Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH3:3].[C:5]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C@@H:23]1[C:18](=[CH:19][C:20](=[O:27])[CH2:21][CH2:22]1)[CH:17]=[CH:16]3)(=[O:7])[CH3:6].[NH4+].[Cl-]>C1COCC1.[Cu]I>[C:5]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C@@H:23]1[C:18](=[CH:19][C:20](=[O:27])[CH2:21][CH2:22]1)[CH2:17][C@H:16]3[CH2:1][CH2:2][CH3:3])(=[O:7])[CH3:6]
Reactant: [Li]CCC
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A solution of propyl lithium (prepared from 1.4 g of Li and 9 ml of propyl bromide in 60 ml of ether at -20 C) was added at -40 C to 7.6 g of CuI in 60 ml of dry THF. After stirring for an additional 0.5 hr, a solution of 5.2 g of (17 beta)-17-(acetyloxy)estra-4,6-dien-3-one (1) in 20 ml of THF was added dropwise at -40 C. Upon stirring for an additional 15 minutes the reaction was complete, and the mixture was poured onto 300 ml of saturated NH4Cl solution, followed by extraction with ethyl acetate. The organic material, isolated after washing, drying and evaporation of the solvent, was taken up in 30 ml of THF and stirred in the presence of 3 ml of 6N H2SO4 to isomerize some Δ5,6 isomer to Δ4,5 isomer. After 1 hr the mixture was neutralized with saturated NaHCO3 solution and extracted with ethyl acetate. Chromatography of the crude product over silica gel (heptane/ethyl acetate 8/2) provided 2.1 g of 2, m.p. 97-100° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])[C:8]([C:10]1[CH:39]=[CH:38][C:13]2[N:14]([CH3:37])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:36])[NH:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:28])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[OH-].[Na+]>ClCCl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])[C:8]([C:10]1[CH:39]=[CH:38][C:13]2[N:14]([CH3:37])[C:15]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25](=[NH:36])[NH:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:28])=[CH:23][CH:24]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)O)c4ccccn4)ccc3n2C)cc1
Yield: 97 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and sodium hydroxide solution. Yield: 97% of theory, C32H37N7O5 (599.7) Rf value: 0.22 (silica gel; dichloromethane/methanol=9:1) ##EQU123##
Reaction SMILES: Cl[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+]>>[CH3:9][C:3]1[C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:18][CH2:19]2)=[N:7][C:6]([CH3:8])=[CH:5][N:4]=1
Reactant: Cc1cnc(C)c(Cl)n1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cnc(C)c(N2CCN(Cc3ccccc3)CC2)n1
Temperature: 125 °C
Yield: 57.7 %

Procedure:
3-Chloro-2,5-dimethylpyrazine (1.0 g, 7.0 mmol) and N-benzylpiperazine (3.7 ml, 21.0 mmol) were mixed under nitrogen and heated to 125° C. for 18 h. Saturated aqueous sodium hydrogen carbonate was added and the product was extracted with chloroform. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give a yellow oil. The crude product was purified by flash chromatography using silica gel eluting with methanol:chloroform (2.5:97.5) to give the pure product as a yellow oil (1.14 g, 58%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:12]([CH:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[O:14])=[CH:20][CH:21]=1
Reactant: O=C(O)C1CCCc2ccc(F)cc21
Reactant: CN(C)c1ccc(CNc2ccc(Br)cc2)cc1
Product: CN(C)c1ccc(CN(C(=O)C2CCCc3ccc(F)cc32)c2ccc(Br)cc2)cc1
Yield: 25.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and (4-bromophenyl)[(4-dimethylaminophenyl)methyl]amine (0.64 g) as starting materials, N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.26 g) was obtained.
Reaction SMILES: Cl.[CH2:2]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].O.O.[Sn](Cl)Cl>C(O)C>[CH2:2]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCOc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCOc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Ethanol (100 ml) and concentrated hydrochloric acid (5 ml) were added to the 4-decyloxynitrobenzene 2 (28.3 g, 101 mmol) thus obtained to prepare a solution which was then cooled in an ice bath. A hydrochloric acid solution of tin(II) chloride dihydrate (101.3 g, 450 mmol/HCl 50 ml) was added thereto. The mixture was stirred at room temperature for about 2 hr and was then stirred with heating at 60° C. for about 30 min. After the completion of the reaction, the resultant precipitate was collected by filtration. A 3 N aqueous sodium hydroxide solution was added to the collected precipitate, followed by extraction with ether. The filtrate was concentrated, and a 3 N aqueous sodium hydroxide solution was then added to the concentrate. The mixture was extracted with ether. The extract was washed with water, was then dried over sodium sulfate, and was concentrated to give 4-decyloxyaniline 3 as a reddish orange liquid (23.4 g, 92.7%).
Reaction SMILES: O1C2C(=CC=CC=2)C=[CH:2]1.[CH2:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.O1C2C(=CC=CC=2)C=C1.C1C2C(=CC=CC=2)C=C1>>[CH3:2][C:12]1([CH3:11])[CH:13]2[CH2:14][CH:15]1[CH2:16][CH2:17][C:18]2=[CH2:10]
Reactant: c1ccc2occc2c1
Reactant: C1=Cc2ccccc2C1
Product: C=C1CCC2CC1C2(C)C

Procedure:
As petroleum resins, known products are obtained by heat-polymerizing a petroleum type unsaturated hydrocarbon such as cyclopentadiene or a higher olefinic hydrocarbon having 5 to 11 carbon atoms in the presence of a catalyst. In the present invention, any of these known petroleum resins may be used for formation of the coating layer 3. As the coumarone-indene resin, there are known resins having a relatively low degree of polymerization, which are obtained by polymerizing a tar fraction composed mainly of coumarone and indene (ordinarlly boiling at 160° to 180° C.) in the presence of a catalyst or under application of heat. Any of these known resins can be used in the present invention. As the terpene resin, there can be used synthetic and natural polymers of terpene type hydrocarbons, particularly resins obtained by polymerizing a terpene oil or nopinene fraction in the presence of a catalyst. As the rosin, there can be used so-called raw rosins such as gum rosin and wood rosin, rosin esters obtained by esterifying abietic acid in the rosin, such as rosin glycerin ester (ester gum), diethylene glycol diabietate, diethylene glycol 2-hydroxyabietate, rosin monoethylene glycol ester and rosin pentaerythritol ester. These rosins may be modified with known thermosetting resins or the like.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:16])[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:8][C:9]1[C:10](=[O:16])[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1
Reactant: Cn1cccc(OCc2ccccc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cn1cccc(O)c1=O

Procedure:
A mixture of 3-(benzyloxy)-1-methyl-1H-pyridin-2-one (23 g, 106.85 mmol) and 10% palladium on carbon (2.3 g) in methanol (250 mL) was stirred under 1 atmosphere of hydrogen for 5 hr at room temperature. The catalyst was removed by filtration. The filtrate was concentrated in vacuo to give the title compound (12 g (90%) as a purple solid: 1H NMR (400 MHz, DMSO) delta 8.96 (s, 1H), 7.15-7.13 (m, 1H), 6.70-6.68 (m, 1H), 6.07 (t, J=7.0 Hz, 1H), 3.47 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][C:6]1[C:7](=[O:14])[NH:8][C:9](SC)=[N:10][CH:11]=1.[CH3:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH2:25][S:26][CH2:27][CH2:28][NH2:29]>C(O)C>[CH3:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH2:25][S:26][CH2:27][CH2:28][NH:29][C:9]1[NH:8][C:7](=[O:14])[C:6]([CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=2[O:2][CH3:1])=[CH:11][N:10]=1
Reactant: COc1ccccc1Cc1cnc(SC)[nH]c1=O
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CCO
Product: COc1ccccc1Cc1cnc(NCCSCc2nc[nH]c2C)[nH]c1=O

Procedure:
5-(2-Methoxybenzyl)-2-methylthio-4-pyrimidone (2.00 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (1.37 g) by the procedure of Example 1(ii) to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-methoxybenzyl)-4-pyrimidone, m.p. 163°-167° C. (ex ethanol).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:10](OCC)(OCC)[O:11][CH2:12][CH3:13].C(OC(=O)C)(=O)C>>[CH2:12]([O:11][CH:10]=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=CC(=O)CC(=O)OCC
Yield: 70 %

Procedure:
Using the procedure of Crombie et al., Journ. of Chem. Soc. Perkin Trans. 1, 464-471 (1979), a solution of ethyl acetoacetate (26 g, 0.20 mol), triethyl orthoformate (29.6 g, 0.20 mol) and acetic anhydride (41 g, 0.40 mol) was refluxed for 90 minutes. Distillation under reduced pressure gave the product (1): 26 g, 70% yield; bp=85°-98° C. at 0.5 mm Hg (The following value is reported in the Crombie et al. publication: bp=85° C. at 0.25 mm Hg); NMR (CDCl3) δ 1.2-1.5 (m,6H), 2.4-2.5 (d,3H), 4.0-4.6 (m,4H), 7.7 (d,1H). The signals were split into pairs of closely spaced lines indicative of the cis and trans isomers.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.[F:8][C:9]1[CH:10]=[C:11]([NH:22][C:23]([C@H:25]2[C:34]3[C:29](=[CH:30][C:31]([O:35][CH2:36][CH3:37])=[CH:32][CH:33]=3)[CH2:28][CH2:27][N:26]2C(OC(C)(C)C)=O)=[O:24])[CH:12]=[C:13]([F:21])[C:14]=1[C:15]([CH3:20])([CH3:19])[CH2:16][O:17][CH3:18]>C(OCC)(=O)C>[ClH:1].[F:8][C:9]1[CH:10]=[C:11]([NH:22][C:23]([C@H:25]2[C:34]3[C:29](=[CH:30][C:31]([O:35][CH2:36][CH3:37])=[CH:32][CH:33]=3)[CH2:28][CH2:27][NH:26]2)=[O:24])[CH:12]=[C:13]([F:21])[C:14]=1[C:15]([CH3:19])([CH3:20])[CH2:16][O:17][CH3:18]
Reactant: CCOc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)[C@H]2C(=O)Nc1cc(F)c(C(C)(C)COC)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c(C(C)(C)COC)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
4N Hydrogen chloride/ethyl acetate (5 mL) was added to a solution of tert-butyl (R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.02 g, 1.97 mmol) in ethyl acetate (2 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the precipitate was collected by filtration with hexane to give (R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (0.917 g, 2.016 mmol, 102%) as a white solid.
Reaction SMILES: [CH2:1]([O:4][NH:5][CH:6]1[CH2:11][NH:10][C@@H:9]([C:12]([NH2:14])=[O:13])[CH:8]=[C:7]1[CH:15]1[CH2:17][CH2:16]1)[CH:2]=[CH2:3].[CH2:18]([O:21]N1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O)C=C>>[CH2:1]([O:4][N:5]1[C:18](=[O:21])[N:10]2[CH2:11][C@H:6]1[C:7]([CH:15]1[CH2:16][CH2:17]1)=[CH:8][C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O
Reactant: C=CCONC1CN[C@@H](C(N)=O)C=C1C1CC1
Product: C=CCON1C(=O)N2C[C@H]1C(C1CC1)=C[C@H]2C(N)=O

Procedure:
The title compound was prepared from (R)-5-(allyloxyamino)-4-cyclopropyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 270, 0.307 g, 1.29 mmol) following the procedure described for Intermediate 16. The desired product was obtained as a yellow oil (0.168 g, 49%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2=[N:26][N:27]=[C:28]([C:29]3[CH:33]=[C:32]([CH3:34])[O:31][N:30]=3)[N:18]2[N:17]=1>>[CH3:34][C:32]1[O:31][N:30]=[C:29]([C:28]2[N:18]3[N:17]=[C:16]([O:14][CH2:13][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[N:12]=4)[C:25]4[C:20]([C:19]3=[N:26][N:27]=2)=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:33]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Reactant: OCc1cccc(N2CCOCC2)n1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4cccc(N5CCOCC5)n4)nn23)no1

Procedure:
The reaction was carried out according to Example 1 step 4 using (6-(morpholin-4-yl)pyridin-2-yl)methanol (96 mg, 0.49 mmol) and 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (141 mg, 0.49 mmol). The crude residue was purified by column chromatography on silica using 2% MeOH/CH2Cl2 containing 1% NH3 to yield, after recrystallisation from CH2Cl2/iso-hexanes, the desired phthalazine (101 mg, 46%). 1H NMR (360 MHz, CDCl3) δ 8.70 (1H, d, J=8.1 Hz), 8.31 (1H, d, J=8.0 Hz), 8.00-7.91 (1H, m), 7.85-7.78 (1H, m), 7.58-7.50 (1H, m), 6.97 (1H, d, J=7.2 Hz), 6.80 (1H, s), 6.61 (1H, d, J=8.5 Hz), 5.60 (2H, s), 3.82 (4H, t, J=5.1 Hz), 3.54 (4H, t, J=5.1 Hz), 2.57 (3H, s). m/z (ES+) 444 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][CH2:12][O:13][CH3:14])[CH3:10])=[CH:5][C:4]=1[NH:15][C:16]([NH2:18])=[S:17].Br.CC(O)=O.CS(C)=O>CC(O)=O>[CH3:1][O:2][C:3]1[C:4]2[N:15]=[C:16]([NH2:18])[S:17][C:5]=2[C:6]([N:9]([CH2:11][CH2:12][O:13][CH3:14])[CH3:10])=[CH:7][CH:8]=1
Reactant: COCCN(C)c1ccc(OC)c(NC(N)=S)c1
Agent: Br
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: COCCN(C)c1ccc(OC)c2nc(N)sc12

Procedure:
From {2-methoxy-5-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-thiourea with HBr—AcOH (2 equiv.) and DMSO (1.1 equiv.) in AcOH. ES-MS m/e (%): 268 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].[OH-].[Na+].O1CCCC1>O>[CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: NCCCCC(=O)O
Reactant: CCN(CC)c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(S(=O)(=O)NCCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
2.5 g of 4-diethylaminobenzenesulphonyl chloride are added to a solution comprising 1.17 g of 5-aminovaleric acid and 1.2 g of sodium hydroxide dissolved in 12 cm3 of water, followed by the addition of 12 cm3 of tetrahydrofuran in order to obtain a solution. The mixture is kept stirring for 2 hours at room temperature, the tetrahydrofuran is evaporated off, the reaction medium is acidified using acetic acid and extracted with chloroform, the organic phase is dried and the solvents are removed under reduced pressure. 2.2 g of expected product are obtained. M.p. 106°-108° C. After crystallization in an isopropanol/water mixture (1:1), the product, melting point 109°-110° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Br:30])[CH:3]=1
Reactant: OCc1cncc(Br)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cncc(Br)c1
Temperature: 0 °C

Procedure:
(5-bromopyridin-3-yl)methanol (475 mg, 2.5 mmol) and triphenylphosphine (1.3 g, 5 mmol) were combined in methylene chloride (20 mL) and cooled to 0° C. carbon tetrabromide (927 mg, 2.8 mmol) was introduced in portions and the reaction was maintained at 0° C. for 1 h. The reaction was concentrated and purified by column chromatography on silica gel (0 to 50% ethyl acetate/hexanes) to produce 254 mg (41%) as a white solid. 1H-NMR (D6DMSO, 400 MHz) δ 8.65 (s, br, 2H), 8.18 (s, 1H), 4.73 (s, 2H). Mass spec.: 249.89 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.F[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][N:11]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:28])([F:30])[F:29])[CH:20]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
3-(3,5-Dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (5.6 g), 4-fluoro-2-trifluoromethylbenzonitrile (4.5 g) and potassium carbonate (5.4 g) were added to N,N-dimethylformamide (50 mL), and the mixture was stirred at 110° C. for 4 hours. After cooling the mixture to room temperature, the solution was diluted with ethyl acetate and washed with water three times. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was then purified by a column chromatography to obtain the title compound (3.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N:9]1[N:13]2[C:14]([C@@H:18](O)[CH3:19])=[CH:15][CH:16]=[N:17][C:12]2=[N:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:18]([C:14]2[N:13]3[N:9]=[CH:10][N:11]=[C:12]3[N:17]=[CH:16][CH:15]=2)[CH3:19])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C[C@H](O)c1ccnc2ncnn12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](Oc1ccc(Cl)cc1)c1ccnc2ncnn12
Temperature: 7.5 °C
Yield: 73 %

Procedure:
The reactor was loaded with 4-chlorophenol (58.5 g), (S)1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (50 g), triphenylphosphine (85 g) and toluene (900 ml). The suspension was cooled to 5-10° C. and diisopropyl azodicarboxylate (65 ml) was added over 2 hours. After complete addition of diisopropyl azodicarboxylate the solution was stirred while warming to ambient temperature. The reaction mixture was re-cooled to 0° C. and filtered. The filtrate, magnesium chloride (anhydrous; 31.1 g) and celite (25.5 g) were combined in the reactor. Toluene (500 ml) was distilled off and the remaining mixture was cooled to 0° C. The suspension formed was removed by filtration. Further magnesium chloride (2.6 g) and celite (2.5 g) were added to the filtrate. Toluene (200 ml) was removed by distillation. The residue was cooled to 0° C. and filtered. The filtercake was washed with toluene. The reactor was loaded with the filtrate, and toluene was removed by azeotropic distillation with propan-2-ol. The product crystallised from propan-2-ol at 40° C. while cooling to 20° C. The product was collected by filtration and washed with propan-2-ol. After drying, the product (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine (61.1 g) was obtained (yield: 73.6%; HPLC analysis: 99.1%; chiral HPLC: ee=100%). No triphenylphosphine oxide was detectable by HPLC analysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:20]([O-])=O)[C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[CH:10]=2)=[N:6][CH:7]=1.[CH2:23](O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[N:20]=[CH:23][N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([N:15]4[CH:19]=[CH:18][N:17]=[CH:16]4)[CH:10]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CCO
Reactant: O=[N+]([O-])c1cc(Br)cnc1Nc1cccc(-n2ccnc2)c1
Product: Brc1cnc2c(c1)ncn2-c1cccc(-n2ccnc2)c1

Procedure:
6-Bromo-3-[3-(imidazol-1-yl)phenyl]-3H-imidazo[4,5-b]pyridine was prepared from N-(5-bromo-3-nitropyridin-2-yl)-N-[3-(imidazol-1-yl)phenyl]amine as described in Example 1. Oxalate salt, cream-coloured powder, m.p. 236-238° C. (from ethanol); δH (400 MHz, d6-DMSO) 7.23 (1H, s), 7.75 (2H, m), 7.92 (1H, s), 8.01-8.03 (1H, m), 8.24 (1H, s), 8.51 (1H, s), 8.57 (2H, dd, J 6 and 2), 9.09 (1H, s); m/z (ES+) 340 and 342 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:24]([C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:30]=[C:29]([CH:38]=O)[CH:28]=1)[CH2:25][CH3:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][NH:21][CH2:38][C:29]3[CH:28]=[C:27]([CH2:24][CH2:25][CH3:26])[N:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:30]=3)[CH2:17][CH2:18]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:22][CH:23]=1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: CCCc1cc(C=O)nn1-c1ccccc1
Product: CCCc1cc(CNCCN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)nn1-c1ccccc1
Yield: 95 %

Procedure:
Compound 94 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 5-propyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17](=[O:24])[CH2:18][C:19](OCC)=[O:20])[CH2:14][CH2:13][N:12]2[C:25]([O:27][CH3:28])=[O:26])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH2:31]O.Cl>CO.O>[C:1]([C:5]1[CH:6]=[C:7]([C@H:11]2[CH2:16][C@@H:15]([C:17]3[O:24][NH:31][C:19](=[O:20])[CH:18]=3)[CH2:14][CH2:13][N:12]2[C:25]([O:27][CH3:28])=[O:26])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(c2cccc(C(C)(C)C)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cccc(C(C)(C)C)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 23.9 %

Procedure:
Methyl 2-(3-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (3.14 g, 8.06 mmol) was dissolved in MeOH (50 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.322 g, 8.06 mmol) dissolved in water (5.00 mL) was added during 5 min and the colourless mixture continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.494 mL, 8.06 mmol) was added during 8 min. The resulting solution was stirred at −55° C. for 6 h 30 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (60 mL, 360.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a brown oil. The crude was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 40-85% Acetonitrile in H2O/MeCN/HOAc 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(3-tert-butylphenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (690 mg, 24%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.29 (s, 9H), 1.81-1.88 (m, 1H), 2.14-2.21 (m, 1H), 2.22-2.31 (m, 1H), 2.35-2.42 (m, 1H), 3.03-3.10 (m, 1H), 3.37-3.44 (m, 1H), 3.66 (s, 3H), 4.16-4.22 (m, 1H), 5.12-5.16 (m, 1H), 5.48 (s, 1H), 6.97-7.01 (m, 1H), 7.17 (s, 1H), 7.21-7.25 (m, 2H). MS m/z 359 (M+H)+