Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2].C(O[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(C)(C)C.CCOC(C)=O>CCO.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][N:8]([C:26]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:32])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Reaction time: 5 h

Procedure:
A mixture of (3S*,4S*)-1-benzyl-pyrrolidine-3,4-dicarboxylic acid monoethyl ester (10 g, 36.1 mmol), di-tert-butylcarbonate (7.9 g, 39.6 mmol) and Pd(OH)2/C 20% (1 g, 50% wet) in EtOH (200 mL) is stirred under hydrogen atmosphere for 5 h. The crude material is filtered over a pad of Celite and concentrated. 1H-NMR indicates that the title compound is obtained cleanly. TLC, Rf (AcOEt)=0.17. MS (LC-MS): 286.1 [M−H]−.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH3:3].CCN(C(C)C)C(C)C.[Br:20][C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:38][C:39]([C:41]3[S:42][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:44][CH:45]=3)=[O:40])[C:35](O)=[O:36])=[CH:29][CH:28]=2)=[N:25][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:20][C:21]1[CH:26]=[N:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([CH2:33][C@H:34]([NH:38][C:39]([C:41]3[S:42][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:44][CH:45]=3)=[O:40])[C:35]([NH:1][C@@H:2]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH3:3])=[O:36])=[CH:31][CH:32]=2)=[N:23][CH:22]=1
Reactant: CC(C)(C)c1ccc(C(=O)N[C@@H](Cc2ccc(-c3ncc(Br)cn3)cc2)C(=O)O)s1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)s1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring solution of tert-butyl D-alaninate (5.60 g, 30.80 mmol) in DMF (50 mL) were added DIEA (8.29 g, 64.18 mmol) and (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoic acid (12.5 g, 25.67 mmol). The solution was cooled to 0° C. at ice bath and then HATU (9.06 g, 38.50 mmol) in 15 mL DMF solution was slowly added. The reaction was stirred 1 hour at 0° C. and then warmed to RT with stirring for 2 hours. The reaction solution was extracted with DCM (3×50 mL) and aqueous NaHCO3 (3×30 mL). The combined organics were dried over MgSO4 and evaporated. The final compound was purified by column chromatography (40% DCM in hexane) to afford 14.7 g (94%) of tert-butyl ((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)-D-alaninateas solid powder. LCMS-ESI (m/z) calculated for C29H35BRN4O4S: 614.2. found 615.3 [M+H]+, tR=3.914 min. (Method 16). 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J=3.6 Hz, 2H), 8.36 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.34 (d, J=3.8 Hz, 1H), 6.81 (d, J=3.8 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 6.34 (d, J=7.2 Hz, 1H), 4.88 (d, J=5.9 Hz, 1H), 4.41 (t, J=7.2 Hz, 1H), 3.31 (dd, J=13.6, 5.8 Hz, 1H), 3.20 (dd, J=13.6, 7.8 Hz, 1H), 1.51-1.32 (m, 18H), 1.27 (d, J=7.1 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 172.02, 171.31, 162.28, 162.13, 161.42, 158.55, 142.27, 136.34, 134.66, 130.20, 128.82, 127.92, 123.07, 118.63, 80.90, 54.45, 48.86, 39.59, 39.38, 32.39, 28.04, 17.68.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]=[CH:5]2
Reactant: CCOC(=O)CBr
Reactant: Fc1ccc2[nH]ncc2c1
Product: CCOC(=O)Cn1ncc2cc(F)ccc21

Procedure:
The title compound was prepared according to the method described for Preparation 93 using 5-fluoro-1H-indazole and ethyl bromoacetate to afford the title compound as an off-white solid in 53% yield, 260 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]([CH2:24][CH2:25][C:26]#[N:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C[O-].[Na+]>CS(C)=O>[NH:17]([CH:24]=[C:25]([CH2:13][C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)[C:26]#[N:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC(=CNc1ccccc1)Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
p-Benzyloxybenzaldehyde (25 g.), β-anilinopropionitrile (22 g.), and dimethylsulphoxide (25 ml.) were heated together to 95° C, and a slurry of sodium methoxide (1 g.) in dimethylsulphoxide (20 ml.) was carefully added such that the temperature rose to 105° C. The mixture was heated to 125°-130° and held at that temperature for 11/2 hr. The reaction mixture was poured into ice-water (500 ml.), and the resulting solid was collected and washed by decantation. The crude product was slurried in cold ethanol to give β-anilino-α-(p-benzyloxybenzyl) acrylonitrile. Wt. = 27 g.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C.[Si]([O:30][CH:31]([C:63]([F:66])([F:65])[F:64])[CH:32]([NH:36][C:37](=[O:62])[CH2:38][N:39]1[C:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:43][CH:42]=[C:41]([NH:51][C:52]([O:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:53])[C:40]1=[O:61])[CH:33]([CH3:35])[CH3:34])(C(C)(C)C)(C)C>O1CCCC1>[O:61]=[C:40]1[C:41]([NH:51][C:52]([O:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)=[O:53])=[CH:42][CH:43]=[C:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:39]1[CH2:38][C:37]([NH:36][CH:32]([CH:33]([CH3:35])[CH3:34])[CH:31]([OH:30])[C:63]([F:65])([F:64])[F:66])=[O:62]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)Oc2ccccc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)Oc2ccccc2)c1=O)C(O)C(F)(F)F
Reaction time: 3 h

Procedure:
R=phenoxycarbonyl: Tetra-n-butylammonium fluoride (1.0M in tetrahydrofuran, 0.34 mL) and glacial acetic acid (0.02 mL) were added to dry tetrahydrofuran (1 mL). A solution of N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-(2-oxo-3-phenoxycarbonylamino-6-phenyl-1,2,-dihydro-1-pyridyl)acetamide in dry tetrahydrofuran (2 mL) was added to the reaction vessel, and the addition syringe was washed out with an additional 2 mL tetrahydrofuran. The reaction mixture was stirred for 3 h; diluted with ethyl acetate (50 mL); washed with water and brine; dried and evaporated to an oil which was purified by flash chromatography, eluting with dichloromethane:ethyl acetate (90:10), to afford 2-(2-oxo-3-phenoxycarbonylamino-6-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide as a white solid (0.110 g); TLC: Rf =0.30, ethyl acetate:dichloromethane (1:9); MS: m/z=518(M+1).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=2[CH2:7][O:6][C:5]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:4]1=2.[N:20]1([CH2:26][CH2:27][N:28]2[C:32]3[CH:33]=[CH:34][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:31]=3[NH:30][C:29]2=[O:46])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[F:19][C:16]1[CH:17]=[CH:18][C:4]2[C:3](=[CH:2][C:35]3[CH:34]=[CH:33][C:32]4[N:28]([CH2:27][CH2:26][N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[C:29](=[O:46])[NH:30][C:31]=4[CH:36]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=3[CH2:7][O:6][C:5]=2[CH:15]=1
Reactant: CC1(C)OB(c2ccc3c(c2)[nH]c(=O)n3CCN2CCOCC2)OC1(C)C
Reactant: Fc1ccc2c(c1)OCc1c(F)cccc1C2=CBr
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: C1COCCO1
Product: O=c1[nH]c2cc(C=C3c4ccc(F)cc4OCc4c(F)cccc43)ccc2n1CCN1CCOCC1
Yield: 66.2 %

Procedure:
Following procedures essentially as described in Example 219, mix 11-bromomethylene-3,7-difluoro-6,11-dihydro-dibenzo[b,e]oxepine (E-isomer, 200 mg, 0.619 mmol) (prepared essentially as described in Preparation 55), 1-(2-morpholin-4-yl-ethyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (220 mg, 0.589 mmol), Na2CO3 (2M in water, 736 □L, 1.47 mmol), dioxane (4 mL), and Pd(PPh3)4 (36 mg, 0.031 mmol). Purify the crude product on silica gel (64 g) eluting with 2% (2M NH3/MeOH)/CH2Cl2 to afford 191 mg (66%) of the title compound as a white foam. HPLC (ISO80-10) t=1.95 min, 98%; MS [ES] 488 (M−H), 490 (M+H); 1H-NMR (DMSO-d6) δ 10.69 (s, 1H), 7.58 (dd, 1H, J=8.8, 7.0 Hz), 7.24 (m, 2H), 7.02 (s, 1H), 6.96 (d, 1H, J=8.4 Hz), 6.80 (m, 3H), 6.64 (m, 2H), 5.56-5.20 (br d, 2H), 3.81 (t, 2H, J=6.4 Hz), 3.46 (t, 4H, 4.4 Hz), 2.48 (m, 2H), 2.37 (s, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10]([C:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)[S:15][CH:16]=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:26][S:27]([O:23][CH:20]1[CH2:21][CH2:22][N:17]([C:14]2[S:15][CH:16]=[C:12]([C:10]([O:9][CH2:8][C:7]3[CH:24]=[CH:25][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:11])[N:13]=2)[CH2:18][CH2:19]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)c1csc(N2CCC(O)CC2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)CC1
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
To a solution of 1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)-4-hydroxypiperidine (0.75 g, 2.06 mmol) (obtained as described in Reference Example 14(4)) in anhydrous methylene chloride (38 ml) were added methanesulfonyl chloride (0.18 ml, 2.33 mmol) and triethylamine (0.35 ml, 2.51 mmol) in an ice bath. The mixture was brought to room temperature in 10 minutes, and then stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1) as the eluant to afford 4-methanesulfonyloxy-1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)piperidine (0.87 g, yield 96%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:28]1[N:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:31]=[N:30][N:29]=1>CN(C=O)C>[CH3:19][N:18]1[CH2:17][CH2:16][C@@:14]23[C:15]4[C:2]([O:1][C:28]5[N:32]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[N:31]=[N:30][N:29]=5)=[CH:3][CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@@H:9]2[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]3
Reactant: Clc1nnnn1-c1ccccc1
Reactant: CN1CC[C@]23CC(=O)CC[C@H]2[C@H]1Cc1cccc(O)c13
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CC[C@]23CC(=O)CC[C@H]2[C@H]1Cc1cccc(Oc2nnnn2-c2ccccc2)c13
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.5 %

Procedure:
A mixture of 1.57 g (5.79 mmol) 4-hydroxy-N-methylmorphinan-6-one, 1.57 g (11.36 mmol) dry K2CO3 and 1.15 g (6.37 mml) 5-chloro-1-phenyl-1H-tetrazole din 30 ml dry DMF was stirred under argon for 24 h at room temperature. Then the reaction mixture was filtered, washed with CHCl3 and the filtrate was evaporated in vacuo (70° bath temperature). The oily residue was dissolved in CHCl3 and extracted with 2×20 ml 5% tartaric acid. The aqueous layer was rendered alkaline with conc. NaOH and extracted with CHcl3. The organic layer was washed with brine, dried and evaporated to give 2.2 g of an oil, which was crystallized with EtOAc/Et2O to yield 2.05 g (85%) of N-methyl-4-(1-phenyl-1H-5-tetrazolyloxy) morphinen-6-one, m.p. 172°-174°, [α]D26 -37.4° (c 1.35, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:35])([F:34])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[NH:27][CH2:26]4)=[O:24])=[C:19]([CH3:31])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C)C=O.[H-].[Na+].FC(F)(F)S(O[CH2:49][C:50]([F:53])([F:52])[F:51])(=O)=O>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:33])([F:34])[F:35])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[N:27]([CH2:49][C:50]([F:53])([F:52])[F:51])[CH2:26]4)=[O:24])=[C:19]([CH3:31])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CC(=O)N(CC(F)(F)F)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]imidazolidin-4-one (80 mg, 0.15 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL). This was followed by the addition of NaH (60%) (12.3 mg, 0.51 mmol, 2.00 equiv) in several batches at 0° C. The resulting solution was stirred for 30 min at 0° C. To this was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (71 mg, 0.31 mmol, 2.00 equiv). The resulting solution was allowed to react, with stirring, for an additional 3 h at room temperature. The reaction was then quenched by the addition of 20 mL of water/ice. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate. This resulted in 14 mg (15%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]-3-(2,2,2-trifluoroethyl)imidazolidin-4-one as a light yellow solid. (ES, m/z): [M+CH3CN]+ 643; 1H NMR (300 MHz, CDCl3): δ 7.82 (s, 1H), 7.76 (s, 1H), 7.697 (s, 1H), 7.58-7.61 (m, 2H), 7.28-7.34 (m, 1H), 5.196 (s, 1H), 4.911 (s, 1H), 4.646 (s, 1H), 4.03-4.18 (m, 2H), 3.998 (s, 1H), 3.70-3.76 (m, 1H), 2.399 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:19]2[CH2:18][CH2:17][CH:16]([O:15][C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[C:12]([F:11])([F:26])[F:27])[CH2:21][CH2:20]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1
Temperature: 82.5 °C

Procedure:
A mixture of 2-chloro-5-nitropyridine (1.6 g, 6.5 mmol), 4-[2-(trifluoromethyl)phenoxy]piperidine (1.2 g, 7.6 mmol), and DBU (2 mL, 13 mmol) in DMF (25 mL) was heated at 80-85° C. for 2 h. The EtOAc extract was washed three times with water, dried (MgSO4) and concentrated. CombiFlash chromatography (120 g, 20-40% EtOAc in hexanes in 20 min, 70 mL/min, 18 mL/fraction) gave the desired product as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:12]1[O:29][C@H:28]([CH2:30][O:31]C(=O)C)[C@@H:23]([O:24]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@H:13]1[O:14]C(=O)C.[I:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=O)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:40][C:39]1[CH:43]=[CH:44][C:36]([I:35])=[CH:37][CH:38]=1)=[CH:5][N:6]2[C@@H:12]1[O:29][C@H:28]([CH2:30][OH:31])[C@@H:23]([OH:24])[C@H:18]([OH:19])[C@H:13]1[OH:14]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)c(F)ccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc(I)cc1
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc(I)cc3)c3c(Cl)c(F)ccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
4-Chloro-5-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)indole obtained in Example 34-(3) and 4-Iodobenzoyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 548/550 (M+H). 1H-NMR (DMSO-d6) δ 3.15-3.45 (m, 4H), 3.62 (m, 2H), 4.21 (s, 2H), 4.52-4.58 (br, 1H), 5.10-5.17 (br, 1H), 5.18-5.30 (br, 2H), 5.40 (d, J=9.0 Hz, 1H), 7.02 (d, J=8.2 Hz, 2H), 7.16 (t, J=9.3 Hz, 1H), 7.42 (s, 1H), 7.57 (dd, J=9.0, 4.0 Hz, 1H), 7.62 (d, J=8.3 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>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>[N+:1]([C:4]1[CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Yield: 73 %

Procedure:
A suspension of 2-nitro-4-bromoaniline (5 g, 23 mmol) in toluene was admixed with 2.8 g (23 mmol) of phenylboronic acid, 9.5 g (0.069 mol) of potassium carbonate and 1.3 g of tetrakis(triphenylphosphine)palladium. The mixture was heated to reflux for 4 hours and the reaction was stopped by adding 100 ml of water. The mixture was extracted with ethyl acetate and dried over sodium sulphate, and the solvent was removed under reduced pressure. Purification by column chromatography gave 3.6 g (73% yield).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[Cl:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:9][C:10]1[CH:15]=[C:14]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 72.6 %

Procedure:
N-Ethylpiperazine (4.3 mL, 34.3 mmol, 1.2 equiv) is added to a mixture of 2-chloro-4-fluoronitrobenzene (5 g, 28.6 mmol) and potassium carbonate (7.9 g, 57.1 mmol, 2 equiv) in DMF (50 mL). The reaction mixture is stirred at 100° C. for 6 h, allowed to cool to RT, diluted with H2O and extracted with EtOAc. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by trituration in diethyl ether to provide 5.6 g of the title compound as a yellow solid: ES-MS: 270.0 [MH]+; tR=2.90 min (system 1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[C:11]([OH:22])[NH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[C:11]([OH:22])[N:10]([CH3:24])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1n[nH]c(O)c1Cc1cccc(Cl)c1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(NC(=O)OC(C)(C)C)c(Cc2cccc(Cl)c2Cl)c1O
Yield: 30 %

Procedure:
To a solution of tert-butyl(4-(2,3-dichlorobenzyl)-5-hydroxy-1H-pyrazol-3-yl)carbamate (160 mg, 0.447 mmol), triphenylphosphine (128 mg, 0.491 mol) and methanol (16 mg, 0.491 mol) in anhydrous THF (25 mL), a solution of DIAD (99 mg, 0.491 mmol) in anhydrous THF (2 mL) was added dropwise at 0° C. with stirring. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated. The resulting residue was purified by silica gel chromatography eluted with PE:EA=2:1 to provide the titled compound (50 mg, 30%), as a white solid; LC/MS: MS (ES+) m/e 372 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.56 (s, 9H), 3.05 (s, 3H), 3.52 (s, 2H), 7.00 (d, J=7.8 Hz, 1H), 7.11 (s, 2H), 7.25 (t, J=7.8 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[C:13]1([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1>CCOCC>[C:13]1([C:19]2[CH:20]=[CH:21][C:22]([C:23](=[O:24])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:26][CH:27]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: Brc1ccccn1
Reactant: O=C(O)c1ccc(C2=CCCCC2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1ccc(C2=CCCCC2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
40 g of 2-bromopyridine in 50 ml of absolute ether are added dropwise slowly at -60° C with stirring and in a nitrogen atmosphere to 175 ml of a 1.5 N solution of butyl-lithium in ether, followed, 15 minutes after the completion of the addition, by a solution of 15 g of p-(1-cyclohexenyl)-benzoic acid in 250 ml of absolute ether. The cooling bath is then removed, the reaction mixture is allowed to warm up to room temperature and it is stirred for 2 hours at room temperature. Working up is carried out by pouring the reaction solution onto a mixture of ice and ammonium chloride and partitioning it between ether and water. The ether phase is separated off and washed successively with water, 0.1 N sodium hydroxide solution and water, dried over sodium sulphate and evaporated under reduced pressure. Distillation under reduced pressure of the evaporation residue yields, in the fraction boiling at 200° C (0.9 mm Hg), crude 2-{[p-(1-cyclohexenyl)-phenyl]-oxomethyl}-pyridine of the formula ##STR3## of melting point 58°-60° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:18][CH2:19][C@@H:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=O)=O>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:18][CH2:19][C@@H:20]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)Cc1ccc(Cl)cc1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCn1cc(Br)cn1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
To a mixture of 4-bromopyrazole (1.26 g, 8.57 mmol) and cesium carbonate (4.66 g, 14.3 mmol) in DMF (20 mL) was added (3S)-3-((tert-butoxycarbonyl)amino)-4-(4-chlorophenyl)butyl methanesulfonate (2.70 g, 7.15 mmol). The mixture was stirred for 16 hours at room temperature. The mixture was diluted with DCM and washed with H2O (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (EtOAc/Hexanes, 0-25%) to give the product as an off-white solid (2.86 g, 93%). LCMS (API-ES) m/z: 428, 430 (M+H+).