Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>O>[OH:27][C:25]([CH3:28])([CH3:26])[CH2:24][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: CC(C)(O)CCl
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Product: COc1ccccc1N1CCN(CC(C)(C)O)CC1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of 7 g of 1-(2-methoxyphenyl)-piperazine, 7.33 g of anhydrous potassium carbonate, 1.75 g of potassium iodide and 5.6 ml of 1-chloro-2-methyl-2-propanol was stirred for 90 minutes at 70° C. and for a further 6 hours at 90° C. The reaction mixture was poured into iced water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo. The title product was obtained as an oil, and was characterized as its dihydrochloride, crystallized from ethanol, melting at 225°-227° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][CH:36]=[CH:37][N:38]=2)=[C:30]([F:39])[C:29]=1[F:40]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[O:35][CH:36]=[CH:37][N:38]=3)=[C:30]([F:39])[C:29]=2[F:40])[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Reactant: Fc1c(CBr)ccc(-c2ncco2)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Reaction time: 2 h
Yield: 47 %

Procedure:
A suspension of 4-chloro-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide Compound 15 (130 mg, 0.43 mmol), cesium carbonate (167 mg, 0.51 mmol), and 2-(4-(bromomethyl)-2,3-difluorophenyl)oxazole (141 mg, 0.51 mmol) in dimethylformamide (2 mL) was stirred for 2 h. The reaction was partitioned between ethyl acetate and saturated sodium bicarbonate, dried over magnesium sulfate, concentrated and purified by flash chromatography on silica gel using a gradient of 0 to 100% ethyl acetate in hexane to give 4-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (100 mg, 47%). Recrystallization from methanol yielded a crystalline product which was analyzed by X-Ray crystallography, verifying the stereochemistry as R,R. 1H NMR (400 MHz, CDCl3) δ ppm 7.77-7.83 (m, 2H), 7.75 (m, 2H), 7.51-7.57 (m, 1H), 7.50 (m, 2H), 7.32 (s, 1H), 4.60 (d, J=15.86 Hz, 1H), 4.40 (d, J=15.86 Hz, 1H), 3.57-3.66 (m, 2H), 2.98-3.17 (m, 1H), 2.45-2.63 (m, 1H), 1.59-1.75 (m, 3H), 1.39-1.54 (m, 2H), 0.98-1.21 (m, 4H). MS [M+H]+=497. HRMS [M+H]+ calc'd 497.1113, found 497.1093. Chiral LC: R.T.=8.21 min, 100% ee.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]2[C:14]=1[C:13](=O)[CH:12]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]1.[CH3:17][NH2:18]>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]2[C:14]=1[C:13](=[N:18][CH3:17])[CH:12]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Cc1ccc(O)c2c1C1CCCCC1C2=O
Reactant: CN
Solvent: CO
Product: CN=C1c2c(O)ccc(C)c2C2CCCCC12

Procedure:
To a methanol solution containing 2 g of 8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone in 20 ml of methanol was added 7.18 ml of methanol solution of 40% methylamine and the mixture was refluxed under heating for 5 hours. After left to stand for cooling, the solvent was removed by concentration and the residue was recrystallized from ethanol to obtain 0.35 g of 8-hydroxy-5-methyl-9-methylimino-1,2,3,4,4a,9a-hexahydrofluorene.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:17][CH2:18][O:19][CH3:20])[C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:17][CH2:18][O:19][CH3:20])=[O:16]
Reactant: [H][H]
Reactant: COCCN(CCOC)C(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCN(CCOC)C(=O)c1cccc(N)c1
Yield: 98.5 %

Procedure:
A mixture of N,N-bis(2-methoxyethyl)-3-nitrobenzamide (4.11 g) and palladium on charcoal (411 mg) in ethyl acetate (41 ml) was hydrogenated under 1 atmospheric pressure to hydrogen for 1 hour at ambient temperature. The catalyst was removed by filtration and washed with ethyl acetate, and the volatiles were removed in vacuo. The residue was purified with column chromatography eluting with dichloromethane-methanol to give 3-amino-N,N-bis(2-methoxyethyl)benzamide (3.62 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1.C([N-]C(C)C)(C)C.[Li+].[I:40]I.C(O)(=O)C>O1CCCC1>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([I:40])[N:6]2[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:30])([F:31])[F:29])[CH:22]=2)=[O:19])=[CH:15][CH:16]=1
Reactant: II
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1ncnc2c1nc(I)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: -70 °C
Yield: 63.2 %

Procedure:
In 18 mL of tetrahydrofuran, 300 mg (0.67 mmol) of 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea was suspended, and the suspension was cooled to −70° C. To the suspension, 3 mL of a tetrahydrofuran solution of lithium diisopropylamide (1.8 M) was added dropwise, and with stirring the temperature of the suspension was raised to 0° C. over two hours. Again, the suspension was cooled to −70° C., and 350 mg (1.38 mmol) of iodine was added thereto, and the suspension was stirred one hour. To the reaction solution, 100 μL of acetic acid was added, and the reaction solution was concentrated, and purified by a silica gel column (dichloromethane:methanol=9:1) to obtain 243 mg (63%) of a target product as a yellow solid.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][C:2]1=[N:14]O.[OH-].[Na+]>C(O)C>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14]
Reactant: ON=C1CCc2c([nH]c3ccccc23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC1CCc2c([nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A suspension of the crude 1,3,4,9-tetrahydrocarbazole-2-one oxime (1.093 g, 5.45 mmol) in ethanol (27.5 mL) was treated while cooling in ice bath with 2.5 N aqueous sodium hydroxide (22 mL). To the stirred dark solution kept under nitrogen was added portionwise over 15 minutes Al—Ni alloy (2.05 g). After 5 minutes the cooling bath was removed and the mixture stirred at room temperature for one hour. The catalysts was filtered off over Celite, the cake quickly washed under nitrogen with a small amount of 1:1 (v/v) ethanol-water and the filtrate was extracted three times with dichloromethane. The combined extracts were washed with water and brine and dried over anhydrous magnesium sulfate. Removal of the solvent provided a dark brown foam that crystallized upon standing. The residue was purified by flash chromatography over silica gel Merck 60 using a gradient from 3% to 10% of ammonia saturated methanol in dichloromethane to provide the title amine as a foam (0.791 g). MS (ES): [M+H]+ @m/z 187.1
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:9]=[C:10]([NH:15][C:16]2[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[N:19]=[C:18]([N:25]3[CH2:30][C@H:29]([CH3:31])[O:28][C@H:27]([CH3:32])[CH2:26]3)[N:17]=2)[CH:11]=[CH:12][C:13]=1[CH3:14].[CH3:33][NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:35]([N:34]([CH3:33])[C:8]1[CH:9]=[C:10]([NH:15][C:16]2[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[N:19]=[C:18]([N:25]3[CH2:30][C@H:29]([CH3:31])[O:28][C@H:27]([CH3:32])[CH2:26]3)[N:17]=2)[CH:11]=[CH:12][C:13]=1[CH3:14])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Cc1ccc(Nc2cc(N(C)C)nc(N3C[C@@H](C)O[C@@H](C)C3)n2)cc1Br
Reactant: CNCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1CCOC1
Product: Cc1ccc(Nc2cc(N(C)C)nc(N3C[C@@H](C)O[C@@H](C)C3)n2)cc1N(C)Cc1ccccc1
Temperature: 110 °C
Yield: 36.2 %

Procedure:
Sodium tert-butoxide (60 mg, 0.63 mmol) was added to a solution of N4-(3-bromo-4-methylphenyl)-2-(cis-2,6-dimethylmorpholinyl)-N6,N6-dimethyl-4,6-pyrimidinediamine (50 mg, 0.12 mmol) and N-methyl(phenyl)methanamine (50 mg, 0.40 mmol) in tetrahydrofuran (2 mL). Tris(dibenzylidineacetone)dipalladium (1 mg, 0.001 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binapthyl (2 mg, 0.003 mmol) were added to this mixture and the resulting mixture was heated at 110° C. for 16 hours. The mixture was then cooled to room temperature, concentrated in vacuo, and purified by preparative thin-layer chromatography [eluent: hexane/EtOAc (3:1)], giving the desired product (20 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([C:21]2[S:22][C:23]([C:26]([O:28]CC)=[O:27])=[CH:24][N:25]=2)[CH2:15]3)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([C:21]2[S:22][C:23]([C:26]([OH:28])=[O:27])=[CH:24][N:25]=2)[CH2:15]3)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cnc(N2Cc3ccc(NC(=O)c4nc(Cl)c(CC)[nH]4)cc3C2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)CN(c2ncc(C(=O)O)s2)C3)nc1Cl
Yield: 55.8 %

Procedure:
The same operation as in Example (90g) was performed using ethyl 2-(5-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-1,3-dihydro-2H-isoindol-2-yl)-1,3-thiazole-5-carboxylate obtained in Example (92b) (92 mg, 0.21 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (5 mL) and dichloromethane (5 mL). Purification by reverse phase chromatography (elution solvent: acetonitrile/water=0/1, 1/1, 4/1) gave 49 mg of the title compound as a light brown solid (57%).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1.C(Br)(Br)(Br)[Br:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.CO>[Br:27][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CCO)c3c2)c1=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CCBr)c3c2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of 3-[3-(2-hydroxyethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.690 g, 0.00185 mol) in methylene chloride is added carbon tetrabromide (0.655 g, 0.00197 mol) followed by triphenylphosphine (0.517 g, 0.00197 mol). The mixture is stirred three hours at ambient temperature and treated with additional carbon tetrabromide (0.328 g, 0.000988 mol) and triphenyl phosphine (0.259 g, 0.000987 mol). The resultant mixture is stirred 85 minutes, diluted with methanol, and concentrated in vacuo. The resultant solid is taken up in methylene chloride, washed with saturated sodium bicarbonate and water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a yellow solid. The yellow solid is chromatographed on silica gel with methylene chloride to give the title product as an off-white solid (0.530 g, 66.0%) which is identified by NMR and elemental analyses.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].[S:7]([O-:11])([O-:10])(=[O:9])=[O:8].[Na+].[Na+].[S-2].[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>>[S:7]([O-:11])([O-:10])(=[O:9])=[O:8].[Na+:5].[Na+:5].[S:1]([O-:4])([O-:3])(=[O:2])=[S:7].[Na+:5].[Na+:5]
Reactant: O=S([O-])[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: O=S([O-])([O-])=S

Procedure:
The concentrated sodium sulfite or sodium bisulfite solution can be mixed with an auxilary fuel containing carbon such as oil or sprayed into the smelter with the auxilary fuel such as gas, carbon, petroleum coke, wood, sawdust or pulverized coal fired separetely. A low ash fuel is preferred to avoid ash buildup problems. Initial burning and evaporation takes place in the oxidation section where the sodium sulfite is concentrated and secondary air is provided for fuel oxidation. Sodium sulfite and carbon particles drop to the bottom of the smelter and form a smelt bed. A limited amount of heated primary air is used in the bottom of the smelter for reduction burning to convert sodium sulfite or sodium sulfate to sodium sulfide and sodium carbonate. Some by-product sodium sulfate and sodium thiosulfate are produced and will circulate through the system. However, the smelting operation also reduces the sodium sulfate and sodium thiosulfate so no buildup is encountered in the system.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:18]([O:20]C)=[O:19])[C:3]=1[Cl:22].[OH-].[Na+]>CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)c(F)c(N)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1c(F)c(-c2ccc([N+](=O)[O-])cc2)nc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
To a solution of methyl 4-amino-3-chloro-5-fluoro-6-(4-nitrophenyl)picolinate (88 mg, 0.27 mmol) in methanol (MeOH; 3 mL) was added 1 Normal (N) aqueous sodium hydroxide solution (NaOH; 3 mL, 3 mmol). The reaction mixture was stirred for 24 hours (h) at ambient temperature. The solution was then concentrated and acidified with 2 N aqueous hydrochloric acid (HCl) solution. The desired product precipitated out of solution, was collected in a Buchner funnel, and allowed to dry overnight to afford a white solid (84 mg, 100%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]#[N:18])=[CH:8][C:7]=2[CH:19]=1.[CH3:20][NH2:21]>C1COCC1>[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:21][CH3:20])=[CH:19][C:7]=2[CH:8]=1)#[N:18]
Reactant: N#Cc1ccccc1-c1cc2cc(CBr)ccc2o1
Reactant: CN
Solvent: C1CCOC1
Product: CNCc1ccc2oc(-c3ccccc3C#N)cc2c1
Temperature: 25 °C

Procedure:
5.3 g (17.0 mmol) 5-(bromomethyl)-2-(2-cyanophenyl)benzofuran (prepared according to EP 434 249) were dissolved in 100 ml THF, and 25 ml of a 40% aqueous solution of methylamine were added via a dropping funnel. The mixture was stirred at room temperature over night. 2×15 ml of the solution of methylamine were added, and the mixture was stirred for additional 5 h in each case. The work-up and the isolation of the title compound was carried out as described in Step A of the preceding example to give a colorless powder after crystallization of the remaining oil upon stirring with t-butylmethylether, m.p. 180° C. Step
Reaction SMILES: [OH-].[K+].[CH3:3]/[C:4](/[CH:11]=[CH:12]/[CH:13]=[C:14](\[CH3:21])/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:5]\[C:6]([O:8]CC)=[O:7]>CC(O)C>[CH3:3]/[C:4](/[CH:11]=[CH:12]/[CH:13]=[C:14](\[CH3:21])/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:5]\[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(\C)CCC=C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)=CCC/C(C)=C/C=C/C(C)=C/C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 18.6 %

Procedure:
Potassium hydroxide (3.0 g) was dissolved in 30 ml of 2-propanol at 100° C. The solution was added with 2-propanol solution (10 ml) of ethyl (2E,4E,6E)-3,7,11-trimethyl-2,4,6,10-dodecatetraenoate obtained in Example 3 (9.1 g, 34.5 mmol), and stirred at the same temperature for 15 minutes. The reaction mixture was added to ice-water and washed with n-hexane. The solution was neutralized with 10% hydrochloric acid and extracted with n-hexane. The resulting organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol twice to obtain 1.5 g of the title compound (yield 18%) as a yellow crystal.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:34]([O:36][CH3:37])=[O:35]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:34]([O:36][CH3:37])=[O:35])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (7.7 g, 21 mmol, HPLC=75%) and DMAP (1.27 g, 10 mmol, 0.5 eq) in dry CH2Cl2 (120 mL), Et3N (6.38 g, 8.45 mL, 63 mmol) was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of methyl chloroformate (8.1 mL, 104.5 mmol, 5 eq) in dry CH2Cl2 (50 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 hr at 0-5° C. The reaction was quenched with water (80 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL), the combined organic layers were washed with 10% citric acid (2×80 mL) and brine, then dried over Na2SO4, filtered and concentrated to the crude product, which was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (4.4 g, HPLC≧98%, the total yield for five steps is 41%).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.S(C1C=CC(C)=CC=1)(O[CH2:22][C@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=O)=O.S(=O)(=O)(O)[O-].[K+]>CCCCCC.CS(C)=O>[C:31]([O:30][C:28]([N:24]1[CH2:25][CH2:26][CH2:27][C@@H:23]1[CH2:22][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]1=2)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CN1c2ccccc2COc2ccccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 22.5 %

Procedure:
60% sodium hydride (1.44 g, 36 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (100 ml). 5,11-dihydrodibenzo[b,e][1,4]oxazepine [H. L. Yale, et al. J. Med. Chem., 7, 609 (1964)] (6.0 g, 30 mmol) was added to the obtained suspension, and the resultant mixture was stirred at 50° C. for 60 minutes. A solution of (R)-N-t-butoxycarbonyl-2-pyrrolidinylmethyl tosylate (12.8 g, 36 mmol) in dimethyl sulfoxide (60 ml) was dropped therein and the obtained mixture was stirred at 50° C. for 3 hours. The reaction solution was poured into 5% aqueous potassium bisulfate solution cooled with ice/water. After the extraction with ethyl acetate, the organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution and dried. The solvent was evaporated under reduced pressure. The residue was treated by the column chromatography. After the elusion with a mixed solvent of ethyl acetate and hexane (1:11), the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(t-butoxycarbonyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine (2.57 g, 22%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1
Reactant: O=C(O)CCC(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(NC(=O)CCC(=O)O)cc1

Procedure:
p-Nitrosuccinanilic acid, prepared according to J. Am. Chem. Soc., 67, 1220 was reduced catalytically in ethanol with 5% palladium on carbon catalyst to give p-aminosuccinanilic acid. m.p. = 180°-181° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.C(O)C.[CH3:19][NH2:20].Cl>C(O)C>[CH3:19][NH:20][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Reactant: CN
Agent: Cl
Solvent: CCO
Product: CNc1cncc(C(=O)Nc2nnn[nH]2)n1

Procedure:
To a suspension of 2.26 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 30 ml of ethanol, 6.50 ml of 30%-methylamine ethanol solution was added, and the mixture was heated for 24 hours at 80°-90 ° C. in a sealed tube. The reaction mixture was adjusted with ethanolic hydrogen chloride to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 1.57 g of the desired compound as pale yellow needles, m.p. 260° C. (decomp.).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17][O:18][C:19]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=5)[N:22]=[CH:21][CH:20]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[O:39]1CCOCC1>>[CH3:30][O:29][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([O:18][CH2:17][C:14]3[N:12]4[N:13]=[C:8]([C:5]5[CH:4]=[CH:3][C:2](=[O:39])[NH:7][CH:6]=5)[CH:9]=[CH:10][C:11]4=[N:16][N:15]=3)=[CH:20][CH:21]=[N:22]2)=[CH:27][CH:26]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(F)nc5)nn34)ccnc2c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(=O)[nH]c5)nn34)ccnc2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
4-((6-(6-Fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.121 g, 0.30 mmol) was suspended in dioxane (1 mL) then added 3M aqueous hydrochloric acid (2.0 ml, 6.0 mmol). The reaction mixture was then heated at 100° C. for 1 hour. The mixture was concentrated under vacuum and the remaining solid was dissolved in methanol (4 mL) then added triethylamine (0.42 ml, 3.0 mmol). The mixture was stirred at room temperature for 1 hour then concentrated under vacuum. The sample was purified by flash chromatography eluting with 15% 7N NH3 in methanol/dichloromethane to afford 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2(1H)-one as a pale orange solid.