Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][Br:17])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C=Cc2ccc(Cl)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(C=Cc2ccc(CBr)cc2)cc1
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of 5.7 g. (0.025 m) of 4-chloro-4'-methylstilbene (m.p. 196°-197° C.) and 4.43 g. (0.025 m) of N-bromosuccinimide in 124 ml. of carbon tetrachloride was heated at reflux for eight hours. The reaction mixture was filtered hot, allowed to cool and stand overnight and again filtered to remove a small amount of amorphous material. The solvent was removed in vacuo and the residue crystallized from cyclohexane to give 4-(4-chlorostyryl)benzyl bromide, m.p. 130°-132° C. in 85% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:14]2[C:15](=[O:33])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25]C(=O)C(C)(C)C)=[C:21]([F:32])[CH:20]=3)[O:18][C:13]=2[C:12]([F:34])=[CH:11][C:10]=1[F:35].S(=O)(=O)(O)O>>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[O:18][C:13]3[C:12]([F:34])=[CH:11][C:10]([F:35])=[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:36])[CH3:1])[C:14]=3[C:15](=[O:33])[CH:16]=2)=[CH:20][C:21]=1[F:32]
Reactant: CN(C)CCCCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Agent: O=S(=O)(O)O
Product: CN(C)CCCCCNc1c(F)cc(F)c2oc(-c3ccc(N)c(F)c3)cc(=O)c12
Yield: 84 %

Procedure:
Substantially the same manner as that in Example 127 (4) was repeated except that 909 mg (1.81 mmol) of the above 5-(5-dimethylaminopentylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one was used, treatment with 15 mL of concentrated sulfuric acid was carried out and the resulting compound was recrystallized from ethyl acetate/n-hexane, to give 638 mg of Compound 139 (yield: 84%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[OH-].[K+].[O:17]1[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18]1>CS(C)=O>[O:17]1[CH2:22][CH2:21][CH:20]([CH2:23][O:24][C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH2:19][CH2:18]1
Reactant: O=C(O)c1ccc(C(F)(F)F)c(Cl)n1
Reactant: OCC1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.4 %

Procedure:
6-Chloro-5-(trifluoromethyl)picolinic acid (330 mg, 1.46 mmol) and powdered potassium hydroxide (328 mg, 5.85 mmol) were dissolved in DMSO (9 mL). The solution was stirred for 15 min. at ambient temperature. (Tetrahydro-2H-pyran-4-yl)methanol (170 mg, 170 μL, 1.46 mmol; CAN 14774-37-9) was added. The mixture was stirred for 1 d at ambient temp., poured onto ice water/brine/1N HCl (75 mL) and extracted with EtOAc (2×150 mL). The combined extracts were washed with ice water/brine (75 mL), dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound as a grey solid (385 mg, 86%) which was used in the next step without further purification. MS: 304.0 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:11][CH2:10][CH2:9]2)=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.C([SiH](CC)CC)C.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][CH2:10][CH2:9]2)=[C:4]([C:13]([F:14])([F:15])[F:16])[CH:3]=1
Reactant: OC1(c2ccc(Br)cc2C(F)(F)F)CCC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1cc(Br)ccc1C1CCC1
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
To a solution in chloroform (10.0 mL) of the compound (1.00 g) obtained in step (1) above and triethylsilane (406 mg), a solution of boron trifluoride/diethyl ether complex (601 mg) in chloroform (4.00 mL) was added at −65° C. After being brought to 0° C., the mixture was stirred at that temperature for 30 minutes. Subsequently, potassium carbonate (1.08 g) and water (10.0 mL) were added and the mixture was brought to room temperature. After phase separation, the organic layer was dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1-90:10) and further purified by NH silica gel column chromatography (n-hexane) to give 4-bromo-1-cyclobutyl-2-(trifluoromethyl)benzene as a colorless oil (490 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:12]=[CH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].C(O)C>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C=CC(=O)OC(C)(C)C)cc1C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c(CCC(=O)OC(C)(C)C)cc1C
Yield: 99.7 %

Procedure:
A solution of 5-(2-tert-butoxycarbonyl-vinyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.48 g) in ethyl acetate (60(mL) and ethanol (30 mL) was hydrogenated using 1% palladium on carbon at room temperature for overnight to give 2.49 g (100%) of 5-(2-tert-butoxycarbonyl-ethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.12 (br s, 1H, NH), 5.74 (d, J=2.3 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H, OCH2), 2.71 (t, J=7.5 Hz, 2H, CH2), 2.47 (t, J=7.5 Hz, 2H, CH2), 2.18 (s, 3H, CH3), 1.36 (s, 9H, 3×CH3), 1.28 (t, J=7.1 Hz, 3H, OCH2CH3). MS 282 [M++1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][N+:7]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][C:15]5[O:23][CH2:22][O:21][C:16]=5[CH:17]=4)[C:8]=3[CH:9]=2)[C:4]=1[O:24][CH3:25].[Cl-].O.[OH-].[Na+].[CH3:30][C:31]([CH3:33])=[O:32]>>[CH3:25][O:24][C:4]1[C:5]2[CH:6]([CH2:30][C:31](=[O:32])[CH3:33])[N:7]3[CH2:20][CH2:19][C:18]4[C:13]([C:8]3=[CH:9][C:10]=2[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])=[CH:14][C:15]1[O:23][CH2:22][O:21][C:16]=1[CH:17]=4
Reactant: COc1ccc2cc3[n+](cc2c1OC)CCc1cc2c(cc1-3)OCO2
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1OC)C(CC(C)=O)N1CCc3cc4c(cc3C1=C2)OCO4
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Berberine hydrochloride (10.0 g, 26.90 mmol), water (40 mL), acetone (10 mL), 50% aqueous sodium hydroxide (15 mL) was introduced into a reaction vessel. The reaction mixture was stirred vigorously for 30 min at room temperature. The resulting precipitate was collected and washed with 80% methanol (2×10 mL) and then dried to afford 1-(9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-8-yl)-propan-2-one (8.5 g, 80%) as a yellow solid. LC/MS m/e calcd for C23H23NO5 (M+H)+: 394.44, observed: 336.0; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.04 (s, 3 H) 2.31 (dd, J=14.65, 4.80 Hz, 1 H) 2.66-2.75 (m, 1 H) 2.75-2.82 (m, 1 H) 2.94 (dd, J=14.65, 6.57 Hz, 1 H) 3.16-3.25 (m, 1 H) 3.25-3.30 (m, 1 H) 3.77 (d, J=2.02 Hz, 6 H) 5.21 (dd, J=6.32, 4.80 Hz, 1 H) 5.97-6.03 (m, 3 H) 6.72 (d, J=8.34 Hz, 1 H) 6.76 (s, 1 H) 6.87 (d, J=8.34 Hz, 1 H) 7.25 (s, 1 H).
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1N2CN3CN(C2)CN1C3.[C:29](O)(C(F)(F)F)=[O:30].Cl>O.CO>[CH:29]([C:17]1[C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:30]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCCCc1cc(=O)c2ccccc2[nH]1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCCCCCc1[nH]c2ccccc2c(=O)c1C=O
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 2-heptyl-4(1H)-quinolone (5 mmol), hexamine (2.5 mmol), and TFA (7.5 ml) was stirred at reflux under nitrogen for 30 hours. MeOH (15 ml) and water (15 ml) were added, and heating was continued for 1 hour. 3 M HCl (5 ml) was added and the heating was continued for a further period of 30 minutes. The mixture was cooled and the precipitate removed by filtration and washed with water. The solid on trituration with acetone afforded the title compound in 40% yield. Recrystallisation from MeOH/EtOAc gave colourless needles, mp 245-248° C. (dec).
Reaction SMILES: [CH3:1][C@H:2]1OS(=O)(=O)[N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:3]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[N-:26]=[N+:27]=[N-:28].[Na+].[Na+].[Cl-].OS(O)(=O)=O>CN(C=O)C>[N:26]([C@@H:2]([CH3:1])[C@H:3]([NH:4][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H]1OS(=O)(=O)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -40 °C

Procedure:
To a solution of 4-benzyl 3-tert-butyl(4S,5R)-5-methyl-1,2,3-oxathiazolidine-3,4-dicarboxylate 2,2-dioxide (17.13 g, 46.1 mmol) in DMF (171 ml) at −40° C. was added sodium azide (3.9 g, 60.0 mmol) in portions, and the mixture was stirred at −40° C. then slowly warmed to rt over 4 h. Added 20% aq. NaCl (100 ml), followed by dropwise addition of 2 N H2SO4 (10 ml). The reaction was stirred at rt for 3 h, then partitioned between H2O and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to afford (2S,3S)-benzyl 3-azido-2-(tert-butoxycarbonylamino)butanoate as a slightly yellowish glue (14.8 g, 96%).
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].[Br:5][C:6]1[CH:7]=[CH:8][C:9](=[O:12])[NH:10][CH:11]=1>>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH:1]([CH3:3])[CH3:2])=[N:10][CH:11]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CC(C)Br
Product: CC(C)Oc1ccc(Br)cn1

Procedure:
The sub-title compound was prepared in accordance with Example 36(b) from isopropylbromide and 5-bromo-1H-pyridin-2-one.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.C[Si](Cl)(C)C.C(N(C(C)C)C(C)C)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCl>[CH2:26]([O:25][C:23]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CNC1
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3-azetidine carboxylic acid (0.50 g, 4.9 mmol), trimethylsilyl chloride (1.25 ml, 9.8 mmol) and N-ethyldiisopropylamine (2.20 ml, 12.6 mmol) was heated under reflux in dichloromethane (20 ml) for 20 minutes. The reaction mixture was cooled in an ice bath and benzyl chloroformate (0.92 ml, 6.4 mmol) added. The mixture was stirred at room temperature for 72 hours before quenching with saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous phase was acidified to pH2 with 2N hydrochloric acid and extracted with ethyl acetate (3×). The combined organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a brown oil, 1.01 g.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[CH2:21][C:22]([OH:24])=[O:23].Cl>O1CCOCC1.[OH-].[Na+]>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][C:22]([OH:24])=[O:23])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CC1CCCCN1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of 3-trifluoromethylbenzenesulfonic acid chloride (2.70 g, 11 mmol) in 1,4-dioxane (10 ml) was added slowly, in the course of 1 h, to a solution of 2-(piperidin-2-yl)acetic acid (1.43 g, 10 mmol) in 1,4-dioxane (5 ml) and 1 N sodium hydroxide solution (22 ml). The mixture was then stirred for 4.5 h at room temperature, then acidified with 1 N hydrochloric acid and subsequently extracted with DCM (3×60 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=2[C:26](O)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(OCC)(=O)C>C(#N)C>[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][C:25]=2[C:26]([N:5]2[CH2:4][CH2:3][N:2]([C:8]3[CH:9]=[N:10][C:11]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:7][CH2:6]2)=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Reactant: c1ccc2ncc(N3CCNCC3)cc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3cnc4ccccc4c3)CC2)c1

Procedure:
Prepared in analogy to example 1.1(b) from 3-piperazin-1-yl-quinoline hydrochloride and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (example 2.3) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([OH:6])[C:4]#[CH:5].[H-].[Na+].[CH2:11]([S:14](Cl)(=[O:16])=[O:15])[CH2:12][CH3:13].O>O1CCCC1>[CH2:11]([S:14]([O:6][C:3]([CH2:7][F:8])([C:4]#[CH:5])[CH2:2][F:1])(=[O:16])=[O:15])[CH2:12][CH3:13]
Reactant: C#CC(O)(CF)CF
Reactant: CCCS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CC(CF)(CF)OS(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An amount (2.4 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol was dissolved in tetrahydrofuran (20 ml); to the solution under cooling with ice, 60% oily sodium hydride (0.96 g) was added under a nitrogen atmosphere. After stirring for 30 minutes under cooling with ice, propanesulfonyl chloride (2.2 ml) was added dropwise. The mixture was stirred for 5 hours while its temperature was raised to room temperature. Water was added to the reaction mixture, followed by extraction with ether. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; 30% ethyl acetate/hexane) to give the titled compound (4.1 g).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]=[O:18]>>[OH:18][CH2:17][N:9]1[C:10]2[C:15](=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8]1
Reactant: Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: C=O
Product: Cc1ccc2c(c1)c(-c1ccccc1)nn2CO
Yield: 83.6 %

Procedure:
By the procedure similar to that described in Example 19, 3-phenyl-5-methylindazole (13.7 g) and paraformaldehyde (2.4 g) were treated to obtain 13.1 g of 1-hydroxymethyl-3-phenyl-5-methylindazole (m.p. 109°-111° C).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:20]([N:39]1[CH:43]=[C:42]([CH2:44][CH2:45][CH2:46][C:47](O)=[O:48])[N:41]=[CH:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([NH:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:47](=[O:48])[CH2:46][CH2:45][CH2:44][C:42]2[N:41]=[CH:40][N:39]([C:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:43]=2)=[CH:9][CH:8]=1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccc(C(=O)CCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6,95 g of N-tert-butyl-p-bromobenzamide is dissolved in 175 ml of tetrahydrofuran at -70° under nitrogen and 20.1 ml of n-butyllithium (2.7M) is added dropwise. After 30 min, a solution of 5.35 g of 4-(1-trityl-4-imidazolyl)-butanoic acid in 10 ml of tetrahydrofuran is added slowly. The reaction mixture is allowed to warm slowly to room temperature and 20 ml of an aqueous ammonium chloride solution is added. The organic layer is separated, dried over sodium sulfate and evaporated to yield 1-(p-N-tert-butylaminocarbonylphenyl)-4-(1-trityl-4-imidazolyl)-1-butanone
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:19][C:20]([C:22]2[O:26][N:25]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=2)=O)=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]=1[Cl:8].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>O1CCOCC1.CCOC(C)=O>[C:27]([C:24]1[CH:23]=[C:22]([C:20]2[NH:1][C:2]3[C:3]([N:19]=2)=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]=3[Cl:8])[O:26][N:25]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cc(C(=O)Nc2nc(-c3ccccc3C(F)(F)F)cc(Cl)c2N)on1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(-c2nc3nc(-c4ccccc4C(F)(F)F)cc(Cl)c3[nH]2)on1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-tert-butyl-isoxazole-5-carboxylic acid [3-amino-4-chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide (36.2 mg, 0.0825 mmol, prepared as described in STEP B above) in 1,4-dioxane (10 mL) was treated with (+)-10-camphorsulfonic acid (38.3 mg, 0.165 mmol), and the mixture was heated to 100° C. for 5 h. The cooled mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO3 (20 mL). The organic extract was dried over MgSO4 and concentrated in vacuo. The residue was purified on an 8-g SEPRA Si 35 SPE column (Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:3 over 40 min) to yield 2-(3-tert-butyl-isoxazol-5-yl)-7-chloro-5-(2-trifluoromethyl-phenyl)-1H-imidazo[4,5-b]pyridine as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 7.77 (d, J=7.8 Hz, 1H), 7.58-7.64 (m, 1H), 7.50-7.58 (m, 2H), 7.49 (s, 1H), 7.16 (s, 1H), 1.88 (br. s., 1H), 1.39 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C20H16N4OClF3: 421.1 (M+H). Measured: 421.1.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:12])=[C:7]([C:10]#[N:11])[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].C([O-])(O)=O.[Na+].Cl.[NH2:19][OH:20]>CO>[OH:20][NH:19][C:10]([C:7]1[S:8][CH:9]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]=1[CH3:12])=[NH:11]
Reactant: NO
Reactant: Cc1c(CC(C)C)csc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1c(CC(C)C)csc1C(=N)NO
Temperature: 60 °C
Reaction time: 20 h
Yield: 120.8 %

Procedure:
To a solution of 4-isobutyl-3-methyl-thiophene-2-carbonitrile (2.10 g, 11.7 mmol) in methanol (50 mL), NaHCO3 (1.38 g, 16.4 mmol) followed by hydroxylamine hydrochloride (977 mg, 14.1 mmol) is added. The mixture is stirred at 60° C. for 20 h before it is filtered. The solvent of the filtrate is evaporated and the remaining residue is dried under HV go give N-hydroxy-4-isobutyl-3-methyl-thiophene-2-carboxamidine (3.0 g) as a yellow solid; LC-MS: tR=0.67 min.
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[CH2:5]([NH2:8])[CH2:6][NH2:7]>C(O)C.CCOCC>[OH:4][CH:2]([CH3:3])[CH2:1][NH:7][CH2:6][CH2:5][NH:8][CH2:1][CH:2]([OH:4])[CH3:3]
Reactant: NCCN
Reactant: CC1CO1
Solvent: CCOCC
Solvent: CCO
Product: CC(O)CNCCNCC(C)O
Temperature: 20 °C
Yield: 28.5 %

Procedure:
(IV-a): Propylene oxide (142.4 g, 2.4 mol) was added dropwise over a period of 11 hours to a solution of ethylenediamine (71.9 g, 1.2 mol) in 25 mL absolute ethanol and 10 mL of nitrogen purged distilled water at 90° C. After addition, the reaction was maintained for an additional hour, then cooled to room temperature (about 20° C.). The reaction solution was concentrated by rotary evaporation to give a milky white suspension which, upon dissolution in anhydrous ether, produced a white precipitate of N,N'-bis(2-hydroxypropyl)ethylenediamine in 28.5 percent yield. The product was crystallized from methanol/ethanol [m.p. 132° C., IR(Nujol): 3250(OH); NMR(MeOHd4): δ3.8(m,2H); 2.6(t,8H); 1.2(d,6H)].
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:18][C:19]2[C:28]3[O:27][CH2:26][CH2:25][O:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)[S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=1)C.[OH-].[Na+]>CO.Cl>[O:24]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:18][N:13]([CH2:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:29])=[O:3])[CH:11]=[CH:10][CH:9]=3)[S:14]([CH3:17])(=[O:15])=[O:16])[C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)Cc1cccc(CN(Cc2cccc3c2OCCO3)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)N(Cc1cccc(CC(=O)O)c1)Cc1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a solution of (3-{[(2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid ethyl ester (210 mg, 0.5 mmol) in MeOH (3 mL) at 0° C. was added aqueous NaOH (2N, 0.5 mL). The reaction was stirred at room temperature for 16 h and was diluted with 1N HCl. The product was extracted into CH2Cl2 and the organic solution was washed with water followed by brine. The organic solution was dried over MgSO4, filtered, and concentrated to provide the title compound (165 mg). 1H NMR (400 MHz, CDCl3) δ7.19-7.32 (m, 4H), 6.73-6.81 (m, 3H), 4.29 (s, 2H), 4.22 (s, 4H), 4.18 (s, 2H), 3.63 (s, 2H), 2.75 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-:2].[Li+:5].[Li+].[Cl:7]([OH:11])(=[O:10])(=[O:9])=[O:8].Cl([O-])(=O)(=O)=[O:13].[Li+]>>[OH2:2].[OH2:8].[OH2:13].[Cl:7]([O-:11])(=[O:10])(=[O:9])=[O:8].[Li+:5]
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: O=C([O-])[O-]
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: O

Procedure:
In the process (IV), lithium carbonate (Li2CO3) is added to an aqueous solution of perchloric acid, and lithium perchlorate is synthesized through a neutralization reaction. In addition, the aqueous solution of lithium perchlorate synthesized by the neutralization reaction is evaporated and crystallized so as to obtain lithium perchlorate trihydrate. The neutralization reaction in the process (IV) is expressed by the following chemical equation (E). 2HClO4+Li2CO3→2LiClO4+CO2+H2O  (D)