Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[Cl-].[NH4+].[O:20]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Fe].C(O)C.O>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:34](=[O:35])[CH2:33][C:30]3[CH:31]=[CH:32][C:27]([O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:28][CH:29]=3)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Reactant: CN(C)CCn1ncc2c([N+](=O)[O-])cccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(C)CCn1ncc2c(NC(=O)Cc3ccc(Oc4ccccc4)cc3)cccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of dimethyl-[2-(4-nitro-indazol-1-yl)-ethyl]-amine (1.6 g, 6.8 mmol), iron powder (3.8 g, 68 mmol), and ammonium chloride (0.18 g, 3.4 mmol) in a 4:1 ethanol/H2O solution (20 mL) was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was taken up and stirred in triethylamine/ethyl acetate (1/4, 10 mL) for 15 minutes and then filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The combined filtrate was concentrated under reduced pressure to provide a play yellow oil. This material was then processed with (4-phenoxy-phenyl)-acetic acid according to the procedure described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 2.85 (s, 6H), 3.62 (t, J=6.24, 2H), 3.80 (s, 2H), 4.78 (t, J=6.24, 2H), 6.99–7.01 (m, 3H), 7.13 (m, 2H), 7.36–7.40 (m, 5H), 7.45 (m, 1H), 7.71 (m, 1H), 8.40 (s, 1H), 9.61 (s, 1H); MS (DCI/NH3) m/z 415 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Na].[CH:17](=[O:26])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C>C(O)C>[C:1]([N:4]1[CH:17]([OH:26])[CH2:18][CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: O=CC=Cc1ccccc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1(C(=O)OCC)C(c2ccccc2)CC(O)N1C(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of diethyl acetamidomalonate (75.0 g, 345 mmol) in ethanol (375 ml) at 0° C. was added sodium metal (6.9 g, 36 mmol). Cinnamaldehyde (50.0 g, 378 mmol) was added dropwise to the resulting solution. The reaction was warmed to rt and allowed to stir for 2 h. Acetic acid (7 ml) was added, and the solution was concentrated. The residue was dissolved in EtOAc, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude solid was triturated with hexanes/EtOAc to yield diethyl 1-acetyl-5-hydroxy-3-phenylpyrrolidine-2,2-dicarboxylate as a white solid (96%).
Reaction SMILES: [Br:1]Br.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[N:5][CH:4]=1.CCOCC>C(O)(=O)C>[Br:1][C:11]1[C:12](=[O:15])[NH:13][CH:14]=[C:9]([C:6]2[CH:7]=[CH:8][N:3]=[CH:4][N:5]=2)[CH:10]=1
Reactant: BrBr
Reactant: O=c1ccc(-c2ccncn2)c[nH]1
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=c1[nH]cc(-c2ccncn2)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.7 g of bromine are added over a period of one minute to a solution of 4.5 g of 5-(4-pyrimidyl)-2(1H)-pyridone in 60 ml glacial acetic acid. The mixture is allowed to cool, stirred at RT for 1 hour and then poured into 100 ml of anhydrous ether and stirred for 30 minutes. The slurry is filtered and the filtered solid washed with ether and dried. The solid is suspended in 100 ml of H2O and the pH adjusted to about 6 with anhydrous K2CO3. The mixture is stirred for 15 minutes, filtered, the solid washed with H2O and briefly dried. The moist solid is added to 40 ml of 5% aqueous hydrochloric acid and the resultant mixture stirred for 30 minutes, diluted with an equal volume of isopropyl alcohol, stirred for an additional 10 minutes and filtered. The resulting solid is washed with isopropyl alcohol ether and dried, giving 3-bromo-5-(4-pyrimidyl)-2 (1H)-pyridone as a green powder, M.P>250° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[CH:18]=[C:19]([C:22]#[N:23])[S:20][CH:21]=1.[H-].[Na+]>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:16][C:17]2[CH:18]=[C:19]([C:22]#[N:23])[S:20][CH:21]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: N#Cc1cc(CBr)cs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2csc(C#N)c2)C1=O
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of (2-oxo-pyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester (3.2 g, 16 mmol), prepared as described in EXAMPLE 1, Part A in 80 mL of THF:DMF (10:1) at 0° C. is added 4-bromomethyl-thiophene-2-carbonitrile (3.23 g, 16 mmol) and sodium hydride (60% dispersion in oil, 0.67 g, 16.8 mmol). After addition, the solution was allowed to warm to ambient temperatures. After 2 h, the solution is quenched by the addition of sat. NH4Cl. The solution is diluted with H2O and EtOAc. The layers are separated. The organic layer is washed with H2O and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with gradient of 20% EtOAc/CH2 Cl2 to 30% EtOAc/CH2Cl2 to afford the title compound (4.0 g, 13.8 mmol) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C(O[CH:25]=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])C>>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([N:8]([CH:25]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:13][CH:14]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(Nc2ccc(CN3CCOCC3)cc2)CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CN(c1ccc(CN2CCOCC2)cc1)C1CCN(C)CC1)C(=O)OCC
Temperature: 150 °C

Procedure:
A flask containing 1-methyl-N-[4-(4morpholinylmethyl)phenyl]-4-piperidinamine (0.52 g) is treated with diethyl ethoxymethylenemalonate (0.55 mL). The flask is tightly capped and heated to 150° C. for 1 hour. The reaction is cooled to room temperature, treated with diethyl ethoxymethylenemalonate (0.55 mL) and heated to 180° C. for 2 hours. The reaction is cooled to room temperature and flash column chromatographed on silica eluting with 5% to 20% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.75 g of diethyl 2-{[(1-methyl-4-piperidinyl)-4-(4-morpholinylmethyl)anilino]methylene}malonate as tan solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][C:8]=2[F:15])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]#[N:18].B(Br)(Br)Br.O>C(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[F:15])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]#[N:18]
Reactant: COc1ccc(-n2nc(C)c(C#N)c2N)c(F)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1nn(-c2ccc(O)cc2F)c(N)c1C#N
Yield: 89.9 %

Procedure:
The crude 5-amino-1-(2-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (256 mg, 1.04 mmol) from above was dissolved in CH2Cl2 (25 mL) and BBr3 (1 M solution in DCM, 5 mL, 5.0 mmol) was added and stirred over night. CH2Cl2 and water were added and the phases separated. The aqueous phase was again extracted with EtOAc/CH2Cl2 (1:1). The solution was dried using a phase separator and concentrated under reduced pressure to give 5-amino-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (217 mg, 76%), which was used as such in the next step.
Reaction SMILES: [C:1]1(=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[O:14]=[C:15]1[N:19]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[NH:16]1.[Na].O>O1CCCC1.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH:1]1([N:23]2[CH2:22][CH2:21][CH:20]([N:19]3[C:18]4[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=4[NH:16][C:15]3=[O:14])[CH2:25][CH2:24]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: O=C1Cc2cccc3cccc1c23
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2ccccc2n1C1CCN(C2Cc3cccc4cccc2c34)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 18.4 %

Procedure:
Acenaphthen-1-one (1.68 g, 10 mmol) was dissolved in tetrahydrofuran (THF, 15 ml). 4-(2-Keto-1-benzoimidazolinyl)piperidine (2.17 g, 10 mmol) and tetraisopropyl orthotitanate (3.4 g, 12 mmol) were added and the mixture was stirred at room temperature for 20 hr. The solvent was evaporated and a mixed solvent (15 ml) of THF/ethanol (1:2) was added to the obtained residue for dissolution. Sodium cyanoborohydrate (2.1 mmol) was added to this solution, and the mixture was stirred at stirred at room temperature for one day. Water was added, and the precipitate was removed by celite filtration and washed with ethanol. The filtrate was extracted with chloroform and washed with water and saturated brine. The extract was dried over sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.68 g) as yellow crystals.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:6]([CH3:16])=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)#[N:2].C(O)(C)(C)C.C(Cl)(Cl)(Cl)[Cl:23].ClOC(C)(C)C>C1(C)C=CC=CC=1>[Cl:23][C:8]1[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([CH3:16])[C:5]([O:4][CH2:3][C:1]#[N:2])=[CH:10][CH:9]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1OCC#N
Reactant: ClC(Cl)(Cl)Cl
Agent: CC(C)(C)OCl
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: Cc1c(OCC#N)ccc(Cl)c1NS(C)(=O)=O
Temperature: -4 °C
Yield: 49 %

Procedure:
N-(3-cyanomethoxy-2-methylphenyl)-methanesulfonamide (1.87 g, 7.78 mmol) was suspended in a 1:1 mixture of t-butanol and carbon tetrachloride (80 ml) and cooled in an ice bath. t-Butyl hypochlorite (TCl, 0.85 g, 7.78 mmol) was added dropwise. The mixture was maintained at -4° C. overnight then warmed to room temperature. The volatiles were removed at reduced pressure. N-(6-chloro-3-cyanomethoxy-2-methylphenyl)-methanesulfonamide (1.05 g, 49% yield) was obtained by recrystallization from toluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:21])=O>N1C=CC=CC=1.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH2:5][Cl:21])=[CH:7][CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: COc1c(CO)cccc1Oc1ccccc1Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1c(CCl)cccc1Oc1ccccc1Cl

Procedure:
A mixture of 2-methoxy-3-(2-chlorophenoxy)benzyl alcohol (5.5 g), thionyl chloride (3 ml) and pyridine (one drop) in benzene (40 ml) was treated in a similar manner to that of Example 3-(6) to give oily 2-chlorophenyl 2-methoxy-3-chloromethylphenyl ether (6.4 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.[NH2:16][CH2:17][CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.CO>>[CH3:27][N:19]([CH2:18][CH2:17][N:16]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[C:3]=2[N+:13]([O-:15])=[O:14])[C:8]1=[O:12])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1ccc2c(=O)occc2c1[N+](=O)[O-]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc2c(=O)n(CCN(C)C(=O)OC(C)(C)C)ccc2c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A microwave vial was charged with 6-methyl-5-nitro-1H-isochromen-1-one (270 mg, 0.0012 mol), tert-butyl 2-aminoethylmethylcarbamate (400 mg, 0.002 mol), triethylamine (0.6 mL, 0.005 mol) and methanol (5 mL, 0.1 mol) and the reaction was heated at 100° C. for 1.5 hours. The solvents were removed under reduced pressure and the residue was purified by flash chromatography to afford the desired product as a brown oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].[C:14]([O:17][C@@H:18]1[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:23]([O:29][C:30](=[O:32])[CH3:31])[C@@H:22]([CH2:33][O:34][C:35](=[O:37])[CH3:36])[O:21][C@@:19]1([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([CH2:45][C:46]2[CH:51]=[CH:50][C:49](OS(C(F)(F)F)(=O)=O)=[CH:48][CH:47]=2)[CH:39]=1)[OH:20])(=[O:16])[CH3:15]>CN(C)C=O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]([O:17][C@@H:18]1[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:23]([O:29][C:30](=[O:32])[CH3:31])[C@@H:22]([CH2:33][O:34][C:35](=[O:37])[CH3:36])[O:21][C@@:19]1([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([C:13]#[C:12][Si:9]([CH3:11])([CH3:10])[CH3:8])=[CH:48][CH:47]=2)[CH:39]=1)[OH:20])(=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C)c(Cc3ccc(OS(=O)(=O)C(F)(F)F)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C)c(Cc3ccc(C#C[Si](C)(C)C)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 90 °C

Procedure:
Under argon, 17.3 mg copper iodide, 31.9 mg bis-(triphenylphosphine)-palladium dichloride, 0.22 ml triethylamine and finally 0.19 ml trimethylsilylacetylene are added to a solution of 0.30 g 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-3-[4-(trifluoromethylsulfonyloxy)-benzyl]-4-methyl-benzene in 1.5 ml of dimethylformamide. The flask is tightly sealed and stirred at 90° C. over night. After 4 h additional 20 mg bis-(triphenylphosphine)-palladium dichloride and 0.2 ml trimethylsilylacetylene are added, and the mixture is further stirred at 90° C. for 4 h. After cooling the reaction mixture to room temperature, the solvent is removed and the residue purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1->1:2).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:23][NH:22][C:19]([NH2:21])=[NH:20])[CH2:8]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1ccsc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccsc1Cl)C2
Temperature: 90 °C
Reaction time: 14 h
Yield: 151 %

Procedure:
A mixture of 7-(2-chlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (147 mg), aminoguanidine hydrochloride (63 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (3 ml) was stirred at 90° C. (bath temperature) for 14 hours. The reaction solution was cooled, and precipitated crystals were filtered, washed with ethanol and dried to give 7-(2-chlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 101) (148 mg) as colorless crystals.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[CH:7][C:6]=1[C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:3])[CH3:2].C1N2CN3CN(C2)CN1C3.Cl.[C:30](OC1C(C(C)(C)C)=CC(O)=C(C=1C(C)C)C=O)(=[O:32])C>FC(F)(F)C(O)=O.O>[C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[C:7]([C:6]=1[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:30]=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)C)cc(O)cc1C(C)(C)C
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C=O)c1C(C)C
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1c(C(C)C)cc(O)c(C=O)c1C(C)(C)C
Temperature: 0 °C
Yield: 48 %

Procedure:
0.75 g of 4-acetoxy-3-t-butyl-5-isopropylphenol and hexamethylenetetramine were dissolved in 2.6 ml of trifluoroacetic acid and the solution was heated under reflux for 15 minutes. After cooling to 0° C., 2 ml of 3N hydrochloric acid was added and the solution was heated under reflux for 1.5 hours. Additional 2 ml of 3N hydrochloric acid was added and the solution was heated under reflux for 5 hours. After cooling to room temperature, the reaction solution was combined with water and extracted with ethyl acetate. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 5% ethyl acetate) to give 0.40 g of a mixture of 5-acetoxy-4-t-butyl-2-hydroxy-6-isopropylbenzaldehyde and 5-acetoxy-6-t-butyl-2-hydroxy-4-isopropylbenzaldehyde as a pale yellow oil (yield 48%).
Reaction SMILES: [ClH:1].Cl.[Br:3][C:4]1[CH:5]=[C:6]([CH:12]([C:21]([CH2:25][CH3:26])([OH:24])[CH2:22][CH3:23])[CH2:13][N:14]2[CH2:19][CH2:18][N:17](C)[CH2:16][CH2:15]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].BrC1C=C(C(C(CC)(O)CC)C(N2CCN(C(OC(C)(C)C)=O)CC2)=O)C=CC=1OC.Cl>>[ClH:1].[ClH:1].[Br:3][C:4]1[CH:5]=[C:6]([CH:12]([C:21]([CH2:22][CH3:23])([OH:24])[CH2:25][CH3:26])[CH2:13][N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCC(O)(CC)C(CN1CCN(C)CC1)c1ccc(OC)c(Br)c1
Agent: CCC(O)(CC)C(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c1ccc(OC)c(Br)c1
Agent: Cl
Product: CCC(O)(CC)C(CN1CCNCC1)c1ccc(OC)c(Br)c1

Procedure:
In an analogous manner to Example 1, step 2 2-(3-bromo-4-methoxyphenyl)-3-ethyl-1-(4-methylpiperazin-1-yl)pentan-3-ol dihydrochloride was prepared from tert-butyl 4-[2-(3-bromo-4-methoxyphenyl)-3-ethyl-3-hydroxypentanoyl]piperazine-1-carboxylate. MS m/z 385/387 ([M+H]+); HRMS: calcd for C18H29BrN2O2.2.00 HCl, 456.0946. found (ESI), 385.1494.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6](=[O:17])[NH:5]2.F[C:19]1C=C2C(NC(=O)C(C(OCC)=O)=N2)=C[CH:20]=1.C(I)C.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:19]([N:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]1=[O:17])[CH3:20]
Reactant: CCOC(=O)c1nc2cc(F)ccc2[nH]c1=O
Reactant: CCOC(=O)c1nc2ccc(F)cc2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCI
Product: CCOC(=O)c1nc2ccc(F)cc2n(CC)c1=O

Procedure:
The mixture of 6-fluoro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester and 7-fluoro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (Example 22a) (2 g), ethyl iodide (4 g) and anhydrous potassium carbonate (5.9 g) in 2-butanone (200 ml) were heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated. The residual oil was chromatographed on silica using a mixture of petroleum ether (b.p. 60°-80°) and ethyl acetate (3:1) as eluent to give the required product, on evaporation of the later fractions, m.p. 99°-101.5°, (50%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][CH2:13][C:14]#[C:15][CH2:16][OH:17].O.[Na+].[Cl-]>C(Cl)Cl>[S:2]([O:17][CH2:16][C:15]#[C:14][CH2:13][O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)(=[O:4])(=[O:3])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: OCC#CCOC1CCCCO1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCC#CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
Methanesulfonyl chloride (1.0 mL, 12.80 mmol) was added dropwise to a stirred solution of 4-(tetrahydro-pyran-2-yloxy)-but-2-yn-1-ol (1.9232 g, 11.30 mmol) and TEA (2.5 mL, 17.85 mmol) in DCM (40 mL) at ° C. for five minutes. And then the resulting mixture was stirred at room temperature for 5.5 hours. Water (20 mL) was added, followed by addition of saturated aqueous NaCl solution (70 mL). The organic phase was separated and washed again with brine (60 mL), dried over Na2SO4, concentrated. The residue was separated by flash column chromatography on silica gel using 5-25% EtOAc/hexane to afford 1.542 g of product (yield 55%, oil), along with 400 mg of Di-4-(tetrahydro-pyran-2-yloxy)-but-2-ynyl ether (yield 22%). 1H-NMR (CDCl3): δ 4.88 (t, J=1.8 Hz, 2 H), 4.76 (t, J=3.0-3.3 Hz, 1 H), 4.37-4.24 (m, 2 H), 3.80-3.76 (m, 1 H), 3.54-3.50 (m, 1 H), 3.11 (s, 3 H), 1.78-1.51 (m, 6 H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[C:7]([CH2:11]Br)[C:6]([CH2:13][CH3:14])=[C:5]([CH2:15]Br)[C:4]=1[CH2:17][CH3:18].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[N:21]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[NH2:26][C:22]1[N:21]=[C:20]([NH:19][CH2:2][C:3]2[C:8]([CH2:9][CH3:10])=[C:7]([CH2:11][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[N:21]=3)[C:6]([CH2:13][CH3:14])=[C:5]([CH2:15][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[N:21]=3)[C:4]=2[CH2:17][CH3:18])[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cccc(N)n1
Reactant: CCc1c(CBr)c(CC)c(CBr)c(CC)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1c(CNc2cccc(N)n2)c(CC)c(CNc2cccc(N)n2)c(CC)c1CNc1cccc(N)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
A mixture of 1,3,5-tris(bromomethyl)-2,4,6-triethyl-benzene (0.79 g, 1.8 mmol), 2,6-diamino-pyridine (1.20 g, 11 mmol), and K2CO3 (0.79 g) in CH3CN (100 mL) was stirred at room temperature for 24 h and then heated under reflux for 2 h. After filtration of the reaction mixture and evaporation of CH3CN, the obtained powder was suspended in CHCl3. The suspension was filtrated, the chloroform solution was washed several times with water, dried, and the solvent was removed under reduced pressure. The crude product was crystallized from THF/hexane. Yield 40%. M.p. 164-165° C.; 1H NMR (500 MHz, CDCl3): δ=1.22 (t, 9H, J=7.5 Hz), 2.75 (q, 6H, J=7.5 Hz), 4.05 (t, 3H, J=4.2 Hz), 4.20 (s, 6H), 4.35 (d, 6H, J=4.2 Hz), 5.83-5.86 (m, 6H), 7.24 (m, 3H); 13C NMR (125 MHz, CDCl3): δ=16.9, 23.0, 40.6, 95.9, 96.9, 133.3, 139.4, 143.8, 157.8, 157.9; HR-MS calcd for C30H39N9: 525.3328; found: 525.3322. Rf=0.21 (CHCl3/CH3OH 7:1 v/v).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[N:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=[N:11]1
Reactant: O=Cc1ccc(F)cc1
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2ccnn2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 100 g (803 mmol) of p-fluorobenzaldehyde in 400 ml of DMF, 95 g (1377 mmol) of 1-H-1,2,3-triazole and 200 g (1449 mmol) of K2CO3 are added successively and the mixture is stirred for 4 h at 100° C. The mixture is cooled to r.t. and filtrated through celite. The filtrate is concetrated under reduced pressure to give crude crystals which are washed with AcOEt several times. The solid which is not well soluble in AcOEt is washed with water and dried in vacuo to give 4-[1,2,3]-triazol-1-yl-benzaldehyde (B). The filtrate is concentrated under reduced pressure, the obtained solid is solved in CH2Cl2 and then absorbed on silica gel for dry CC (n-Hexane:AcOEt=2:1˜1:2 ) to provide 4-[1,2,3]-triazol-2-yl-benzaldehyde (A) and further compound (B) as pale yellow solids: 1H-NMR (400 MHz, CDCl3): compound A, 7.88 (s, 2H), 8.01 (d, 2H, J=8.56 Hz), 8.29 (d, 2H, J=8.56 Hz), 10.06 (s, 1H); compound B: 7.90 (s, 1H), 7.98 (d, 2H, J=8.56 Hz), 8.07 (d, 2H, J=8.56 Hz), 8.13 (s, 1H), 10.09 (s, 1H).