Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:27][S:28]SC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([S:28][CH3:27])=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc2c(OCCNC(=O)OC(C)(C)C)noc12
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(C)c2onc(OCCNC(=O)OC(C)(C)C)c12
Temperature: -70 °C
Yield: 86.4 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-7-methyl-1,2-benzisoxazole (0.15 g) in tetrahydrofuran (20 ml) was added butyl lithium (0.75 ml, 1.6M hexane solution) dropwise with stirring at -70° C. under nitrogen atmosphere, and the mixture was stirred at the same temperature for 15 minutes, then followed by addition of dimethyldisulphide (0.11 g). The reaction mixture was poured into ice water (40 ml), extracted with ethyl acetate (twice each with 40 ml) and the combined extracts were dried over anhydrous magnesium sulphate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (9/1) as an eluent, to give the title compound (0.15 g, 88%) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[C:9]([NH:20][C@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[N:10][C:11](S(C)(=O)=O)=[N:12][C:13]=2[O:14][CH3:15])=[N:6][CH:7]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CC#N>[F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[C:9]([NH:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[N:10][C:11]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:12][C:13]=2[O:14][CH3:15])=[N:6][CH:7]=1
Reactant: COc1nc(S(C)(=O)=O)nc(N[C@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1ncc(F)cn1
Reactant: C1COCCN1
Solvent: CC#N
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1ncc(F)cn1
Temperature: 100 °C

Procedure:
To (S)-tert-butyl 3-((5-fluoro-6′-methoxy-2′-(methylsulfonyl)-[2,5′-bipyrimidin]-4′-yl)amino)piperidine-1-carboxylate (0.05 g, 0.104 mmol) in MeCN (3.5 mL) was added morpholine (0.027 ml, 0.311 mmol) in a pressure tube. The reaction was heated to 100° C. for 18 h. Upon completion of the reaction, the solvent was removed and reaction was purified via column chromatography (0-50% EtOAc/Hex) to afford the desired product as a white solid. MS (m/z)=490 (M+H).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.Cl>CS(C)=O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([C:11]2[CH:12]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]([OH:17])=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=2)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 90 °C
Reaction time: 17 h
Yield: 68.1 %

Procedure:
A mixture of 12.0 g (300 mmol) of powdered sodium hydroxide, 24.7 g (120 mmol) of 2,6-di-tert-butylphenol, 15.7 g (100 mmol) of 1-chloro-4-nitrobenzene, and 120 mL of DMSO was stirred for 17 hours at 90° C. and poured into one liter of 1N HCl. The resulting aqueous mixture was extracted with three 250 mL portions of diethyl ether. Combination, drying (MgSO4), and concentration of the organic layers afforded a residue which was purified by two recrystallizations from ethanol-dichloromethane to give 22.3 g (68% yield) of 4-(4'-nitrophenyl)-2,6-di-tert-butylphenol which an also be named 3,5-bis-(1,1-dimethylethyl)-4'-nitro-(1,1'-biphenyl)-4-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:21]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23]([N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:36]=3[N:35]=[C:34]2[CH:44]([F:46])[F:45])[N:22]=1>C1COCC1.C(O)(=O)C.O>[F:46][CH:44]([F:45])[C:34]1[N:33]([C:23]2[N:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:26]=[C:21]([NH:1][C:2]3[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][N:3]=3)[N:22]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:36]=2[N:35]=1
Reactant: COc1cc(N)ncn1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)ncn1
Reaction time: 0.17 h
Yield: 28.3 %

Procedure:
To 0.282 g (2.25 mmol) of 4-amino-6-methoxypyrimidine in THF (4 mL) was added 1.30 mL of NaHMDS (2 M solution in THF) and the mixture was stirred for 10 min. A solution of 0.297 g (0.75 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) in THF (5 mL) was added. The resulting mixture was stirred at room temperature for 1 hr. After neutralization with acetic acid, the mixture was diluted with water, and extracted with EtOAc. The organic layer was washed successively with water and aqueous NH3, and dried. Removal of the solvent, followed by chromatography on silica eluting with CH2Cl2/EtOAc (1:1) gave a white powder. Recrystallization from ethanol/CH2Cl2 gave 0.103 g (30% yield) of 4-(2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl)-N-(6-methoxypyrimidin-4-yl)-6-morpholino-1,3,5-triazin-2-amine: mp 256-259° C.; 1H NMR (CDCl3) δ8.52 (s, 1H), 7.96-7.94 (m, 2H), 7.59 (s, 1H), 7.49 (t, JHF=53.5 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 4.06 (s, 3H), 4.00 (s, 3H), 3.99-3.96 (m, 4H), 3.84 (s, 4H); HRMS (FAB MH+) Calcd for C21H22F2N9O3: m/z 486.1808. Found: m/z 486.1808.
Reaction SMILES: C([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[NH:19][C:18](=[O:20])[N:17]([C@H:21]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][C:36]([I:38])=[CH:37][C:31]=4[N:30]=3)[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]2=[O:39])=[CH:11][CH:10]=1)(C)(C)C.ClCCl.C(#N)C.[I-].[Na+].Cl[Si](C)(C)C>C(OCC)(=O)C>[OH:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[NH:19][C:18](=[O:20])[N:17]([C@H:21]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][C:36]([I:38])=[CH:37][C:31]=4[N:30]=3)[CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:16]2=[O:39])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OCCOc1ccc([C@H]2NC(=O)N([C@@H](Cc3ccccc3)c3nc4cc(I)ccc4[nH]3)C2=O)cc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1N[C@H](c2ccc(OCCO)cc2)C(=O)N1[C@@H](Cc1ccccc1)c1nc2cc(I)ccc2[nH]1
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of (R)-5-[4-(2-tert-butoxy-ethoxy)-phenyl]-3-[(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethyl]-imidazolidine-2,4-dione (140 mg, 0.22 mmol) in 1:1 v/v dichloromethane/acetonitrile (2 mL) at 0° C. under an atmosphere of nitrogen was added sodium iodide (62 mg, 0.42 mmol) followed by chlorotrimethylsilane (78 μL, 0.61 mmol), the resulting solution was allowed to stir for 30 minutes. Additional sodium iodide (62 mg, 0.42 mmol) followed by chlorotrimethylsilane (78 μL, 0.61 mmol) was added and stirring continued for a further 45 minutes. The reaction was poured into ethyl acetate (30 mL) and washed with 10% aqueous sodium thiosulfate solution. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 60 to 80% v/v ethyl acetate/hexanes to give (R)-5-[4-(2-hydroxy-ethoxy)-phenyl]-3-[(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethyl]-imidazolidine-2,4-dione (83 mg, 65%).
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:20][CH:21]([F:25])[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[F:20][CH:21]([F:25])[C:22](=[O:23])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C=CN1CCCCC1
Reactant: O=C(Cl)C(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C(=CN1CCCCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
Methyl 3-piperidin-1-ylacrylate (99%, 26.6 g, 155 mmol) and triethylamine (17.3 g, 171 mmol) were initially charged in toluene (300 ml) and cooled to −30° C. At this temperature, difluoroacetyl chloride (20 g, 171 mmol) was introduced. The reaction mixture was stirred at −30° C. for 3 h, another 200 ml of toluene were added to keep the suspension stirrable and the mixture was then warmed to room temperature over a period of 1 hour. The reaction mixture was washed with deionized water (200 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml), and the solvent was then removed under reduced pressure. This gave methyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orange oil (amount: 37.6 g; purity according to quant. NMR: 82.2%; yield: 80.3%).
Reaction SMILES: [CH3:1][C:2]([O:5][CH2:6][CH:7]1[O:9][CH2:8]1)([CH3:4])[CH3:3].[CH2:10]([OH:16])[CH2:11][O:12][CH2:13][CH2:14][OH:15].O>ClCCl.B(F)(F)F.CCOCC.[OH-].[Na+]>[C:2]([O:5][CH2:6][CH:7]([OH:9])[CH2:8][O:16][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15])([CH3:1])([CH3:3])[CH3:4]
Reactant: OCCOCCO
Reactant: CC(C)(C)OCC1CO1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OCC(O)COCCOCCO
Yield: 39 %

Procedure:
A solution of 100 g (0.77 mole) t-BGE in 100 ml dichloromethane was slowly added with stirring to a glass round bottom flask containing a solution of 250 g (2.4 moles) diethylene glycol and 0.5 ml boron trifluoride etherate catalyst in 150 ml dichloromethane that had first been preheated to 36° C. Over the course of addition (approximately 1.25 hr) the reaction temperature rose to about 45° C. and the dichloromethane began to reflux. The reaction was continued with stirring for about 2 hours after completion of t-BGE addition. A small quantity, approximately 1 g of sodium hydroxide and 20 ml of water were added to the reaction vessel contents. The solvent was then removed by evaporation and the product residue distilled at 0.7 mm Hg pressure. Tertiary butoxymethyl triethylene glycol (71 g, 39 percent yield) was recovered having a boiling point range from 139°-145° C. Analysis by nuclear magnetic resonance (NMR) and infrared (IR) absorption spectroscopy confirmed the product's identity.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[C:20]([C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1C(Cl)=O)([CH3:23])([CH3:22])[CH3:21].CN(C)[CH:35]=[O:36]>>[C:20]([C:24]1[CH:25]=[CH:29][C:30]([C:35]([NH:13][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[O:36])=[CH:31][CH:32]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1ccccc1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])cc2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a mixture of 5-nitroanthranilic acid (24.6 g, 135 mmol) and pyridine (14.2 mL, 175 mmol) in N,N-dimethylformamide (140 mL) cooled to 0° C. was added tert-butylbenzoyl chloride (31.6 mL, 162 mmol). After stirring for 1 h, the reaction mixture was heated at 75° C. for 4 h, cooled, and poured into an ice/water mixture. The resulting solid was filtered, washed with water and a 1:2 mixture of diethyl ether/hexanes, and dried in vacuo at 150° C. for 2 h to give 37.1 g (80%) of the title compound as a light brown solid; mp 245-9° C. MS-FD m/e 342 (p) Analysis for C18H18N2O5: Calc: C, 63.15; H, 5.30; N, 8.18; Found: C, 62.85; H, 5.05; N, 8.48.
Reaction SMILES: O=[Al-:2]=O.[Na+].[Si:5]([OH:9])([OH:8])([OH:7])[OH:6].Cl>>[Si:5]([O-:9])([O-:8])([O-:7])[O-:6].[Al+3:2].[Si:5]([O-:9])([O-:8])([O-:7])[O-:6].[Si:5]([O-:9])([O-:8])([O-:7])[O-:6].[Al+3:2].[Al+3:2].[Al+3:2]
Reactant: O[Si](O)(O)O
Reactant: O=[Al-]=O
Agent: Cl
Agent: [Na+]
Product: [Al+3]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
neutralizing a second mixture of a solution of sodium aluminate and a soluble silicic acid-containing material by adding hydrochloric acid to form an aluminum silicate gel;
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([O:10][CH:4]([O:5]3)[C:3](=[O:12])[O:2]1)[CH2:9]2.[BH4-].[Na+].O>CO.C(O)(=O)C>[OH:12][CH2:3][CH:4]1[O:10][CH:8]2[CH2:7][CH:6]([CH2:11][CH:1]([OH:2])[CH2:9]2)[O:5]1
Reactant: O=C1OC2CC3CC(C2)OC1O3
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: OCC1OC2CC(O)CC(C2)O1

Procedure:
To a solution of 340 mg (2mmols) of 2,5,11-trioxatricyclo[4,3,1,14,8 ]undecan-3-one in 10 ml of methanol are added all at once 150 mg of sodium borohydride while stirring and cooling to 12°-15°C(water bath). After 11/2 hours, during which time the bath temperature is allowed to rise to 20°C, a further 150 mg of sodium borohydride are added and the mixture is stirred for 21/2 hours at 20°C. The reaction mixture is then treated with 10 ml of water, the pH adjusted to 8 with a few drops of acetic acid, and concentrated under reduced pressure to about 3 ml. The concentrate is extracted three times with 25 ml of methylene chloride on each occasion, the combined extracts are dried over sodium sulphate and the solvent is distilled off (at the conclusion under reduced pressure) to give crystalline 3-hydroxymethyl-2,4-dioxabicyclo[ 3,3,1]nonan-7-ol of the formula IIa (m.p.146° -149°C).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:15]1[C:24]2[CH:23]([NH2:25])[CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:25][CH:23]2[C:24]3[N:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH2:20][CH2:21][CH2:22]2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: NC1CCCc2cccnc21
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NC2CCCc3cccnc32)CC1
Yield: 98 %

Procedure:
Using general procedure B: Reaction of Boc-4-piperidone (641 mg, 3.22 mmol 5,6,7,8-Tetrahydro-quinolin-8-ylamine (476 mg, 3.22 mmol), sodium triacetoxyborohydride (1.36 g, 6.44 mmol) and acetic acid (0.25 mL) in THF (25 mL) at room temperature under N2 for 20 min afforded the title compound (1.05 g, 98%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.[F:50][C:51]([F:62])([F:61])[C:52]1[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=1)[CH:55]([OH:57])[CH3:56]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:39](=[O:41])[O:57][CH:55]([C:54]1[CH:58]=[CH:59][CH:60]=[C:52]([C:51]([F:61])([F:62])[F:50])[CH:53]=1)[CH3:56]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: CC(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4cccc(C(F)(F)F)c4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Yield: 42.2 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (76 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-trifluoromethyl-α-methylbenzyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (53 mg, yield 39%).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:15][S:14][N:13]=1)[CH3:4]>CC(C)=O>[I-:2].[CH2:3]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17]2[CH:18]=[N+:19]([CH3:1])[CH:20]=[CH:21][CH:22]=2)=[N:15][S:14][N:13]=1)[CH3:4]
Reactant: CI
Reactant: CCOCCOCCOc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: CCOCCOCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 9 mmol) and 3-(3-(2-(2-ethoxyethoxy)-ethoxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[C:23](=[O:26])([O-])[O-].[Na+].[Na+].O.[CH3:30][N:31](C)[CH:32]=[O:33]>[I-].[K+]>[CH2:2]([O:26][CH2:23][CH3:30])[CH3:3].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:23][C:32]([NH2:31])=[O:33])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CCOCC
Product: NC(=O)CN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 15.2 g (0.05 mole) of α,α-bis(4-fluorophenyl)-4-piperidinemethanol (U.S. Pat. No. 3,956,296), 5.1 g (0.055 mole) of 1-chloroacetamide, 15.9 g (0.15 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 150 ml of dimethylformamide was heated on a steam bath for 22 h. The mixture was poured into 1.5 L of water and a gum precipitated which crystallized upon standing overnight. The solid was collected by filtration, washed with water, dried, and recrystallized from 2-propanol/petroleum ether (30°-60° C.) to yield 11.7 g (65%) of the amide as an off-white solid. An analytical sample, mp 117°-119° C. (dec), was prepared from benzene-ethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=[N:58][C:53]2[CH:54]=[CH:55][CH:56]=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CCC1>CN(C=O)C>[CH:53]1([NH:58][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:19]([C:18]3[C:13]4[CH:12]=[CH:11][C:10](=[O:42])[N:9]([C:3]5[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=5[F:8])[C:14]=4[N:15]=[C:16]([N:29]4[CH2:34][CH2:33][CH:32]([N:35]5[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]5)[CH2:31][CH2:30]4)[N:17]=3)[CH:20]=2)[CH2:54][CH2:55][CH2:56]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CCC2)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and cyclobutanamine (7.04 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (24.8 mg, 72%). LC-MS m/z 627 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[O:5]([C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[OH:24])=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[N+:1]([C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:24])=[C:14]([C:12]([O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:13])[CH:23]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(Oc1ccccc1)c1ccc2ccccc2c1O
Solvent: ClC(Cl)Cl
Product: O=C(Oc1ccccc1)c1cc([N+](=O)[O-])c2ccccc2c1O
Reaction time: 0.5 h
Yield: 62 %

Procedure:
12 ml of fuming nitric acid (d=1.5) was added dropwise to a solution of 53 g of 2-phenoxycarbonyl-1-naphthol dissolved in 200 ml of chloroform was added dropwise 12 cc of fuming nitric acid (d=1.5) at 10° C. to 30° C. After 30 minutes, the precipitated crystals were filtered, washed well with cooled chloroform to obtain the desired product at a yield of 62%. The product had m.p. of 157° C., and was confirmed by NMR, Mass spectra.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[C:4]2[CH:3]=[CH:2]1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][S:15][C:13]1[O:14][C:10]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[NH:1][CH:2]=[CH:3][C:4]=23)=[N:11][N:12]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Sc1nnc(-c2ccnc3[nH]ccc23)o1
Product: Fc1cccc(CSc2nnc(-c3ccnc4[nH]ccc34)o2)c1
Yield: 64 %

Procedure:
In the same manner as in Example 1 and using 5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,3,4-oxadiazole-2-thiol 5/6 triethylamine salt instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-fluorobenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 64%) was obtained as pale-yellow crystals.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]([C:13]([CH3:34])([CH3:33])[CH2:14][C:15]([OH:32])([C:28]([F:31])([F:30])[F:29])[CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:27])[CH:19]=[CH:18]2)[CH:10]=[CH:11][CH:12]=1.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[F:31][C:28]([F:29])([F:30])[C:15]([OH:32])([CH2:16][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[CH:19]=[CH:18]1)[CH2:14][C:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH:2]=[O:1])([CH3:33])[CH3:34]
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(C2OCCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCO
Product: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(C=O)c1
Temperature: 25 °C

Procedure:
A mixture of 1-[4-(3-[1,3]dioxan-2-ylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (0.99 g, 2.09 mmol), ethanol (66 mL), water (13.2 mL), and pyridinium p-toluenesulfonic acid (262 mg, 1.04 mmol) was heated at reflux for 3 hours, cooled to room temperature and concentrated in vacuo to remove ethanol. The residue was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. Removal of the volatile in vacuo afforded 3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]benzaldehyde. Yield: 77 mg (89%).