Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].O.[OH-].[Li+].[ClH:24].CCOCC>C1COCC1.O>[ClH:24].[C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)CCc1cncn1Cc1ccc(C#N)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: N#Cc1ccc(Cn2cncc2CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the methyl ester 5 (1.10 g) in 10 mL of THF and 5 mL of water was added lithium hydroxide monohydrate (172 mg). After two hours, the reaction was cooled to 0° C., and a 1 M solution of HCl/ether (8.2 mL) was added. The solution was concentrated and dried in vacuo next to P2O5 to provide the product 6 as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][O:31][CH2:30]1>>[CH3:8][C@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][O:31][CH2:30]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCC1CCCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 243 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(2-bromoethyl)tetrahydro-2H-pyran.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[CH:33]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34]1>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:37]([CH:33]3[CH2:36][CH2:35][CH2:34]3)=[O:38])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3CCC3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 mmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, cyclobutanecarbonyl chloride (23 mg, 193 mmol, 3 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (21.9 mg, 68% of theory).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C1C=CC(C2(C[O:32][S:33]([CH3:36])(=O)=[O:34])CCCC2)=CC=1>>[CH3:36][S:33]([O:15][CH2:14][C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:34])=[O:32]
Reactant: CS(=O)(=O)OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reactant: OCC1(c2cccc(C(F)(F)F)c2)CCCC1
Product: CS(=O)(=O)OCC1(c2cccc(C(F)(F)F)c2)CCCC1

Procedure:
(1-(3-(Trifluoromethyl)phenyl)cyclopentyl)methyl methanesulfonate (471) was synthesized from ((1-(3-(trifluoromethyl)phenyl)cyclopentyl)methanol (470) following the procedure described for methanesulfonic acid 1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl ester (240).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C1COCC1.C(Cl)Cl>[N:28]1([C:26]([C:23]2[CH:22]=[CH:21][C:20]([S:17]([N:14]3[CH2:15][CH2:16][CH:11]([NH:10][C:34](=[O:37])[CH:35]=[CH2:36])[CH2:12][CH2:13]3)(=[O:19])=[O:18])=[CH:25][CH:24]=2)=[O:27])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C=CC(=O)Cl
Reactant: NC1CCN(S(=O)(=O)c2ccc(C(=O)N3CCCCC3)cc2)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)N3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
Diisopropylethylamine (0.33 ml, 1.9 mmol) was added in one portion to a stirred solution of [4-(4-amino-piperidine-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone (0.13 g, 0.39 mmol) in THF (7 ml) followed by the drop wise addition of acryloyl chloride (0.03 ml, 0.43 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 100% EtOAc) to give the title compound (0.09 g, 58% yield) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][CH3:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].Br[CH:17]([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][CH3:15])=[N:10][N:11]2[CH:17]([CH3:19])[CH3:18])=[CH:7][CH:6]=1)=[O:4]
Reactant: CCc1n[nH]c2cc(C(=O)OC)ccc12
Reactant: CC(C)Br
Product: CCc1nn(C(C)C)c2cc(C(=O)OC)ccc12
Yield: 39.7 %

Procedure:
This compound was prepared according to the method of Preparation 3, using 750 mg (3.67 mmol, 1.0 equiv) 3-ethyl-1H-indazole-6-carboxylic acid methyl ester and 0.38 mL (4.04 mmol, 1.1 equiv) 2-bromopropane as starting materials to give 359 mg (40%) of a clear oil: HRMS calcd for C14H18N2O2+H: 247.1448. Found: 247.14530.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.C([SiH](CC)CC)C>CO.[Pd]>[NH2:16][C:12]1[CH:11]=[C:10]([C:8]([N:5]2[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]2)=[O:9])[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1cccc([N+](=O)[O-])c1)N1CCC(O)CC1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CO
Product: Nc1cccc(C(=O)N2CCC(O)CC2)c1

Procedure:
To a stirred solution of (4-hydroxypiperidin-1-yl)(3-nitrophenyl)methanone (1 g, 4.00 mmol) and Pd—C (10%, 0.425 g,) in Methanol (10 ml) was added triethylsilane (3.19 ml, 19.98 mmol) dropwise at room temperature. The reaction mixture was filtered through celite bed. The filtrate was concentrated under vacuum to give the title compound. (0.8 gm)
Reaction SMILES: [C:1]([O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([S:20](O)(=[O:22])=[O:21])=[CH:12][C:11]=1[N:24]=[N:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:34])=O>CN(C)C=O>[C:1]([O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([S:20]([Cl:34])(=[O:22])=[O:21])=[CH:12][C:11]=1[N:24]=[N:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1c(N=Nc2ccccn2)cc(S(=O)(=O)O)c2ccccc12)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Oc1c(N=Nc2ccccn2)cc(S(=O)(=O)Cl)c2ccccc12)c1ccccc1
Reaction time: 1 h

Procedure:
4-Benzoyloxy-3-(2-pyridylazo)-1-naphthalenesulfonic acid (70 g) was added to thionyl chloride (300 ml). Dimethylformamide (30 ml) was added in portions while the reaction mixture was being stirred. After 1 hour the starting material was all in solution. The reaction mixture was poured into a large quantity of ice after a further 4 hours' stirring. The product was filtered off and dissolved in chloroform. The chloroform layer was shaken with water to destroy any remaining thionyl chloride and dried over magnesium sulfate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu](I)I>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: Brc1ccccn1
Reactant: c1c[nH]nn1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(-n2ccnn2)nc1
Temperature: 110 °C

Procedure:
1,2,3-Triazole (5 g), 2-bromo pyridine (8.5 ml) and copper iodide (0.68 g) was taken in dry DMF under Nitrogen atmosphere. 1,2-(N,N-dimethyl) cyclohexyl diamine (1.02 g) and potassium phosphate (30.73 g) was added into above mixture. The reaction mixture was reflux at 110° C. for over night. TLC was checked no starting material and the reaction mixture was filtered through celite. The filtrate was diluted with water and product was extracted with dichloromethane. The organic layer was evaporated and the crude product was purified by column chromatography using 60-120 silica gel and pet ether \ ethyl acetate as eluent to give compound 2-(1H-1,2,3-triazol-1-yl)pyridine as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13](=[O:22])[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13](=[O:22])[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][CH2:10][O:11][S:31]([CH3:30])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC(CCO)c1ccccc1Br)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCC(NC(=O)c1c(F)cccc1F)c1ccccc1Br
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 15.0 g of N-[1-(2-bromophenyl)-3-hydroxypropyl]-2,6-difluorobenzamide, 4.5 g of triethylamine in 150 ml of dichloromethane at room temperature, was added dropwise 5.1 g of methylsulfonyl chloride and stirring continued for an additional 30 minutes. The reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to afford 18.0 g of N-[1-(2-bromophenyl)-3-(methylsulfonyloxy)propyl]-2, 6-difluorobenzamide.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[C:18]([O-])(=[O:20])C.[Na+]>CN(C)C=O>[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[O:20])=[CH:10][CH:9]=1
Reactant: CC(=O)[O-]
Reactant: COc1cccc2ccccc12
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c2ccccc12

Procedure:
Phosphorus oxychloride (315 g, 1.6 mole) was added dropwise over 4 hours to a stirred solution of 1-methoxynaphthalene (250 g) (2) in dried dimethylformamide (150 g). the reaction mixture was heated on a water bath for a further 4 hours, cooled, and poured onto ice (1 k) and 2M aqueous sodium acetate (1.5 l). The organic layer was extracted with dichloromethane (1 l) and washed with dilute hydrochloric acid and then with water. The organic layer was dried (MgSO4), filtered, and the solvent removed. 4-Methoxy-1-naphthaldehyde (3) was obtained as a pale yellow oil.
Reaction SMILES: O.NN.C[O:5][C:6](=[O:15])[C:7]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[CH3:14])=O.[OH-].[K+].Cl>C(O)COCCO.O>[CH3:14][C:13]1[CH:12]=[CH:11][S:10][C:9]=1[CH2:7][C:6]([OH:15])=[O:5]
Reactant: COC(=O)C(=O)c1sccc1C
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: Cc1ccsc1CC(=O)O
Temperature: 3040 °C
Reaction time: 5 h
Yield: 65.5 %

Procedure:
112.5 ml (116 g, 2.312 mol) of hydrazine hydrate were added slowly to a solution of 90 g (0.489 mol) of methyl(3-methylthiophen-2-yl)oxoacetate in 260 ml of diethylene glycol, and the mixture was heated under reflux for 30 min. After cooling to 3040° C., 82 g (1.246 mol) of potassium hydroxide were added a little at a time, which was accompanied by a temperature increase to 70-80° C. with simultaneous evolution of nitrogen. The mixture was then slowly heated to reflux and stirred at this temperature for a total of 5 h. After cooling to room temperature, the mixture was poured into 2 l of water, adjusted to pH=1 using 250 ml of semi-concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and filtered off and the solvent was removed, which gave 50 g of (3-methylthiophen-2-yl)acetic acid. Yield: 66%. 1H-NMR (DMSO): δ=7.25 (d, 1H), 6.84 (d, 2H), 3.67 (s, 2H), 2.11 (s, 3H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=O)C.C[O-].[Na+]>CO>[C:11]([NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][OH:4])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(=O)OCCOCCNC(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)NCCOCCO
Reaction time: 3 h
Yield: 68.3 %

Procedure:
2-(2-t-Butylaminoethoxy)ethyl acetate (1.2 g, 5.9 mmol) was stirred for 7 hours with sodium methoxide (0.015 g, 0.28 mmol) in methanol (15 mL) at room temperature. The NMR analysis of the reaction mixture showed approximately 20% conversion. Additional sodium methoxide (0.015 g, 0.28 mmol) was added to the reaction mixture and it was stirred for an additional 3 hours. Solvent was evaporated and the liquid phase was separated from the solid by filtration. The solid was washed with diethyl ether. The combined filtrates were evaporated under reduced pressure to remove a solvent to give 2-(2-t-butylamino-ethoxy)ethanol (EETB) as yellowish liquid (0.65 g, 70%) 1H NMR δ 1.12 (s, 9H), 2.76 (t, J=5.1 Hz, 2H), 3.59-3.66 (m, 4H), 3.70-3.73 (m, 2H); 13C NMR δ 28.8, 42.2, 50.3, 61.8, 71.3, 72.6.
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[CH:19][CH:18]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:30][C:31]1([F:38])[C:35]([F:37])([F:36])[CH2:34][NH:33][CH2:32]1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])(O)=O.[Na+]>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:28][C:3]1[C:2]([N:33]2[CH2:34][C:35]([F:37])([F:36])[C:31]([F:38])([F:30])[CH2:32]2)=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:9]1
Reactant: COc1cn(-c2cccc(Br)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: FC1(F)CNCC1(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cn(-c2cccc(N3CC(F)(F)C(F)(F)C3)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Yield: 37.9 %

Procedure:
A suspension of 1-(3-bromo-2-fluorophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (221 mg, 0.500 mmol), 3,3,4,4-tetrafluoropyrrolidine hydrochloride (108 mg, 0.600 mmol), sodium tert-butoxide (125 mg, 1.300 mmol), Xantphos (23 mg, 0.040 mmol), and tris(dibenzylideneacetone)dipalladium(0) (9 mg, 0.010 mmol) in 1,4-dioxane (2.5 mL) was stirred at 90° C. under Ar atmosphere. The reaction mixture was poured into 5% NaHCO3 aqueous solution (20 mL) and extracted with AcOEt (20 mL×3). The combined organic phase was washed with brine (40 mL), dried with MgSO4, and evaporated. The residue was purified by silica gel column chromatography (AcOEt/hexane=60%-100%) to give the title compound (95.4 mg, 38% yield) as an amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.84-3.96 (7H, m), 6.11 (1H, t, J=7.5 Hz), 6.60 (1H, td, J=8.3, 1.5 Hz), 6.90-6.98 (1H, m), 7.25 (1H, d, J=1.9 Hz), 7.33-7.41 (5H, m), 7.70 (1H, d, J=2.6 Hz), 7.78 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 504 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N+:11]([O-:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[N:26]1([CH2:25][CH2:24][CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][N+:11]([O-:14])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: ClCCCN1CCCCC1
Reactant: [O-][n+]1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: [O-][n+]1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1
Temperature: 25 °C

Procedure:
A A mixture of 4-(4-hydroxyphenyl)pyridine 1-oxide (250 mg), potassium carbonate (560 mg) and 1-(3-chloropropyl)piperidine, hydrochloride in N,N-dimethylformamide (10 mL) is heated at a temperature close to 65° C. overnight, then cooled back to room temperature and filtered. The filtrate is concentrated under reduced pressure and the residue purified by chromatography over silica gel (eluent dichloromethane/methanol from 100/0 to 90/10). Fraction containing the compound are pooled and concentrated under reduced pressure. Crude base is diluted with ethanol, oxalic acid (28 mg) is added and solvent removed under reduced pressure to give 40 mg of 4-[4-(3-piperidino-propoxy)phenyl]pyridine 1-oxide, oxalate as a viscous yellow product.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:4].[N+](C1C=CC=C([N+]([O-])=O)C=1)([O-])=O.[F:30]OC(F)(F)F>FC(Cl)(Cl)Cl>[F:30][C:10]12[CH2:11][CH:12]3[CH2:14][CH:8]([CH2:7][C:6]([O:5][C:3](=[O:4])[C:2]([F:16])([F:17])[F:1])([CH2:13]3)[CH2:15]1)[CH2:9]2
Reactant: FOC(F)(F)F
Reactant: O=C(OC12CC3CC(CC(C3)C1)C2)C(F)(F)F
Agent: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Solvent: FC(Cl)(Cl)Cl
Product: O=C(OC12CC3CC(CC(F)(C3)C1)C2)C(F)(F)F
Yield: 45.9 %

Procedure:
A solution of 1-trifluoroacetoxyadamantane (1.0 g, 4.0 mmole, prepared by reacting adamantan-1-ol with trifluoroacetic anhydride in dry pyridine) in fluorotrichloromethane (10 ml), containing m-dinitrobenzene (80 mg, 0.48 mmole), was treated with trifluoromethyl hypofluorite (4.5 mmole) at -25° for 24 hours, air being admitted to the reaction vessel during this time. The product was recovered in a similar manner to that described in Example 3 and was chromatographed on silica (100 g). Elution with chloroform:hexane (1:5) afforded unreacted starting material (152 mg), while elution with chloroform: hexane (1:4) gave liquid 3-fluoro-1-trifluoroacetoxyadamantane (489 mg) which appeared homogeneous by g.l.c. This product sublimed at 70° (bath)/1 mm Hg to give a crystalline solid m.p. 28°-32°; vmax (film) 1780 cm-1 ; PMR 1.5-2.6 (m, adamantyl protons); FMR φ*+76.2 (s, CF3COO--) and +133.5 (broad s) ppm.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([NH2:42])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30])[CH2:25][C:26](=[O:28])[OH:27])=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:50]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[C@H:51]([C:62]([O:64]N1C(=O)CCC1=O)=O)[CH2:52][C:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[NH:55][CH:54]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[NH:50]([C:72]([O:74][C:75]([CH3:76])([CH3:77])[CH3:78])=[O:73])[C@@H:51]([C:62]([NH:1][C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([NH2:42])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30])[CH2:25][C:26](=[O:27])[OH:28])=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:64])[CH2:52][C:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[NH:55][CH:54]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Yield: 61.1 %

Procedure:
In the same manner as in (1) of Example 1, 10.45 g (0.015 mole) of Boc-Trp-Met-Asp-Phe-NH2 [cf. (1) of Example 3] was condensed with 9.00 g (0.022 mole) of Boc-Trp-OSu. The resulting reaction liquid was concentrated, and a precipitate was formed by adding 1N citric acid and washed with water. Recrystallization thereof from methanol-water gave 8.09 g of Boc-D-Trp-Trp-Met-Asp-Phe-NH2 ; yield 61.1%, m.p. 225°-227° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.CC1(C)C(C)OB([C:36]2[CH:37]=[CH:38][C:39]([OH:42])=[N:40][CH:41]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC#N.O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:36]5[CH:37]=[CH:38][C:39]([OH:42])=[N:40][CH:41]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CC1OB(c2ccc(O)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Oc1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 120 °C
Yield: 7.3 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (416 mg, 1.0 mmol), 5-(4,4,5-Trimethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ol (268 mg, 1.2 mmol), Cs2CO3 (650 mg, 2.0 mmol), Pd(dppf)Cl2 (73 mg, 0.10 mmol) and CH3CN—H2O (1:1, 4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 120° C. for 20 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 295 (34.7 mg, yield: 7.1%). 1HNMR (DMSO-d6, 400 MHz): δ8.30 (s, 1H), 8.10 (s, 1H), 7.98-7.92 (m, 2H), 7.78 (t, J=4.8 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.49 (t, J=8.8 Hz, 1H), 7.20 (s, 1H), 6.43 (d, J=8.8 Hz, 1H), 4.29 (s, 2H), 3.14 (s, 2H), ESI-MS: m/z=475 [M+H+]
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:14][CH:15]=1.CC(C)=O>O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH:7]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CC(C)=O
Solvent: O
Product: FC(F)(F)c1cccc(Nc2cc(Cl)ncn2)c1

Procedure:
A stirred mixture of 4,6-dichloropyrimidine (18.6 g, 125 mmol), 3-aminobenzotrifluoride (16.5 mL, 133 mmol), acetone (60 mL) and H2O (90 mL) is kept at reflux for 3 h. Acetone is removed in vacuo, the remaining aqueous layer is basified with conc. aqueous ammonia solution and extracted with ethyl acetate. The organic extract is dried over Na2SO4 and evaporated. The residue is suspended in a small amount of acetone, filtered and the filter cake dried in vacuo to afford the title compound.