro-phenyl)-thiazole-4-carboxylic acid (1.02 g, 3.38 mmol) was dissolved in acetonitrile (20 ml) followed by the addition of TBTU (1.19 g, 3.72 mmol) and DIPEA (547 mg, 4.22 mmol). Stirring was continued for 30 min. at rt. A solution of (S)-piperidin-2-ylmethyl-carbamic acid tert-butyl ester (725 mg, 3.38 mmol) in acetonitrile (20 ml) was added to the reaction mixture within 10 minutes and stiring was continued at rt for 24 h. The reaction mixture was concentrated under reduced pressure followed by the addition of aq. HCl (0.5 M, 50 ml). Stirring was continued for 30 min. The precipitated product was filtered off, washed with cold water and dried at HV to give the expected product (1.57 g). LC-MS: tR=1.03 min; [M+H]+=500.38.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[C:22](Cl)(=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O1CCOCC1>[C:16]1([C:14](=[O:15])[CH:13]=[CH:12][C:4]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]([OH:8])=[C:2]([O:1][C:22](=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCC(=O)Oc1cc(C=CC(=O)c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 90 °C
Yield: 16.5 %

Procedure:
A solution containing 2.0 g of the product obtained in Example 8 and 10.0 g of stearoyl chloride in 10 ml of dioxane was stirred and heated for 18 h at 90° C. After cooling petroleum ether was added and the product was filtered. Recrystallization from dichloromethane-petroleum ether yielded 0.64 g (17%) of the desired product desired, m.p. 112°-118° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:25]([O:29][C:30](=[O:43])[N:31]=[C:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])SC)([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C=O)C.[Hg](Cl)Cl>[C:39]([O:38][C:36]([NH:35][C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:23][CH:24]=1)=[N:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:43])=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
3-{4-[(4-Aminophenethyl)oxy]phenyl}-2(S)-ethoxypropanoic acid (223 mg, 0.61 mmol) and tert-butyl-[(tert-butoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate (186 mg, 0.64 mmol) were mixed in 3 ml DMF. Triethylamine (0.34 ml, 2.44 mmol) was added. The mixture was then cooled in an ice-bath. Mercury (II)chloride (180 mg, 0.66 mmol) was added. After 30 minutes, the cooling bath was removed. The reaction mixture was stirred overnight. Water and ethyl acetate were added into the mixture. The organic phase was separated, dried with magnesium sulfate and the solvent was evaporated in vacuum. Column chromatography of the residue on silica gel using ethyl acetate/heptane (10:90, then 25:75) as eluant gave 135 mg, yield 39% of the desired product.