Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@H:14](OS(C(F)(F)F)(=O)=O)[CH:13]([O:24][CH3:25])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C.O>[C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([N:26]=[N+:27]=[N-:28])[C@H:13]([O:24][CH3:25])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1O[C@H](COC(=O)c2ccccc2)C[C@@H]1OS(=O)(=O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@@H]1O[C@H](COC(=O)c2ccccc2)C[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 141.7 %

Procedure:
To a solution of [(2S,4S)-5-methoxy-4-(trifluoromethylsulfonyloxy)tetrahydrofuran-2-yl]methyl benzoate (compound 32c, 1.1 g, 2.8 mmol) in DMF (5 mL) was added sodium azide (372 mg, 5.7 mmol) at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc, the organic layers were combined and concentrated in vacuo to afford 1.1 g crude product of [(2S,4R,5R)-4-azido-5-methoxy-tetrahydrofuran-2-yl]methyl benzoate (compound 33a) as an oil, which was used in next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:17]([CH2:18]O)=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:20][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:22])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:34])=O>ClCCl>[C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:17]([CH2:18][Cl:34])=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:20][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:22])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: C[C@H](Cn1ncc2ccc(OCC(=O)OC(C)(C)C)c(CO)c21)O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Product: C[C@H](Cn1ncc2ccc(OCC(=O)OC(C)(C)C)c(CCl)c21)O[Si](C)(C)C(C)(C)C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a stirred solution of the product from Step A (2.78 g, 6.18 mmol) in anhydrous dichloromethane (100 mL) was added thionyl chloride (0.68 g, 9.27 mmol). After 1.5 h more thionyl chloride was added (0.23 mL) and stirring was continued for 20 min. Evaporation of this mixture under high vacuum gave an oil (2.90 g) which was used in next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]([C:25]([O:27][CH3:28])=[O:26])([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[NH:3][C:4]([O:6][CH:7]1[CH:14]2[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)=[O:5].[C:29](=O)([O-])[O-].[K+].[K+].IC>>[CH3:29][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C:2]([CH3:1])([C:25]([O:27][CH3:28])=[O:26])[NH:3][C:4]([O:6][CH:7]2[CH:8]3[CH2:16][CH:12]4[CH2:11][CH:10]([CH2:15][CH:14]2[CH2:13]4)[CH2:9]3)=[O:5])=[CH:23][CH:22]=1
Reactant: COC(=O)C(C)(Cc1ccc(O)cc1)NC(=O)OC1C2CC3CC(C2)CC1C3
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COC(=O)C(C)(Cc1ccc(OC)cc1)NC(=O)OC1C2CC3CC(C2)CC1C3

Procedure:
The title compound was prepared from methyl α-methyl-N-[(tricyclo[3.3.1.13,7 ]dec-2-yloxy)carbonyl]-DL-tyrosinate (0.671 g, 0.0017 mmol, prepared usingthe procedure described in Example 47, Step A), potassium carbonate (0.345 g, 0.0025 mmol) and iodomethane (0.368 g, 0.0025 mol) using the procedure described in Example 47, Step B. MS: 402.4 (MH+).
Reaction SMILES: C([O:8][C:9](=[O:24])[C@H:10]([CH3:23])[C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12](O)=O)C1C=CC=CC=1.CN1CCOCC1.ClC(OCC(C)C)=O.[C:40]([C:44]1[CH:45]=[C:46]([NH2:51])[C:47]([NH2:50])=[CH:48][CH:49]=1)([CH3:43])([CH3:42])[CH3:41]>O1CCCC1>[C:19]([O:18][C:16]([NH:15][C@H:11]([C:12]1[NH:50][C:47]2[CH:48]=[CH:49][C:44]([C:40]([CH3:43])([CH3:41])[CH3:42])=[CH:45][C:46]=2[N:51]=1)[C@@H:10]([CH3:23])[C:9]([OH:24])=[O:8])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: C[C@@H](C(=O)OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a cooled solution (−78° C.) of (2S,3R)-4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-3-methyl-4-oxobutanoic acid (Preparation 66, 4.10 g, 12.2 mmol) in tetrahydrofuran (50 mL) was added N-methylmorpholine (2.0 mL, 18.23 mmol) followed by isobutyl chloroformate (1.67 mL, 12.8 mmol) and the resulting white suspension stirred at −78° C. for 30 minutes. A solution of 4-(tert-butyl)benzene-1,2-diamine (2.40 g, 14.6 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The crude product was dissolved in ethyl acetate (200 mL) and washed with aqueous saturated sodium bicarbonate (3×50 mL), water (2×50 mL). The organic layer was concentrated in vacuo and purified by silica gel column chromatography eluting with a gradient of dichloromethane: EtOAc. The residue was dissolved in methanol (50 mL) and palladium hydroxide was added (20% wt % on carbon, 0.43 g). The reaction mixture was stirred under a hydrogen atmosphere (2 atm) at room temperature for 1 hour. The reaction mixture was filtered through a small pad of Arbocel and concentrated in vacuo. The residue was dissolved in acetic acid (100 mL) and stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase column chromatography eluting with a gradient of water/MeCN to afford the title compound as off-white solid (3.54 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([OH:8])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.[NH2:39][CH2:40][CH2:41]O>C1(C)C=CC=CC=1>[N:39]1([C:6]([C:5]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:8])[CH2:41][CH2:40]1
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: NCCO
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)N2CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of 3-methoxy-4-nitrobenzoic acid (1 equiv) in toluene (0.21 M) was added triphenyl phosphine (1.5 equiv), carbon tetrabromide (1.6 equiv), TEA (2 equiv) and 2-aminoethanol (0.7 equiv). Then the resulting mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered, the filtrate was concentrated and the crude was purified by reverse phase HPLC (10%-95% acetonitrile in water) to give the title compound (34% yield) as a yellow solid. MS (ESI) m/z 223.1 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][C:15]3([C:29]4[CH:28]=[N:27][N:26]([CH3:30])[C:25]=4[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:18]3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([OH:31])[CH:5]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH:39]([CH3:41])[CH3:40]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][C:15]3([C:29]4[CH:28]=[N:27][N:26]([CH3:30])[C:25]=4[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:18]3)[CH2:16][CH2:17]2)=[O:11])=[C:6]([O:31][CH:39]([CH3:41])[CH3:40])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)c(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)c(OC(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.8 %

Procedure:
To a vial containing a solution of (4-ethoxy-2-hydroxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (41 mg, 0.1 mmol) in DMF (0.8 mL) was added K2CO3 (69 mg, 0.5 mmol), and 2-iodopropane (15 μL, 0.15 mmol). The mixture was stirred for 3 hours at 25° C. The crude reaction mixture was filtered and purified by HPLC (1-99%) MeOH:H2O to yield (4-ethoxy-2-isopropoxy-phenyl)-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (17 mg, 33%). ESI-MS m/z calc. 461.5, found 462.2 (M+1)+. Retention time: 3.16 minutes (4 min run).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][NH:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:18][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)NCC(=O)c1ccc(Br)cc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc(-c2ccc(Br)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A mixture of ethyl [[2-(4-bromophenyl)-2-oxoethyl]amino]oxoacetate (35 g, 0.11 mole) and phosphorus oxychloride (150 ml) was maintained at reflux for 10.5 hours and cooled to room temperature. The solution was poured into a mixture of ice and water (3 liter) and stirred for 1.0 hour. The resulting solid was collected by filtration and air-dried. Recrystallization from methylcyclohexane gave 22.3 g (0.075 mole) of product (yield, 68%), m.p. 119.5°-122°.
Reaction SMILES: CC1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]([CH2:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:16][CH:15]=3)[N:9]=2)C(C)=CC=1.Cl.NO.O.Cl>C(O)C>[CH:31]1([CH2:30][N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:10]3[N:9]=[C:8]([NH2:3])[CH:13]=[CH:12][CH:11]=3)=[CH:19][CH:18]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: Cc1ccc(C)n1-c1cccc(-c2ccc(CCN(CC3CCCCC3)CC3CCCCC3)cc2)n1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2ccc(CCN(CC3CCCCC3)CC3CCCCC3)cc2)n1
Temperature: 80 °C

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 134 mg (0.277 mmol) 2-(2,5-dimethylpyrrol-1-yl)-6-{4-[2-(bis-cyclohexylmethyl-amino)-ethyl]-phenyl}-pyridine, 96 mg (1.387 mmol) hydroxylamine hydrochloride, 1 mL water and 5 mL ethanol. The solution was heated at 80° C. for 35 h, cooled, and poured into dilute aqueous hydrochloric acid. The aqueous layer washed with ethyl acetate, the pH adjusted to 11 with 1 N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The resulting oil was taken up in ether and precipitated using 1 N HCl in ether. The product was collected as a tan solid, mp 75-85° C., 68 mg (51%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].C1C(=O)N([Br:20])C(=O)C1.O>CN(C=O)C>[Br:20][C:9]1[CH:10]=[CH:11][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(Br)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.3 %

Procedure:
A solution of 3-(dimethylamino)benzoic acid (5.13 g, 31.0 mmol) in DMF (20 mL) was cooled to 5° C. To this cold solution was added NBS (6.23 g, 35.0 mmol) in several portions in order to keep the internal reaction temperature at 5° C. The reaction mixture was allowed to stir at this temperature for 15 min and then to warm to rt. The mixture was poured into water and extracted with EtOAc. The organic solutions were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated to give 2-bromo-5-(dimethylamino)benzoic acid (7.89 g, 93%) which was used without purification in the next step.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[CH3:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49].[Cl-].[NH4+]>O1CCCC1>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[CH3:41])(=[O:50])=[O:49])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1)C(=O)OC(C)(C)C
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccccc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)cc1-c1cccnc1C#N
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26.0 mg) in tetrahydrofuran (3 mL) was added tert-butyl {[5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (156 mg) at room temperature, and the mixture was stirred for 15 min. After stirring, 15-crown-5 (143 mg) and 2-methylbenzenesulfonyl chloride (203 mg) were added dropwise and the mixture was further stirred at room temperature for 1 hr. Saturated aqueous ammonium chloride solution was added, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as a pale-yellow oil (yield 202 mg, 87%).
Reaction SMILES: C([O-])(=O)C.[Na+].C([O:9][C:10]1[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:14][C:13]([CH:20]([NH:22][OH:23])[CH3:21])=[CH:12][C:11]=1[C:24]([CH3:27])([CH3:26])[CH3:25])(=O)C.[C:28](Cl)(=[O:32])[CH:29]([CH3:31])[CH3:30]>O.O1CCOCC1>[CH3:25][C:24]([C:11]1[CH:12]=[C:13]([CH:20]([N:22]([OH:23])[C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH3:21])[CH:14]=[C:15]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:10]=1[OH:9])([CH3:27])[CH3:26]
Reactant: CC(C)C(=O)Cl
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(C(C)NO)cc1C(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(=O)N(O)C(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.82 g (0.01 mole) of sodium acetate in H2O (7 mL) is added to a solution of 1.07 g (0.0033 mole) of 2,6-bis(1,1-dimethylethyl)-4-[ 1-(hydroxyamino)ethyl]phenol acetate (Example 2) in dioxane (35 mL). Isobutyryl chloride (0.488 g, 0.00458 mole) is added dropwise and the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated to half volume, diluted with H2O, and extracted with Et2O. The Et2O extracts are washed with saturated NaHCO3, brine, dried over Na2SO4, and evaporated to dryness. The residue is recrystallized from n-hexane to give white crystals, 0.62 g (56%), m.p. 147°-148.5° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([O:19][C:17](=[O:18])[C:16]([N:15]([CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)[CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:22])[CH3:21]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(=O)O)cc1)CC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(=O)N(Cc1ccc(C(=O)O)cc1)CC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 176 %

Procedure:
To a solution of 4-({{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}[ethoxy(oxo)acetyl]-amino}methyl)benzoic acid (5.80 g, 12.93 mmol) in DCM (150 mL) was added TFA (9.90 mL) and the resulting reaction mixture was stirred at rt for 3 h, evaporated under vacuum to give the title compound as a pink oil (7.93 g, 99.9%). 1H NMR (DMSO-d6, 300 MHz) δ 8.7 (m, 1H), 8.39 (m, 1H), 7.96 (d, 1H, J=8.3 Hz), 7.94 (d, 1H, J=8.3 Hz), 7.39 (d, 1H, J=8.3 Hz), 7.37 (d, 1H, J=8.3 Hz), 4.64 (s, 1H), 4.58 (s, 1H), 4.33 (q, 0.9H, J=7.2 Hz), 4.23 (q, 1.1H, J=7.2 Hz), 3.33-3.22 (m, 2H), 3.18 (d, 1H, J=7.6 Hz), 3.10 (d, 1H, J=7.2 Hz), 2.90-2.69 (m, 2H), 1.98 (m, 1H), 1.40-1.21 (m, 3H), 1.16 (t, 2H, J=7.1 Hz). HPLC (Condition A), Rt: 1.87 min (HPLC purity 98.9%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17](C=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:22][NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([N:23]([CH3:22])[CH:17]2[CH2:16][CH2:15][N:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:13][CH:12]=3)[CH2:19][CH2:18]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=CC1CCN(c2ccc(CN3CCOCC3)cc2)CC1
Reactant: CNC1CCCCC1
Product: CN(C1CCCCC1)C1CCN(c2ccc(CN3CCOCC3)cc2)CC1

Procedure:
Prepared from the product of Example 18 and N-methyl-N-cyclohexylamine.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([O:28][CH3:27])[CH:34]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: COc1cccc(-c2cncc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)c1

Procedure:
By following a procedure analogous to Example 27 starting 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3-methoxyphenyl-boronic acid, 5-(3-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside is obtained in the form of a white powder (yield=77%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][CH:6]1[N:15]2[C:10]3[C:11](=[CH:20][CH:21]=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:9]=3[CH2:8][CH2:7]1)[C:12](=[O:19])[C:13]([C:16]([OH:18])=[O:17])=[CH:14]2>>[CH3:5][CH:6]1[N:15]2[C:10]3[C:11](=[CH:20][CH:21]=[C:22]([C:23]4[CH:28]=[CH:27][C:26]([N+:1]([O-:4])=[O:2])=[CH:25][CH:24]=4)[C:9]=3[CH2:8][CH2:7]1)[C:12](=[O:19])[C:13]([C:16]([OH:18])=[O:17])=[CH:14]2
Reactant: CC1CCc2c(-c3ccccc3)ccc3c(=O)c(C(=O)O)cn1c23
Reactant: O=[N+]([O-])O
Product: CC1CCc2c(-c3ccc([N+](=O)[O-])cc3)ccc3c(=O)c(C(=O)O)cn1c23
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, cold (5° C.) 400 ml portion of 90% nitric acid was added 2.3 g of 6,7-dihydro-5-methyl-1-oxo-8-phenyl-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. The solution was stirred at 5°-10° C. for one hour, then diluted with 1.5 liters of ice-water. The solid was separated by filtration and dried to provide 6,7-dihydro-5-methyl-8-(4-nitrophenyl)-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. >300° C. Analysis: Calculated for C20H16N2O5 : %C, 65.9; %H, 4.4; %N, 7.7; Found: %C, 65.3; %H, 4.6; %N, 7.4. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.[CH3:36][O+](C)C.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:36])[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCO)c(-c3ccccc3)nn12
Reactant: C[O+](C)C
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCOC)c(-c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
A mixture of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol (65 mg), trimethyloxonium tetrafluoroborate (27.5 mg) and 2,6-di-t-butyl-4-methylpyridine (47.8 mg) in 1,2-dichloroethane (3 mL) was stirred at ambient temperature for 4 hours. The solution was washed with water, 1N hydrochloric acid, water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-5:1) to give 4-(3-chlorophenyl)-7-ethyl-3-(5-methoxypentyl)-2-phenylpyrrolo[1,2-b]pyridazine as an yellow oil (60 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C:25](=[O:28])[CH:26]=[CH2:27])=[CH:10][N:9]=1.[CH3:29][OH:30]>S(=O)(=O)(O)O>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C:25]([CH2:26][CH2:27][O:30][CH3:29])=[O:28])=[CH:10][N:9]=1
Reactant: C=CC(=O)c1cnc(N2CCC[C@H]2CO)nc1NCc1ccc(OC)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COCCC(=O)c1cnc(N2CCC[C@H]2CO)nc1NCc1ccc(OC)c(Cl)c1

Procedure:
A mixture of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(acryloyl)pyrimidine (31 mg), methanol (1 ml) and conc. sulfuric acid (one drop) is heated under reflux for 2 days. After the reaction is complete, the solvent is evaporated under reduced pressure, and the residue is separated by silica gel thin layer chromatography (solvent; chloroform:methanol=30:1) to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-methoxyethyl)carbonyl]pyrimidine (27 mg) as colorless oil, MS (m/z): 435 (MH+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O[C:25]1[CH:33]=[C:32]2[C:28]([CH2:29][CH2:30][CH:31]2[CH2:34][C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:25]1[CH:33]=[C:32]2[C:28]([CH2:29][CH2:30][CH:31]2[CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=2)=[CH:27][CH:26]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(CC2CCc3ccc(O)cc32)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CC2CCc3ccc(OS(=O)(=O)C(F)(F)F)cc32)cc1
Temperature: 25 °C

Procedure:
Trifluoromethanesulfonic anhydride (0.08 mL, 0.48 mmol) was dropwise to a solution of toluene (2 mL) and aqueous 30% K3PO4 (2 mL) containing the intermediate from Step D (63 mg, 0.22 mol). The solution was stirred at room temperature until no starting material remained by HPLC analysis. The solution was partitioned between ethyl acetate and water. The organic phase was washed with water and brine. The solution was then dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 8.01 (d, J=8.2 Hz, 2H); 7.27 (d, J=8.1 Hz, 2H); 7.08 (dd, J=2.3, 8.2 Hz, 1H); 6.95 (d, J=2.1 Hz, 1H); 3.95 (s, 3H); 3.56-3.50 (m, 1H); 3.15 (dd, J=6.2, 13.5 Hz, 1H); 2.92-2.80 (m, 3H); 2.28-2.20 (m, 1H); 1.90-1.83 (m, 1H). LCMS2 2.71 min. (M+H)=415
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:5]([O:16]C(=O)C)=[CH:6][CH:7]=[C:8]([O:12]C(=O)C)[C:9]=1[CH2:10]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C1(C)C(C)=CC=CC=1>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([C@@H:2]2[CH2:3][C:4]3[C:5]([OH:16])=[CH:6][CH:7]=[C:8]([OH:12])[C:9]=3[CH2:10][C@H:11]2[OH:1])[CH2:30][CH2:29]1
Reactant: CC(=O)Oc1ccc(OC(C)=O)c2c1CC1OC1C2
Reactant: COc1ccccc1N1CCNCC1
Solvent: Cc1ccccc1C
Product: COc1ccccc1N1CCN([C@@H]2Cc3c(O)ccc(O)c3C[C@H]2O)CC1
Yield: 21.6 %

Procedure:
A solution of 13.1 g of 6,7-epoxy-5,6,7,8-tetrahydro-1,4-diacetoxynaphthalene and 29.8 g of 1-(o-methoxyphenyl)-piperazine in 200 ml of xylene is refluxed under nitrogen for 48 hours. The reaction mixture is then cooled, the crystalline precipitate filtered, washed with ether, and dried in vacuo to afford 10.55 g of crude crystalline product. Recrystallization of 7.50 g of this material from ethyl acetate/ethanol gives 4.0 g of the title compound, melting point 222°-224° C.