Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:31](I)=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:33].[NH:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39].CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[NH2:1][C:2]1[C:31]([N:34]2[CH2:38][CH2:37][CH2:36][C:35]2=[O:39])=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:33]
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(I)c4)CS(=O)(=O)C[C@@H]32)c1
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(N5CCCC5=O)c4)CS(=O)(=O)C[C@@H]32)c1
Temperature: 115 °C

Procedure:
To a solution of (3aR,7S,7aS)-7-(4-amino-3-fluoro-5-iodo-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (0.10 g, 0.17 mmol), 2-pyrrolidin-one (0.02 mL, 0.26 mmol) and N,N′-dimethylethylenediamine (0.002 mg, 0.017 mmol) in dioxane (10 mL) was added CuI (0.002 g, 0.009 mmol) and K3PO4 (0.077 g, 0.36 mmol) and the reaction mixture was heated at 115° C. for 4 h. The reaction mixture was filtered over Celite and concentrated. The crude product was purified on the flashmaster (10 g silicagel, cyclohexane-EtOAc 100:0 to 0:100) to yield the title compound as a yellow solid, which was directly used as such in the next step: HPLC RtC=4.728 min; ESIMS [M+H]+=544.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH:12]1[CH2:16][CH2:15][CH2:14]C1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(N)CCC1.[Si](OCC=O)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][NH:11][CH:12]1[CH2:16][CH2:15][CH2:14]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CCCC1
Agent: CC(C)(C)[Si](C)(C)OCC=O
Agent: NC1CCC1
Product: CC(C)(C)[Si](C)(C)OCCNC1CCC1

Procedure:
This compound was prepared following the same method as described for [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopentyl-amine (8e) from cyclobutylamine (1 g, 14.27 mmol) and 2-(tert-butyl-dimethylsilanyloxy)acetaldehyd (2.6 mg, 14.26 mmol). The product was obtained as a yellow gummy mass (400 mg, 12.22%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[Cl:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([F:47])=[CH:44][CH:45]=[CH:46][C:41]=2[Cl:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: OB(O)c1c(F)cccc1Cl
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3Cl)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-6-fluorophenyl)boronic acid gave 328. 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 7.69 (s, 1H), 7.58-7.51 (m, 1H), 7.49-7.45 (m, 1H), 7.40-7.33 (m, 1H), 7.00-6.60 (m, 2H), 4.74 (dd, J=11.1, 3.6 Hz, 1H), 4.41-4.23 (m, 1H), 4.16-3.86 (m, 2H), 3.76 (s, 3H), 2.07-1.97 (m, 1H), 1.89-1.77 (m, 1H), 1.69 (d, J=9.1 Hz, 2H). LCMS (ES+) m/z 483 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:15][C@@H:14]([O:16][CH2:17][CH:18]=[CH2:19])[CH2:13][N:12]2[CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:9]C(=O)[NH:7]1.FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@@H](OCC=C)CN2)OC(=O)N1.[Br-].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:17]([O:16][C@H:14]1[CH2:13][N:12]([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:11]([C@@H:10]([OH:9])[C@@H:6]([NH2:7])[CH2:5][C:4]2[CH:34]=[C:35]([F:37])[CH:36]=[C:2]([F:1])[CH:3]=2)[CH2:15]1)[CH:18]=[CH2:19]
Reactant: C=CCO[C@@H]1C[C@H]([C@H]2OC(=O)N[C@H]2Cc2cc(F)cc(F)c2)N(C(c2ccccc2)c2ccccc2)C1
Agent: C=CCO[C@H]1CN[C@@H]([C@H]2OC(=O)N[C@H]2Cc2cc(F)cc(F)c2)C1
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)N(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 87 %

Procedure:
Step C (9): (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4R)-4-(allyloxy)-1-benzhydrylpyrrolidin-2-yl)oxazolidin-2-one. A mixture of (4S,5R)-4-(3,5-difluorobenzyl)-5-((2R,4R)-4-(allyloxy)pyrrolidin-2-yl)oxazolidin-2-one (Step C (8), 2.03 g, 6.0 mmol), benzylhydryl bromide (2.22 g, 9.0 mmol), and potassium carbonate (1.24 g, 9.0 mmol) in acetonitrile (40 mL) was stirred at reflux for 35 min. After cooling to rt, the mixture was filtered and concentrated in vacuo. The crude mixture was purified by Flash Chromatography (silica gel, 0-7.5% methanol/chloroform) to give a slightly yellow oil as the title compound (2.64 g, 87% yield): 1H NMR (CDCl3, 300 MHz) δ 1.95-2.23 (2H, m), 2.36 (1H, t, J=12 Hz), 2.70 (1H, m), 3.02 (2H, d, J=6 Hz), 3.48 (1H, m), 3.71-3.99 (4H, m), 4.70 (1H, s), 4.78 (1H, t, J=6 Hz), 4.93 (1H, s), 5.12 (1H, m), 5.22 (1H, dd, J=3, 18 Hz), 5.84 (1H, m), 6.49 (1H, d, J=6 Hz), 6.67 (1H, m), 7.20-7.39 (11H, m).
Reaction SMILES: S([O-])(O)=O.[Na+].[CH2:6]([O:8][C:9]([C:11]1[NH:12][C:13]([CH3:19])=[C:14]([CH:17]=O)[C:15]=1[CH3:16])=[O:10])[CH3:7].[O:20]([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([NH2:34])[CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[CH2:6]([O:8][C:9]([C:11]1[NH:12][C:13]([CH3:19])=[C:14]([C:17]2[NH:34][C:29]3[CH:28]=[C:27]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:32]=[CH:31][C:30]=3[N:33]=2)[C:15]=1[CH3:16])=[O:10])[CH3:7]
Reactant: CCOC(=O)c1[nH]c(C)c(C=O)c1C
Reactant: Nc1ccc(Oc2ccccc2)cc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1[nH]c(C)c(-c2nc3ccc(Oc4ccccc4)cc3[nH]2)c1C
Temperature: 110 °C
Reaction time: 18 h
Yield: 75.6 %

Procedure:
Sodium hydrogensulfite (0.87 g, 8.4 mmol) and 3,5-dimethyl-4-formylpyrrole-2-carboxylic acid ethyl ester (1.64 g, 8.4 mmol) were added to an N,N-dimethyl acetamide (25 ml) solution of 4-phenoxy-1,2-phenylenediamine (1.60 g, 8.0 mmol) reported in the references, and the reaction mixture was heated to 110° C. and stirred for 18 hours. The reaction mixture was allowed to cool to room temperature, and a 5% sodium carbonate was added. The mixture was extracted with ethyl acetate, and the extract was washed with water and a saturated sodium chloride, and then dried with anhydrous sodium sulfate. The desiccant was filtered off, and then the residue obtained by evaporation at reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:100 to 1:30) to afford 4-(5-phenoxybenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxylic acid ethyl ester (2.27 g, 76%) as a light yellow solid.
Reaction SMILES: C([C:5]#[C:6][CH2:7][O:8][CH2:9][C:10]#[C:11][C:12]#CCC)#CCC.[CH3:16][O:17][C:18]([C:20]#[C:21][C:22]([O:24][CH3:25])=[O:23])=[O:19]>C1(C)C=CC=CC=1>[CH2:7]1[C:6]2[CH:5]=[C:21]([C:22]([O:24][CH3:25])=[O:23])[C:20]([C:18]([O:17][CH3:16])=[O:19])=[CH:12][C:11]=2[CH2:10][CH2:9][O:8]1
Reactant: COC(=O)C#CC(=O)OC
Reactant: CCC#CC#CCOCC#CC#CCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(cc1C(=O)OC)COCC2
Temperature: 105 °C
Yield: 19.2 %

Procedure:
A mixture of 3-butynyl-2-propynyl ether (37.2 g, 0.344 mol), dimethylacetylenedicarboxylate (48.9 g, 0.344 mol) and toluene is divided into 2 portions and transferred to 2 addition funnels connected to the reaction vessel. The apparatus is fitted with a condenser and evacuated 4 times with a Firestone valve and nitrogen. The cobalt catalyst is added in equal amounts to each addition funnel. The reaction vessel which contains approximately 2L toluene is heated to 105° C. under a nitrogen atmosphere with stirring. The contents of the addition funnels are added dropwise at equivalent rates, at 105° C., over a 4 hour period. The reaction mixture is stirred overnight at 100° C. under a heat lamp (Visible light), cooled to room temperature and filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a brown oil, which is flash chromatographed (silica gel, 95% hexane:ether acetate eluent) to afford the title product as a pale orange solid (16.5 g, 19.2%) identified by NMR analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([NH2:17])=S)=[CH:4][CH:3]=1.O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C.[OH-].[K+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]#[N:17])=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ccccc1-c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CNc1ccccc1-c1ccc(F)cc1

Procedure:
A mixture of N-(4'-fluoro-2-biphenylyl)thiourea (1.4 g), lead acetate trihydrate (2.15 g) and potassium hydroxide (3.18 g) in water (60 ml) was heated at 90°-95° C. for 1 hour to yield 4'-fluoro-2-biphenylylcyanamide as a colourless solid (m.p. 95°-96° C.).
Reaction SMILES: [C:1]([N:6]=[C:7]=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:9][C:10](=[N:13][OH:14])[CH2:11][CH3:12]>ClCCCl>[C:1]([NH:6][C:7]([O:14][N:13]=[C:10]([CH2:11][CH3:12])[CH3:9])=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCC(C)=NO
Reactant: C=C(C)C(=O)N=C=O
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)ON=C(C)CC
Yield: 95.9 %

Procedure:
To a solution of methacryloyl isocyanate (2.22 g; 20 mmol) in 1,2-dichloroethane (7.7 g), methylethylketone oxime (1.74 g; 20 mmol) was dropwise added under nitrogen stream while cooling with ice. After completion of the addition, the solvent was removed under reduced pressure to give 2-methacryloylcarbamoyloxyiminobutane (3.80 g) as a pale yellow liquid. Viscosity, 4600 cp.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([S:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4cccc(Cl)c4)cc3)cc2C1=O

Procedure:
The compound of example 87 was prepared analogous to compound of example 77 by reaction of compound of example 6 with 3-chlorobenzene sulfonyl chloride. The compound of example 87 was used directly without isolation for the preparation of compound of example 88.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH:27]=[O:28]>O1CCCC1.C1(C)C=CC=CC=1.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[CH2:31]([O:30][C:26](=[O:29])[CH:27]([OH:28])[CH:13]([CH3:14])[C:12](=[O:15])[C:9]1[S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][CH:10]=1)[CH3:32]
Reactant: CCC(=O)c1cnc(-c2ccccc2)s1
Reactant: CCOC(=O)C=O
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(O)C(C)C(=O)c1cnc(-c2ccccc2)s1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 195.7 %

Procedure:
To a −78° C. solution of 0.26 g (1.2 mmol) of the above-prepared 1-(2-phenyl-thiazol-5-yl)-propan-1-one was added 0.24 g (1.4 mmol) of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran. The mixture was allowed to stir for 0.5 hours and then 0.38 g (1.5 mmol) of 1M chlorotitanium triisopropoxide in hexanes was added. The reaction was allowed to warm to −20° C. and stirred for 15 minutes. The reaction was recooled to. −78° C. and 0.25 g (0.24 mmol) of ethyl glyoxalate in toluene(50%) was added. The solution was warmed to room temperature and allowed to stir for 0.5 hours. The reaction was quenched with aqueous potassium sodium tartrate tetrahydrate and partitioned with ethyl acetate. The organic phase was twice washed with aqueous potassium sodium tartrate tetrahydrate, once with water, once with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 1:9 ethyl acetate:hexanes to give 0.15 g of the title compound (40%). 1H NMR (500 MHz, CDCl3) δ 8.42 (s, 1H) 8.01 (d, 2H) 7.48 (m, 3H) 5.8 (m, 1H) 4.27 (q, 2H) 3.75 (m, 1H) 3.28 (m, 1H) 1.37 (d, 3H) 1.26 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:30])[NH:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:31]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]n(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12

Procedure:
6-Chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (Intermediate 3B; 194 mg, 0.471 mmol), K2CO3 (132 mg, 0.955 mmol), and iodomethane (0.044 mL, 0.707 mmol) were stirred in DMF (5 mL) at room temperature for 2 h. Water was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated in MeOH to give 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine, which was carried onto the next step without further purification. MS ESI calc'd. For C26H20ClN3O [M+1]+ 426. found 426.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)[CH:12]([CH3:14])[CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[N:4]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C(=O)c1ccccc1
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1cc(C)c(N=C(c2ccccc2)C(C)C)c(C)c1
Temperature: 220 °C

Procedure:
2,4,6-Trimethylaniline (16.9 mL, 120 mmol, Aldrich) was mixed with isobutyrophenone (12.0 mL, 80 mmol, Acros) and p-TsOH (1.5 g, 8.0 mmol, Aldrich). The resulting mixture was heated for 10 h at 220° C. in a flask equipped with a Dean-Stark trap. Vacuum distillation afforded two fractions: 1. unreacted starting materials, 40–48° C./40 Pa; 2. product as a yellow oil, 98–108° C./13 Pa (6.2 g, 29.2%). 1H NMR (toluene-d8, 353 K) 7.28–6.78 (m, 4H); 6.62 (s, 2H); 2.96 (septet, 1H; J=6.7 Hz); 2.07 (s, 3H); 1.97 (s, 6H); 1.23 (d, 6H; J=6.7 Hz).
Reaction SMILES: C([Sn](Cl)(Cl)CCCC)CCC.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]([CH:24]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:25]OCC3CCCCC3)[C:22]3[CH:40]=[C:41]([F:45])[C:42]([F:44])=[CH:43][C:21]=3[N:20]=2)=[CH:15][CH:14]=1.[NH2:46][C:47]1[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][CH:48]=1.C1([SiH3])C=CC=CC=1>O1CCCC1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]([CH:24]([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)[CH2:25][NH:46][C:47]3[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][CH:48]=3)[C:22]3[CH:40]=[C:41]([F:45])[C:42]([F:44])=[CH:43][C:21]=3[N:20]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(NCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Temperature: 100 °C
Yield: 67 %

Procedure:
To a solution of 7 mg (0.023 mmol) dibutyltin dichloride in 1 ml tetrahydrofuran were added 0.10 g (0.23 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetaldehyde (Example 143, intermediate c), 0.038 g (0.23 mMol) 4-aminobenzonitrile (commercially available) and 0.06 ml (0.46 mmol) phenylsilane (commercially available). The pale yellow solution was heated to 100° C. under microwave irradiation for 21 min. The light yellow solution was treated with silica gel and the suspension evaporated to dryness. The remaining solid was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:0 to 70:30). The fractions containing the product were pooled and chromatographed a second time under the same conditions to give the title compound as a white solid (67%). MS (Turbo Spray): m/z=491.2 [M+H].
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]([O:16]C)=[O:15].[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:18][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2ccc(OC)cc2c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2ccc(C(=O)O)c(OC)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3.7 g (0.016 mole) of 1-hydroxy-7-methoxy-2-naphthalenecarboxylic acid, methyl ester and 2.9 g (0.021 mole) of anhydrous potassium carbonate in 20 ml of N,N-dimethylformamide under a nitrogen atmosphere was treated with 3.0 ml (6.8 g; 0.048 mole) of iodomethane. The mixture was stirred at room temperature for 24 hours, and then added to 150 g of ice/water. The crude intermediate ester was separated by extracting with dichloromethane (3×50 ml). The combined organic layers were washed with water (2×50 ml), dried (anhydrous magnesium sulfate) and evaporated (vacuum).
Reaction SMILES: Cl[C:2]1[C:7]2=[N:8][O:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH:23]=1)[C:17]([NH:19][CH2:20][CH2:21][F:22])=[O:18]>>[N:10]1[O:9][N:8]=[C:7]2[CH:2]=[C:3]([C:23]3[C:16]([C:17]([NH:19][CH2:20][CH2:21][F:22])=[O:18])=[CH:15][N:14]=[CH:13][CH:12]=3)[CH:4]=[CH:5][C:6]=12
Reactant: O=C(NCCF)c1cncc(Br)c1
Reactant: Clc1cccc2nonc12
Product: O=C(NCCF)c1cnccc1-c1ccc2nonc2c1

Procedure:
Starting from 4-chloro-benzo[1,2,5]oxadiazole and 5-bromo-N-(2-fluoro-ethyl)-nicotinamide. Beige powder. MS(ES−): 285 (M−1).
Reaction SMILES: [Br-].[OH:2][C@@H:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][C:12](=[O:19])[NH:13][C:14]3[CH:18]=CO[N:15]=3)([CH2:6][CH2:7]2)[CH2:4]1.[Br:20][CH2:21][C:22]([NH:24]C1C=NC=CN=1)=O>>[Br-:20].[OH:2][C@@H:3]1[CH:8]2[CH2:7][CH2:6][N+:5]([CH2:11][C:12](=[O:19])[NH:13][C:14]3[CH:18]=[N:24][CH:22]=[CH:21][N:15]=3)([CH2:10][CH2:9]2)[CH2:4]1
Reactant: O=C(CBr)Nc1cnccn1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1cnccn1

Procedure:
This compound is prepared by an analogous method to (R)-3-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate A) by replacing 2-bromo-N-isoxazol-3-yl-acetamide with 2-bromo-N-pyrazin-2-yl-acetamide [H(i)].
Reaction SMILES: CC1C=NN([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27](=[O:35])[CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[S:25])=[CH:19][CH:18]=3)[CH:8]=2)C=1.CC1C=NNC=1.[CH3:42][C:43]1[CH:47]=[C:46]([CH3:48])[NH:45][N:44]=1>>[CH3:42][C:43]1[CH:47]=[C:46]([CH3:48])[N:45]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27](=[O:35])[CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[S:25])=[CH:21][CH:22]=3)[CH:8]=2)[N:44]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Cc1cnn(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4)c3s2)c1
Agent: Cc1cn[nH]c1
Product: Cc1cc(C)n(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4)c3s2)n1

Procedure:
Following the procedures described above for the synthesis of compound 258a (example 215, scheme 58) but replacing 4-methyl-1H-pyrazole in the step 1 with 3,5-dimethyl-1H-pyrazole, title compound 258c was obtained. Characterization of 258c is provided in the table 23.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:11]=[C:12]([CH:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=2)[C:21]#[N:22])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1.C(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]([C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=2)([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21]#[N:22])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1
Reactant: N#CC(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#CC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a solution of LDA (2.0 M in THF, 3.7 mL) in THF (20 mL) at −78° C. under argon was added dropwise a solution of 2-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)acetonitrile (1.7 g, 5.7 mmol), prepared as described in Procedure 3, in THF (4 mL). The resulting solution was stirred at −78° C. for 1 h. Benzylbromide (0.88 mL, 7.4 mmol) was added to the reaction mixture and allowed to warm to room temperature. The reaction mixture was stirred at rt for 1 h, concentrated under reduced pressure and diluted with EtOAc (approx 100 mL). The resulting solution was washed with water (30 mL) and sat. NaCl (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a yellow oil. The yellow oil was dissolved in CH2Cl2 and loaded directly onto a silica gel ISCO cartridge (40 g) with elution at 35 mL/min gradient 0 to 30% EtOAc in hexane over 35 min (RT=27-32 min). 2-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)-3-phenylpropanenitrile (1.6 g, 72% yield) was isolated as a pale yellow oil. LCMS: RT=2.17 min [M+H] 389.0 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=4.24 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) ppm 3.59 (d, J=13.18 Hz, 1 H), 3.90 (d, J=13.62 Hz, 1 H), 6.89 (d, J=6.59 Hz, 2 H), 7.09-7.15 (m, 3 H), 7.20 (d, J=7.91 Hz, 1 H), 7.32 (td, J=8.35, 3.08 Hz, 1H), 7.37 (d, J=9.23 Hz, 1 H), 7.45-7.48 (m, 1 H), 7.49 (s, 1 H), 8.50 (d, J=2.64 Hz, 1H).