Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5].[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19]>>[C:17]([O:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5])(=[O:21])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: CC(C)C(=O)Cl
Product: CC(C)=CCCC(C)=CCCC(C)=CCOC(=O)C(C)C
Yield: 7.7 %

Procedure:
A mixture of farnesol (356 mg, 1.6 mmol) and isobutyryl chloride (407 mg, 3.8 mmol) was refluxed for 2 hours. Extraction with hexane, and purification yielded 35.9 mg (yield: 7.8%) of oil having the following physical properties.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]2[N:12]=[C:11]([NH:13][C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH3:15])[N:10]=[C:9]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH:8]=2)[CH2:4]1.[C:30](OC(=O)C)(=[O:32])[CH3:31].N1C=CC=CC=1>ClCCCl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C@@H:14]([NH:13][C:11]2[N:12]=[C:7]([N:5]3[CH2:4][CH:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])[CH2:6]3)[CH:8]=[C:9]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:10]=2)[CH3:15])=[CH:21][CH:20]=1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(CN)C2)n1)c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)NCC1CN(c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
23 mg of (S)-6-[3-(aminomethyl)azetidin-1-yl]-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine was dissolved in 2 ml of 1,2-dichloroethane, and 7 μl of acetic anhydride and 11 μl of pyridine were added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 20 mg of the objective compound as a brown amorphous solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[Br:20][C:21]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:22]=1[CH:23]=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:20][C:21]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[CH:25][C:22]=1[CH:23]=[O:24]
Reactant: N#Cc1cnc(Cl)cc1OCCOC1CCCCO1
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cnc(Oc2ccc(Br)c(C=O)c2)cc1OCCOC1CCCCO1
Temperature: 80 °C
Yield: 64.6 %

Procedure:
To a mixture of 6-chloro-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile (4.8 g, 16.62 mmol) and 2-bromo-5-hydroxy-benzaldehyde (4.01 g, 19.94 mmol) in DMF (30 mL) was added potassium carbonate (3.44 g, 24.93 mmol). The resulting mixture was heated at 80° C. overnight. DMF was removed under reduced pressure and the residue was diluted with EtOAc (200 mL). The organic layer was washed with water (20 mL) and brine (3×20 mL), dried over Na2SO4, filtered, and concentrated to give white solid. Purification was accomplished by flash chromatography on silica gel using 2-25% EtOAc/hexanes as gradient elution yielding the title compound (4.8 g, 64%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.19 (s, 1 H), 8.46 (s, 1 H), 7.88 (d, J=8.6 Hz, 1 H), 7.60 (d, J=2.7 Hz, 1 H), 7.49 (dd, J=8.6, 2.7 Hz, 1 H), 7.09 (s, 1 H), 4.75-4.67 (m, 1 H), 4.49-4.45 (m, 2 H), 4.00-3.89 (m, 1 H), 3.85-3.74 (m, 2 H), 3.49-3.41 (m, 1 H), 1.78-1.53 (m, 2 H), 1.39-1.53 (m, 4 H).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)=[CH:5][NH:4][N:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[CH:22]([N:25](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CN>CN(C=O)C.C1COCC1>[CH3:22][NH:25][C:12](=[O:14])[C:11]1[CH:15]=[C:7]([C:6]2[C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:4][CH:5]=2)[CH:8]=[N:9][CH:10]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cncc(-c2c[nH]n(-c3ccccn3)c2=O)c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1cncc(-c2c[nH]n(-c3ccccn3)c2=O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
45.0 mg (159 μmol) of the compound from Example 44 are dissolved in 1 ml DMF, 1.9 mg (16 μmol) 4-N,N-dimethylaminopyridine, 24.7 mg (191 μmol) N,N-diisopropylethylamine and 100 mg (191 μmol) (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate are added and the mixture is stirred at RT for 15 min. 120 μl (239 μmol) of a 2 M solution of methylamine in THF are added and the mixture is stirred overnight at RT. To bring the conversion to completion, a further 120 μl (239 μmol) of the 2 M solution of methylamine in THF are added and the mixture is stirred again overnight at RT. The reaction mixture is purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([NH:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])=[O:12])=[O:8])=[O:4].[CH3:33][N:34]1[C@@H:51]2[CH2:52][C:39]3[CH:40]=[CH:41][C:42]([O:53][CH3:54])=[C:43]4[O:44][C@H:45]5[C:46]([CH2:48][CH2:49][C@@H:50]2[C@:37]5([C:38]=34)[CH2:36][CH2:35]1)=[O:47].Cl>O1CCOCC1>[NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([NH:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])=[O:12])=[O:8])=[O:4].[CH3:33][N:34]1[C@@H:51]2[CH2:52][C:39]3[CH:40]=[CH:41][C:42]([O:53][CH3:54])=[C:43]4[O:44][C@H:45]5[C:46]([CH2:48][CH2:49][C@@H:50]2[C@:37]5([C:38]=34)[CH2:36][CH2:35]1)=[O:47]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)CNC(=O)CNC(=O)CNC(=O)CN)C(=O)O
Reaction time: 18 h

Procedure:
To the Boc-Gly-Gly-Gly-Gly-Leu-Hydrocodone (0.304 g) was added 25 ml of 4N HCl in dioxane. The resulting mixture was stirred at ambient temperatures for 18 hours. Solvent was removed and final product dried under vacuum. Solid was collected as a slightly yellow solid (0.247 g, 97% yield): 1H NMR (DMSO-d6) δ 0.87 (m, 6H), 1.23 (s, 1H), 1.51-1.86 (m, 4H), 2.18 (m, 1H), 2.71 (m, 2H), 2.77 (s, 3H), 2.96 (m, 2H), 3.17 (m, 2H), 3.61 (s, 3H), 3.81-3.84 (m, 10H), 4.22 (m, 1H), 4.36 (m, 1H), 5.09 (m, 1H), 5.59 (d, 1H), 6.74 (dd, 2H), 8.16 (br s, 4H), 8.38 (br s, 1H), 8.74 (br s, 1H), 11.42 (br s, 1H).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH2:5].[OH-].[Na+].[C:8]1([O:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[Cl:2][CH2:3][CH2:4][NH:5][C:15](=[O:16])[O:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCCl
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCl)Oc1ccccc1

Procedure:
1500 ml of an aqueous solution of 696 g (6 moles) of 2-chloroethylamine hydrochloride and 1500 g of sodium hydroxide solution containing 480 g (12 moles) of sodium hydroxide are simultaneously added dropwise to a solution of 936 (6 moles) of phenylchloroformate in 3 l of methylene chloride at 15° to 20° C. The mixture is worked up as described under Example 7 to give 1161 g of O-phenyl N-(2-chloroethyl)-carbamate of melting point 65° to 67° C.; purity according to gas chromatography: 95.7% (93% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH:23]([O:36][C:37]([NH:39][C:40]1[NH:41][C:42](=[O:53])[C:43]2[N:44]=[CH:45][N:46]([CH2:49][C:50](O)=[O:51])[C:47]=2[N:48]=1)=[O:38])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:50](=[O:51])[CH2:49][N:46]1[CH:45]=[N:44][C:43]2[C:42](=[O:53])[NH:41][C:40]([NH:39][C:37]([O:36][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:38])=[N:48][C:47]1=2)[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OC(c3ccccc3)c3ccccc3)nc21
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(=O)[nH]c(NC(=O)OC(c3ccccc3)c3ccccc3)nc21
Yield: 70.1 %

Procedure:
The title compound (2.61 g, 70%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [2-N-(benzhydryloxycarbonyl)-guanin-9-yl]-acetic acid (2.10 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 11.63 (bs, 1H), 11.23 (bs, 1H), 8.27 (d, 1H), 8.17 (t, 1H), 7.80 (s, 0.6H), 7.76 (s, 0.4H), 7.65 (m, 2H), 7.50˜7.25 (m, 10H), 6.86 (s, 1H), 5.12 (s, 1.2H), 4.93 (s, 0.8H), 4.44 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (s, 1.2H), 4.04 (q, 1.2H), 3.65 (t, 1.2H), 3.45 (t, 1.2H), 3.41 (t, 0.8H), 3.21 (t, 0.8H), 1.23 (t, 1.2H), 1.17 (t, 1.8H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a suspension of 4-(4-pyridyl)piperazine (13.1 g) in ethyl acetate (200 ml) was added triethylamine (56 ml) followed dropwise, over 5 hours, by a solution of methyl 4-bromomethylbenzoate (18.41 g). The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between water and ethyl acetate. The organic extracts were dried (MgSO4) and evaporated to give a gum, which was purified by column chromatograhy on silica eluting with increasing concentrations of methanol/dichloromethane to give methyl 4-(4-(4-pyridyl)piperazin-1-ylmethyl)benzoate (13.1 g) as a solid;
Reaction SMILES: [CH3:1][NH2:2].O.Br[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1>C1COCC1>[CH3:1][NH:2][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
To a stirred solution of 40 wt % methylamine in H2O (50 mL, 581 mmole) in THF (50 mL) at 0° C. was added 2-(bromomethyl)naphthalene (10 g, 43 mmole) in one portion. The reaction was allowed to warm to RT and stirred for 16 hr, then was then concentrated under vacuum. The residue was taken up in Et2O and washed with 1.0 N NaOH then with brine, dried (Na2SO4), and concentrated to dryness. Purification by flash chromatography on silica gel (98:2 to 9:1 CHCl3/methanol containing 5% NH4OH) gave the tide compound (3.95 g, 54%) as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 3 H), 7.79 (s, 1 H), 7.49 (m, 3 H), 3.94 (s, 2 H), 2.53 (s, 3 H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:12][O:13][CH3:14])[C:10]#[N:11].[Cl:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:12][O:13][CH3:14])[C:10]#[N:11]
Reactant: Oc1cccc(Cl)c1
Reactant: CON=C(C#N)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CON=C(C#N)c1ccccc1COc1cccc(Cl)c1
Yield: 61.5 %

Procedure:
2-Bromomethyl-α-methoxyiminophenylacetonitrile (5.0 g, 20 mmol) and 3-chlorophenol (3.0 g, 23 mmol) were dissolved in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 2 hours in the presence of potassium carbonate (3.3 g, 24 mmol). After completion of the reaction, diethyl ether (ca. 100 ml) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) and crystallized from diethyl ether/n-hexane to give 2-(3-chlorophenoxymethyl)-α-methoxyiminophenylacetonitrile (3.7 g, 62%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20][CH2:21][CH2:22][OH:23])[CH:9]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1.CN(C1C=CC=CN=1)C>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20][CH2:21][CH2:22][O:23][C:36](=[O:37])[NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH3:27])[CH:30]=2)[CH:9]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: Cc1cccc(C=NNc2cc(CCCO)nc(N3CCOCC3)c2)c1
Agent: CN(C)c1ccccn1
Solvent: CC#N
Product: COc1cccc(NC(=O)OCCCc2cc(NN=Cc3cccc(C)c3)cc(N3CCOCC3)n2)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
3-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrid-2-yl}-propan-1-ol (1 mmol) is dissolved in acetonitrile (4 mL). To the mixture is added m-methoxyphenylisocyanate (149 mg., 1 mmol) and a catalytic amount of dimethylaminopyridine. The reaction is stirred at 60° C. for 16 hours. The reaction is then cooled to 4° C., and the precipitate is filtered, washed with acetonitrile (1 mL) and dried to give Compound 102, (3-methoxy-phenyl)-carbamic acid 3-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrid-2-yl}-propyl ester.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=1.C(O)=O>C(O)(C)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: Fc1cccc(C2=CCNCC2)c1F
Agent: [Pd]
Solvent: CC(C)O
Solvent: O=CO
Product: Fc1cccc(C2CCNCC2)c1F
Reaction time: 6 h

Procedure:
A mixture of 4-(2,3-difluorophenyl)-1,2,3,6-tetrahydropyridine (2.4 g, 12.3 mmol), palladium on active carbon (0.5 g) and formic acid (2.4 ml) in isopropanol (50 ml) was hydrogenated at 50 psi for 6 h under hydrogen gas. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and evaporated to dryness. Aqueous sodium carbonate (10%, 50 ml) was added. The aqueous phase was extracted with ethylacetate (3×60 ml) and the combined organic phases was dried (MgSO4), filtered and evaporated to dryness. Yield: 2.11 g. MS m/z (rel. intensity, 70 eV) 197 (M+, bp), 196 (53), 140 (11), 127 (10), 114 (6).
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][CH:9]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:10]([NH:12][NH:13][C:14]2[S:15][CH2:16][C:17]([CH3:20])=[N:18][N:19]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(=O)C>O>[CH3:20][C:17]1[CH2:16][S:15][C:14]2=[N:13][N:12]=[C:10]([CH:9]([O:8][C:7]3[CH:33]=[CH:34][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:19]2[N:18]=1
Reactant: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)NNC1=NN=C(C)CS1
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)c1nnc2n1N=C(C)CS2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a solution of 46.8 g (0.122 m) of 2-(4-nitrophenoxy)tetradecanoyl chloride (3b) in 225 ml of ethyl acetate is added 16.6 g (0.244 m) of imidazole. The mixture is stirred at room temperature for 30 min and filtered to remove the precipitated imidazole hydrochloride. The filtrate containing 1-(2-[4-nitrophenoxy]tetradecanoyl)-1H -imidazole (5iib) is added to a mixture of 22.0 g (0.122 m) of (5-methyl-6H-1,3,4-thiadiazin-2-yl)-hydrazine hydrochloride (2b) and 12.3 g (0.122 m) of triethylamine in 200 ml of ethyl acetate. The mixture is stirred at room temperature for an hour. At this point, if it is necessary, the acylhydrazine 1b can be isolated by collecting the solid, washing with ethyl acetate, drying, reslurrying in water, collecting and drying to give 54.0 g (90%) with 98 area % by HPLC. However, the reaction mixture can be used directly in the next ring closure step without isolation of the substituted acylhydrazine 1b. Thus, at the end of reaction, 45 ml of acetic acid is added to the reaction mixture, and the mixture is heated under reflux (approximately 80° C.) for an hour, after which the ring closure reaction is complete. To the reaction mixture is added 400 ml of water and the mixture is stirred at 60° C. for 15 min. After the layers settle, the lower water layer is discarded and the upper ethyl acetate solution is concentrated under reduced pressure to about 40% of the original volume. The resulting mixture is cooled to 20° C. and stirred at that temperature for 30 min. The solid is collected, washed with heptane, and dried to give 48.5 g (84% overall from 2b or 3b) of 6-methyl-3-(1-[4-nitrophenoxy]tridecyl)- 7H-1,2,4-triazolo-(3,4-b)-1,3,4-thiadiazine (4) with 99 area % by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23]([C:25]2[C:26](=[O:38])[N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]([CH3:31])[C:29]=2[CH3:30])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:45][C:46]1([O:49][CH2:48]1)[CH3:47]>CN(C=O)C.CC(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23]([C:25]2[C:26](=[O:38])[N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]([CH3:31])[C:29]=2[CH3:30])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:45][C:46]([OH:49])([CH3:48])[CH3:47])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: CC1(C)CO1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3F)ccnc2cc1OCC(C)(C)O
Temperature: 50 °C
Reaction time: 72 h
Yield: 39.9 %

Procedure:
To a mixture of N-(3-fluoro-4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carb oxamide (5.00 g, 9.73 mmol) and Cs2CO3 (1.35 g, 4.14 mmol) in DMF/t-BuOH (15.60 mL/3.90 mL) was added isobutylene oxide (8.60 mL, 97.30 mmol). The reaction was warmed to 50° C. and stirred for three days. The reaction mixture was concentrated in vacuo and purified by a silica gel column chromatography (1:25 (v/v)=methanol/dichloromethane) to give the title compound as a white solid (2.28 g, 40%).
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(OCC)(=O)C>C(#N)C>[O:38]1[CH2:39][CH2:40][N:35]([CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)[CH2:18][CH2:19]2)[CH2:36][CH2:37]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCC(CCN3CCOCC3)CC2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
The 4-tosyloxyethyl-N-(4-nitrophenyl)piperidine (2.02 g, 5.0 mmol) obtained in Example 6(2) was dissolved in acetonitrile (20 ml), and potassium carbonate (1.38 g, 10 mmol) and morpholine (0.65 ml, 7.5 mmol) were added thereto, followed by stirring at 80° C. for 15 hours. After the reaction mixture was allowed to cool to room temperature, ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:50 to 1:20), thereby obtaining 4-morpholinoethyl-N-(4-nitrophenyl)piperidine (1.23 g, 77%) as a yellow solid.
Reaction SMILES: [C@H:1]([NH:5][C:6]1[C:7](=[O:20])[NH:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].N1C=CC=CC=1.[O:27](S(C(F)(F)F)(=O)=O)[S:28]([C:31]([F:34])([F:33])[F:32])(=O)=[O:29]>ClCCl>[C@H:1]([NH:5][C:6]1[C:7]([O:20][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:27])=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC[C@@H](C)Nc1nc2cc(C(=O)OC)ccc2[nH]c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
To a solution of (R)-methyl 3-(sec-butylamino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (300 mg, 1.10 mmol) in dichloromethane (40 mL) was added pyridine (344 mg, 4.36 mmol) and then Tf2O (615 mg, 2.18 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature and then washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford (R)-methyl 3-(sec-butylamino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (400 mg, crude).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:11][C:12]1[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=1[Cl:19])[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O.[CH3:28][C:29]1(C)C(C)(C)OB(C=C)O1>COCCOC.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:1]([O:5][C:6](=[O:20])[N:7]([CH2:11][C:12]1[CH:17]=[C:16]([CH:28]=[CH2:29])[CH:15]=[CH:14][C:13]=1[Cl:19])[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Br)ccc1Cl)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
To a sol. of (5-bromo-2-chloro-benzyl)-cyclopropyl-carbamic acid tert-butyl ester (105 g, 0.292 mol) in DME (800 mL) under N2 at rt was added Pd(PPh3)4 (16.9 g, 14.6 mmol). The mixture was stirred at rt for 30 min, and K2CO3 (40.7 g, 292 mmol), water (350 mL) and 4,4,5,5-tetramethyl-2-vinyl-[1,3,2]dioxaborolane (52.0 mL, 292 mmol) were added. The mixture was heated to reflux for 3 h. The mixture was allowed to cool to rt, and water (500 mL) was added. The mixture was extracted with Et2O (4×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc 9:1) yielded the title compound (70.9 g, 79%). LC-MS: tR=1.10 min; ES+: 293.38.