Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[Cl:10][C:11]([Cl:15])=[C:12]([F:14])[F:13].ClC(F)=C(Cl)F>CC(C)=O>[Cl:10][CH:11]([Cl:15])[C:12]([F:14])([F:13])[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: FC(F)=C(Cl)Cl
Agent: FC(Cl)=C(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: FC(F)(Oc1ccccc1)C(Cl)Cl
Temperature: 10 °C

Procedure:
In a 500 ml stirred reaction flask equipped with thermometer, air condenser, dropping funnel and ice water bath was placed 94 g (one mole) of phenol and 300 ml of acetone and the mixture was cooled to 10° C. 11.0 Grams of powdered KOH (85 percent) was then added. After the mixture was stirred for one-half hour at 10° C., 2,2-dichloro-1,1-difluoroethene was introduced over a period of one hour while maintaining the temperature at about 10-12° C. At the end of the addition of the dichlorodifluoroethene, a rapid reaction increased the temperature to 50° C. A Dry Ice(R) bath was substituted for the ice bath to cool the reaction mixture to 10° C. rapidly. After stirring overnight, the reaction mixture was poured over two liters of ice, stirred, allowed to settle and the oil layer was separated. The oil layer was washed with bicarbonate of soda solution and with water and the nearly colorless organic layer was separated. After drying over desiccant-grade magnesium sulfate, the organic layer was filtered to give the first-step product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[C:26]([CH:28]2[CH2:30][CH2:29]2)[N:25]=[C:24]([O:31][C:32]2[CH:41]=[C:40]([CH3:42])[C:35]3[NH:36][C:37](=[O:39])[O:38][C:34]=3[CH:33]=2)[CH:23]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH:28]1([C:26]2[N:25]=[C:24]([O:31][C:32]3[CH:41]=[C:40]([CH3:42])[C:35]4[NH:36][C:37](=[O:39])[O:38][C:34]=4[CH:33]=3)[CH:23]=[C:22]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[N:27]=2)[CH2:30][CH2:29]1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Oc2cc(Cl)nc(C3CC3)n2)cc2oc(=O)[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5[nH]c(=O)oc5c4)nc(C4CC4)n3)CC1)C(=O)N2

Procedure:
39 mg (0.14 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 39 mg (0.12 mmol) 6-(6-chloro-2-cyclopropylpyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 0.10 mL (0.57 mmol) DIPEA in 1.0 mL DMF were stirred for 2 h at 90° C. The reaction mixture was mixed with water. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: Cl[CH:2]([CH3:12])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].[Cl:13]C(CCC)CC(OC(C)C)=O>CO>[Cl:13][CH2:12][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7]
Reactant: CCCC(Cl)CC(=O)OC(C)C
Reactant: CC(Cl)CCCC(=O)OC(C)C
Solvent: CO
Product: CC(C)OC(=O)CCCCCCl
Reaction time: 90 h

Procedure:
A solution of 10.5 gm(0.03 mol) of diamine 15, 6.2 gm(0.03 mol) of isopropyl 5-chlorohexanoate, and 10.0 gm of MeOH was charged to the flask and heated to reflux. After 90 hours, 1.0 gm(5 mmol) of isopropyl 3-chlorohexanoate was added to the mixture. At least 5% amine was present after refluxing 6 hours and the heating was stopped. The crude product was removed of volatiles by rotary evaporation and washed until all of the residue was removed leaving 15 gm(94%) of Quat 7.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[N:34]1.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O.N.CO>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl.CCO.O.COCCOC>[OH:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:35]2[NH:34][N:33]=[CH:37][CH:36]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1-c1ccn[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 26.1, 113 mg, 0.25 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (69.5 mg, 0.25 mmol), Pd(PPh3)2Cl2 (0.018 g, 0.025 mmol), Na2CO3 (0.106 g, 1.000 mmol), DME (1.061 mL), water (0.303 mL) and EtOH (0.152 mL) were added to a MW vial, which was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 min. The RM was diluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.43 mmol/g, 0.105 g, 0.150 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc from 20% to 90% EtOAc). The resulting intermediate was treated with a mixture of TFA (0.963 mL, 12.50 mmol) and DCM (2.5 mL) and for stirred for 2 h at RT. The solvent was evaporated off under reduced pressure and the residue was basified with a solution of NH3 7 M in MeOH (2 mL, 14 mmol). The solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative SFC (Column DEAP, isocratic 28% in 9 min) to afford the title compound as a yellow solid. UPLC-MS (Condition 3) tR=1.01 min, m/z=438.2 [M+H]+, m/z=436.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.77 (s, 3H) 3.38-3.61 (m, 4H) 4.61 (br. s, 1H) 6.47 (s, 1H) 7.68 (d, J=8.56 Hz, 2H) 7.83 (br. s, 1H) 7.93 (d, J=8.80 Hz, 2H) 8.15 (br. s, 1H) 8.71 (br. s, 1H) 10.36 (s, 1H) 12.83-13.15 (m, 1H).
Reaction SMILES: [Cl:1][C:2](=[CH2:5])[CH2:3][NH2:4].[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]=1[C:20]([F:23])([F:22])[F:21]>C(O)C>[Cl:1][C:2](=[CH2:5])[CH2:3][NH:4][C:11]1[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]([C:20]([F:21])([F:22])[F:23])=[C:7]([Cl:6])[C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: C=C(Cl)CN
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCO
Product: C=C(Cl)CNc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]

Procedure:
The compound was prepared by reacting 2-chloroallylamine with 2,4-dichloro-3,5-dinitrobenzotrifluoride in ethanol. After recrystallization from ethanol, the compound melts at 78°-80° C.
Reaction SMILES: C[O-].[Na+].[O-2].[Al+3].[O-2].[O-2].[Al+3].C1(C=CC(O)=CC=1)[OH:10].CCC(OOC(OO)(CC)C)(OO)C.CN(C)C1C=CC=CC=1.[C:40]([O:49][O:50][C:51]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)(C)C)([C:43]1C=CC=CC=1)([CH3:42])[CH3:41].C(OCCOCCOC(=O)C=C)(=O)C=C>ClCCl.C1(C)C=CC=CC=1>[C:40]([O:49][O:50][C:51](=[O:10])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(OOC(C)(C)c1ccccc1)c1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: C=CC(=O)OCCOCCOC(=O)C=C
Agent: CCC(C)(OO)OOC(C)(CC)OO
Agent: C[O-]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OOC(=O)c1ccccc1

Procedure:
Sodium methoxide (NaOCH3), toluene (anhydrous), dichloromethane, hexanes, activated neutral aluminum oxide (60 to 50 mesh), hydroquinone, methyl ethyl ketone peroxide, dimethylaniline, dicumylperoxide, diethylene glycol diacrylate, and tert-butylperoxybenzoate were obtained from commercial sources and used as received.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([NH2:26])=[CH:21][CH:20]=2.Cl.O1CCOCC1.CCO.ClC(Cl)C>>[CH3:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([NH:26][C:2]1[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=1)=[CH:21][CH:20]=2
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: CC(Cl)Cl
Product: Cc1cc2cc(Nc3ccnc4cc(C(F)(F)F)ccc34)ccc2[nH]1
Temperature: 90 °C
Yield: 17.2 %

Procedure:
A suspension of 4-chloro-7-(trifluoromethyl)quinoline 1-A (158 mg, 0.68 mmol), 2-methyl-1H-indol-5-amine 1-B (100 mg, 0.68 mmol) and 4N HCl in dioxane (0.25 ml, 1.0 mmol) in a mix solvent (EtOH/dichloroethane, 1:1, 6 ml) was heated to 90° C. in a sealed tube overnight. The reaction mixture was concentrated and dissolved in 2 ml of DMSO. The solution was purified by HPLC (DionexSystem, 20-60% CH3CN/H2O over 30 minutes). 40 mg of N-(2-methyl-1H-indol-5-yl)-7-(trifluoromethyl)quinolin-4-amine 1 was obtained.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[O:15]=[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][N:10]=2)[N:5]([CH2:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=2[C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)[CH:6]=[C:7]1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cn(Cc2ccccc2Br)c2cccnc2c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2-c2ccc(C(F)(F)F)cc2)c2cccnc2c1=O
Temperature: 100 °C
Reaction time: 15 h
Yield: 7.6 %

Procedure:
To a mixture of ethyl 1-(2-bromobenzyl)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (136 mg, 0.35 mmol), 4-(trifluoromethyl)phenylboronic acid (133 mg, 0.7 mmol), palladium(II) acetate (15.7 mg, 0.07 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (57.5 mg, 0.140 mmol), and tribasic potassium phosphate (371 mg, 1.75 mmol) in a 20 mL vial were added previously degassed toluene (4.5 mL) and water (1.0 mL) at room temperature under a nitrogen atmosphere. The resulting suspension was heated to 100° C. and stirred for 15 h at which time LCMS analysis indicated the absence of starting material. Then, the black reaction mixture was cooled to room temperature and poured into a mixture of water and brine solution and the organic compound was extracted into ethyl acetate (2×100 mL). The combined extracts were washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave a crude brown oil which was purified using ISCO (40 g) column chromatography, eluting with ethyl acetate in hexanes (0 to 100%) and 10 to 20% methanol in dichloromethane. The desired fractions were combined and the solvent was removed under vacuum to obtain ethyl 4-oxo-1-((4′-(trifluoromethyl)biphenyl-2-yl)methyl)-1,4-dihydro-1,5-naphthyridine-3-carboxylate (37) (12 mg, 7.6% yield) as a brown solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][C:14](=[O:22])[CH:13]=1.C(N(C(C)C)CC)(C)C.C(OC([NH:39][C:40](N1C=CC=N1)=[N:41]C(OC(C)(C)C)=O)=O)(C)(C)C>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:22]=[C:14]1[CH:13]=[C:12]([O:11][CH2:10][CH2:9][NH:8][C:40]([NH2:41])=[NH:39])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15]1
Reactant: NCCOc1cc(=O)oc2ccccc12
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N=C(N)NCCOc1cc(=O)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
4-(2-Amino-ethoxy)-1-benzopyran-2-one trifluoroacetate (0.313 mmol, 100 mg) is placed in a small vial along with 2 mL of acetonitrile. Diisopropylethylamine is added dropwise until the pH of the solution is ˜9 by pH paper. N,N′-Bis(tert-butoxycarbonyl)-1-H-pyrazole-1-carboxamidine (0.24 mmol, 74.5 mg) is added and the reaction is mixed at ambient temperature for 5 hrs. The reaction mixture is concentrated in vacuo, then is redissolved in neat TFA and is stirred at ambient temperature for 30 min. The TFA is removed under reduced pressure and the residue is purified by reversed-phase HPLC to afford the title compound as the trifluoroacetic acid salt (35.0 mg, 31%). 1H NMR (DMSO-d6, 300 MHz) δ 7.88 (1H, dd, J=1.5, 8 Hz), 7.81 (1H, br t), 7.68 (1H, m), 7.39 (2H, m), 7.28 (3H, br s), 5.49 (1H, s), 4.30 (2H, t, J=5 Hz), 3.67 (2H, q, J=5.5 Hz); MS (ESI, Pos.) calcd for C12H13N3O3 m/z [M+H]=248.1, found 248.1.
Reaction SMILES: [CH3:1][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[N:44]([CH3:45])[N:43]=[N:42][N:41]=1)=[C:22]2[C:26]([O:28]CC1C=CC([N+]([O-])=O)=CC=1)=[O:27])([O:4]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:3].C(O)C.P([O-])([O-])(O)=O.[K+:54].[K+].O>O1CCOCC1.O.[Pt](=O)=O>[OH:4][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[N:44]([CH3:45])[N:43]=[N:42][N:41]=1)=[C:22]2[C:26]([O-:28])=[O:27])([CH3:3])[CH3:1].[K+:54]
Reactant: Cn1nnnc1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](C(C)(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H]2C1
Agent: O=[Pt]=O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: Cn1nnnc1SC1=C(C(=O)[O-])N2C(=O)[C@@H](C(C)(C)O)[C@H]2C1
Temperature: 25 °C

Procedure:
A mixture of 4-nitrobenzyl (5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-(1-methyl-1H-tetrazol-5-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (50 mg) and platinum (IV) oxide monohydrate (25 mg) in a mixture of dioxane (10 ml), ethanol (0.5 ml), 0.1M aqueous dipotassium hydrogen phosphate (2.35 ml) and water (3.5 ml) was shaken for an hour under a hydrogen atmosphere (40 psi) at ambient temperature. The catalyst was filtered off and the filtrate was concentrated to half of the original volume. The aqueous concentrate was washed three times with diethyl ether and evaporated in vacuo. The residue was dissolved in water (25 ml) and potassium chloride (1.25 g) was added thereto. The aqueous solution was chromatographed on non-ionic adsorption resin "Diaion HP-20 AG" (1.35×17.5 cm), eluting with water (100 ml) and 10% aqueous isopropyl alcohol (100 ml). The fractions, whose UV spectra showed λmax 289 nm, were combined and lyophilized to give potassium (5R,6R)-6-(1-hydroxy-1-methylethyl)-3-(1-methyl-1H-tetrazol-5-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (17 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](O)=O)[CH:2]=1.[NH2:11][C:12]1[C:13](=[O:34])[N:14]([CH2:31][CH2:32][CH3:33])[C:15](=[O:30])[N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C:17]=1[NH2:18]>>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][N:16]2[C:17]3[N:18]=[C:8]([CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[NH:11][C:12]=3[C:13](=[O:34])[N:14]([CH2:31][CH2:32][CH3:33])[C:15]2=[O:30])=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: O=C(O)Cc1cccnc1
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Product: CCCn1c(=O)c2[nH]c(Cc3cccnc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, 3-pyridylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine. By the method of Example 3, this substance is reacted with sodium carbonate, 1,2-dichloroethane and ethylamine to yield 4,7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine. By the method of Example 4, 7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-7-(2-ethylamino)ethyl-1-propyl-8-[(3-pyridyl)methyl]xanthine free base. The corresponding hydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[N:7][CH:8]=1.[NH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>C1C=CC=CC=1>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH:13][CH2:14][CH2:15][CH2:16][NH2:17])=[N:7][CH:8]=1
Reactant: O=Cc1ccc(C(F)(F)F)cn1
Reactant: NCCCN
Solvent: c1ccccc1
Product: NCCCNCc1ccc(C(F)(F)F)cn1
Yield: 75.1 %

Procedure:
5-Trifluoromethylpicolinealdehyde (3.5 g) was added dropwise at room temperature to a solution of trimethylenediamine (7.4 g) in benzene (70 ml). After the addition, the mixture was gradually heated with stirring, and then refluxed for 2 hours while removing water that azeotroped. Benzene was distilled off under reduced pressure. The residue was dissolved in ethanol (100 ml), and sodium borohydride (0.9 g) was added little by little while the solution was stirred at 10° to 15° C. The mixture was then stirred at room temperature for 2 hours, and ethanol was distilled off at less than 30° C. Dichloromethane was added to the residue, and a portion soluble in dichloromethane was separated. Dichloromethane was distilled off under reduced pressure, and volatile materials were removed at 1 mmHg and less than 60° C. to give N-(5-trifluoromethyl-2-pyridylmethyl)trimethylenediamine (3.5 g) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:12][C:8]1[CH2:7][CH2:6][CH:5]2[C:9]=1[CH2:10][CH2:11][C:2](=[O:1])[CH2:3][C:4]2=[CH2:13]
Reactant: C=C1CC(O)CCC2=C(C)CCC12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C=C1CC(=O)CCC2=C(C)CCC12
Yield: 77.7 %

Procedure:
A solution, cooled to -10°, of 26.7 g of 6-hydroxy-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene in 1500 ml of acetone was treated dropwise within 30 minutes with 65 ml of Jones reagent (172 mM CrO3). The mixture was poured on to excess ice-cold bicarbonate solution and exhaustively extracted with ether. The organic phase was washed with bicarbonate solution and water, dried with anhydrous magnesium sulphate and concentrated under reduced pressure. The crude product which was obtained in the form of a yellow oil, was fractionated under reduced presdure and yielded 20.5 g (yield 77%) of pure 1-methyl-4-methylen-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.005 62°-65°; IR(film)νmax = 3090, 1708, 1640, 1450/38, 1345, 1322, 1305, 1262, 1240, 1195, 1140, 1108, 950, 900, 800 cm-1. The compound has a herb-like, camphorous, terpin oil-like odour.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7](/[C:10](/[CH:13]2[CH2:15][CH2:14]2)=[N:11]/[OH:12])=[CH:6][CH:5]=1.Cl[CH2:18][C:19]1[C:20]([CH3:31])=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1.[OH-].[K+]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:31][C:20]1[C:19]([CH2:18][O:12]/[N:11]=[C:10](/[C:7]2[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:16])[F:1])=[CH:9][CH:8]=2)\[CH:13]2[CH2:14][CH2:15]2)=[CH:24][CH:23]=[CH:22][C:21]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1c(CCl)cccc1-c1ccccc1
Reactant: O/N=C(/c1ccc(OC(F)F)cc1)C1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(CO/N=C(/c2ccc(OC(F)F)cc2)C2CC2)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.5 %

Procedure:
Under a dry argon atmosphere a solution of 1.0 g (0.0044 mole) of (E)-(4-difluoromethoxyphenyl)(cyclopropyl)methanone oxime in 50 ml of dry tetrahydrofuran was added to a stirred solution of 0.95 g (0.0044 mole) of 3-chloromethyl-2-methyl [1,1'-biphenyl], 0.29 g (0.0044 mole) of powdered potassium hydroxide, and 0.14 g (0.00044 mole) of tetrabutylammonium bromide in 45 ml of dry tetrahydrofuran. The reaction mixture was stirred at room temperature for approximately 18 hours then evaporated under reduced pressure to give a liquid. The liquid was diluted with methylene chloride, and the mixture washed with water. The aqueous wash was extracted with methylene chloride. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give an oil. The oil was subjected to column chromatography on silica gel, eluting with toluene to give 1.73 g of (E)-(4-difluoromethoxyphenyl)(cyclopropyl)methanone O-[(2-methyl[1,1'-biphenyl]-3-yl)methyl]oxime as an oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:43])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:42])[CH2:21][CH2:22][NH:23][C:24]([C:26]3[N:27]=[C:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[Cl:41])[O:29][C:30]=3[C:31]([F:34])([F:33])[F:32])=[O:25])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[Cl:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:28]1[O:29][C:30]([C:31]([F:34])([F:32])[F:33])=[C:26]([C:24]([NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([C@H:10]3[CH2:9][CH2:8][C@H:7]([CH2:6][C:5]([OH:43])=[O:4])[CH2:12][CH2:11]3)=[CH:18][CH:17]=2)=[O:42])=[O:25])[N:27]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4Cl)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4Cl)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
NaOH (108 mg, 2.7 mmol) was added to trans-{4-[4-(3-{[2-(2-chlorophenyl)-5-trifluoromethyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (160 mg, 0.27 mmol) dissolved in THF/MeOH/water (25 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 5 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH of 2 and extracted with ethyl acetate. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. Acetonitrile was added thereto and cooled to obtain a filtrate, and the filtrate was filtered and separated to obtain the desired compound (130 mg, 83%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[C:10]2([CH2:13][NH:12][CH2:11]2)[CH2:9][O:8]1.CO.CN(C=O)C.Cl[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1>O>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([N:12]2[CH2:13][C:10]3([CH2:9][O:8][CH2:7]3)[CH2:11]2)=[N:23][CH:24]=1)([O-:30])=[O:29]
Reactant: C1NCC12COC2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CC3(COC3)C2)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.9 %

Procedure:
Potassium carbonate (78 mg) and 2-oxa-6-azaspiro[3.3]heptane (30 mg) were added to a methanol/DMF (1 ml/2 ml) solution containing 2-chloro-5-nitropyridine (30 mg), followed by stirring at 80° C. for 3 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1 to 1:4), and a white solid of 6-(5-nitropyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane (23 mg) was thus obtained.