Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([OH:30])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.Br[CH:32]1[CH2:36][CH2:35][N:34]([CH3:37])[C:33]1=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([O:30][C@@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(Oc3ccc(C(=O)N4CCC4)nc3)c2)cn1
Reactant: CN1CCC(Br)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@@H]3CCN(C)C3=O)c2)cn1
Temperature: 25 °C
Reaction time: 21 h
Yield: 76 %

Procedure:
3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (442 mg, 1.1 mmol) (Intermediate 1) and 3-bromo-1-methyl-pyrrolidin-2-one (385 mg, 2.2 mmol) (Intermediate 4) were dissolved in DMF and treated with potassium carbonate (377 mg, 2.7 mmol) and stirred at room temperature for 21 hours. The DMF was evaporated, the residue was partitioned between ethyl acetate (90 mL) and water (20 mL). The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give an oil which was purified by chromatography on silica eluting with 0-6% methanol in DCM to give the racemic product (420 mg). 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide was separated from its enantiomer by chiral HPLC using a Merck 50 mm 20 μm Chiralcel OJ No. CE001 column eluting with methanol at a flow rate of 50 mL/min; 420 mg of racemic material was separated in 3 injections of 15 mL at 11 mg/ml in 1:1:1 acetonitrile/ethanol/methanol to afford the product (187 mg, 33%) which eluted before its enantiomer. 1H NMR δ (400 MHz, CDCl3): 2.08-2.18 (m, 1H), 2.28 (quintet, 2H), 2.47-2.57 (m, 1H), 2.48 (s, 3H), 2.86 (s, 3H), 3.29-3.37 (m, 1H), 3.42-3.48 (m, 1H), 4.18 (t, 2H), 4.64 (t, 2H), 4.86 (t, 1H), 6.91 (s, 1H), 7.14 (s, 1H), 7.32 (d, 1H), 7.39 (s, 1H), 8.05 (d, 1H), 8.07 (s, 1H), 8.26 (s, 1H), 8.37 (s, 1H), 9.45 (s, 1H); m/z 503 (M+H)+
Reaction SMILES: [CH3:1][C:2]12[C:23](=[O:24])[CH2:22][CH2:21][CH:3]1[CH:4]1[C:9]([CH2:10][CH2:11]2)=[C:8]([CH2:12][CH2:13][C:14]2([CH3:19])[O:18][CH2:17][CH2:16][O:15]2)[C:7](=[O:20])[CH2:6][O:5]1.C(=O)(O)[O-:26].[Na+]>ClCCl>[CH3:1][C:2]12[C:23](=[O:24])[CH2:22][CH2:21][CH:3]1[CH:4]1[CH:9]3[CH:10]([O:26][C:8]3([CH2:12][CH2:13][C:14]3([CH3:19])[O:15][CH2:16][CH2:17][O:18]3)[C:7](=[O:20])[CH2:6][O:5]1)[CH2:11]2
Reactant: O=C([O-])O
Reactant: CC1(CCC2=C3CCC4(C)C(=O)CCC4C3OCC2=O)OCCO1
Agent: [Na+]
Solvent: ClCCl
Product: CC1(CCC23OC4CC5(C)C(=O)CCC5C(OCC2=O)C43)OCCO1
Temperature: -30 °C
Reaction time: 16 h

Procedure:
A solution of 70% meta-perobenzoic acid (939 mg, 3.8 mmol) in dichloromethane (20 mL) was added dropwise to a suspension of 3a-methyl-6-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-1,2,4,5,9a,9b-hexahydro-3aH-9-oxa-cyclopenta[a]naphthalene-3,7-dione (800 mg, 2.53 mmol) and sodium bicarbonate (213 mg, 3.8 mmol) in dichloromethane (51 mL) at −30° C. The resulting mixture was stirred at −30° C. for 16 h. The reaction was then quenched with saturated solution of sodium thiosulfate. The resulting mixture was treated with saturated sodium carbonate solution and then extracted with dichloromethane (2×50 mL). The combined organic layer was dried with magnesium sulfate. The resulting solution was filtered and concentrated to yield the title compound as a white foam.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[OH:34][CH2:35][CH2:36][CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][CH:37]([CH2:36][CH2:35][OH:34])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: OCCC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(CCO)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-(2-hydroxyethyl)-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.69 (m, 1H), 4.16 (s, 1H), 3.89 (m, 1H), 3.70 (m, 2H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.15 (m, 3H), 1.03 (m, 1H), 0.83 (d, 3H), 0.74 (m, 1H). m/z: 446 [M+H]
Reaction SMILES: C1COCC1.[C:6]1([CH:12]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:13]2[N:14]=[N:15][N:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li]CCCC.[CH:41]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]([CH3:52])[CH3:51])[C:45]=1[N:53]=[C:54]=[O:55])([CH3:43])[CH3:42]>O>[CH3:43][CH:41]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]([CH3:51])[CH3:52])[C:45]=1[NH:53][C:54](=[O:55])[C:12]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:13]1[N:14]=[N:15][N:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:17]=1)[CH3:42]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCCCCCn1nnc(C(c2ccccc2)c2ccccc2)n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCn1nnc(C(C(=O)Nc2c(C(C)C)cccc2C(C)C)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
To a THF solution (30 mL) of 5-(diphenylmethyl)-2-dodecyl-2H-tetrazole (1.0 g, 0.0025 mol) at -30° C. under a nitrogen atmosphere with stirring was added n-BuLi (1.62 mL, 1.6M in hexanes, 0.0026 mol). The resulting deep-red solution was stirred for 30 minutes before a THF solution (10 mL) of 2,6-diisopropylphenylisocyanate (0.53 mL, 0.0024 mol) was added dropwise over 10 minutes. The resulting yellow solution was allowed to warm to room temperature over 24 hours. Water (10 mL) was then added and the solution partitioned between ethyl acetate and water. The organic extract was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo to yield a yellow oil which was flash chromatographed (5% EtOAc-Hex as eluant, SiO2) to yield 1.16 g of the title product as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH:47]([C:49](=[O:72])[CH2:50][CH2:51][C@@H:52]([NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])[CH2:53][C:54]1[CH:55]=[N:56][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:58][CH:59]=1)[NH2:48]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:5]([NH:48][NH:47][C:49](=[O:72])[CH2:50][CH2:51][C@@H:52]([NH:64][C:65](=[O:71])[O:66][C:67]([CH3:68])([CH3:69])[CH3:70])[CH2:53][C:54]2[CH:55]=[N:56][C:57]([C:60]([F:61])([F:62])[F:63])=[CH:58][CH:59]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)NN)Cc1ccc(C(F)(F)F)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)NNC(=O)c1ccc([N+](=O)[O-])c(F)c1)Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 262.3 %

Procedure:
A mixture of 3-fluoro-4-nitrobenzoic acid (130 mg, 701 μmol) (commercially available from 3B Scientific Corporation Product List (Order Number 3B3-068221)), HATU (267 mg, 701 μmol), and N,N-diisopropylethylamine (132 μL, 760 μmol) in DMF (4 mL) was stirred at room temperature for 1 hour. This mixture was added dropwise to a mixture of tert-butyl ((1R)-4-hydrazino-4-oxo-1-((6-(trifluoromethyl)-3-pyridinyl)methyl)butyl)carbamate (220 mg, 585 μmol), prepared as shown in Scheme 24, and N,N-diisopropylethylamine (132 μL, 760 μmol) in DMF (3 mL) and the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the remaining residue partitioned between saturated aqueous NaHCO3 (20 mL) and DCM (20 mL). The layers were separated and the aqueous layer was extracted with DCM (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting colorless solid was dissolved in MeOH/DCM, absorbed onto silica gel and purified by flash chromatography (silica gel, 2% to 8% MeOH/DCM) to provide tert-butyl ((1R)-4-(2-((3-fluoro-4-nitrophenyl)carbonyl)hydrazino)-4-oxo-1-((6-(trifluoromethyl)-3-pyridinyl)methyl)butyl)carbamate (834 mg, 77%) as a light yellow solid. LCMS (API-ES) m/z: 566.0 (M+Na+).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].FC(F)(F)C1C=C(O)C=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[OH:31]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[O:31][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: Oc1cc(Cl)ccc1Cl
Agent: Oc1cccc(C(F)(F)F)c1
Product: O=C(O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl

Procedure:
2-(2,5-Dichloro-phenoxy)-5-fluoro-nicotinic acid was prepared in analogy to Example 1, Step 1, replacing 2-chloro-nicotinic acid with 2-chloro-5-fluoro-nicotinic acid ([CAS RN 38186-88-8]) and 3-trifluoromethyl-phenol with 2,5-dichloro-phenol ([CAS RN 583-78-8]). 1H NMR (400 MHz, DMSO): δ7.38 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 8.23 (dd, J=8.1 Hz, J=3.2 Hz, 1H), 8.34 (d, J=3.2 Hz, 1H), 13.65 (s, 1H). 19F NMR (376.5 MHz, DMSO): −134.6. MS (ISN): 302.0 [M−H]−.
Reaction SMILES: FC1C=CC([N:8](CC2C=CC=CN=2)[C:9](=O)[C:10]2[CH:15]=[CH:14][C:13](Cl)=[N:12][CH:11]=2)=CC=1.[SH2:25].[Na]>CN(C)C=O.C(OCC)(=O)C>[C:9]([NH2:8])(=[S:25])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1
Reactant: S
Reactant: O=C(c1ccc(Cl)nc1)N(Cc1ccccn1)c1ccc(F)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=S)c1cccnc1
Reaction time: 1 h
Yield: 82 %

Procedure:
In a round bottom flask, N-(4-fluoro-phenyl)-N-pyridin-2-ylmethyl-6-chloro-nicotinamide intermediate X (1.078 g, 3.16 mmol) and anhydrous sodium hydrogen sulfide (0.354 g, 6.32 mmol) was suspended in anhydrous dimethylformamide (10 mL). The suspension was heated to reflux, and the reaction mixture turned a deep green color. After 1 h, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (20 mL). The aqueous layer was back extracted with ethyl acetate (2×20 ml), and the organic layers combined and washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and evaporated by rotary evaporation to yield 0.88 g (82%) of thionicotinamide intermediate XI as a dark yellow oil. TLC (EtOAc/hexanes, 2:1) Rf=0.1; ESI-MS m/z=339.9 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH3:13])[CH:6]=[C:7]([I:10])[C:8]=1[OH:9].Cl.[CH3:16][O:17][NH2:18].C>N1C=CC=CC=1.C(O)C>[CH3:16][O:17][N:18]=[C:11]([C:5]1[CH:6]=[C:7]([I:10])[C:8]([OH:9])=[C:3]([CH2:2][NH2:1])[CH:4]=1)[CH2:12][CH3:13]
Reactant: CCC(=O)c1cc(I)c(O)c(CN)c1
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCC(=NOC)c1cc(I)c(O)c(CN)c1
Yield: 54.8 %

Procedure:
To a solution of 2.0 g of 3'-aminomethyl-4'-hydroxy5'-iodopropiophenone in 15 ml of pyridine and 7 ml of ethanol is added 1.4 g of O-methylhydroxylamine hydrochloride, and the mixture is refluxed with heating for 45 minutes. The reaction mixture is treated with activated charcoal and filtered. The filtrate is concentrated under reduced pressure and to the residue is added ice-cold water. To the mixture is added 1.4 g of sodium hydrogencarbonate and stirred. The precipitated crystals are collected by filtration, washed with water and then recrystallized from methanol to give 1.2 g of 3'-aminomethyl-4'-hydroxy-5'-iodopropiophenone O-methyloxime, melting at 156°-157° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:18])([CH3:17])[O:6][CH:7]([CH2:15][CH3:16])[CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH:12]=[CH:11]1)([CH3:4])[CH3:3].[Cl:19][C:20](Cl)([Cl:24])[C:21](Cl)=[O:22].P(Cl)(Cl)(Cl)=O>CCOCC.[Zn].[Cu]>[Cl:19][C:20]1([Cl:24])[CH:12]2[CH:11]([CH:10]([CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:2]([CH3:3])([CH3:1])[CH3:4])([CH3:17])[CH3:18])[CH2:15][CH3:16])[CH2:14][CH2:13]2)[C:21]1=[O:22]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCC(CCC1C=CCC1)O[Si](C)(C)C(C)(C)C
Agent: [Cu]
Agent: [Zn]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCC(CCC1CCC2C1C(=O)C2(Cl)Cl)O[Si](C)(C)C(C)(C)C
Yield: 62.5 %

Procedure:
In the next step, the procedure of Example 6C is used, but there are substituted: 3-(3-[(1,1-dimethylethyl)dimethylsiloxy]pent-1-yl)cyclopentene ([3-(2-cyclopenten-1-yl)-1-ethylpropoxy](1,1-dimethylethyl)dimethylsilane) (15 g, 0.056 moles) dissolved in ether (100 ml), trichloroacetyl chloride (20.3 g, 0.11 moles) and phosphorous oxychloride (17.2 g, 0.11 moles) both dissolved in ether (50 ml), zinc/copper couple (10 g, 0.16 moles). The crude product is subjected to short path vacuum distillation leaving a clear yellow oil (13.5 g, 0.035 moles) of 7,7-dichloro-4-[3-[[1,1-dimethylethyl)dimethylsilyloxy]pentyl]bicyclo[3.2.0]heptan-6-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](Br)=[C:9]([S:12]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=3)(=[O:14])=[O:13])[S:8][C:5]2=[N:6][CH:7]=1.C(O)C.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:27])[CH:33]=3)=[C:9]([S:12]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=3)(=[O:14])=[O:13])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: N#Cc1cc(F)cc(S(=O)(=O)c2sc3ncc(N)cc3c2Br)c1
Reactant: OB(O)c1cccc(Cl)c1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1cc(F)cc(S(=O)(=O)c2sc3ncc(N)cc3c2-c2cccc(Cl)c2)c1

Procedure:
5-Amino-3-bromo-2-(3-cyano-5-fluoro-benzenesulfonyl)-thieno[2,3-b]pyridine (1.25 g, 30 mmol) was dissolved in toluene (18 ml) and ethanol (20 ml) under argon atmosphere. To the solution Pd(PPh3)4 (175 mg, 0.15 mmol), 3-chlorophenylboronic acid (0.58 g, 37 mmol) and 2M solution of Na2CO3 (15 ml) was added. The reaction mixture was refluxed for 1 hour then it was filtered through celite and washed with toluene (2×5 ml). The filtrate was tightened in vacuum; water (13 ml) and ethyl acetate (13 ml) were added to the residue. It was separated and the water phase was extracted with ethyl acetate (2×5 ml). The organic phase was washed with water (5.0 ml), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (Kieselgel 60, ethyl acetate:hexane=2:1) to yield the title compound which was purified by stirring with methanol (5 ml) to give 0.84 g (63%) yellow amorphous material. LC-MS: (M+H)+ 444.2. 1H NMR (400 MHz, DMSO-d6, 25° C.): 5.68 (s, 2H); 6.80 (d, J=2.6 Hz, 1H); 7.13-7.22 (m, 2H); 7.53 (t, J=7.9 Hz, 1H); 7.56-7.65 (m, 3H); 8.24 (dm, J=8.4 Hz, 1H); 8.27 (d, J=2.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23](C)(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:7]=1.C(B(CC)CC)C.C([O-])(=O)C.[Na+].[NH2:39]OS(O)(=O)=O>C1COCC1.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:39])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:5]=[N:4][CH:3]=1
Reactant: NOS(=O)(=O)O
Reactant: Cc1cncc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)c1
Agent: CC(=O)[O-]
Agent: CCB(CC)CC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cncc(-c2nc(C(F)(F)F)cn2-c2ccc(S(N)(=O)=O)cc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 9.6 %

Procedure:
To a solution of 3-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (Example 41) (1.9 mmol) in 25 mL of dry THF was added n-Bu4MgCl (3.8 mL of 2.0M THF solution, 7.5 mmol) slowly at 0° C. After stirring for additional 15 minutes, the solution was stirred at room temperature for 2 hours. The reaction mixture was re-cooled to 0° C. and triethylborane (9.5 mL of 1.0M THF solution, 9.5 mmol) was added. After stirring at for 2 hours, the mixture was heated to reflux for 72 hours. The reaction mixture was cooled to room temperature and treated with a solution of sodium acetate (2.3 g) in 10 mL of water. After stirring for 5 minutes, hydroxylamine-O-sulfonic acid (2.3 g) was added and the mixture was stirred for 20 hours. The reaction mixture was extracted with ether (2×100 mL). The ethereal layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (isopropanol/toluene, 5:95) to give 0.07 g of 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl) -1H-imidazol-1-yl]benzenesulfonamide as a colorless solid (8%): mp 242°-243° C. Anal. Calc'd. For C16H13F3N4O2S: C, 50.26, H, 3.43, N, 14.65, S, 8.39. Found: C, 50.02, H, 3.63, N, 14.26, S, 8.41.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([C:21]3[C:26]([F:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:29](O)=[O:30])[CH2:12]1)(=[O:10])=[O:9].[NH2:32][C@@H:33]([CH2:42][CH2:43][CH3:44])[C@H:34]([OH:41])[C:35]([NH:37][CH:38]1[CH2:40][CH2:39]1)=[O:36]>>[Cl:28][C:24]1[CH:25]=[C:26]([F:27])[C:21]([C:18]2([C:16]([N:14]3[CH2:15][C@H:11]([S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:9])=[O:10])[CH2:12][C@H:13]3[C:29]([NH:32][C@@H:33]([CH2:42][CH2:43][CH3:44])[C:34](=[O:41])[C:35]([NH:37][CH:38]3[CH2:40][CH2:39]3)=[O:36])=[O:30])=[O:17])[CH2:20][CH2:19]2)=[N:22][CH:23]=1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide in step 1. MS (m/e)=653.14 [M+H+].
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:27]1[N:32]=[C:31]([N:33]2[CH2:38][CH2:37][CH:36]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:35][CH2:34]2)[CH:30]=[N:29][CH:28]=1)CCC>CN(C=O)C.[Cu]I.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:42]([O:41][C:40]([NH:39][CH:36]1[CH2:37][CH2:38][N:33]([C:31]2[N:32]=[C:27]([C:2]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=4)[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:3]=3)[CH:28]=[N:29][CH:30]=2)[CH2:34][CH2:35]1)=[O:46])([CH3:45])([CH3:43])[CH3:44]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Reactant: COC(=O)c1ccc2c(c1)c(I)cn2C(=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: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)c(-c1cncc(N3CCC(NC(=O)OC(C)(C)C)CC3)n1)cn2C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
A mixture of 1-tert-butyl 5-methyl 3-iodo-1H-indole-1,5-dicarboxylate (6 g, 14.96 mmol) and tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-4-ylcarbamate (1d) (10.2 g, 17.95 mmol) in DMF (60 mL) was purged with argon gas for 5 min, added CuI (4.27 g, 22.44 mmol), palladium tetrakis (1.7 g, 1.5 mmol) and again purged with argon gas for 5 min. The reaction mixture was stirred at 90° C. under nitrogen atmosphere for 1 h. The reaction mixture was then poured into water. The resulting precipitate was collected by filtration. The filtrate was extracted with diethyl ether. The organic layer was concentrated and combined with the above precipitate to give the crude product. Purification was carried out by column chromatography to obtain the title compound as a brown solid (2.5 g, 30%). MS (ESI, pos. ion) m/z: 552.2 (M+1).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:20])[N:2]([NH:1][C:30](=[O:31])[CH2:29][C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=3)[N:11]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(Cc2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(Cc2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 144A and 2-(3,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.68 (s, 1H), 8.32 (dd, J=7.9, 1.4 Hz, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.91-7.95 (m, 1H), 7.85-7.89 (m, 1H), 7.32-7.38 (m, 4H), 7.11-7.19 (m, 3H), 4.33 (s, 2H), 3.76 (s, 2H); LC/MS (APCI) M/Z 440 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]2[N:6]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[N:8][C:4]=2[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:28][C:29](N(C)C)=[O:30]>O1CCCC1.CCCCCCC>[CH3:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]2[N:6]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:16])[CH3:15])[C:7]([C:29](=[O:30])[CH3:28])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(=O)N(C)C
Reactant: Cc1cc2ncn(COCC[Si](C)(C)C)c2cc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(=O)c1nc2cc(C)c(C)cc2n1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole [5.01 g, Reference Example 4(a)] in dry tetrahydrofuran (55 mL), at −78° C., was treated with a solution of lithium diisopropylamide in a mixture of tetrahydrofuran and heptane (11.9 mL, 2M) over 10 minutes. The mixture was stirred for 15 minutes then treated dropwise with dimethylacetamide (2.15 mL) over 10 minutes. After stirring at −78° C. for a further 30 minutes the reaction mixture was poured into ice (50 g) and then left until all the ice had melted. This mixture was extracted with dichloromethane and the extracts were washed with brine, then with water, then dried over magnesium sulfate and then evaporated. The residual orange oil (5.91 g) was subjected to column chromatography on silica eluting with a mixture of petroleum ether and ethyl acetate (4:1, v/v) to give 1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone (3.93 g) as a yellow crystalline solid.