Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C[N:27](C=O)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([NH2:27])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CC=C(c2cn(N)c3ccc(F)cc23)CC1
Temperature: 25 °C
Yield: 94 %

Procedure:
A solution of 4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (730 mg, 2.31 mmol) in anhydrous DMF is added slowly to a stirred solution of 60% NaH (1108 mg, 27.72 mmol) in anhydrous DMF (20 mL) at 0° C. under N2 and stirred at rt for an hour. HOSA (1305 mg, 11.55 mmol) is added portion-wise at 0° C., stirred at 0° C. for 5 hours, poured into ice/water (350 mL) and extracted with ether (3×35 mL). The combined organic extract is washed with water (2×20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is washed with heptane (3×5 mL) to afford 4-(1-Amino-5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (715 mg, 94%) as a solid. MS: 332 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.52 (d, H), 7.36 (m, H), 7.20 (s, H), 7.04 (t, H), 6.06 (s, H), 4.78 (s, 2H), 4.15(m, 2H), 3.69 (t, 2H), 2.54 (s, 2H), 1.55 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCOCC1
Product: CCN(Cc1ccc(OCCN2CCOCC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 34.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-1-morpholin-4-ylethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.4 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[S:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[F:19][C:20]([F:33])([F:32])[S:21]([O:24]S(C(F)(F)F)(=O)=O)(=[O:23])=[O:22]>ClC(Cl)(F)C(Cl)(F)F>[F:19][C:20]([F:33])([F:32])[S:21]([O-:24])(=[O:23])=[O:22].[F:1][C:2]([F:18])([F:17])[S+:3]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]1=2
Reactant: O=S(c1ccccc1-c1ccccc1)C(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: FC(F)(F)[s+]1c2ccccc2c2ccccc21
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.7 %

Procedure:
To a solution of 4.05 g (15 mmol) of 2-(trifluoromethylsulfinyl)biphenyl in 30 ml of 1,1,2-trichloro -1,2,2-trifluoroethane was added 2.52 ml (15 mmol) of trifluoromethanesulfonic anhydride, and the mixture was stirred at room temperature for 2 days. The white precipitate formed in the reaction system was collected by filtration to give 4.51 g (74.8%) of S-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate. The properties of the product are shown in Table 1.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:24]([CH:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]4)[N:25]=[CH:26][C:10]=13)[CH2:2]2.C(=O)=O.[H][H]>O1CCCC1.[Pd]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:12]=[C:11]3[N:24]([CH:27]4[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:31][CH2:32]4)[N:25]=[CH:26][C:10]3=[C:9]([N:3]3[CH2:2][CH:1]4[O:8][CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:14]=2)=[CH:20][CH:19]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc([N+](=O)[O-])cc4)nc32)CC1
Agent: [Pd]
Agent: O=C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(N)cc4)nc32)CC1

Procedure:
A solution of tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (0.13 g, 0.24 mmol) in tetrahydrofuran (5 mL) was degassed by the addition of crushed solid carbon dioxide. Palladium-on-carbon (5%, 20 mg) was then added. The mixture was stirred magnetically overnight under a balloon of hydrogen gas. The mixture was filtered through a pad of diatomaceous earth, eluting with ethyl acetate. The filtrate was concentrated under reduced pressure to provide tert-butyl 4-(6-(4-aminophenyl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate as a pale yellow foam. MS (ES+): 506.4 (M+H)+
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[CH3:18][C:19]([C:22]1[CH:23]=[C:24]([S:33][CH2:34][CH2:35][CH:36]=[O:37])[CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])([CH3:21])[CH3:20].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:32][C:29]([C:26]1[CH:25]=[C:24]([S:33][CH2:34][CH2:35][CH:36]([OH:37])[CH2:14][C:13]([O:16][CH3:17])=[O:15])[CH:23]=[C:22]([C:19]([CH3:18])([CH3:20])[CH3:21])[C:27]=1[OH:28])([CH3:30])[CH3:31]
Reactant: COC(C)=O
Reactant: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CC(O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1.5 g of diisopropylamine in 25 ml of tetrahydrofuran (THF), stirred at -78° C. in an atmosphere of nitrogen, was added 6.5 ml of 1.6M n-butyllithium in hexane. The mixture was stirred at -78° C. for 5 min after which a solution of 1.2 g of methyl acetate in 5 ml of THF was added. The mixture was again stirred at -78° C. for 5 min. Then a solution of 1.75 g of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanal, the product of Example 3, in 20 ml of THF was added. The reaction mixture was stirred at -78° C. for 1/2 hr. A saturated solution of ammonium chloride was carefully added, and the resultant mixture was allowed to warm to room temperature. The mixture was extracted with ether. The ether extract was washed with water, dried over anydrous MgSO4, and distilled to dryness under reduced pressure. The residual oil was chromatographed on silica gel. Elution with hexane-ethyl acetate followed by crystallization from aqueous methanol gave the product mp. 77°-80° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH2:24][CH3:25])=[C:13]([C:15]2[CH:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[CH:16]=2)[CH:14]=1.B(O)(O)[C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH2:24][CH3:25])=[C:13]([C:15]2([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[CH:16]=[C:17]([NH2:22])[N:18]=[C:19]([NH2:21])[CH2:20]2)[CH:14]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(N)nc(N)c1
Reactant: Cc1ccc(B(O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Cl)cc1C1(c2ccc(C)cc2)C=C(N)N=C(N)C1
Yield: 17 %

Procedure:
Following the method described in Example 8, 4-(5-chloro-2-ethoxy-phenyl)-pyridine-2,6-diamine trifluoroacetic acid salt and p-tolylboronic acid provided the title compound (17% yield). 1H NMR (acetone-d6) δ1.35 (t, 3H, J=7.0 Hz, CH3), 2.27 (s, 3H, CH3), 4.08 (q, 2H, J=7.0 Hz, CH2), 5.24 (bs, 2H, NH2), 6.14 (d, 1H, J=1.0 Hz, Ar), 6.32 (t, 1H, J=0.9 Hz, Ar), 7.06-7.10 (m, 3H, Ar), 7.29-7.34 (m, 2H, Ar), 7.51-7.54(m, 2H, Ar), 7.67 (s, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[N:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][C:69](O)=[O:70])=[C:64]([F:72])[CH:63]=1>CN(C)C(=O)C>[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][C:69]([NH:1][C:2]2[CH:3]=[CH:4][N:5]([CH3:27])[C:6]3[C:7]=2[CH:8]=[N:9][C:10]2[N:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:18][CH:17]=[C:12]4[NH:13][C:14](=[O:16])[C:15]=3[C:11]=24)=[O:70])=[C:64]([F:72])[CH:63]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1F
Reactant: CN1C=CC(N)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN1C=CC(NC(=O)Cc2ccc(Cl)cc2F)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1

Procedure:
A stock solution of Example 14e and N,N-diisopropylethylamine (0.11 M and 0.33 M in N,N-dimethylacetamide, respectively, 350 μL, 0.038 mmol Example 14e and 0.11 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.13 M in N,N-dimethylacetamide, 350 μL, 0.046 mmol), and 2-(4-chloro-2-fluorophenyl)acetic acid (0.40 M in N,N-dimethylacetamide, 113 μL, 0.050 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to yield the title compound as an impure mixture. The material was dissolved in methanol (1 mL) and manually injected into the HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0036 g (19%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.52 (d, J=2.75 Hz, 1H), 8.43 (d, J=2.75 Hz, 1H), 7.76 (s, 1H), 7.47 (t, J=8.24 Hz, 1H), 7.42 (dd, J=9.77, 1.83 Hz, 1H), 7.30 (dd, J=8.09, 1.68 Hz, 1H), 7.07 (s, 1H), 6.87 (m, 2H), 6.58 (m, 2H), 4.61 (s, 2H), 4.05 (s, 3H), 3.82 (s, 2H). MS (APCI+) m/z 532.0 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([OH:19])=[CH:8][CH:7]=2)([CH3:3])[CH3:2].[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([O:19][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[C:12]2[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)([CH3:26])[CH3:25])[CH3:21]
Reactant: CC(C)c1[nH]c2ccc(O)cc2c1-c1ccncc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C(C)C)c(-c3ccncc3)c2c1

Procedure:
The above compound was prepared from 2-isopropyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH:26]1[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]1>>[OH:32][CH:29]1[CH2:30][CH2:31][N:26]([C:22]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:25])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)=[O:24])[CH2:27][CH2:28]1
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: OC1CCNCC1
Product: CC1(C)c2cc(C(=O)N3CCC(O)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and piperidin-4-ol.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([CH3:21])[C:17](=O)[O:16]C(C)(C)[O:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[NH3:24]>>[F:1][C:2]([F:23])([F:22])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:14])([CH3:21])[C:17]([NH2:24])=[O:16])=[CH:9][CH:8]=1)(=[O:5])=[O:4]
Reactant: N
Reactant: CC1(C)OC(=O)C(C)(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)O1
Product: CC(O)(C(N)=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A solution of 4-(2,2,4-trimethyl-5-oxo-1,3-dioxolan-4-yl)phenyl trifluoromethanesulfonate (15.5 g, 0.044 mol) in ammonia solution (30 mL, 7N in methanol) was left under stirring overnight at room temperature. After solvent evaporation under vacuum a crude was obtained that, after purification by flash chromatography (CH2Cl2/MeOH 98:2) afforded pure 2-[4-(trifluoromethanesulfonyloxy)phenyl]-2-hydroxy propanamide (9.7 g, 0.031 mol) as a white solid. Yield 70%. mp 105-107° C. 1H-NMR (CDCl3) δ 7.80 (d, 2H, J=7 Hz), 7.35 (d, 2H, J=7 Hz), 6.50 (bs, 1H, CONH), 5.42 (bs, 1H, CONH), 3.05 (bs, 1H, OH), 1.94 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.COC(C1C=NC(OCC2C(C3C=CC(Cl)=CC=3)=NOC=2)=CN=1)=O>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]2[C:14]([CH2:13][O:12][C:9]3[N:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=3)=[C:18]([CH3:19])[O:17][N:16]=2)=[N:21][CH:22]=1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(Cl)cn3)noc2C)nn1
Agent: COC(=O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Product: Cc1onc(-c2ccc(Cl)cn2)c1COc1ccc(C(=O)O)nn1
Yield: 92.4 %

Procedure:
As described for example 112a, 6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (1.82 g, 4.9 mmol) was converted, instead of 5-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester, to the title compound (1.57 g, 93%) which was obtained as a white solid. MS: m/e=345.3 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].ClC1C=C(C=CC=1)C(OO)=[O:15]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]1[O:15][CH2:6]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cccc(Br)c1
Solvent: ClCCl
Product: Brc1cccc(C2CO2)c1
Reaction time: 18 h
Yield: 73.6 %

Procedure:
A solution of 3-bromostyrene (1.0 g, 5.46 mmol) in CH2Cl2 (10 mL) was cooled in an ice bath. 3-Chloroperoxybenzoic acid (57% pure) (1.82 g, 6.01 mmol) was added in one batch and the stirring was continued over 18 h. The reaction mixture was concentrated to a residue and diluted with CCl4 (20 mL). Precipitated m-chlorobenzoic acid was removed by filtration and the filtrate was washed with a 50:50 mixture of 5% aq. NaHCO3 and 5% aq. NaHSO3 (100 mL). The organic extract was dried over Na2SO4 and concentrated under reduced pressure to yield 0.80 g (64%) of product as a yellow oil. 1H NMR (CDCl3) δ2.74 (m, 1, CH), 3.14 (m, 1, CH--), 3.82 (m, 1, --CH--), 7.21 (m, 2, phenyl), 7.42 (m, 2, phenyl).
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]2[CH2:18][O:17][C:16]3([CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:19]3)[O:15]2)=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].[Li+].[OH-]>CO>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]2[CH2:18][O:17][C:16]3([CH2:22][CH2:21][CH:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19]3)[O:15]2)=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSCC2COC3(CCC(CC(=O)OCC)C3)O2)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCSCC2COC3(CCC(CC(=O)O)C3)O2)ccc(C(C)=O)c1O

Procedure:
The ester of Example 13 (4.87 g, 10 mmol) is stirred overnight at room temperature under N2 with aqueous LiOH solution (2M, 13 ml) in methanol (60 ml). The reaction is concentrated on a rotary evaporator and the residue diluted with water. The resulting solution is washed once with ethyl ether and then acidified to pH 2.5 with 0.5N KHSO4 solution. The aqueous mixture is extracted with ethyl acetate and the organic layer dried over MgSO4.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[O:27]([CH2:34][C:35](Cl)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:27]([CH2:34][C:35]([N:21]1[CH2:20][CH2:19][C:16]2([C:15](=[O:24])[N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=3)[CH2:18][CH2:17]2)[CH2:23][CH2:22]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)COc1ccccc1
Solvent: CC(=O)O
Product: O=C(COc1ccccc1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 7 step A from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and phenoxy-acetyl chloride. White solid. MS (ESI): 449.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][OH:14])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1.N1CCCC1>CO>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19](/[C:20](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:11][CH2:12][CH2:13][OH:14])/[C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1
Reactant: O=Cc1cc(Cl)ccc1OCCCO
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Cl)ccc1OCCCO
Temperature: 70 °C
Yield: 87.6 %

Procedure:
5-Chloro-2-(3-hydroxy-1-propoxy)-benzaldehyde (8 g, 37 mmol) and 6-chlorooxindole (6.2 g, 37 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (3 mL, 37 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration to give title compound as a yellow solid (Yield: 11.8 g).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[C:8]([O:10]CC)=[O:9])=[CH:4][N:3]=[CH:2]1>CO.Cl>[NH:3]1[CH:4]=[C:5]([C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[C:8]([OH:10])=[O:9])[N:1]=[CH:2]1
Reactant: CCOC(=O)c1ccccc1-c1cnc[nH]1
Agent: Cl
Solvent: CO
Product: O=C(O)c1ccccc1-c1c[nH]cn1
Temperature: 80 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a stirred solution of ethyl 2-(1H-imidazol-5-yl)benzoate (0.25 mmol) in MeOH, 2 mL of HCl solution (2 mL, 1.0M in MeOH) was added. The solution was allowed to stir at 80° C. for 24 h and then the solution was evaporated and purified by column chromatography to give the pure desired product in 86% yield. 1H NMR: 7.31-7.44 (m, 2H), 7.50 (t, 1H, J=7.2 Hz), 7.59 (d, 1H, J=7.6 Hz), 7.85 (d, 1H, J=7.2 Hz), 8.04 (br s, 1H)
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=O)[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:28])([CH3:27])[C:25]#[N:26])=[CH:20][C:19]=1[CH3:29])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[C:25]([C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH:16]([NH:15][C:12](=[O:14])[CH2:11][N:8]2[C:7]3[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=3[N:10]=[CH:9]2)[CH3:17])=[C:19]([CH3:29])[CH:20]=1)([CH3:27])[CH3:28])#[N:26]
Reactant: O=C(O)Cn1cnc2cccc(F)c21
Reactant: Cc1cc(C(C)(C)C#N)ccc1C(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(C(C)(C)C#N)ccc1C(C)NC(=O)Cn1cnc2cccc(F)c21
Yield: 62.7 %

Procedure:
To a solution of (7-fluoro-1H-benzimidazol-1-yl)acetic acid (250 mg, 1.29 mmol) prepared according to scheme 5, 2-[4-(1-aminoethyl)-3-methylphenyl]-2-methylpropanenitrile (260 mg 1.29 mmol) prepared according to scheme 15 and DMAP (156 mg, 1.29 mmol) stirred in anhydrous DMF (4.0 mL) is added HATU (490 mg, 1.29 mmol) after 18 hours of stirring, the mixture is diluted with Methanol (200 μL) the solution is purified directly on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product (+) and (−)-N-{1-[4-(1-cyano-1-methylethyl)-2-methylphenyl]ethyl}-2-(7-fluoro-1H-benzimidazol-1-yl)acetamide (306 mg, 63%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.44 (d, J=6.84 Hz, 3H) 1.66 (s, 6H) 2.35 (s, 3H) 5.02-5.14 (m, 2H) 5.19 (q, J=7.03 Hz, 1H) 6.99 (dd, J=11.52, 7.42 Hz, 1H) 7.19 (dt, J=8.15, 4.98 Hz, 1H) 7.26 (d, J=2.15 Hz, 1H) 7.32 (dd, J=8.01, 2.34 Hz, 3H) 7.39 (d, J=8.20 Hz, 1H) 7.45 (d, J=7.62 Hz, 1H) 8.09 (s, 1H), MS [M+H], calcd: 379.2. found: 379.2.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23]>>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:8]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: O=[N+]([O-])c1ccc(Cn2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (382 mg, 1 mmol) was treated as described in general procedure K using 4-nitrobenzyl bromide (432 mg, 2 mmol) to give 2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-1-(4-nitro-benzyl)-1H-imidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[C:8]([C:18]4[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=4)[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][O:28][CH2:29][CH2:30]Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:24][C:21]1[N:20]=[CH:19][C:18]([C:8]2[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]3[NH:12][C:13]4[C:5]([C:6]=3[CH:7]=2)=[CH:4][CH:3]=[C:2]([N:1]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:14]=4)=[CH:23][CH:22]=1
Reactant: ClCCOCCCl
Reactant: Cc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(N)ccc4c3c2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(N5CCOCC5)ccc4c3c2)cn1
Temperature: 200 °C

Procedure:
7-Amino-3-(6-methylpyridin-3-yl)-9H-carbazole-1-carboxamide (134 mg, 0.284 mmol), 1-chloro-2-(2-chloroethoxy)ethane (101 mg, 0.709 mmol) and Na2CO3 (180 mg, 1.703 mmol) were mixed with DMF (4 mL) in a sealed microwave vial. The mixture was heated in microwave at 200° C. for 2 hrs. The mixture was filtered and then purified using preparative HPLC to give titled product. MS (ESI) m/z 387.00 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.16 (s, 1H), 8.97 (s, 1H), 8.53 (s, 1H), 8.3 (s, 1H), 8.18 (s, 1H), 8.15 (dd, 1H, J=8.0, 2.5), 8.05 (d, 1H, J=8.5), 7.51 (s, 1H), 7.37 (d, 1H, J=8.2), 7.24 (s, 1H), 6.94 (d, 1H, J=8.6), 3.8 (m, 4H), 3.19 (m, 4H), 2.53(s, 3H).
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[S:16][C:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[N:18][N:19]=1>[Cu]I>[N:23]1[CH:22]=[CH:21][C:20]([C:17]2[S:16][C:15]([N:3]3[CH2:4][C@:5]4([CH:10]5[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]5)[CH2:6]4)[O:1][C:2]3=[O:13])=[N:19][N:18]=2)=[CH:25][CH:24]=1
Reactant: Brc1nnc(-c2ccncc2)s1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Agent: [Cu]I
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1nnc(-c2ccncc2)s1

Procedure:
The compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-bromo-5-(4-pyridyl)-1,3,4-thiadiazole using 5 equivalents of copper (I) iodide. The title compound was obtained as a beige solid, m/z 344 (MH+).