Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][O:5][C:6](=[O:23])/[C:7](/[CH2:12][C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[CH:8]\[C:9]([O-:11])=[O:10])[CH3:2].[S:28]([O-:31])([OH:30])=[O:29].[Na+:32].O.C(O)C>C(OCC)(=O)C>[CH2:1]([CH:3]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][O:5][C:6](=[O:23])[C:7]([CH2:12][C:13]([F:21])([F:22])[C:14]([F:19])([F:20])[C:15]([F:17])([F:18])[F:16])([S:28]([OH:31])(=[O:30])=[O:29])[CH2:8][C:9]([O-:11])=[O:10])[CH3:2].[Na+:32]
Reactant: CCCCC(CC)COC(=O)/C(=C\C(=O)[O-])CC(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCCCC(CC)COC(=O)C(CC(=O)[O-])(CC(F)(F)C(F)(F)C(F)(F)F)S(=O)(=O)O
Yield: 31.7 %

Procedure:
80.3 g (0.196 mol) of mono(2-ethylhexyl)mono(2,2,3,3,4,4,4-heptafluorobutyl)maleate, 20.4 g (0.196 mol) of sodium hydrogen sulfite and 80 mL of water/ethanol (1/1 v/v) were mixed together and heated under reflux for 10 hr. Thereafter, 1000 mL of ethyl acetate was added, and the organic phase was washed with a saturated aqueous sodium chloride solution. The resultant organic layer was collected, and the organic solvent was distilled off in vacuum. Purification by silica gel column chromatography (chloroform/methanol: 9/1 v/v) was performed. The collected organic phase was washed with a saturated aqueous sodium chloride solution, and the organic solvent was distilled off in vacuum, thereby obtaining 32 g (yield: 32%) of desired compound as a colorless transparent solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7](Br)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14]>[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:14]#[C:13][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:7]([C:14]#[C:13][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(Br)c(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C#C[Si](C)(C)C)c(C#C[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
4-tert-butyl-1,2-dibromobenzene (5.0 g, 17 mmol), copper iodide (0.17 g, 0.9 mmol), tetrakis(triphenylphosphine)palladium (1.04 g, 0.9 mmol), ethynyltrimethylsilane (4.2 g, 43 mmol), and triethylamine (25 ml) were heated to 20° C. and stirred for 4 hours. The reaction mixture was then heated to 80° C. for 44 hours. Additional ethynyltrimethylsilane (2.5 g, 25 mmol) was added and the reaction mixture was stirred at 47° C. for 60 hours. Column chromatography (silica) was performed to remove metals and salts, using heptane as eluent. The crude product mixture was used without further purification.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[NH2:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[C:16]([N:17]=[C:2]=[O:4])[CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cc(N=C=O)c1
Reaction time: 0.5 h

Procedure:
Triphosgene (17.01 g, 0.0573 mol) was dissolved in 200 ml of toluene in a 1 liter flask. 150 ml of a toluene solution of 3-chloro-5-methylaniline (21.9 g, 0.155 mol) and triethylamine (36.0 ml) was added dropwise thereto over 30 minutes at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9](F)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:26][OH:27]>C1COCC1>[F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([O:27][CH3:26])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(F)c([N+](=O)[O-])cc1F
Reactant: CO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl 2,5-difluoro-4-nitrobenzoate (Apollo, 500 mg; 2.30 mmol; 1 eq.) was dissolved in MeOH (10 mL). The solution was cooled down to 0° C. Lithium bis(trimethylsilyl)amide (2.30 mL; 1 M; 2.30 mmol; 1 eq.) was added as solution in THF. After addition, the reaction mixture was stirred at RT overnight. Solvents were evaporated and the crude mixture was dissolved in EtOAc, washed with water, brine and dried over MgSO4. The resulting crude product was purified by flash chromatography (c-hex/EtOAc 90:10), affording the title product as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 7.60-7.52 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H). HPLC (Method A) Rt 3.88 min (Purity: 88.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:27])[C:24]([OH:26])=[O:25])=[CH:18][C:17]=2[F:28])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=2[CH:13]=1.[BH4-].[Na+].O>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:27])[C:24]([OH:26])=[O:25])=[CH:18][C:17]=2[F:28])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([OH:12])[C:6]=2[CH:13]=1
Reactant: CC(Cc1ccc(OCc2cc(Cl)cc3c2OC(C)(C)C3=O)c(F)c1)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(Cc1ccc(OCc2cc(Cl)cc3c2OC(C)(C)C3O)c(F)c1)C(=O)O

Procedure:
To a solution of 3-(4-((5-chloro-2,2-dimethyl-3-oxo-2,3-dihydrobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpropanoic acid (106) (80 mg, 0.197 mmol) in tetrahydrofuran/methanol (2:1, 2 mL) was added sodium borohydride (15 mg, 0.393 mmol). After the reaction was stirred at room temperature for 1.5 hours water was added and the solution was extracted with ethyl acetate, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 3-(4-((5-chloro-3-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpropanoic acid (109). 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 7.31 (s, 1H), 6.92 (m, 2H), 6.82 (d, J=12.0 Hz, 1H), 5.04 (s, 2H), 4.75 (s, 1H), 2.93 (m, 1H), 2.71 (m, 1H), 2.64 (m, 1H), 1.49 (s, 3H), 1.34 (s, 3H), 1.18 (d, J=6.9 Hz, 3H). LC-MS ESI m/z: found 407.3 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)(=[O:37])=[O:36])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ncccn3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 1 from 3-{3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11z, and pyridine-2-sulfonyl chloride hydrochloride salt, of Preparation 47, using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.80 (d, 2H), 8.68 (m, 1H), 8.27 (d, 2H), 7.98 (m, 1H), 7.86 (m, 1H), 7.46 (m, 1H), 7.20 (m, 3H), 7.12 (m, 1H), 7.02 (d, 1H), 6.96 (d, 1H), 6.91 (s, 1H), 4.55 (s, 2H), 4.48 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.50 (t, 2H); MS 503 (M+1).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[CH:15]([NH:18][CH2:19][CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])([CH3:17])[CH3:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][CH:15]([N:18]([CH2:19][CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])[S:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)(=[O:13])=[O:12])[CH3:17]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)NCCNC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)(=O)N(CCNC(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Acetaminobenzene sulfonyl chloride (23.3 g, 0.1 mole) as a slurry in 400 ml methylene chloride was added to N,N'-diisopropyl ethylene diamine (14.46 g, 0.1 mole) and triethylamine (10.1 g, 0.1 mole) in methylene chloride (600 ml). The reaction was stirred overnight at room temperature. The reaction was washed with water, insoluble by-product filtered off, and the filtrate stripped to a brown gum. After filtration through silica gel in 20% MeOH/EtOAc the crude crystalline product was recrystallized from isopropanol to provide the title product as the hydrochloride salt (3.00 g, m.r. 176°-178° C.).
Reaction SMILES: [CH2:1](F)[O:2][CH:3]([C:8]([F:11])([F:10])[F:9])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(O)C(F)(F)F.BrC[C:25]([O:27]CC)=[O:26]>>[F:5][C:4]([F:7])([F:6])[CH:3]([O:2][CH2:1][C:25]([OH:27])=[O:26])[C:8]([F:11])([F:10])[F:9]
Reactant: CCOC(=O)CBr
Reactant: FCOC(C(F)(F)F)C(F)(F)F
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: O=C(O)COC(C(F)(F)F)C(F)(F)F
Yield: 66 %

Procedure:
U.S. Pat. No. 6,271,422 describes the synthesis of sevoflurane by fluoromethylation of alcohols via decarboxylative halogenation. In this way, hexafluoroisopropanol is submitted to reaction with ethyl alpha-bromoacetate providing alpha-(hexafluoroisopropoxy)acetic acid in a yield of 66%. This intermediate is subjected to reaction with highly toxic lead tetra-acetate, using carcinogenic benzene as the solvent. In the reaction sequence, the homogeneous benzene/sevochlorane solution, which is inseparable by distillation, is reacted with potassium fluoride providing at the end of the process sevoflurane with a low yield of 28%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[CH2:21][CH2:20]2)=[O:18])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C1(N=C=NC2CCCCC2)CCCCC1.FC1C(O)=C(F)C(F)=C(F)C=1F.[C:63](O)([CH3:66])([CH3:65])[CH3:64].C([Li])(CC)C.C1CCCCC1>CN(C)C=O.O1CCCC1>[C:63]([O:14][C:13](=[O:15])[CH:12]([NH:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH2:23][CH2:24]1)=[O:18])[CH2:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[NH:9][N:8]=[CH:7]2)([CH3:66])([CH3:65])[CH3:64]
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc2cn[nH]c12
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)OC(C)(C)C)cc2cn[nH]c12
Reaction time: 8 h

Procedure:
A solution of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid (50 mg, 0.105 mmol) and dicyclohexylcarbodiimide (25 mg, 0.12 mmol) in dimethylformamide was stirred for 30 min at room temperature, and then pentafluorophenol (26 mg, 1.3 mmol) was added. Stirring was continued at room temperature overnight, and then the solvent was removed, the residue was dried under high vacuum for 4 h. The crude pentafluorophenyl ester was used without further purification in the next step. To a solution of tert-butyl alcohol (10 equiv.) in tetrahydrofuran at −78° C. under nitrogen was added 1.4M sec-butyllithium in cyclohexane (10 equiv.). After 10–15 min, a solution of pentafluorophenol ester (1 equiv.) in tetrahydrofuran was added. The reaction mixture was stirred at room temperature overnight. The solvents were removed in vacuo, and the residue was purified by preparative-HPLC to give the desired compound. 1H-NMR(CD3OD) δ 1.40 (s, 9H) 1.56 (m, 4H), 2.54 (s, 3H) 2.85 (m, 2H) 3.05 (m, 1H) 3.19 (m, 1H) 4.14 (m, 4H) 4.44 (m, 2H) 6.76 (d, J=7.68 Hz, 1H) 6.93 (t, J=7.5 Hz, 1H) 7.10 (m, 3H) 7.14 (s, 1H) 7.97 (s, 1H). LC/MS: tR=2.19 min, 533.36 (MH)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1C)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[N:16]1([C:21]2[CH:22]=[C:23]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=2)[NH2:24])[CH:20]=[CH:19][N:18]=[CH:17]1.[CH:32](N(C(C)C)CC)(C)C>C(Cl)Cl>[N:16]1([C:21]2[CH:22]=[C:23]([NH:24][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[C:3]=3[CH3:32])[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=2)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: Nc1cc(-n2ccnc2)cc(C(F)(F)F)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(C(=O)O)cc1I
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1c(I)cccc1C(=O)Nc1cc(-n2ccnc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 84.3 %

Procedure:
To 3-iodo-4-methylbenzoic acid (3.07 g, 0.0117 mol) was added thionyl chloride (10 mL) and refluxed for 2 h. The excess thionyl chloride was carefully removed and the resulting acid chloride was dried in vacuo for 2 h. The residue was then dissolved in DCM (anhydrous, 25 mL) and cooled on ice. To the cooled solution was added 3-1H-imidazol-1-yl-5-(trifluoromethyl)aniline (3.46 g, 0.0152 mol) in DCM followed by the dropwise addition of diisopropylethylamine (8.2 mL, 0.047 mol). This was stirred at ambient temperature for 21 h. The white solid that separated was filtered and washed with water and dried to provide 4.65 g of product. Additional product could be obtained from the filtrate following concentration and purification by silica gel flash chromatography in EtOAc/hexanes.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:21]([O-])([N+]([O-])=O)=[O:22]>>[Cl:1][CH2:2][CH2:3][N:4]([N:21]=[O:22])[C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(CC1CC1)C1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: O=NN(CCCl)C(=O)N(CC1CC1)C1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 67.8 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(D-ribofuranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 31-(2). 2.3 g of 1-(2-chloroethyl)-1-nitroso-3-cyclopropylmethyl-3-(D-ribofuranosyl)urea are thereby obtained as yellow liquid.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]3[N:23]([CH2:24][CH2:25][O:26][CH2:27][CH:28]=[CH2:29])[C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[N:16]=3)[CH2:10][CH2:9]2)C=CC=CC=1.CC1C=CC=CC=1.[C:37](Cl)(=[O:41])[O:38][CH2:39][CH3:40].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:27]([O:26][CH2:25][CH2:24][N:23]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1[CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:37]([O:38][CH2:39][CH3:40])=[O:41])[CH2:13][CH2:12]1)[CH:28]=[CH2:29]
Reactant: CCOC(=O)Cl
Reactant: C=CCOCCn1c(CC2CCN(Cc3ccccc3)CC2)nc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOCCn1c(CC2CCN(C(=O)OCC)CC2)nc2cccnc21
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a stirred and refluxed mixture of 13.5 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-3-[2-(2-propenyloxy)ethyl)-3H-imidazo[4,5-b]-pyridine and 90 parts of methylbenzene were added dropwise 5.4 parts of ethyl carbonochloridate. Upon complete addition, stirring was continued for 1 hour at reflux temperature. After cooling, the reaction mixture was diluted with water and the whole was treated with potassium carbonate. The product was extracted with methylbenzene. The extract was dried, filtered and evaporated, yielding 14 parts (75.1%) of ethyl 4-[[3-[2-(2-propenyloxy)ethyl]-3H-imidazo[4,5-b]pyridine-2-yl]methyl]-1-piperidinecarboxylate as a residue (compound 43).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: COc1ccncc1B(O)O
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Product: COc1ccncc1-c1cccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 33 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 4-methoxypyridine-3-boronic acid (640 mg, 4.20 mmol) were reacted. After purification the title compound (52 mg, 33% yield) was obtained as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.58 (d, J=5.8 Hz, 1H), 8.57 (bm, 1H), 8.44 (s, 1H), 7.91 (m, 1H), 7.74 (m, 2H), 6.94 (d, J=5.8 Hz, 1H), 3.77 (s, 3H), 2.96 (m, 1H), 0.86 (m, 2H), 0.64 (m, 2H). MS APCI, m/z=336.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[C:19]([OH:21])=O)=[O:7])(C)(C)C.[O:22]=[C:23]1[C:28](C(Cl)=O)=[CH:27][CH:26]=[C:25]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:24]1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH2:42][NH2:43]>>[C:15]([O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:28]2[C:23](=[O:22])[O:24][C:25]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:26][CH:27]=2)=[O:7])[C@H:9]([C:19]([NH:43][CH2:42][C:41]2[CH:44]=[CH:45][C:46]([O:47][CH3:48])=[C:39]([O:38][CH3:37])[CH:40]=2)=[O:21])[CH2:10]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: CC(C)(C)ON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COc1ccc(CN)cc1OC
Product: CCCCCc1ccc(C(=O)N2CC(=NOC(C)(C)C)C[C@H]2C(=O)NCc2ccc(OC)c(OC)c2)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 3,4-dimethoxybenzylamine the title compound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=542.4.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2]C.[NH2:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)([OH:12])[CH3:11].[CH2:27]1CCN2C(=NCCC2)CC1>C1COCC1>[OH:12][C:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)([CH3:11])[CH2:9][NH:8][S:4]([CH:1]([CH3:2])[CH3:27])(=[O:5])=[O:6]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(O)(CN)c1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
In a 1000 mL-3n flask fitted with a stirrer and thermometer, 5.69 g. of propanesulfonyl chloride was added dropwise to 8.60 g. of 1-amino-2-[4-(phenylmethoxy)phenyl]propan-2-ol and 6.21 g. of DBU in THF (300 mL) while stirring at 0° C. under a nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred overnight at this temperature. In the morning, reaction was concentrated under reduced vacuum. The resulting oil was taken into ethyl acetate and the organic layer was washed two times with H2O, dried over Na2SO4, and concentrated under reduced vacuum to yield 10.2 g. as a solid. This material was purified via silica gel chromatography employing the Water's prep. 2000 and eluting with a solvent of hexane/ethyl acetate 9:1 to yield intermediate title compound (6.14 g, 50%) as a white solid. Ion spray M.S. 362.2 (M*−1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[CH3:17]N(C)C=O.[H-].[Na+].Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31]Cl>O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)[CH3:17])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(-c2ccccn2)[nH]n1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccn2)nn1C(C)c1ccccn1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 5-(2-pyridinyl)pyrazole-3-carboxylic acid ethyl ester (4.34 g) and anhydrous dimethylformamide (40 ml) at room temperature, 1.92 g of 60% sodium hydride oil suspension were added. After the bubbling had stopped, 3.60 g of 2-picolyl chloride hydrochloride were added. The resulting mixture was stirred at 50° C. overnight, poured into 300 ml of water and extracted with ethyl acetate (2×300 ml). The organic solution was dried over sodium sulfate and rotavaped. The residue was chromatographed (silica gel, EtOAc)to afford 1.93 g of 1-(1-(2-pyridinyl)ethyl)-3-(2-pyridinyl)pyrazole-5-carboxylic acid ethyl ester, as a viscous oil. NMR: 1.31 (t, 3H), 4.29 (q, 2H), 6.00 (s, 2H, 1-pyrazolyl CH2), 7.59 (s, 1H, 4-pyrazolyl H), 6.85, 7.16, 7.32. 7.81, 7.99, 8.57, 8.65 (8 m, 8H, pyridinyl H's). The column also yielded 0.58 g of 1-(1-(2-pyridinyl)ethyl)-5-(2-pyridinyl)pyrazole-3-carboxylic acid ethyl ester, as a viscous oil. NMR: 1.42 (t, 3H), 4.45 (q, 2H), 6.20 (s, 2H, 1-pyrazolyl CH2), 7.26 (s, 1H, 4-pyrazolyl H), 6.74, 7.09, 7.19, 7.51, 7.61, 7.72, 8.49, 8.53 (8 m, 8H, pyridinyl H's).
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.[OH-].[Na+]>O1CCOCC1>[O:15]1[CH2:14][CH:13]1[CH2:11][O:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: Oc1cccc2nsnc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: c1cc(OCC2CO2)c2nsnc2c1
Yield: 69 %

Procedure:
7.6 g (50 mM) 4-hydroxy-2,1,3-benzthiadiazole were dissolved in 100 ml. dioxan and mixed with 50 ml. epichlorohydrin and 55 ml. 1 N aqueous sodium hydroxide solution and the reaction mixture stirred for 4-5 hours at 55°-60° C. When the reaction was finished, the reaction mixture was diluted with 300 ml. water and extracted with chloroform. The dried chloroform solution was evaporated and the residue was chromatographed on a silica gel column (elution agent: chloroform). The residue obtained after evaporation of the elution fractions crystallized upon treatment with diisopropyl ether. There were obtained 7.2 g (69% of theory) 4-(2,3-epoxypropyloxy)-2,1,3-benzthiadiazole, which had a melting point of 65°-67° C.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[NH2:18].F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27]>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[NH:18][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1ccncc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccncc1Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
1M LiHMDS solution (9.25 mL, 9.25 mmol) in THF was added drop wise to a cooled solution of 4-Methyl-pyridin-3-ylamine (1 g, 9.25 mmol) in THF (10 mL) at 0° C. under nitrogen atmosphere. The resulting mixture was added drop wise to a solution of 1-fluoro-2-nitro-benzene (0.98 mL, 9.25 mmol) in THF at 0° C. The resulting reaction mass was stirred at room temperature overnight. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was diluted with ethyl acetate and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (50% ethyl acetate in hexane) to afford 600 mg of the product (28.32% yield).