Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[C:12](=[N:13]O)[CH:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:10][C:9](=[O:21])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Ni]>[NH2:13][CH:12]1[CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:10][C:9](=[O:21])[CH2:8][CH:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC(c2ccccc2)C(=NO)C(c2ccccc2)N1
Agent: [Ni]
Product: NC1C(c2ccccc2)CC(=O)NC1c1ccccc1
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a solution of 4,6-diphenyl-5-oximino-2-oxopiperidine (700 mg, 2.5 mmol) was added ca. 2 g of wet Raney nickel which had been washed with water (until washings had a neutral pH) followed by ethanol, and the mixture was placed under an atmosphere of hydrogen (40 psi, Parr apparatus) overnight. The mixture was filtered through a pad of diatomaceous earth (Celite (trademark)), and the filter cake was rinsed well with ethanol. The filtrate was concentrated to afford 500 mg of 5-amino-4,6-diphenyl-2-oxopiperidine as a foam.
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:14][N:13]([CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[C:26]([Cl:34])[CH:25]=3)[C@@H:20]([CH3:35])[C:19]2=[O:36])[CH2:12][CH2:11][C:8]21[CH2:10][CH2:9]2)(C)(C)C>CC#N>[Cl:34][C:26]1[CH:25]=[C:24]([N:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][N:13]3[CH2:12][CH2:11][C:8]4([CH2:10][CH2:9]4)[C@H:7]([OH:6])[CH2:14]3)[C:19](=[O:36])[C@@H:20]2[CH3:35])[CH:29]=[CH:28][C:27]=1[C:30]([F:33])([F:31])[F:32]
Reactant: C[C@H]1C(=O)N(CCCN2CCC3(CC3)[C@H](O[Si](C)(C)C(C)(C)C)C2)CCN1c1ccc(C(F)(F)F)c(Cl)c1
Solvent: CC#N
Product: C[C@H]1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1c1ccc(C(F)(F)F)c(Cl)c1
Yield: 57.3 %

Procedure:
A solution of (S)-1-{3-[(S)-4-(tert-butyl-dimethyl-silanyloxy)-6-aza-spiro[2.5]oct-6-yl]-propyl}-4-(3-chloro-4-trifluoromethyl-phenyl)-3-methyl-piperazin-2-one (65 mg, 0.11 mmol) and hydrogen fluoride pyridine complex (70% HF; 0.26 mL) in CH3CN (3 mL) was heated at 50° C. for 16 h, then partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (IST Isolute® Flash NH2; EtOAc-MeOH gradient) afforded the title compound (29 mg, 56%) in a diastereomeric ratio of 97:3. Colourless gum, MS: 460.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](NCC1C=CC=CC=1)=[O:15].COCCCCCCCCCCCC(O)=O.C(Cl)(=O)C([Cl:43])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([Cl:43])=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCCCCCCCCCCC(=O)NCc1ccccc1
Agent: COCCCCCCCCCCCC(=O)O
Solvent: Cc1ccccc1
Product: COCCCCCCCCCCCC(=O)Cl

Procedure:
Reaction Scheme 4 illustratively shows the preparation of 12-methoxy-N-(phenyl-methyl)dodecanamide wherein 12-methoxydodecanoic acid (8) is treated with oxalyl chloride in anhydrous toluene to form 12-methoxydodecanoyl chloride (9) which in turn reacts with benzylamine in methylene chloride to give the desired fatty acid amide (10).
Reaction SMILES: FC1C(C(C(F)(F)F)(C(F)(F)F)C(F)(F)F)=C(O)C(F)=C(F)C=1F.F[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1>C(COC)OC>[N+:32]([C:29]1[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Oc1c(F)c(F)c(F)c(F)c1C(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Solvent: COCCOC
Product: O=[N+]([O-])c1ccccc1

Procedure:
Yet another alternative strategy for the formation of calixarene conjugates involves first derivatizing pre-calixarene monomers followed by the formation of a calixarene structure. For example, perfluoro-tert-butylphenol monomers may be prepared by reacting p-fluoro-nitrobenzene with Cs+C(CF3)3 -- in monoglyme to yield nitrobenzene, followed by reduction of the nitro group to an amino group, diazotization of the amino group to yield a diazonium salt, and hydrolysis to yield a hydroxy group. In the same manner that 4-tert-butylphenol is reacted with formaldehyde to yield a simple calixarene, 4-perfluoro-tert-butylphenol may be reacted with formaldehyde to yield a calixarene conjugate wherein the imaging moiety is perfluoro-tert-butyl (--C(CF3)3) in the 4-position.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.ClC1N=CC(OC2CCN(C)CC2)=CN=1.[F:30][C:31]1([F:77])[CH2:36][CH2:35][CH:34]([C:37]2[C:46]3[CH:45]([O:47]CC4C=CC(OC)=CC=4)[CH2:44][C:43]([CH3:58])([CH3:57])[CH2:42][C:41]=3[N:40]=[C:39]([CH:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)[C:38]=2[CH:65]([F:76])[C:66]2[CH:71]=[CH:70][C:69]([C:72]([F:75])([F:74])[F:73])=[CH:68][CH:67]=2)[CH2:33][CH2:32]1>>[F:77][C:31]1([F:30])[CH2:36][CH2:35][CH:34]([C:37]2[C:46]3[CH:45]([OH:47])[CH2:44][C:43]([CH3:57])([CH3:58])[CH2:42][C:41]=3[N:40]=[C:39]([CH:59]3[CH2:64][CH2:63][N:62]([C:2]4[N:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=4)[CH2:61][CH2:60]3)[C:38]=2[CH:65]([F:76])[C:66]2[CH:71]=[CH:70][C:69]([C:72]([F:74])([F:75])[F:73])=[CH:68][CH:67]=2)[CH2:33][CH2:32]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: FC(F)(F)CCOc1cnc(Cl)nc1
Agent: CN1CCC(Oc2cnc(Cl)nc2)CC1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCCC(F)(F)F)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of Reference Example 29 and Example 38 were performed except for using 2-chloro-5-(3,3,3-trifluoropropoxy) pyrimidine, which was prepared by a method similar to that of Reference Example 31, instead of 2-chloro-5-[(1-methylpiperidin-4-yl)oxy]pyrimidine, and from 150 mg (222 μmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 85 mg of the title compound was obtained as a white solid (yield: 51%).
Reaction SMILES: [C:1]([C:5]1[O:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH3:22][Sn:23](Cl)([CH3:25])[CH3:24].[Cl-].[NH4+]>C1COCC1>[C:1]([C:5]1[O:6][C:7]([Sn:23]([CH3:25])([CH3:24])[CH3:22])=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Sn](C)(C)Cl
Reactant: CC(C)(C)c1nc(-c2ccc(F)cc2)co1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(-c2ccc(F)cc2)c([Sn](C)(C)C)o1
Reaction time: 0.75 h

Procedure:
Dissolve 2-tert-butyl-4-(4-fluorophenyl)oxazole (0.61 g, 2.77 mmol) in THF (15 ml) and add tert-butyl lithium (3.3 ml, 1.7 M) at −78° C. Stir the mixture for 45 min. Add trimethylstannanyl chloride (0.58 g, 2.90 mmol) and allow the temperature to reach RT. Stir for 2 h and add an ammonium chloride solution (200 μL, pH=8 with ammonia) and concentrate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:24][CH2:25][CH3:26])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:6](=[O:8])[CH:7]=1.C([O-])(=O)C.[Na+].[Br:32]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:32][C:7]1[C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:4]([CH2:24][CH2:25][CH3:26])=[N:3][C:2]=1[CH3:1]
Reactant: CCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of 4′-[(4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (8.44 g) and sodium acetate (2.22 g) in acetic acid (100 mL) was added bromine (1.39 mL), and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (6.68 g, 64%) as a colorless solid.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N([O-])=[O:11].[Na+]>O.S(=O)(=O)(O)O>[C:7]([OH:9])(=[O:8])[C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[OH:11]
Reactant: CC(C)C[C@@H](N)C(=O)O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.7 %

Procedure:
400 g of D-leucine was dissolved in 5 l of water containing 296 ml of concentrated sulfuric acid and cooled to -2°. A solution of 421 g of sodium nitrite in 1.25 l of water was added slowly while holding the temperature at -2°. The mixture was stirred at 0° for 1.5 hours and then allowed to warm to room temperature overnight. The mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give 168 g of D-leucic acid as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:2].[C:18](OCC)(=[O:20])[CH3:19]>[Pd]>[NH:9]([C:7]1[CH:6]=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]([C:1]#[N:2])[CH:8]=1)[C:18]([CH3:19])=[O:20]
Reactant: CCOC(C)=O
Reactant: N#Cc1cc([N+](=O)[O-])ccc1-c1ccccc1
Agent: [Pd]
Product: CC(=O)Nc1ccc(-c2ccccc2)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Cyano-4-nitrobiphenyl (0.067 moles, 15.0 g.) was dissolved in 100 ml ethyl acetate/100 ml ethanol and hydrogenated at 40 psi over 3.0 g of 10% palladium on carbon. The catalyst was removed by filtering though celite. The solvents were removed in vacuo. The residue was dissolved in 175 ml of methylene chloride. Acetic anhydride (15 ml) was added. The reaction was stirred at room temperature for 30 minutes and poured over ice. The organic layer was dried, concentrated, and then purified by HPLC over silica gel eluted with a gradient of 0-10% ethyl acetate in chloroform. (MS)
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].O=C1C[N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])C1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH2:1]=[C:2]1[CH2:5][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:3]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.7 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (23.0 g, 0.0649 mol) and potassium tert-butoxide (7.3 g, 0.0649 mol) in diethyl ether (140 mL) was stirred at room temperature for 20 min, and then heated to 35° C. for 1 h. To this bright yellow reaction mixture was slowly added a dilute solution of phenylmethyl 3-oxoazetidine-1-carboxylate (3.33 g, 0.0162 mol) in diethyl ether (50 mL). The reaction mixture was stirred at 35° C. for 12 hours then filtered through a bed of celite and rinsed with ethyl ether. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash chromatography (SiO2, 5-10% ethyl acetate in hexanes) to afford phenylmethyl 3-methylideneazetidine-1-carboxylate (2.46 g, 75% yield) as a clear and colorless oil). 1H NMR (400 MHz, CDCl3): 7.27-7.22 (m, 5H), 5.02 (s, 2H), 4.93-4.90 (m, 2H), 4.48-4.47 (m, 4H). MS (EI) for C12H13NO2: 203 (M+).
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@@H:17]([OH:19])[CH3:18])[C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[F:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C1COCC1.CN(C=O)C>[C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@@H:17]([OH:19])[CH3:18])[C:14]([NH:28][NH:27][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:30][CH:29]=2)=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)O
Reactant: NNC(=O)c1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a mixture of (2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoic acid (intermediate 60a) (0.52 g, 1.88 mmol), 4-fluorobenzoic hydrazide (295 mg, 1.91 mmol), HOBt (259 mg, 1.92 mmol) in THF:DMF (1:1) (30 mL) was added EDC (550 mg, 2.87 mmol) and Et3N (0.40 mL, 2.87 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min., then at room temperature overnight. The reaction was quenched by adding water and extracted with EtOAc. The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent and purification of the residue gave the title compound N′-((2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)-4-fluorobenzohydrazide (0.55 g, 71%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.02 (dd, J=5.7, 8.6 Hz, 2H), 7.82 (d, J=5.5 Hz, 1H), 7.74 (d, J=5.5 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.27 (t, J=8.6 Hz, 2H), 6.66 (d, J=8.0 Hz, 1H), 6.20 (d, J=7.2 Hz, 1H), 4.41 (m, 1H), 4.22 (dd, J=3.6, 7.2 Hz, 1H), 1.39 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:11][C:12](=[O:13])[CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C=CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.2 %

Procedure:
4-Methoxybenzaldehyde (1e, 0.63 ml, 5.2 mmol) and acetone (19, 4.00 ml, 54.0 mmol) were combined in ethanol (4 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.40 g, 10.0 mmol) and water (4 ml) was added dropwise and the mixture stirred for 1 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from ether/hexane to give 0.57 g (62%) of a yellow solid: mp 71-73° C. [expected mp 68° C.]; 1H NMR: δ 2.34 (s, 3H), 3.83 (s, 3H), 6.59 (d, 1H, 0.1=16.3 Hz), 6.90 (d, 2H, J=8.7 Hz), 7.46 (d, 1H, J=16.3 Hz), 7.48 (d, 2H, J=8.7 Hz); 13C NMR: δ 27.5, 55.4, 114.4, 125.0, 127.1, 129.9, 143.1, 161.5, 198.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[CH3:33][C:34]1[CH:35]=[C:36]([CH:38]=[C:39]([CH3:41])[CH:40]=1)[NH2:37].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CCCCCC.C1(C)C=CC=CC=1>[CH3:33][C:34]1[CH:35]=[C:36]([NH:37][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:14]4[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=4)=[CH:4][CH:3]=2)[CH:38]=[C:39]([CH3:41])[CH:40]=1
Reactant: Brc1ccc(C2(c3ccccc3)c3ccccc3-c3ccccc32)cc1
Reactant: Cc1cc(C)cc(N)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(C)cc(Nc2ccc(C3(c4ccccc4)c4ccccc4-c4ccccc43)cc2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
In a 200 mL three-neck flask were put 3.6 g (9.1 mmol) of 9-(4-bromophenyl)-9-phenylfluorene and 2.7 g (27.7 mmol) of sodium tert-butoxide. The air in the flask was replaced with nitrogen. To this mixture were added 46.0 mL of toluene and 1.2 mL (9.6 mmol) of 3,5-dimethylaniline. The temperature of this mixture was set to 60° C., and 53.2 mg (0.1 mmol) of bis(dibenzylideneacetone)palladium(0) was added to the mixture. The temperature of the mixture was raised to 80° C., followed by stirring for 0.5 hours. Then, 0.30 mL of a 10% hexane solution of tri(tert-butyl)phosphine was added to the mixture, which was then stirred for 4.5 hours. After the stirring, the mixture was suction-filtered through Florisil, Celite, and alumina to give a filtrate. The filtrate was concentrated to give a solid, which was then purified by silica gel column chromatography (the developing solvent has a 1:1 ratio of hexane to toluene) to give a while solid. Recrystallization of the obtained white solid from toluene and hexane gave 3.7 g of a white solid in 92% yield, which was the substance to be produced. The synthesis scheme of this Step 1 is shown in the following (E9-1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11](OC2C=CC=CC=2)[N:10]=1.[C:30]1([CH:37]=[CH:36][CH:35]=[C:33]([OH:34])[CH:32]=1)[OH:31].[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCCCCCC.C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11]([C:35]2[CH:36]=[CH:37][C:30]([OH:31])=[CH:32][C:33]=2[OH:34])[N:10]=1
Reactant: Cc1ccc(-c2nc(Oc3ccccc3)nc(-c3ccc(C)cc3C)n2)c(C)c1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Solvent: CCCCCCC
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Temperature: 160 °C

Procedure:
To a 250 mL round-bottomed flask fitted with a magnetic stirrer, a condenser and a nitrogen atmosphere are charged 6.26 g (0.0164 mol) of the product of Example 2, 12.8 g (0.116 mol) of resorcinol, 2,4 g of NAFION® NR50 beads 10-35 and 2 mL of xylene. The mixture is heated to 160° C. for 8.5 hours and then allowed to cool to room temperature. A 2.13 g (0.0160 mol) of aluminum chloride is added all at once. The mixture is then heated to 160° C. for two hours. An aliquot is worked up by adding portions of 2N hydrochloric acid and heptane and collecting the solid by vacuum filtration. 1H nmr (CDCl3) reveals a complete conversion to the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)#[N:2].[OH-].[K+].C[N:16](C)C=O>>[C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH2:16])[CH:5]=1)#[N:2]
Reactant: N#CCc1c[nH]c2ccccc12
Reactant: CN(C)C=O
Agent: [K+]
Agent: [OH-]
Product: N#CCc1cn(N)c2ccccc12

Procedure:
To a cold solution of 3-cyanomethyl-1H-indole (25 g) in 200 ml dimethylformamide (DMF), was added milled KOH (48 g) portionwise maintaining the temperature at 0° to 5° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([OH:24])[CH:12]=[C:13]([Cl:23])[C:14]=1[O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C(=O)N([Br:32])C(=O)C1>CN(C=O)C.O>[Br:32][C:12]1[C:13]([Cl:23])=[C:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:10][C:11]=1[OH:24]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(O)cc(Cl)c1O[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc(O)c(Br)c(Cl)c1O[Si](C)(C)C(C)(C)C
Yield: 70 %

Procedure:
A solution of 0.050 g (0.12 mmol) of 16 and 0.023 g (0.12 mmol) of NBS in 2 mL of DMF under argon was stirred at 25° C. for 1 day. The reaction mixture was diluted with 30 mL of water, extracted three times with diethyl ether (40 mL each), and the combined extracts were washed with brine (30 mL), dried (MgSO4), and concentrated to give 0.042 g (70% yield). This material was used in next step without purification. 1H NMR (CDCl3) δ 6.53 (s, 1H, Ar, C6-H), 1.03 (s, 9H, t-Bu), 0.96 (s, 9H, t-Bu), 0.22 (s, 6H, Me), 0.17 (s, 6H, Me); 13C NMR (CDCl3) δ 148.3 (s), 147.4 (s), 138.8 (s), 127.0 (s), 106.9 (d), 102.9 (s), 26.2 (q, t-Bu), 18.8 (s), −3.3 (q, Me), −3.5 (q, Me).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[C:18]1([CH2:24][C@H:25]2[CH2:30][C@H:29]([N:31]3[CH2:36][CH2:35][CH:34]([N:37]4[C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=5[NH:39][C:38]4=[O:46])[CH2:33][CH2:32]3)[CH2:28][CH2:27][NH:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:26]1[CH2:27][CH2:28][C@@H:29]([N:31]2[CH2:36][CH2:35][CH:34]([N:37]3[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[NH:39][C:38]3=[O:46])[CH2:33][CH2:32]2)[CH2:30][C@@H:25]1[CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=c1[nH]c2ccccc2n1C1CCN([C@@H]2CCN[C@@H](Cc3ccccc3)C2)CC1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@@H](N2CCC(n3c(=O)[nH]c4ccccc43)CC2)C[C@@H]1Cc1ccccc1

Procedure:
Using the same reaction procedure as described in example B5, 3,5-bis(trifluoromethyl)benzoyl chloride was reacted with intermediate 8 to form (±)-trans-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]-2-(phenylmethyl)piperidine (compound 43, mp. 156.1° C.).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O=[C:7]1[C:12]([C:13]#[N:14])=[CH:11][C:10]([CH3:15])=[C:9]([CH3:16])[NH:8]1>>[Cl:3][C:7]1[C:12]([C:13]#[N:14])=[CH:11][C:10]([CH3:15])=[C:9]([CH3:16])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C#N)c(=O)[nH]c1C
Product: Cc1cc(C#N)c(Cl)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
Phosphorus oxychloride (15 mL) was added to 2-oxo-1,2-dihydro-5,6-dimethyl pyridine-3-carbonitrile (2.00 g, 13.5 mmol) in a two neck 50 mL round bottom flask, and this mixture was stirred at RT for 1 h, and then refluxed for 12 h. Afterwards, the excess phosphorous oxychloride was distilled off, and the residue was poured into ice cooled water. The aqueous solution was basified with saturated sodium bicarbonate solution, and the precipitate that formed was filtered off to afford the title compound (1.50 g, yield: 66.7%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21]O)[CH:18]=[N:19][CH:20]=1.S(Cl)([Cl:25])=O>>[Cl:25][CH2:21][C:17]1[CH:18]=[N:19][CH:20]=[C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])[CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1cncc(CO)c1
Product: Cc1oc(-c2ccccc2)nc1COc1cncc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of 5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethanol (1.33 g) and thionyl chloride (4 ml) was stirred at room temperature for 1 hour. After the reaction mixture was concentrated, saturated aqueous sodium bicarbonate solution was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 3-chloromethyl-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (911 mg, yield 64%) as colorless crystals from the fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio). This was recrystallized from tetrahydrofuran-hexane. Melting point: 98–99° C.