Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Li+].Cl.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-:16]>CN(C)C=O>[N:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-:16])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [O-][n+]1ccccc1Br
Reactant: c1c[nH]cn1
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: [O-][n+]1ccccc1-n1ccnc1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
A 0.76 g portion of imidazole was added to 7 ml of N,N-dimethylformamide and mixed with 0.2 g of 90% lithium hydride under ice-cooling and then the mixture was stirred for 40 minutes. Next, 2.17 g of 2-bromopyridine N-oxide hydrochloride was gradually added thereto, the mixture was stirred at room temperature for about 1 hour and further heated at 80° C. for about 1 hour, and then the solvent was evaporated and the thus obtained mixture was subjected to a silica gel column chromatography and eluted with chloroform-methanol-28% aqueous ammonia (10:0.9:0.1, v/v/v) to obtain 1.21 g of the title compound as light yellow crystals.
Reaction SMILES: C([Li])CCC.[O:6]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:16]Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:22][C:23]1[CH:36]=[CH:35][C:26]([C:27]([CH:32]2[CH2:34][CH2:33]2)=[C:28]([F:31])[CH:29]=[O:30])=[CH:25][CH:24]=1>O1CCCC1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([CH:32]2[CH2:34][CH2:33]2)=[C:28]([F:31])[CH:29]([OH:30])[CH2:16][C:15]2[CH:18]=[CH:19][C:20]([F:21])=[C:13]([O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:14]=2)=[CH:35][CH:36]=1
Reactant: O=CC(F)=C(c1ccc(Cl)cc1)C1CC1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(Cc1ccc(F)c(Oc2ccccc2)c1)C(F)=C(c1ccc(Cl)cc1)C1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of lithium n-butyltellurolate (10.5 mmol, n-BuTeLi), generated in situ from n-butyllithium (4.2 mL of 2.5 M solution in hexane, 10.5 mmol) and Te powder (1.34 g, 10.5 mmol) in tetrahydrofuran (10 mL) at 0° C., is treated with a solution of 3-phenoxy-4-fluorobenzyl bromide (2.81 g, 10 mmol) in tetrahydrofuran (10 mL) at 0° C., stirred for 30 minutes, cooled to −78° C., treated with a solution of n-butyllithium (4.2 mL of 2.5 M solution in hexane, 10.5 mmol), stirred for 30 minutes at −78° C., treated with a solution of p-chloro-β-cyclopropyl-α-fluorocinnamaldehyde (2.24 g, 10 mmol) in tetrahydrofuran (5 mL), warmed to room temperature with stirring for 3 hours, quenched with 2 N hydrochloric acid, and extracted with ethyl acetate. The combined organic extracts are washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash chromatography of the residue on silica gel using a 1:4 ethyl acetate/hexanes solution gives the title product (3.5 g, 82% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=2)[C:7]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:10][CH2:9][C:8]=2[N:24]=1)[CH3:3].[BH4-].[Na+]>CO>[CH3:3][CH:2]([C:4]1[N:5]=[C:6]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([CH:32]([OH:34])[CH3:33])=[CH:30][CH:31]=2)[C:7]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:10][CH2:9][C:8]=2[N:24]=1)[CH3:1]
Reactant: CC(=O)c1ccc(Nc2nc(C(C)C)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nc2c(c(Nc3ccc(C(C)O)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
To a solution of 1-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanone (Example 96; 37 mg, 0.079 mmol) in MeOH was added NaBH4 (4.1 mg, 0.11 mmol). The mixture was stirred at rt for 4 h, then concentrated. The residue was redissolved in water and extracted with EtOAc. The organic layers were combined, dried, and concentrated. The crude residue was purified (FCC) to give the title compound (32.1 mg, 86%). MS (ESI): mass calcd. for C25H28F3N5O, 471.22; m/z found, 472.2 [M+H]+. 1H NMR (CDCl3): 8.40-8.38 (m, 1H), 7.87 (dd, J=7.8, 1.8 Hz, 1H), 7.67-7.64 (m, 2H), 7.38-7.34 (m, 2H), 6.97-6.92 (m, 1H), 6.51 (s, 1H), 4.93-4.88 (m, 1H), 3.69-3.60 (m, 4H), 3.24-3.18 (m, 2H), 3.06-2.98 (m, 1H), 2.98-2.94 (m, 2H), 1.76 (d, J=3.6 Hz, 1H), 1.52 (d, J=6.4 Hz, 3H), 1.31 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([C@@H:11]2[CH2:14][C@H:13]([NH:15]C(=O)OCC3C=CC=CC=3)[C:12]2([CH3:27])[CH3:26])=[O:10])[CH2:5][CH2:4]1)[CH3:2]>CCOC(C)=O>[NH2:15][C@H:13]1[CH2:14][C@@H:11]([C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]2)=[O:10])[C:12]1([CH3:26])[CH3:27]
Reactant: CCN1CCN(C(=O)[C@@H]2C[C@H](NC(=O)OCc3ccccc3)C2(C)C)CC1
Solvent: CCOC(C)=O
Product: CCN1CCN(C(=O)[C@@H]2C[C@H](N)C2(C)C)CC1
Reaction time: 12 h

Procedure:
To a stirred solution of benzyl (1S,3R)-3-(4-ethylpiperazine-1-carbonyl)-2,2-dimethylcyclobutylcarbamate (above step 1, 780 mg) in EtOAc (20 ml) 10% Pd/C (catalytic amount) was added at room temperature and the reaction mixture was stirred under H2 gas atmosphere for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite bed and the obtained filtrate concentrated under reduced pressure to afford the title compound as a liquid which was proceeded as such for next reaction without characterization. Yield has been calculated as 100%.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Cl:12]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:12][C:7]1[CH:8]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Cl)cc(F)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
2-Chloro-4-fluoro-6-nitroaniline was prepared using an adaptation of the method of Mitchell, et al. (Mitchell, R. H. et al., J. Org. Chem. 44:4733 (1979)). To a solution of 4-fluoro-2-nitroaniline (500 mg, 3.2 mmol) in dry DMF (10 mL) under N2 was added dropwise a solution of N-chlorosuccinimide (426 mg, 3.2 mmol) in dry DMF (16 mL). The reaction was allowed to stir overnight. The solution was then poured into 100 mL H2O and the resulting cloudy suspension extracted with 4×25 mL ethyl acetate. The combined organic phases were washed with 4×25 mL H2O and 25 mL saturated NaCl solution and dried (MgSO4). The MgSO4 was vacuum filtered and the solvent rotary evaporated to yield a brown crystalline solid which was purified further by flash chromatography (2:1 hexanes:ethyl acetate) to yield 424 mg of an orange crystalline solid (69.5%) 1H NMR (CDCl3) δ6.46 (br s, 2H, NH2), 7.42 (dd, JH5-3 =3 Hz, JH3-F =7.2 Hz, H-4), 7.85 (dd, JH5-3 =3 Hz, JH5-F =8.7 Hz, H-5)
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:15][CH2:16][CH3:17])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1>>[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23]1[N:24]=[CH:25][C:26]([NH:29][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[CH2:15][CH2:16][CH3:17])=[O:14])=[CH:27][CH:28]=1
Reactant: CCCc1oc(-c2ccccc2)nc1C(=O)O
Reactant: COCCN(C)c1ccc(N)cn1
Product: CCCc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-propyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H26N4O3 (m/e) 394, obsd 395 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[N:12][O:13][CH:14]=1)([O-])=O>Cl>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[N:12][O:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccccc1-c1cnoc1
Agent: Cl
Product: Nc1ccccc1-c1cnoc1
Temperature: 10 °C
Reaction time: 10 h
Yield: 71.2 %

Procedure:
To a suspension of 108 g of stannous chloride dihydrate in 270 ml of concentrated hydrochloric acid was added portionwise 30 g of 4-(2-nitrophenyl)isoxazole prepared in Example 10 at less than 30° C. The suspension was stirred at about 20°-35° C. for 10 hours, then cooled to 10° C. and filtered. The solid was added to ice-water (400 ml), 50% NaOH was added to make the suspension basic to a pH of about 10, and the resultant suspension filtered. The solid was washed 3×100 ml of water and suction dried to give 18 g of the title compound; m.p. 48°-51° C.
Reaction SMILES: [Cl-].[CH2:2]([P+:6]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:3][CH2:4][CH3:5].COC1C=CC(O)=CC=1.[C:29]([Cl:34])(=[O:33])[C:30]([CH3:32])=[CH2:31]>C(#N)C>[Cl-:34].[CH2:12]([P+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:29](=[O:33])[C:30]([CH3:32])=[CH2:31])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC[P+](CCCC)(CCCC)CCCCO
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Agent: [Cl-]
Solvent: CC#N
Product: C=C(C)C(=O)OCCCC[P+](CCCC)(CCCC)CCCC
Reaction time: 2 h

Procedure:
Into a 1 L-four-necked flask equipped with a stirrer, a thermometer and a distillation line, was added the obtained tri-n-butyl(4-hydroxybutyl)phosphonium chloride dissolved in 500 ml of acetonitrile. The solution was heated under a normal pressure while stirring and about 200 ml of acetonitrile was distilled. A condenser having a calcium chloride tube was installed, 1.5 g of hydroquinone monomethyl ether was added as a polymerization inhibitor, and 70.5 g (0.674 mol) of methacryloyl chloride was added thereto dropwise at 50° C. over 2 hours through a dropping funnel, then the solution was maturated for 3 hours at the same temperature.
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([O:10]CC)=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[O:1]1[C:6]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([OH:10])=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CCCCCCON=C(C(=O)OCC)C1=CSCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCON=C(C(=O)O)C1=CSCCO1
Temperature: 25 °C
Reaction time: 43 h
Yield: 25.4 %

Procedure:
Ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetate (mixture of syn isomer and anti isomer, 186.8 g.), 1 N aqueous solution of sodium hydroxide (472 ml.) and methanol (1.8 l.) were stirred at room temperature for 35 minutes and the insoluble substance was removed by filtration. The filtrate was stirred at room temperature for 43 hours and treated in a similar manner to that of Example I-(iii) to give 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 43 g.).
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[CH3:13][C:14]1[C:23]([CH3:24])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[CH:25]=[CH:26][C:27](=[O:29])[CH3:28].[OH-].[K+].Cl>C(O)C>[OH:29][C:27]1[CH2:26][CH:25]([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:22]=[C:23]([CH3:24])[C:14]=2[CH3:13])[CH2:2][C:3](=[O:4])[CH:28]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1c(C)c(C)cc2ccccc12
Agent: Cl
Agent: [K+]
Agent: [Na]
Solvent: CCO
Product: Cc1cc2ccccc2c(C2CC(=O)C=C(O)C2)c1C

Procedure:
Diethyl malonate (9.82 g) was added to a solution of sodium metal (1.41 g) in anhdrous absolute ethanol (50 ml). 1-(2,3-Dimethylnaphth-1-yl)but-1-en-3-one (12.5 g) was added to the solution and the mixture was heated under reflux for 2 hr. A slight excess of an aqueous solution of potassium hydroxide was added and the mixture was heated under reflux for a further 5 hr. The hot mixture was acidified by dropwise addition of a dilute aqueous hydrochloric acid solution. After cooling, the product was filtered off and washed with a little diethyl ether to give 3-hydroxy-5-(2,3-dimethylnaphth-1-yl)-cyclohex-2-en-1-one as a white solid, mp 242° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CN.C1COCC1.[CH3:29][N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:30][CH3:29])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(F)cc(-c2ccc3ncnc(N)c3n2)c1

Procedure:
Following the same reaction and purification procedure, the acid 3 (50 mg, 0.18 mmol) was reacted with methyl amine 2M in THF (0.18 mL, 0.35 mmol), HATU (103 mg, 0.6 mmol) and DIPEA (0.15 mL, 0.88 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-N-methylbenzamide 5. LC/MS (ESI+): m/z 298 (M+H). 1H NMR (400 MHz, DMSO) δ 8.71 (d, J=4.5 Hz, 1H), 8.59 (dd, J=7.4, 4.0 Hz, 2H), 8.54 (d, J=8.9 Hz, 1H), 8.47 (s, 1H), 8.28 (s, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.06 (s, 1H), 7.72 (d, J=9.2 Hz, 1H), 2.87 (d, J=4.5 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=O)(C)(C)C.[ClH:19]>CCOC(C)=O>[ClH:19].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCOCC1CCC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)CCC1COCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 3-(4-(tert-butoxycarbonyl)morpholin-3-yl)propanoic acid (0.3 g, 1.2 mmol) in EtOAc (2 mL) was added the solution of HCl in EtOAc (6 mol/L, 6 mL). The mixture was stirred closedly at 25° C. for 2 hours and filtered. The residue was washed with EtOAc (4 mL) to give the title compound as a white solid (0.21 g, 90%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC.C1C=CC=CC=1>[CH2:23]([O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: Nc1ncccc1O
Reactant: CCCCCCCCCCCCCl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCOc1cccnc1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A mixture of 2-amino-3-pyridinol (0.10 mol), sodium hydroxide (50%) (30 ml), 1-chlorododecane (0.20 mol) and methyl-tri-octylammonium chloride (8 g) in benzene (300 ml) was stirred overnight at 80° C. The reaction mixture was cooled. The organic layer was separated, washed with 2N NaOH, dried (MgSO4), filtered and the solvent was evaporated. The residue was cooled and the resulting precipitate was filtered off, washed with hexane, petroleum ether and dried, yielding 21 g (75%) of 3-(dodecyloxy)-2-pyridinamine (interm. 2).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](O)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH3:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH3:24])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccccc1C1(O)CCN(C(=O)OCc2ccccc2)CC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 18 h
Yield: 67.7 %

Procedure:
The product of Step 2 (5.1 g) in CH2Cl2 (50 mL) was treated sequentially with trifluoroacetic acid (8.9 mL) and triethylsilane (34.5 mL). After 18 h, the solution was treated with saturated NaHCO3 (150 mL). After a further 1 h, the organic layer was separated and the aqueous extracted with CH2Cl2 (100 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel chromatography, eluting with EtOAc/hexane mixtures to give 1-benzyloxycarbonyl-4(2-methylthiophenyl)piperidine (3.3 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[OH:28][CH2:29][C:30]([NH:33][S:34]([C:37]1[S:41][C:40]([NH2:42])=[N:39][C:38]=1[CH3:43])(=[O:36])=[O:35])([CH3:32])[CH3:31]>>[OH:28][CH2:29][C:30]([NH:33][S:34]([C:37]1[S:41][C:40]([NH:42][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([CH3:1])[CH:3]=4)=[N:13][C:14]=23)=[O:27])=[N:39][C:38]=1[CH3:43])(=[O:36])=[O:35])([CH3:32])[CH3:31]
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4nc(C)c(S(=O)(=O)NC(C)(C)CO)s4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 635.0 [(M+H)+]; mp 272° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([OH:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([OH:33])[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][CH2:8][C:7]4[CH:16]=[CH:17][CH:18]=[CH:19][C:6]3=4)[CH2:31][CH2:32]2)=[CH:23][CH:22]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: BrCCC=C1c2ccccc2CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: OC1(c2ccc(Cl)cc2)CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 88.2 %

Procedure:
To a solution of 5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (described in JP 48-030064)(200 mg) in DMF (10 ml) were added 4-(4-chlorophenyl)-4-hydroxypiperidine (230 mg), potassium carbonate (360 mg), and potassium iodide (50 mg). The mixture was stirred at 70° C. for 24 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:1) to give the titled compound (250 mg) . 1H-NMR (CDCl3) δ: 1.65-2.11 (5H,m) , 2.32-3.10 (8H,m), 3.22-3.67(4H,m), 5.87(1H,t), 7.03-7.44(12H,m). MS m/z: 444(M+1).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.BrC1C=CC(C(O)C2C=CC=CC=2)=CC=1>C(Cl)(Cl)Cl>[C:16]1([CH:15]([OH:22])[C:11]2[CH:12]=[CH:13][C:8]([CH2:7][C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[CH:9][CH:10]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: Brc1ccc(Cc2ccccc2)cc1
Agent: OC(c1ccccc1)c1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Product: OC(c1ccccc1)c1ccc(Cc2ccccc2)cc1
Yield: 86 %

Procedure:
α,α′-Diphenyl-α-hydroxyl-p-xylene was prepared as shown in Scheme 4 by using 29.0 g (117 mmol) of 4-bromo diphenylmethane and 11.2 g (106 mmol) of benzaldehyde/19.7 g (106 mmol) by the similar procedure to the method for preparing 4-bromobenzhydrol. The crude product was dissolved in chloroform and filtered through G60 column filled with silica gel. After evaporating the solvent, the result product was recrystallized with hexane/chloroform (9:1 v/v) to provide a yield of 86%. MP: 64° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:5][NH:6][C:7]([C:9]1[C:18]([OH:19])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[C:11](Br)[N:10]=1)=[O:8].[C:25]1([SH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:5][NH:6][C:7]([C:9]1[C:18]([OH:19])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[C:11]([S:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:10]=1)=[O:8]
Reactant: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(Br)c2cccnc2c1O
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(Sc2ccccc2)c2cccnc2c1O
Temperature: 135 °C

Procedure:
To a 5 mL pyrex pressure vessel with a stirring bar was added 5-bromo-8-hydroxy-[1,6]naphthyridine-7-carboxylic acid 3,5-dichloro-benzylamide (0.055 g, 0.13 mmol), thiophenol (0.056 g, 0.50 mmol) and triethylamine (0.28 mL, 2.00 mmol). The vessel was sealed under nitrogen and the stirred mixture heated in a 135° C. oil bath for 24 h. The cooled reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel (15 g) using methanol:chloroform (5:95) as eluant to give 8-hydroxy-5-phenylsulfanyl-[1,6]naphthyridine-7-carboxylic acid 3,5-dichlorobenzylamide as a solid.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8](OCC)=[O:9])[C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[O:30][CH:31]=[CH:32][CH:33]=4)[O:26][C:27]=3[CH3:28])=[C:17]([O:34][CH3:35])[CH:16]=2)=[N:4]1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][OH:9])[C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[O:30][CH:31]=[CH:32][CH:33]=4)[O:26][C:27]=3[CH3:28])=[C:17]([O:34][CH3:35])[CH:16]=2)=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCn1cc(CO)c(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of ethyl 1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylate (2.80 g) in tetrahydrofuran (50 mL) was added lithium aluminum hydride (0.22 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (1.87 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated to give {1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}methanol as colorless crystals (2.32 g, yield 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 117-118° C.