Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[N:16]1([CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][CH2:35]4)=[CH:31][C:29]=3[N:30]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[N:16]1([CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][CH2:35]4)=[CH:31][C:29]=3[N+:30]=2[O-:4])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: [O-][n+]1nc(CCCN2CCCCC2)nc2cc3c(cc21)CCC3
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [O-][n+]1nc(CCCN2CCCCC2)[n+]([O-])c2cc3c(cc21)CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.1 %

Procedure:
H2O2 (70%, 2.0 mL, 39 mmol) was added dropwise to a stirred solution of TFAA (5.4 mL, 39 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 86 (1.33 g, 4.2 mmol) and TFA (1.5 mL, 19.5 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 0° C. for 4 h, diluted with dilute aqueous NH3 solution (40 mL) and extracted with DCM (3×150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 87 (1.05 g, 76%) as a red gum: 1H NMR δ 8.30 (s, 1H, H-9), 8.26 (s, 1H, H-5), 3.34-3.40 (m, 4H, 2×CH2), 3.27 (t, J=7.1 Hz, 2H, CH2N), 3.12-3.21 (m, 4H, H-6, H-8), 3.05-3.12 (m, 2H, CH2), 2.42-2.51 (m, 2H, CH2), 2.22-2.32 (m, 2H, H-7), 1.64-1.73 (m, 4H, 2×CH2), 1.40-1.51 (m, 2H, CH2); 13C NMR δ 161.8, 155.2, 150.8, 139.1, 134.0, 115.8, 113.9, 58.9, 53.7, 53.4, 33.4, 32.9, 28.0, 25.6, 24.0 (2), 19.7, 13.6; HRMS (FAB+) calcd for C18H25N4O2 (MH+) m/z 329.1974, found 329.1974.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:21])/[CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:3]\[CH2:4][NH2:5].[CH2:22]([O:24][P:25]([CH2:30][C:31](O)=[O:32])([O:27][CH2:28][CH3:29])=[O:26])[CH3:23].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[O:32]=[C:31]([NH:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:21])/[CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:30][P:25](=[O:26])([O:24][CH2:22][CH3:23])[O:27][CH2:28][CH3:29]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CN
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)NC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
A solution of compound 35 (0.360 g, 1.24 mmol), diethylphosphonoacetic acid (0.266 g, 1.36 mmol, prepared as disclosed by M. P. Cooke, K. B. Bicunas, Synthesis, 283, 1981, and 1-hydroxybenzotriazole (0.251 g, 1.86 mmol) in anhydrous THF (15 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.285 g, 1.49 mmol). The mixture was stirred at rt for 24 h, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on 230-400 mesh silica gel (Macherey-Nagel Silica Gel 60 Art. Nr. 81538) eluting with CH2Cl2-hexane-MeOH (98:70:4) and collecting 4 mL fractions. The appropriate fractions were combined, evaporated, and pump-dried to give intermediate 36 (0.464 g, 80%) as an oil: 1H-NMR (CDCl3, 80 Mhz) δ 1.33 (t, 6H, J=7.1 Hz, 2×CH3CH2), 1.60 (s, 9H, 3×CH3), 1.67 (s, 6H, 2×CH3), 2.02 (m, 12H, 6×CH2), 2.83 (d, 2H, J=20 Hz, CH2P), 3.86 (d, 2H, J=7.1 Hz, CH2), 4.14 (q, 4H, J=7.1 Hz, 2×CH3CH2), 5.10 (br, 3H, 3×CH), 5.20 (t, 1H, J=7.1 Hz, CH); MS (FAB+) m/e 468 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[CH3:26][O:27][CH2:28][C@H:29]1[O:31][CH2:30]1>>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([CH2:30][C@@H:29]([OH:31])[CH2:28][O:27][CH3:26])[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:15][C:14]([C:16]#[N:17])=[CH:13][N:12]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: COC[C@@H]1CO1
Product: COC[C@H](O)Cc1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=CCC(C)(C)CC2)c1

Procedure:
This compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 14, step (c)) according to the procedure in Example 46 step (a) using (S)-glycidyl methyl ether as the electrophile. 1H-NMR (400 MHz, CD3OD): δ 8.10 (d, J=8.3 Hz, 1H), 7.98 (s, 1H), 7.15 (dd, J=8.3, 2.1 Hz, 1H), 7.07 (d, J=2.1 Hz, 1H), 5.73 (m, 1H), 3.91 (m, 1H), 3.36 (s, 3H), 2.80 (dd, J=13.7, 5.7 Hz, 1H), 2.69 (dd, J=13.7, 7.5 Hz, 1H), 2.31 (m, 2H), 2.07 (m, 2H), 1.58 (t, J=6.3 Hz, 2H), 1.07 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C23H28N4O3, 409.2 (M+H). found 409.1.
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]([C:8]([O:10][C:11]([CH:28]2[CH2:30][CH2:29]2)([C:24]([F:27])([F:26])[F:25])[C:12]#[C:13][Si](C(C)C)(C(C)C)C(C)C)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C:11]([CH:28]2[CH2:29][CH2:30]2)([C:24]([F:25])([F:26])[F:27])[C:12]#[CH:13])=[O:9])=[CH:31][CH:32]=1)([O-:3])=[O:2]
Reactant: CC(C)[Si](C#CC(OC(=O)c1ccc([N+](=O)[O-])cc1)(C1CC1)C(F)(F)F)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#CC(OC(=O)c1ccc([N+](=O)[O-])cc1)(C1CC1)C(F)(F)F

Procedure:
To a solution of crude 1-cyclopropyl-1-(trifluoromethyl)-3-(triisopropylsilyl)prop-2-yn-1-yl 4-nitrobenzoate from Step 3 (˜8.14 mmol) in THF (30 mL) at room temperature was added a THF solution of tetrabutylammonium fluoride (1.0 M, 9.77 mL, 9.77 mmol). After 1.5 h the reaction mixture was poured in H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine, dried (Na2SO4) and concentrated. The residue was subjected to chromatography on silica gel (toluene/hexane 40:60 to 60:40) affording the title compound. 1H NMR (400 MHz, acetone-d6): 8.44 (d, 2H), 8.29 (d, 2H), 3.64 (s, 1H), 1.53 (m, 1H), 1.26 (m, 1H), 0.88 (m, 2H), 0.78 (m, 1H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:13]=[C:14]([NH:19][CH2:20][CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[CH:15]=[CH:16][C:17]=1[CH3:18].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[Br:11][C:12]1[CH:13]=[C:14]([N:19]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(CNc1ccc(C)c(Br)c1)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(CN(c1ccc(C)c(Br)c1)S(=O)(=O)c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
Under a nitrogen stream, benzenesulfonyl chloride (3.12 mL g, 24.48 mmol) was added dropwise under ice cooling to a mixture of (3-bromo-4-methylphenyl)-(2,2-diethoxyethyl)-amine (4.91 g, 16.25 mmol), pyridine (10.1 mL, 124.88 mmol) and dichloromethane (41 mL), and the resultant mixture was then stirred at the same temperature for 1 hour. After stirring at room temperature for 2 hours, the reaction mixture was added to saturated aqueous sodium hydrogen carbonate. The resultant mixture was extracted with dichloromethane. The organic layer was washed with 5% aqueous hydrochloric acid and dried (anhydrous potassium carbonate). Solvent was then removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:4)), to thereby obtain the titled compound (5.94 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.OP([O-])([O-])=O.[K+].[K+].[Cl:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].[OH2:21]>C(Cl)Cl>[Cl:14][CH2:15][CH2:16][CH2:17][C:18]([NH:1][C:2]1[CH:6]=[CH:5][N:4]([C:18](=[O:21])[CH2:17][CH2:16][CH2:15][Cl:14])[N:3]=1)=[O:19]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1cc[nH]n1
Reactant: O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: ClCCl
Product: O=C(CCCCl)Nc1ccn(C(=O)CCCCl)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
To a solution of 3-aminopyrazole (300 mg, 3.61 mmol) in anh. CH2Cl2 (6 mL), at r.t., under N2, was added K2HPO4 (1.26 g, 2 eq) and the reaction mixture was stirred at r.t. for 15 min. 4-Chloro-butyryl chloride (406 μL, 3.6 mmol) was then added and the reaction mixture was stirred for 24 hr. It was then poured into water and the phases were separated. The aqueous layer was extracted with EtOAc (2×20 mL) and the combined organic extracts were dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 7:3) to give the title compound as a white solid (354 mg, 34%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](C(C)(C)C)[N:5]=[CH:4][C:3]=1[C:12]1[NH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.N[C:22]1C=CN=CC=1C1NC2C=CC=CC=2N=1.N>O1CCOCC1>[CH:4]1[C:3]2[C:12]3[N:16]([CH:22]=[N:1][C:2]=2[CH:7]=[CH:6][N:5]=1)[C:15]1[C:14](=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:13]=3
Reactant: CC(C)(C)c1cc(N)c(-c2nc3ccccc3[nH]2)cn1
Reactant: Nc1ccncc1-c1nc2ccccc2[nH]1
Agent: N
Solvent: C1COCCO1
Product: c1ccc2c(c1)nc1c3cnccc3ncn21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 26.6 g (100 mmol) of 2-(4-amino-6-tert-butylpyridin-3-yl)benzimidazole (employed as equimolar mixture with 2-tert-butylbenzimidazole as obtained from synthesis 18)) and 1 mol of the corresponding carboxylic acid chloride is heated for 8 to 40 h under reflux in the case of carboxylic acid chlorides which boil below 150° C. or at 150° C. to 180° C. in the case of carboxylic acid chlorides which boil above 150° C., until the 2-(4-aminopyridin-3-yl)benzimidazole derivative has reacted. The reaction mixture is allowed to cool to 80° C., optionally diluted with 100 ml of dioxane, then stirred into a mixture of 500 ml of conc. ammonia solution and 500 g of ice and stirred for a further 3 h. The solid is subsequently filtered off with suction, washed twice with 100 ml of water each time and dried in vacuo. The solid is taken up in 1000 ml of ethyl acetate, filtered through a short silica-gel column, rinsed with 500 ml of ethyl acetate, the ethyl acetate is removed in vacuo, and the brown residue is recrystallised from methanol. The solids obtained in this way are freed from low-boiling components and non-volatile secondary components by sublimation (p about 1×10−5 mbar, T about 180-220° C.). Purity according to 1H-NMR typically >99.5%.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.C(N(CC)CC)C.[CH:27]1([CH2:39][NH2:40])[C:37]2=[C:38]3[C:33](=[CH:34][CH:35]=[CH:36]2)[CH:32]=[CH:31][CH:30]=[C:29]3[CH2:28]1>C(O)C>[CH:27]1([CH2:39][NH:40][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:37]2=[C:38]3[C:33](=[CH:34][CH:35]=[CH:36]2)[CH:32]=[CH:31][CH:30]=[C:29]3[CH2:28]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCC1Cc2cccc3cccc1c23
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4Cc5cccc6cccc4c56)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 85 %

Procedure:
Six chloropurine riboside (1.7 g, 6 mmol), triethyl amine (1.5 g, 15 mmol) and the N-[(1,2-dihydro-1-acenaphthylenyl)methyl]amine, B, as prepared in the following Example B (1.4 g, 6.4 mmol) were stirred at reflux in ethanol (100 ml) overnight. The solution was cooled to room temperature and filtered free of solid. The solution was washed with ethanol (50 ml) and dried at 65° C. in vacuo for four hours, to give 2.2 g (85%) of a white solid, mp 173°-175° C. Anal. (C23H23N5O4); calc: C=63.73, H=5.35, N=16.16; found: C=63.55, H=5.49, N=16.00.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](OC(=O)C)(=O)[CH3:14].C(O)(C(F)(F)F)=O>O.CO>[CH3:12][O:11][C:10]1[C:2]2[N:1]=[C:13]([CH3:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C(=O)O)c1N
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cccc2c(=O)oc(C)nc12
Temperature: 140 °C
Reaction time: 3 h

Procedure:
2-Amino-3-methoxybenzoic acid (10.1 g, 60.4 mmol) was suspended in acetic anhydride (50 ml, 530 mmol). The mixture was heated to 140° C. with stirring for 180 min. The reaction mixture was cooled to room temperature and concentrated to provide Intermediate A18A (11.51 g, 100%): HPLC: RT=0.795 min (H2O/MeOH with TFA, SunFire C18 2.5 μM, 2.1×30 mm, gradient=2 min, wavelength=220 nm); MS(ES): m/z=292 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.59 (dd, J=6.9, 2.3 Hz, 1H), 7.52-7.42 (m, 2H), 3.89 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: C([N:8]([C@H:10]([C:21]#[CH:22])[C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH3:12])[CH3:9])(OC(C)(C)C)=O.[F:23][C:24]1[C:25](I)=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:34]\[C:35]1[NH:36][CH:37]=[CH:38][C:39]=1[O:40][CH3:41]>CN(C=O)C.CCN(CC)CC.CCOC(C)=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.[Cu]I>[F:23][C:24]1[C:25]([C:22]#[C:21][C@@H:10]([NH:8][CH3:9])[C@H:11]([OH:13])[CH3:12])=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:34]\[C:35]1[NH:36][CH:37]=[CH:38][C:39]=1[O:40][CH3:41]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN[C@H](C#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2)[C@@H](C)O
Reaction time: 2 h

Procedure:
Using Method C above, (2R,3R)-3-(N-Boc-N-methylamino)-2-(tert-butyldimethylsilyloxy)-pent-4-yne (370 mg, 1.13 mmol) (Example 117C above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.39 mmol) (Starting Material 6) using (Ph3P)4Pd (45 mg, 0.04 mmol) and a catalylic amount of CuI in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-40% EtOAc in hexanes gradient. The resulting intermediate was dissolved in 5 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.5 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (Z)-1,3-Dihydro-5-fluoro-4-[(3R,4R)-4-hydroxy-3-methylamino-1-pentynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2Cl2 gradient and precipitation out of THF with excess pentane. (Yield 53 mg, 37%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].C(N(CC)CC)C.[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:34](Cl)=[O:35]>ClCCl.O>[F:29][C:30]([F:44])([F:45])[C:31]1[CH:32]=[C:33]([C:34]([N:13]2[CH2:14][CH2:15][C@H:10]([C:5]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=3)[C@H:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12]2)=[O:35])[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ccc([C@H]2CCNC[C@H]2c2ccccc2)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccc(Cl)c(Cl)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a suspension of rac-cis-4-(3,4-dichlorophenyl)-3-phenyl-piperidine hydrochloride (200 mg, 0.58 mmol) in 20 mL dichloromethane was added triethylamine (0.35 mL, 2.5 mmol) and 3,5-bistrifluoromethyl-benzoyl chloride (0.11 mL, 0.60 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with 20 mL water. The organic phase was separated and the aqueous layer was extracted twice with 20 mL dichloromethane. Organic phases were pooled, dried with magnesium sulfate and evaporated. Recrystallization of the crude product from diisopropylether and hexanes gave the desired product (268 mg, 84%) as white crystalls, MS: m/e=546.1 (M+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:17])[C:6]([NH:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:7][CH:8]=1)#[CH:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28](I)=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:2]#[C:1][C:3]3[CH:4]=[C:5]([CH3:17])[C:6]([NH:9][CH2:10][CH2:11][N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[N:7][CH:8]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1cnc(NCCN2CCCC2)c(C)c1
Reactant: Clc1ccc(-c2ccc(I)nc2)cc1
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cnc1NCCN1CCCC1

Procedure:
Prepared analogously to Example 15e from 69 mg (0.3 mmol) (5-ethynyl-3-methyl-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine and 95 mg (0.3 mmol) 5-(4-chloro-phenyl)-2-iodo-pyridine, while after working up the crude product is purified by chromatography on Alox (cyc/EtOAc 6:4).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:11]2[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=2[CH:9]=1)=O)(C)(C)C.[CH3:31][C:32]1[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[CH3:31][C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:6]([C:8]2[CH:19]=[C:18]([O:20][C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=3)[C:11]3[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=3[CH:9]=2)=[O:5])=[N:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)OC(C)(CO)C2
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(C)(CO)C3)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227d) and 5-methyl-pyridin-2-ylamine. 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=8.84 Hz, 1 H) 8.05 (s, 1 H) 7.92 (d, J=8.84 Hz, 3 H) 7.28 (s, 1 H) 7.24 (s, 1 H) 7.15 (d, J=8.84 Hz, 2 H) 3.76 (d, J=11.87 Hz, 1 H) 3.62 (d, J=11.87 Hz, 1 H) 3.22 (d, J=16.67 Hz, 1 H) 3.07 (s, 3 H) 2.83 (d, J=16.67 Hz, 1 H) 2.42 (s, 3 H) 1.47 (s, 3 H); LCMS for C24H24N2O6S m/z 469.00 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:17](=[O:19])[CH3:18])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[BH4-].[Na+]>C(O)C.C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:17]([OH:19])[CH3:18])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: CC(=O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 105.4 %

Procedure:
To a stirred suspension of 1-[2-chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-ethanone (0.47 g, 1.29 mmol) in ethanol (8 mL) and THF (8 mL) was added sodium borohydride (49 mg, 1.30 mmol). The reaction mixture was stirred at room temperature for 1.5 h, then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate and aqueous sodium bicarbonate and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic fractions were dried (Na2 SO4), filtered and concentrated in vacuo to give 1-[2-Chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-ethanol (0.50 g, quantitative). LCMS RT=3.20 min, [M+H]+=368/370
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([NH2:20])=[CH:18][CH:17]=[C:16]([CH3:21])[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@@H:6]([N:13]1[C:14]2=[N:15][C:16]([CH3:21])=[CH:17][CH:18]=[C:19]2[NH:20][C:28]1=[O:29])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C[C@@H](Nc1nc(C)ccc1N)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of (R)-3-(3-amino-6-methyl-pyridin-2-ylamino)-3-phenyl-propionic acid ethyl ester (390 mg, 1.30 mmol) in THF (10 mL) was added CDI (317 mg, 1.95 mmol). The reaction mixture was stirred at room temperature for 2 hours and then heated to 60° C. for another 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 250 mg (59%) of the title compound as a light brown foamy residue. LCMS, M++1, m/z: 326.43
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[I:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:10][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([I:9])[CH:4]=1
Reactant: Cc1ccc(F)c(I)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)cc1I
Temperature: 25 °C
Yield: 51.1 %

Procedure:
4-Fluoro-3-iodotoluene (50 g, 210 mMol), N-bromosuccinimide (37.7 g, 212 mMol) and 2,2′-azobis-(2-methylpropionitrile) (348 mg, 2.12 mMol) were dissolved in carbon tetrachloride (300 mL) under an atmosphere of dry N2. The mixture was heated to reflux for 4 hours and then cooled to ambient temperature. The mixture was concentrated under vacuum and triturated with Et2O. The filtrate was successively washed with water, aqueous saturated NaHCO3 and brine. The ether layer was dried over MgSO4, filtered and concentrated under vacuum to give a red oil. The oil was chromatographed on flash silica gel eluting with hexanes to give 33.8 g of the titled compound as a white solid.
Reaction SMILES: Cl.[CH2:2]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[S:27])[O:26][C:22]=2[CH:21]=1>C(O)(C)C>[CH2:2]([CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:19][C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[S:27])[O:26][C:22]=3[CH:21]=2)=[O:18])[CH2:13][CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccc2[nH]c(=S)oc2c1
Reactant: O=C(O)CN1CCC(Cc2ccccc2)CC1
Agent: Cl
Solvent: CC(C)O
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc2[nH]c(=S)oc2c1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-acetic acid hydrochloride and 6-amino-3H-benzoxazole-2-thione according to the method described in Example 161c. Melting Point: 183-184° C. (isopropanol)