Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=2)[N:13]=[CH:12][C:11]=1[C:21]#[N:22].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O-:27].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][N:16]=[C:17]([O:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH:18]=2)[N:13]=[CH:12][C:11]=1[C:21]#[N:22]
Reactant: CN(C)CC[O-]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCOc1cc2c(Nc3ccc(Cl)cc3Cl)c(C#N)cnc2cn1
Yield: 59 %

Procedure:
To 250 mg of 4-(2,4-dichloro-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile under an inert atmosphere was added 8 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 2 hours, the reaction was stripped of tetrahydrofuran and water was added. The product was filtered, washed with water, dried, and recrystallized from chloroform/ether/hexanes to give 186 mg (59%) of 4-(2,4-dichloro-phenylamino)-6-(2-dimethylamino-ethoxy)-[1.7]naphthyridine-3-carbonitrile as a yellow solid: melting point 75-9° C.; mass spectrum (m/e): M+H 401.9.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][N:22]=1>>[Cl:20][C:21]1[N:22]=[CH:23][C:24]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)=[CH:25][CH:26]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Product: O=C(O)c1cccc(COc2ccc(-c3ccc(Cl)nc3)cc2)c1

Procedure:
3-[4-(6-Chloro-pyridin-3-yl)-phenoxymethyl]-benzoic acid was prepared using the procedure described above for the synthesis of Example 4 from 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 2-chloropyridine-5-boronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=340.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]3[C:6](=[CH:7][N:8]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.[Br:23]N1C(=O)CCC1=O>CN(C=O)C>[Br:23][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[N:9]=[C:10]2[C:6]=1[CH:5]=[C:4]([CH:1]1[CH2:3][CH2:2]1)[C:12]([N+:13]([O-:15])=[O:14])=[CH:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-n2cc3cc(C4CC4)c([N+](=O)[O-])cc3n2)nc1
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc3cc([N+](=O)[O-])c(C4CC4)cc3c2Br)nc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of (v) (1.08 g, 3.67 mmol) in DMF (15 mL) was added N-bromosuccinimide (780 mg, 4.40 mmol) and the resulting mixture stirred at 80° C. for 1.5 h. The reaction mixture was then cooled to RT and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with aq. saturated sodium bicarbonate (20 mL) and brine (20 mL). The organic phase was dried (MgSO4) and the volatiles removed in vacuo to give (vi) (1.37 g, >99%). ESI-MS: calculated [M+H]+ 373.0/375.0, observed [M+H]+ 373.1/375.1
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CCOC(C)=O.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>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([C:17]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=3[F:15])=[CH:3][C:4]([C:13]#[N:14])=[N:5]2)=[CH:10][CH:9]=1
Reactant: N#Cc1cc(Cl)c2ccc(Cl)cc2n1
Reactant: COc1ccc(B(O)O)c(F)c1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(C#N)nc3cc(Cl)ccc23)c(F)c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 52.3 %

Procedure:
To a stirred solution of 4,7-dichloroquinoline-2-carbonitrile (6 g, 26.9 mmol), (2-fluoro-4-methoxyphenyl)boronic acid (5.03 g, 29.6 mmol), 2M sodium carbonate (29.6 ml, 59.2 mmol) in 10:1 toluene (48.9 ml) ethanol (4.89 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.777 g, 0.672 mmol). The mixture was stirred at 75° C. under N2 for 18 hours. The reaction was allowed to cool to ambient temperature. The cooled reaction mixture was diluted with EtOAc and then washed with H2O, brine, dried (MgSO4) and concentrated. The residue was mostly dissolved in warm EtOAc (100 ml), added 100 ml of Et2O, allowed to stand at ambient temperature for 1 hour. The solid was collected and washed with cold Et2O (50 ml) to give 7-chloro-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carbonitrile (4.4 g, 14.07 mmol, 52.3% yield) as a yellow solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6]1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>ClCCl>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]([OH:11])=[O:12])=[CH:16][CH:15]=1
Reactant: Fc1ccccc1
Reactant: O=C1CCCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCCC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 57.5 %

Procedure:
A suspension of 22.32 g (0.167 mol) of aluminum chloride in 35 ml of dichloromethane is prepared. It is cooled to 0° C. and a mixture of 8.3 g (0.0728 mol) of glutaric anhydride (dihydro-2H-pyran-2,6(3H)-dione) and 8.4 ml (0.0895 mol) of fluorobenzene in 20 ml of dichloromethane is added slowly. The mixture is stirred for 15 hours at room temperature and then hydrolyzed in acidified iced water. The precipitated product is filtered off, washed with water and then dried under reduced pressure. The crude product is then recrystallized from 90 ml of ethyl acetate to give 8.8 g of the expected product in the form of beige crystals (yield=57.5%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].FC1C=CC(C(O)=O)=CC=1[N+]([O-])=O.S(Cl)(Cl)=O.[Br:31][C:32]1[CH:38]=[C:37]([C:39]([F:48])([C:44]([F:47])([F:46])[F:45])[C:40]([F:43])([F:42])[F:41])[CH:36]=[C:35]([C:49]([F:52])([F:51])[F:50])[C:33]=1[NH2:34]>>[Br:31][C:32]1[CH:38]=[C:37]([C:39]([F:48])([C:40]([F:42])([F:43])[F:41])[C:44]([F:45])([F:47])[F:46])[CH:36]=[C:35]([C:49]([F:50])([F:51])[F:52])[C:33]=1[NH:34][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Agent: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1ccc(F)c([N+](=O)[O-])c1

Procedure:
According to the method of 4-3 of Example 4, a target compound was prepared from 4-fluoro-3-nitrobenzoyl chloride prepared from 4-fluoro-3-nitrobenzoic acid and thionyl chloride, and 2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)aniline obtained in 1-2 of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Cl)=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:12][C:13]1[C:18]([NH:19][CH2:8][CH:7]=[CH:6][C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: Nc1cccnc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncccc1NCC=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 50 h
Yield: 42.2 %

Procedure:
7.71 g of p-chlorocinnamyl chloride and 13.5 g of 2,3-diaminopyridine were dissolved in 220 ml of dimethylformamide, and to the solution was added 8.6 g of potassium carbonate, and the mixture was stirred at a room temperature for 50 hours, and after adding 300 ml of water, extracted twice with 200 ml of chloroform. The extract was dried over magnesium sulfate and concentrated under a reduced pressure, and resulting residue was applied to a silica gel column and eluted with chloroform/methanol (100:1 to 50:1), to obtain 4.52 g of the title compound as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na].[OH-].[Na+].S(OC)(O[CH3:23])(=O)=O>O.C(O)C>[CH3:23][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1ccc2ccc(O)cc2c1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2ccc(S(=O)(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 7-hydroxynaphthalene-2-sulfonic acid, sodium salt (15 g, 60.9 mmol) in H2O/ethanol (150 mL, 2:1) is added solid NaOH (2.68 g, 67 mmol)at room temperature. The mixture is stirred until a homogenous solution forms and dimethyl sulfate (6.34 mL, 67 mmol) is then added. A precipitate slowly forms and the mixture is stirred over a period of 16 hours. The crude mixture is concentrated in vacuo and the residue is stirred in absolute EtOH (100 mL) as a slurry for 2 hours. The precipitate is filtered and dried. The solid is heated at reflux in 95% EtOH (100 mL) for 2 h, allowed to cool to room temperature, filtered and dried to give 12.6 g of crude 7-methoxynaphthalene-2-sulfonic acid, sodium salt. A mixture of the sulfonic acid, sodium salt (12.6 g, 48.6 mmol) in phosphorous oxychloride (20 mL) and phosphorous pentachloride (13.2 g, 63.2 mmol) is heated slowly to 60° C. until a homogenous solution forms and then is heated at 120° C. for 4 hours. The resulting mixture is cooled in an ice bath and a mixture of ice/ice water is added slowly with stirring. The mixture is diluted with water and extracted with CHCl3 (2×100 mL). The combined organic layers are washed successively with water, saturated NaHCO3 solution and saturated NaCl. The organic phase is dried over anhydrous MgSO4, filtered and concentrated to give 10 g of a crude oil. The crude product is purified by column chromatography in a gradient of 5% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (3.8 g, 14.8 mmol) as a white crystalline solid.
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:7]=[N:6][CH:5]=[N:4]1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Br.[Cl-].[Na+]>O1CCCC1>[O:19]1[CH2:18][CH:17]1[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:13][CH:12]=1
Reactant: BrCC1CO1
Reactant: Oc1ccc(-n2cncn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ncn(-c2ccc(OCC3CO3)cc2)n1
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
The intermediate 2,3-epoxypropoxy-4-(1,2,4-triazol-1-yl)-benzene is prepared in the following manner: 2.9 g (0.067 mole) of sodium hydride, as a 55% strength suspension in liquid paraffin, are introduced into 70 ml of anhydrous tetrahydrofuran, and a solution of 10.8 g (0.067 mole) of 4-(1,2,4-triazol-1-yl)-phenol in 50 ml of tetrahydrofuran is added dropwise. 9.2 g (0.067 mole) of epibromohydrin are then added dropwise. The reaction mixture is stirred for from 5 to 10 hours at room temperature and then poured onto 500 ml of aqueous sodium chloride solution, and the precipitate which separates out is filtered off under suction and washed thoroughly with water. The crude product is recrystallized from toluene/petroleum ether. 11.2 g (77%) of product of melting point 104°-105° C. are isolated.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[N:20]3[C:15]([CH:16]=[N:17][C:18](O)=[N:19]3)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH2:22]([S:24](C1C=C(C2N3C(C=NC(SC)=N3)=CC=2)C=CC=1)(=[O:26])=[O:25])C.OO.[O-]S([O-])(=S)=O.[Na+].[Na+]>CO.CC(O)=O>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[N:20]3[C:15]([CH:16]=[N:17][C:18]([S:24]([CH3:22])(=[O:26])=[O:25])=[N:19]3)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc3cnc(SC)nn23)c1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCS(=O)(=O)c1cccc(-c2ccc3cnc(S(C)(=O)=O)nn23)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
7-(3-Ethanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol: To a mixture of Na2WO4.2H2O (62 mg, 0.19 mmol) and 7-(3-Ethanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (1.25 g, 3.76 mmol) in methanol (40.0 mL) was added 50% H2O2 (0.65 mL, 11 mmol) and the reaction was stirred at 60° C. for 5 h. The mixture was treated with HOAc (700 uL), 50% H2O2 (0.65 mL, 11 mmol) and Na2WO4.2H2O (65 mg, 0.2 mmol) and warmed at 60° C. until reaction was completed as analyzed by LC/MS. At this time, the mixture was treated with 10% aqueous solution of Na2S2O3 (5 mL) and the resultant solids were collected on a Buchner funnel, washed with water (5×5 mL) and dried in vacuo to afford 7-(3-ethanesulfonyl-phenyl)-2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazine (1.33 g; Yield=97%, HPLC RT=2.51). To the above sulfone in 1,4-dioxane (4 mL) and DMSO (2.5 mL) was added an aqueous solution of 5N NaOH (11.1 mL, 55.4 mmol). The mixture was heated at 80° C., O/N, cooled in an ice bath and treated with 3M HCl until pH 4. The resulting solids were collected on a Buchner funnel, washed with water (5×5 mL) and dried in vacuo to afford the title compound (0.675 g; Yield=88%). LC/MS: 304 (M+H); HPLC: RT=1.81 min; 1H NMR: (DMSO, δ) 11.88 (br s, 1H), 9.05 (s, 1H), 8.68 (s, 1H), 8.59 (d, J=7.7, 1H), 7.87 (d, J=7.7, 1H), 7.80 (t, 1H, J=7.7), 7.45 (d, J=4.9, 1H), 7.06 (d, J=4.9, 1H), 3.39 (q, J=7.2, 2H), 1.15 (t, J=7.2, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][O:5][CH:4]([CH2:7][NH2:8])[O:3]1.[N+:9]([C:12]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])=[CH:20][C:13]=1[O:14][CH:15]([CH3:19])[C:16](Cl)=[O:17])([O-:11])=[O:10]>C(Cl)Cl>[CH3:1][CH:2]1[CH2:6][O:5][CH:4]([CH2:7][NH:8][C:16](=[O:17])[CH:15]([O:14][C:13]2[CH:20]=[C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[Cl:32])[CH:22]=[CH:23][C:12]=2[N+:9]([O-:11])=[O:10])[CH3:19])[O:3]1
Reactant: CC1COC(CN)O1
Reactant: CC(Oc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Solvent: ClCCl
Product: CC1COC(CNC(=O)C(C)Oc2cc(Oc3ccc(Cl)cc3Cl)ccc2[N+](=O)[O-])O1
Temperature: -15 °C

Procedure:
N-(4-Methyl-1,3-dioxolan-2-ylmethyl)amine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(2,4-dichlorophenoxy)phenoxy]propionyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. The residue is then recrystallized from a toluene/hexane mixture to yield the desired product N-(4-methyl-1,3-dioxolan-2-ylmethyl)-2-[2-nitro-5-(2,4-dichlorophenoxy)phenoxy]propionamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]3)=[N:23]2)=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH:32]([NH:35][C:11]([C:8]4[CH:7]=[C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)[O:10][N:9]=4)=[O:13])[CH2:33][CH2:34]3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1cc(-c2cccs2)on1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4cc(-c5cccs5)on4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.8 %

Procedure:
5-Thiophen-2-yl-isoxazole-3-carboxylic acid (43 mg, 0.22 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70 mg, 0.22 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL), followed by 1-hydroxybenzotriazole (32 mg, 0.24 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (47 mg, 0.25 mmol, 1.15 eq) and N,N-diisopropylethylamine (83 μL, 0.48 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 5-thiophen-2-yl-isoxazole-3-carboxylic acid {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide as an orange solid (15 mg, 13% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][C:7]1[C:8]2[CH2:29][NH:28][CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:16][CH:15]=2)[N:12]=1.[CH2:33]=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][C:7]1[C:8]2[CH2:29][N:28]([CH3:33])[CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:18][CH:19]=2)[N:12]=1
Reactant: C=O
Reactant: COc1cccc(Cc2nc(Nc3ccc(-n4ccnc4C)cc3)nc3c2CNCC3)c1
Product: COc1cccc(Cc2nc(Nc3ccc(-n4ccnc4C)cc3)nc3c2CN(C)CC3)c1
Yield: 10.4 %

Procedure:
4-(3-Methoxybenzyl)-6-methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (14.3 mg, 10.4%) was synthesised from 4-(3-methoxybenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and formaldehyde according to the general procedure for reductive amination. MS (ES+) m/z 441.3 (M+H)+
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][O:9][C:6]([CH3:11])([O:7][CH2:8]1)[O:5][CH2:4]2.CC(C)=[O:14].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:2]([C:3]12[CH2:4][O:5][C:6]([CH3:11])([O:7][CH2:8]1)[O:9][CH2:10]2)([OH:14])=[O:1]
Reactant: CC(C)=O
Reactant: CC12OCC(CO)(CO1)CO2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC12OCC(C(=O)O)(CO1)CO2

Procedure:
To a solution of 4-(hydroxymethyl)-1-methyl-2,6,7-trioxabicyclo[2.2.2]octane (10.0 g, 0.062 mol) in 200 mL of acetone is added Jones reagent (chromium trioxide and sulfuric acid) until an orange color persisted. The excess oxidant is removed by the addition of 2-propanol until a green color is obtained and the solvents are evaporated under reduced pressure. The residue is partitioned between dichloromethane (100 mL) and water (50 mL) and the layers are separated. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 4-carboxy-1-methyl-2,6,7-trioxabicyclo[2.2.2]octane.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[N:18]([C:24]([C:26]1[C:30]3[CH:31]=[CH:32][C:33]([OH:35])=[CH:34][C:29]=3[S:28][N:27]=1)=[O:25])[CH2:17][CH2:16]2.[CH:36]1([CH2:39]O)[CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:36]1([CH2:39][O:35][C:33]2[CH:32]=[CH:31][C:30]3[C:26]([C:24]([N:18]4[CH:19]5[CH2:20][CH2:21][N:15]([CH2:23][CH2:22]5)[CH2:16][CH2:17]4)=[O:25])=[N:27][S:28][C:29]=3[CH:34]=2)[CH2:38][CH2:37]1
Reactant: OCC1CC1
Reactant: O=C(c1nsc2cc(O)ccc12)N1CCN2CCC1CC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1nsc2cc(OCC3CC3)ccc12)N1CCN2CCC1CC2
Temperature: 25 °C
Yield: 39 %

Procedure:
Diisopropyl azodicarboxylate (0.396 mmol) was added dropwise to a solution of 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-ol (0.359 mmol), cyclopropyl carbinol (0.432 mmol), and triphenylphosphine (0.541 mmol) in tetrahydrofuran (2.2 mL). The reaction mixture was maintained at rt for 16 h, and then the reaction mixture was concentrated. The residue was purified by chromatography using a gradient of 50/50 to 0/100 ethyl acetate/[(70/30/1) ethylacetate/methanol/ammonium hydroxide)]. The compound was further purified by preparative HPLC to provide the product in 39% yield. 1H NMR (CD3OD) δ 8.06 and 8.05 (two d, J=9.0 ea, 1H), 7.56 (d, J=1.8, 1H), 7.14 and 7.13 (two dd, J=8.7, 2.2 ea, 1H), 5.00 (m, 0.79H), 4.50 (m, 0.34H), 4.25 (t, J=5.6, 0.68H), 4.09 (t, J=5.6, 1.34H), 3.95 (d, J=6.9, 2H), 3.63 (t, J=5.7, 0.70H), 3.62-3.36 (m, 5H), 2.45-2.37 (m, 2H), 2.26-2.02 (two m, 2H), 1.37-1.27 (m, 1H), 0.69-0.62 (m, 2H), 0.42-0.37 (m, 2H); LC/MS (EI) tR3.91 min, m/z 358 (M++1).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]#[N:22])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]2[NH:28][N:27]=[N:26][N:22]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCc1ccc(OCc2cccc(Oc3ccccc3)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(Oc2cccc(COc3ccc(CCc4nnn[nH]4)cc3)c2)cc1
Yield: 42.4 %

Procedure:
A solution of 3-(4-((3-phenoxybenzyl)oxy)phenyl)propanenitrile (0.5 g, 1.52 mmol), sodium azide (0.49 g, 7.54 mmol) and ammonium chloride (0.41 g, 7.66 mmol) in N,N-dimethylformamide (20 ml) was stirred at 110° C. for 28 hrs. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (ethyl acetate:hexane=2:3-2:1) to give an oil, which was crystallized from ethyl acetate-tetrahydrofuran to give the title compound (0.24 g, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](O)=O)=[CH:4][CH:3]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([C:8]2[S:17][C:16]([NH2:18])=[N:15][N:14]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(Cl)cc1)C(=O)O
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC(Oc1ccc(Cl)cc1)c1nnc(N)s1
Reaction time: 16 h

Procedure:
Into a 100 milliliter, 3-neck flask adapted with a Claisen adaptor, paddle stirrer, thermometer, an addition funnel and condensor, was charged with 10.0 grams (0.050 mole) of 2-(4-chlorophenoxy)propanoic acid, (4.6 grams, 0.050 mole) of thiosemicarbazide and 30 ml. of dioxane. The slurry was heated to 90 degrees centigrade and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (8.4 gram, 0.055 mole) was slowly added (for 30 minutes) while maintaining the temperature within 85-90 degrees centigrade. The resulting mixture was refluxed for 75 minutes and stood at ambient temperature for 16 hours. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane) at sixty degrees centigrade and then the solution was cooled. Fifty (50) milliliters of water was added and 50 percent solution of NaOH was also added until the pH of the solution was 10; a solid precipitate formed. The solid precipitate was filtered off, washed with water, then dried in a vacuum oven at 70 degrees centigrade to white crystals which were recrystallized from the minimum amount of H2O/ethanol mixture, filtered and then dried in a vacuum oven at 80 degrees centigrade to white crystals of 5-[1-(4-chlorophenoxy) ethyl]-2-amino-1,3,4-thiadiazole. (Melting point 162-166 degrees centigrade).