Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[C:25](OC)(=[O:30])[CH2:26][C:27]([CH3:29])=O>>[OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:25](=[O:30])[CH2:26][C:27]([CH3:29])=[N:10][CH2:9][CH2:8]1
Reactant: CCCCCCCCCCCCCCC(O)CNCCNCCN
Reactant: COC(=O)CC(C)=O
Product: CCCCCCCCCCCCCCC(O)CNCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 339.5 g (1 mole) of N-(2-hydroxy)hexadecyldiethylenetriamine and 116.1 g (1 mole) of methyl acetoacetate. At 140° to 150° C., 18 g of water and 32 g of methanol were distilled off to obtain 4-(2-hydroxyhexadecyl)aminoethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([SH:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].[F:26][C:27]1[CH:28]=[C:29]([CH:37]=[C:38]([F:46])[C:39]=1[CH2:40]OS(C)(=O)=O)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:40][C:39]3[C:38]([F:46])=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])=[CH:28][C:27]=3[F:26])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CC(C)(C)OC(=O)c1cc(F)c(COS(C)(=O)=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)OC(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 2 h
Yield: 98450.5 %

Procedure:
A mixture of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (60 g, 0.16 mmol), tert-butyl 3,5-difluoro-4-((methylsulfonyloxy)methyl)benzoate (51 g, 0.16 mol, 1.0 eq.) and Cs2CO3 (62 g, 0.19 mol, 1.2 eq.) in MeCN (680 mL) was stirred for 2 h and evaporated to give a residue. The residue was diluted with water (1.5 L) and extracted with CH2Cl2 (1 L). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give tert-butyl 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzoate (95 g, quant). 1H NMR (400 MHz, CDCl3) δ 7.40-7.42 (d, 2H), 7.19 (s, 1H), 7.14-7.16 (d, 1H), 6.76-6.80 (t, 2H), 6.51 (s, 1H), 6.41-6.49 (m, 3H), 4.07 (s, 2H), 3.75 (s, 3H), 1.58 (s, 9H), 1.47 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[CH:16][C:15]([CH3:23])=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:21][CH2:20][CH:19]([OH:22])[CH2:18][C:17]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]3[C:14](=[C:15]([CH3:23])[CH:16]=2)[CH2:13][CH2:12][CH2:11]3)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1cc(CC(O)CO)c(OCc2ccccc2)c2c1CCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)Cc2cc(C)c3c(c2OCc2ccccc2)CCC3)cc1
Temperature: 0 °C

Procedure:
To a solution of (±)-3-[4-(benzyloxy)-7-methyl-2,3-dihydro-1H-inden-5-yl]propane-1,2-diol (9.12 g, 0.029 mol) in anhydrous pyridine (290 mL) cooled to 0° C. was added p-toluenesulfonyl chloride (5.84 g, 0.031 mol) and the reaction mixture was allowed to stir for at 0° C. 12 h. The reaction mixture was quenched by the addition of water (10 mL) and the reaction mixture was allowed to stir at room temperature for 15 min. The reaction mixture was diluted with ethyl acetate (800 mL) and washed with aqueous hydrogen chloride (4×1000 mL, 2.0 N), water (500 mL), saturated aqueous sodium chloride (500 mL), dried (magnesium sulfate), and the solvent was removed in vacuo to afford (±)-3-[4-(benzyloxy)-7-methyl-2,3-dihydro-1H-inden-5-yl]-2-hydroxypropyl 4-methylbenzenesulfonate as a crude solid. Treatment of the tosylate with palladium on carbon (10 wt. %, 1.50 g) generally according to the procedure described for Intermediate 11 provided (±)-2-hydroxy-3-(4-hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)propyl 4-methylbenzenesulfonate. Treatment of the phenyl with triphenylphoshine (10.17 g, 0.039 mol) and diethylazodicarboxylate (6.75 g, 0.039 mol) generally according to the procedure described for Intermediate 12 gave 9.44 g (91%) of (±)-(5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=0.62 (silica, ethyl acetate:hexanes 1:4); mp 61-64° C.; Anal. calcd. for C20H22O4S: C, 67.01; H, 6.19. Found: C, 67.02; H, 6.15.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Br[CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]>C(Cl)Cl>[Si:46]([O:45][CH2:44][CH2:43][NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1)([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 75 °C

Procedure:
To a scintillation vial containing N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-(3-fluorobenzyl)-2,4′-bipyridine-2′,6-diamine (17 mg, 0.040 mmol) and K2CO3 (22.06 mg, 0.160 mmol) was added DMF (0.3 ml) and (2-bromoethoxy)(tert-butyl)dimethylsilane (9.55 mg, 0.040 mmol). The reaction mixture was capped and heated to 75° C. for 7 hr. The reaction mixture was diluted with DCM and washed with H2O, sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The crude solid was purified by reverse phase preparative HPLC. Collected fractions were combined, neutralized with Saturated NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated and used directly in next step. LCMS (m/z): 584.3 (MH+), retention time=0.87 min.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7][C:6](=[O:8])[NH:5][CH2:4][CH2:3]1.[H-].[Na+].[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>C1COCC1>[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:5]1[CH2:4][CH2:3][C:2]([CH3:1])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7][C:6]1=[O:8]
Reactant: CC1(c2ccccc2)CCNC(=O)O1
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(c2ccccc2)CCN(Cc2cccc(Br)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
A solution of 6-methyl-6-phenyl-1,3-oxazinan-2-one (500 mg, 2.62 mmol) and NaH (189 mg, 7.86 mmol) in dry THF (10 mL) was stirred for 1 h. A solution of m-bromobenzyl bromide (1.31 g, 5.24 mmol) in dry THF (3 mL) was added. The mixture was stirred overnight at rt. The reaction mixture was quenched water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by preparative TLC to afford 3-(3-bromobenzyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (300 mg, 32%). 1H NMR (CDCl3): 1.60-1.70 (s, 3H), 2.15-2.30 (m, 1H), 2.35-2.48 (m, 1H), 2.79-2.90 (m, 1H), 3.00-3.10 (m, 1H), 4.30-4.40 (m, 1H), 4.50-4.60 (m, 1H), 6.90-7.00 (m, 1H), 7.00-7.10 (m, 1H), 7.20-7.45 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21]>C(#N)C>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:23][C:24]([NH:1][C:2]1[N:7]=[C:6]([N:8]([CH3:9])[CH3:10])[CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)=[O:25])(=[O:22])=[O:21]
Reactant: COc1cc(N(C)C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Solvent: CC#N
Product: COc1cc(N(C)C)nc(NC(=O)NS(=O)(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 700 ml of acetonitrile containing 25 g of 2-amino-4-dimethylamino-6-methoxypyrimidine at ambient temperature was added, dropwise, 32.5 g of 2-chlorobenzenesulfonylisocyanate. The mixture was warmed to 40° and then allowed to stir for five hours at ambient temperature. The solid product named above was isolated by filtration and washed with a small amount of cold ethyl ether. It melted at 224°-226°.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][N:3]=1.[O:17]1[CH2:21][CH2:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18]1>>[O:17]1[CH2:21][CH2:20][C:19]([C:2]2[C:10]3[C:5](=[CH:6][N:7]=[C:8]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[NH:4][N:3]=2)=[CH:18]1
Reactant: CC1(C)OB(C2=COCC2)OC1(C)C
Reactant: Ic1n[nH]c2cnc(-c3cccnc3)cc12
Product: C1=C(c2n[nH]c3cnc(-c4cccnc4)cc23)CCO1
Yield: 40 %

Procedure:
Following the procedures Example 281, 3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine from Example 4 and 2-(4,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were reacted to give 284 as a white solid (0.1 g, 40%). 1H NMR (400 MHz, DMSO): δ 9.42 (s, 1H), 9.09 (s, 1H), 8.56-8.57 (m, 2H), 8.51 (s, 1H), 7.86 (s, 1H), 7.47-7.49 (m, 1H), 4.46-4.50 (m, 2H), 3.12-3.14 (m, 2H). ESI MS m/z=265 (M+1)
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.Cl.[CH:22]12[CH2:29][CH2:28][CH:25]([NH:26][CH2:27]1)[CH2:24][NH:23]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:22]12[CH2:29][CH2:28][CH:25]([NH:26][CH2:27]1)[CH2:24][N:23]2[C:10]1[C:11]([F:13])=[C:12]2[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: C1CC2CNC1CN2
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCC3CN4)c(F)c21
Yield: 62.4 %

Procedure:
A solution of 0.81 g (3.0 mmole) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.74 g (4.0 mmole) of 2,5-diazabicyclo[2.2.2]octane dihydrochloride [P. A. Sturm et al., J. Med. Chem., 17, 481 (1974)], 1.65 ml (11 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 40 ml of acetonitrile was stirred at room temperature for 25 hours and heated under reflux for two hours. The reaction mixture was filtered and the solid was washed with methanol to give 0.68 g of the title compound, mp 255°-257°.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].C([Li])CCC.[B:26](OC)([O:29]C)[O:27]C.[Cl-].[NH4+]>O1CCCC1>[F:20][C:17]1[CH:18]=[CH:19][C:2]([B:26]([OH:29])[OH:27])=[C:3]([CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])[CH:16]=1
Reactant: COB(OC)OC
Reactant: CC(C)[Si](OCc1cc(F)ccc1Br)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1cc(F)ccc1B(O)O)(C(C)C)C(C)C
Temperature: 23 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 6.00 g (16.6 mmol) [(2-bromo-5-fluorobenzyl)oxy](triisopropyl)silane which was prepared according to intermediate example 299c in 60 mL tetrahydrofuran were added 7.31 mL n-butyllithium (2.5M in hexane) at −78° C. After 20 minutes of stirring 5.58 mL trimethyl borate were added and stirring was continued for additional 60 minutes. The mixture was allowed to warm to 23° C., poured into a saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by chromatography to give 3.16 g (58%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C1(=O)O[CH2:13][CH2:12][O:11]1>[Br-].C([N+](CC)(CC)CC)C>[OH:11][CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1OCCO1
Reactant: O=Cc1ccc(O)cc1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Product: O=Cc1ccc(OCCO)cc1
Yield: 66 %

Procedure:
Synthesized from 30 g of 4-hydroxybenzaldehyde, 21 g of ethylene carbonate and 62 g of tetraethylammonium bromide as described in Example XIIa. Purified by distillation (boiling point 0.1 140°-150° C.). Yield 66%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:9]#[N:10].[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22]Br.[OH-].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:22][CH:21]([O:24][CH3:25])[O:20][CH3:19])([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:9]#[N:10]
Reactant: N#CC(CCN1CCCCC1)c1ccccc1Cl
Reactant: COC(CBr)OC
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COC(CC(C#N)(CCN1CCCCC1)c1ccccc1Cl)OC

Procedure:
The synthesis outlined in Scheme II comprises (a) reacting commercially available 2-chlorobenzeneacetonitrile with 1-(2-chloroethyl)piperidine in the presence of a base, such as sodium hydroxide, and methyltributylammonium chloride to give (±)-α-(2-chlorophenyl)-1-piperidinebutanenitrile; (b) alkylating the resulting piperidinebutanenitrile with bromoacetaldehyde dimethyl acetal in dimethylsulfoxide (DMSO) in the presence of potassium hydroxide to produce (±)-α-(2-chlorophenyl)-α-(2,2-dimethoxyethyl)-1-piperidinebutanenitrile; (c) hydrolyzing the resulting piperidinebutanenitrile in a solvent such as toluene with hydrochloric acid to produce (±)-α-(2-chlorophenyl)-α-(2-oxoethyl)-1-piperidinebutanenitrile; (d) reacting the resulting piperidinebutanenitrile with isopropylamine in a solvent such as toluene in the presence of potassium carbonate to form an imine substituted piperidinebutanenitrile; (e) reducing the resulting imine substituted piperidinebutanenitrile with sodium borohydride and ethanol to form an amino substituted piperidinebutanenitrile; (f) acetylating the resulting amino substituted piperidinebutanenitrile with acetic anhydride in a solvent such as toluene to produce an acetylated amino substituted piperidinebutanenitrile; (g) hydrolyzing the resulting acetylated amino substituted piperidinebutanenitrile with sulfuric acid to produce an acetylated amino substituted-1-piperidinebutanamide; and (h) isolating the resulting 1-piperidinebutanamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:10]=2[CH:29]=[O:30])=[CH:5][CH:4]=1.[Si]([C:35]([F:38])([F:37])[F:36])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[F:36][C:35]([F:38])([F:37])[CH:29]([C:10]1[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:12]2[C:17]([C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:30]
Reactant: COc1ccc(-c2c(C=O)n(Cc3cccc(C(F)(F)F)c3)c3ccccc23)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C(O)C(F)(F)F)n(Cc3cccc(C(F)(F)F)c3)c3ccccc23)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21 %

Procedure:
To a solution of 3-(4-methoxyphenyl)-1-{[3-(trifluoromethyl)phenyl]methyl}indole-2-carbaldehyde (Example 218, 200 mg, 0.49 mmol) in tetrahydrofuran (5 mL) was added a 0.5 M solution of TMSCF3 in tetrahydrofuran (4.9 mL, 2.4 mmol). The resulting solution was cooled to 0° C. and a 1.0 M solution of TBAF in tetrahydrofuran (0.10 mL, 0.10 mmol) was added. The mixture was stirred for 10 min at 0° C. and then let warm to RT and quenched by the addition of water. The resulting mixture was extracted with tetrahydrofuran, adsorbed onto silica, and purified by flash chromatography on silica in 4:1 hexane:ethyl acetate (v/v) to yield 49 mg (21%) of an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 7.60-7.26 (m, 6H), 7.22-7.01 (m, 6H), 5.81 (s, 2H), 3.83 (s, 3H); mass spectroscopy gave MH+=480.2 (calc'd exact mass for C25H19F3NO2=479.13).
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22](=[O:38])[N:23]([CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]1=[O:37])[C:24]2=[O:29])=[O:17])=O)(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:1].[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22](=[O:38])[N:23]([CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]1=[O:37])[C:24]2=[O:29])=[O:17]
Reactant: CC(C)(C)OC(=O)NCCCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 17 h
Yield: 41 %

Procedure:
A 4N HCl solution in dioxane (1.5 mL) was added to a stirred solution of 7-[(tert-butoxy)carbonylamino]-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}heptanamide (0.72 g, 1.40 mmol) in CH2Cl2 (25 mL) and stirred for 17 hours. The resulting suspension was filtered to give 7-amino-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}heptanamide hydrochloride (0.26 g, 41%) as a white solid. mp 187-189° C.; 1H NMR (DMSO-d6) δ 11.12 (s, 1H), 8.52 (t, J=5.7 Hz, 1H), 7.93 (b, 3H), 7.88-7.67 (m, 3H), 5.18-5.11 (dd, J=5.3 and 12.4 Hz, 1H), 4.72 (d, J=5.7 Hz, 2H), 2.91-2.50 (m, 5H), 2.21 (t, J=7.2 Hz, 2H), 2.08-2.04 (m, 1H), 1.57-1.52 (m, 4H), 1.31-1.29 (m, 4H), 13C NMR (CDCl3) δ 172.70, 172.55, 169.77, 167.44, 166.90, 139.54, 134.68, 133.08, 131.47, 127.01, 121.77, 48.82, 38.64, 37.53, 35.00, 30.90, 28.05, 26.73, 25.50, 24.89, 21.95; Anal. Calcd. For C21H27N4O5Cl+0.64H2O: C, 54.95; H, 6.13; N, 12.21; Cl, 7,72. Found: C, 54.56; H, 6.10; N, 11.96; Cl, 8.04.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1(O)[C:18]2[C:13](=[CH:14][C:15]([C:23]([NH2:25])=[O:24])=[CH:16][C:17]=2[C:19]([F:22])([F:21])[F:20])[N:12]([CH2:26][C@H:27]2[CH2:30][C@H:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH2:28]2)[C:11]1=[O:36].C(=O)(O)[O-].[Na+].C(N(S(F)(F)[F:49])CC)C>>[ClH:2].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1([F:49])[C:18]2[C:13](=[CH:14][C:15]([C:23]([NH2:25])=[O:24])=[CH:16][C:17]=2[C:19]([F:20])([F:21])[F:22])[N:12]([CH2:26][C@H:27]2[CH2:28][C@H:29]([N:31]([CH2:32][CH3:33])[CH2:34][CH3:35])[CH2:30]2)[C:11]1=[O:36]
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(C(N)=O)cc3C(F)(F)F)C1
Reactant: CCN(CC)S(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(F)(c3ccc(Cl)cc3Cl)c3c2cc(C(N)=O)cc3C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the compound of Example 1-4 (150.0 mg, 0.26 mmol) was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in dichloromethane (2.6 mL), and thereto was added diethylaminosulfur trifluoride (207.9 mg, 1.29 mmol) at −78° C., and the mixture was allowed to warm to room temperature and stirred for 24 hours. To the reaction solution was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and then purified by silica gel column chromatography (chloroform/methanol/ammonia water 20/1/0 to 10/1/0 to 100/10/1), and then by preparative liquid chromatography. To the purified substance were added tetrahydrofuran and 1M hydrochloric acid (0.5 mL), and the mixture was concentrated. The resulting solid was suspended in diethyl ether and filtered to give the titled compound (65.0 mg, 43%).
Reaction SMILES: [CH2:1]([CH:8]1[C:13](=[O:14])[C:12]([Br:15])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O-].[Na+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:20]([N:10]1[CH:11]=[C:12]([Br:15])[C:13](=[O:14])[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: O=C1C(Br)=CN=CC1Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1c(Br)cn(Cc2ccccc2)cc1Cc1ccccc1

Procedure:
A mixture of 3-benzyl-5-bromopyridin-4-one 12 (0.57 g, 2.16 mmol) and NaOEt (0.89 mL, 2.37 mmol) in absolute ethanol (20 mL) was refluxed with benzyl chloride (0.30 mL, 2.59 mmol) for 1 h under nitrogen. The solvent was distilled off to give a yellow residue which was purified by flash column chromatography on silica gel (dichloromethane:methanol, 98:2). Yield 1.31 g (96.7%), yellow solid, mp 120-121° C. 1H NMR (CDCl3, 500 MHz): δ 7.67 (d, 1H, J=2.4), 7.32-7.07 (m, 10H), 4.83 (s, 1H), 3.78 (s, 2H). 13C NMR (CDCl3, 125 MHz): δ 172.2, 139.6, 139.1, 137.6, 134.7, 129.9, 129.9, 129.3, 129.3, 129.2, 129.0, 128.6, 128.6, 127.5, 127.6, 126.4, 114.1, 60.3, 34.4. HRMS (M+H)+ calcd for C19H16BrNO 354.0494, found 354.0499.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=2)[CH:29]=O)[CH:25]=[CH:24][CH:23]=[N:22]1>>[N:21]1([C:26]2[CH:27]=[C:28]([CH2:29][N:1]3[CH:2]([C:11]4[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=4[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]3=[O:9])[CH:31]=[CH:32][N:33]=2)[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: O=Cc1ccnc(-n2cccn2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccnc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 2-(1H-pyrazol-1-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.83 min.; [M+H]+: 407.11 g/mol.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[C:13](=[N:21]O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[N+:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1)([O-:26])=[O:25]>>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:32][C:31]([C:30]3[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:34][CH:33]=3)=[N:21][C:13]=2[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(C(=O)C(=NO)C(=O)OC(C)(C)C)cc1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Product: CC(=O)OCc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)OC(C)(C)C)cc1
Yield: 15.3 %

Procedure:
tert-Butyl 3-(4-acetoxymethylphenyl)-2-hydroxyimino-3-oxopropionate (33.9 g) and 4-nitrobenzylamine (19.3 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give tert-butyl 5-(4-acetoxymethylphenyl)-2-(4-nitrophenyl)-imidazole-4-carboxylate (7.07 g), melting point 178-180° C. (decomposition).
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:3][C@H:2]([C@H:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Reactant: O=Cc1ccccc1
Product: C[C@@H](C(=O)n1c(=O)oc2ccccc21)[C@H](O)c1ccccc1

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolinone with benzaldehyde; mp 155–158° C. 1H NMR (CDCl3): δ 8.10 (m, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 7.26 (m, 4H), 5.30 (d, 1H), 4.26 (dq, J=3, 6 Hz, 1H), 1.26 (d, 3H). 13C NMR (CDCl3): δ 175.6, 151.0, 142.2, 141.0, 128.4, 127.7, 126.0, 125.5, 124.9, 116.3, 110.0, 73.2, 46.0, 10.3.