Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH:17](OC)[O:18]C)[NH:14][C:13]1=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[BH4-].[Na+].CC(C)=O>O1CCCC1.Cl.C(O)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH2:17][OH:18])[NH:14][C:13]1=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C[C@H]1NC(=O)[C@@H]1NC(=O)OCc1ccccc1)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C(N[C@H]1C(=O)N[C@@H]1CCO)OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 61.1 %

Procedure:
A solution of (3R,4R)-3-benzyloxycarbonylamino-4-(2,2-dimethoxyethyl)azetidin-2-one (0.60 g) in a mixture of tetrahydrofuran (10 ml) and 0.5N hydrochloric acid (2 ml) was heated at 50° C. for 1 hour. The mixture was cooled to 0° C. and 1N aqueous sodium bicarbonate (1.2 ml) was added to the mixture at 0° C. After stirring for 5 minutes at 0° C., sodium borohydride (0.10 g) was added to the mixture at 0° C. After stirring for 15 minutes at 0° C., acetone (0.77 ml) and acetic acid (0.30 ml) were added to the mixture at 0° C. The mixture was evaporated in vacuo and the residue was dissolved in methylene chloride (60 ml). The solution was dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in xylene (20 ml) and the solution was evaporated in vacuo. The residue was chromatographed on silica gel (12 g) eluting with a mixture of methylene chloride and methanol (20:1-10:1) to give (3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one (314 mg) as a crystalline solid.
Reaction SMILES: C(OC(O[CH2:9][CH3:10])OCC)C.[NH:11]([C:13]1C=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[NH2:12]>>[CH:13]1[N:14]2[C:15]3[C:20]([N:21]=[CH:9][C:10]2=[N:12][N:11]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: CCOC(OCC)OCC
Reactant: NNc1cnc2ccccc2n1
Product: c1ccc2c(c1)ncc1nncn12

Procedure:
One hundred ml. of triethylorthoformate was mixed with 8.98 g. of 2-hydrazinoquinoxaline. The mixture was stirred at reflux and cooled as in the example above, and 9 g. of crude product was collected. After recrystallization from ethanol, the product was identified as s-triazolo[ 4,3-a]quinoxaline, m.p. 238°-39° C. The final yield was 5 g.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][C:8]1([CH3:27])[C:12](=[O:13])[C:11]2[C:14]([CH3:26])=[C:15]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:16]([CH3:19])=[C:17]([CH3:18])[C:10]=2[O:9]1.[C:28](N1CCNCC1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:7][C:8]1([CH3:27])[C:12](=[O:13])[C:11]2[C:14]([CH3:26])=[C:15]([N:20]3[CH2:21][CH2:22][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:25]3)[C:16]([CH3:19])=[C:17]([CH3:18])[C:10]=2[O:9]1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2=O
Temperature: 25 °C
Yield: 52.8 %

Procedure:
Sodium t-butoxide (13.45 g, 140 mmol) was added to a mixture of toluene (300 mL) containing 4-(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)piperazine (28.32 g, 100 mmol) synthesized in Reference Example 36, N-Boc-piperazine (22.35 g, 120 mmol), palladium acetate (448 mg, 2 mmol) and BINAP (3.74 g, 6 mmol) at room temperature, and the mixture was heated to reflux under argon atmosphere. After a reaction for 16 hours, it was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with saturated saline, and then dried using anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 9:1 to 4:1), and recrystallized from hexane to give 20.5 g of the title compound (yield: 53%).
Reaction SMILES: [I:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[I:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Ic1ncnc2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2c(I)ncnc21

Procedure:
405 mg (1.65 mmol) of 6-iodo-9H-purine was dissolved in 2 mL DMF. 72 mg (1.81 mmol) of 60% sodium hydride was added followed by 320 μL (1.81 mmol) of trimethylsilylethoxymethyl chloride. Yield: 343 mg of an oily product.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=[O:11])[CH2:2]1)[CH2:8]2.[NH2:12]OS(O)(=O)=O>C(O)=O>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([NH:12][C:4]3=[O:11])[CH2:2]1)[CH2:8]2
Reactant: O=C1C2CC3CC1CN(C3)C2
Reactant: NOS(=O)(=O)O
Solvent: O=CO
Product: O=C1NC2CC3CC1CN(C3)C2
Temperature: 25 °C

Procedure:
A solution of azaadamantan-4-one (2.0 g, 13.2 mmol; Synthesis 1992, 1080) in formic acid (10 mL) at room temperature was treated with a solution of hydroxylamine-O-sulfonic acid (2.24 g, 19.8 mmol; Aldrich) in formic acid (7 mL) added dropwise. The resulting mixture was then heated at reflux for 3.5 hours. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure, and the resulting oil was diluted with 1 NNaOH and extracted with chloroform (3×). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude material was purified by flash chromatography over silica gel (115 g), eluting with 5-10% methanol (containing 1% ammonium hydroxide)-chloroform to afford the title compound: MS (DCI/NH3) m/z 167 (M+H)+, 184 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]1([OH:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(=O)([O-])O.[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2nccc(Oc3cccc4ccccc34)c2cc1OC
Temperature: 150 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (97 mg) and commercially available 1-naphthol (340 mg) were mixed and stirred at 150° C. for 8 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting first with hexane/ethyl acetate (3/1) and then with chloroform/methanol (100/1), and further purified by thin layer chromatography on silica gel eluting with hexane/ethyl acetate (1/1) to obtain 57 mg of the title compound (yield: 40%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:20](=O)([O-])[O-].[K+].[K+].CI.C(OCC)C>CC(C)=O.C(OCC)(=O)C.CCCCCC>[CH3:20][O:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Combine methyl 2-hydroxy-5-(t-butyldimethylsilyloxy)benzoate (14.2 g, 50.2 mmol), potassium carbonate (13.88 g, 100.4 mmol), and methyl iodide (20 mL, 321 mmol) in acetone (125 mL). Heat to reflux. After 17 hours, add methyl iodide (10 mL). After 23 hours, cool the reaction mixture to ambient temperature and add diethyl ether (600 mL), filter, and evaporate the filtrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 10% ethyl acetate/hexane to give methyl 2-methoxy-5-(t-butyldimethylsilyloxy)benzoate. Rf=0.39 (silica gel, 5% ethyl acetate/hexane).
Reaction SMILES: [C:1]([NH:8][N:9]1[C:15](=[O:16])[CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C.C(Cl)Cl>[C:1]([NH:8][N:9]1[C:15](=[O:16])[CH:14]([CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)NN1C(=O)Cc2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN1C(=O)C(CC(=O)C(C)(C)C)c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.2 g, 0.617 mmol) (Example 7-E) in DMF was treated with Cs2CO3 (0.3 g, 0.925 mmol) and warmed to 60° C. To the reaction mixture was added 1-chloro-3,3-dimethyl-2-butanone (0.096 ml, 0.74 mmol) (Aldrich) and stirring continued for 17 h. After cooling to 23° C., the mixture was diluted with CH2Cl2, washed with several portions of brine and dried over Na2SO4. The title compound was isolated as a colorless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][C:22]([O:24]CC)=[O:23].Cl>[OH-].[Na+].[Cl-].[Na+].O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)COCCOCCOCCOCCOCCOCCOC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COCCOCCOCCOCCOCCOCCOCC(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.1 %

Procedure:
The product of step (a) (4.54 g) was dissolved in an aqueous sodium hydroxide solution (0.1M) (45 ml) and the reaction was stirred at room temperature for 20 hours. The reaction mixture was acidified to pH 2 by the addition of hydrochloric acid (2M), then this was diluted with brine (300 ml) and extracted with dichloromethane (3×300 ml). The combined organic layers were dried and the solvent removed in vacuo to give the title compound as a yellow oil (3.75 g).
Reaction SMILES: [N+:1]([C:4]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:5][OH:6])([O-:3])=[O:2].[CH2:11]1OCO[CH2:13][O:12]1.S(=O)(=O)(O)O>C(Cl)Cl>[CH3:5][C:4]([N+:8]([O-:10])=[O:9])([N+:1]([O-:3])=[O:2])[CH2:11][O:12][CH2:13][O:6][CH2:5][C:4]([N+:8]([O-:10])=[O:9])([N+:1]([O-:3])=[O:2])[CH3:7]
Reactant: C1OCOCO1
Reactant: CC(CO)([N+](=O)[O-])[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(COCOCC(C)([N+](=O)[O-])[N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Reaction time: 2 h
Yield: 82 %

Procedure:
To a stirred solution of 15 g (0.1 mole) of 2,2-dinitropropanol and 1.5 g (0.05 mole) of s-trioxane in 13 mL of methylene chloride at 0° C., 15 g (98%) of a concentrated sulfuric acid solution was injected with syringe pump over 2 hours. During the reaction, temperature was controlled not to exceed 5° C. After addition was completed, the reaction was stirred for further 30 minutes. Upon completion of the reaction, the reaction solution was quenched with water. The reaction mixture was extracted with 130 mL of methylene chloride, and then, the extract was successively washed with 5% sodium hydroxide aqueous solution (130 mL×4) and saturated sodium chloride aqueous solution (130 mL×2), dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. Further evaporation under 60° C., about 10 mmHg for 5 hours gave 12.8 g of BDNPF.
Reaction SMILES: [OH:1][CH:2]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12]>C(O)(C)C>[CH3:12][O:11][C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[C@@H:2]([CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)[OH:1]
Reactant: COc1cccc(C(O)C2CCNCC2)c1OC
Solvent: CC(C)O
Product: COc1cccc([C@H](O)C2CCNCC2)c1OC
Temperature: 25 °C

Procedure:
Dissolve 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11) (11.0 g, 43.8 mmol) and 17.0 g (40.1 mmol) (2R,3R)-(−)-di-(p-anisoyl)tartaric acid in 400 mL refluxing isopropanol. Allow the mixture to cool to room temperature. Collect the precipitate, rinse with isopropanol and dry to give the (R)-α-(2,3-dimethoxyphenyl)-4-piperidinemethanol, (2R,3R)-(−)-di-(p-anisoyl)tartaric acid. Recrystallize the (R)-α-(2,3-dimethoxyphenyl)-4-piperidinemethanol, (2R,3R)-(−)-di-(p-anisoyl)tartaric acid salt from 250 mL isopropanol.
Reaction SMILES: [CH3:1][O:2][C@@:3]1([C:11]#[C:12][C:13]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[OH:14])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1.B.[H-].[Na+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>C1COCC1>[CH3:1][O:2][C@@:3]1([C:11]#[C:12][C:13]([O:14][CH2:29][C:30]([O:32][CH3:33])=[O:31])([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1
Reactant: CO[C@]1(C#CC(O)(c2cccs2)c2cccs2)CN2CCC1CC2
Reactant: COC(=O)CBr
Agent: B
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COC(C#C[C@@]1(OC)CN2CCC1CC2)(c1cccs1)c1cccs1
Reaction time: 0.33 h

Procedure:
A solution of the 3-[(3R)-3-methoxy-1-azabicyclo[2.2.2]oct-3-yl]-1,1-di(2-thienyl)-2-propyn-1-ol compound complexed with borane 193 (200 mg, 0.54 mmol) in THF (10 ml) under nitrogen and at room temperature was treated with NaH (60% dispersion in oil, 23 mg, 0.59 mmol). After 20 minutes, methyl bromoacetate (55 μL, 0.59 mmol) was added in one portion. After 16 hours, the reaction was quenched with water, and the mixture was then diluted with AcOEt. The organic phase was washed with brine, dried over MgSO4 and evaporated to dryness to afford the methyl {[3-[(3R)-3-methoxy-1-azabicyclo[2.2.2]oct-3-yl]-1,1-di(2-thienyl)-2-propynyl]oxy}acetate compound complexed with borane (1:1) 194 as an oil (130 mg, 55%). This compound was used without other purification in the next step.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.CCOC(C)=O.S(O)(C1C=CC(C)=CC=1)(=O)=O.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:9])[O:13][CH2:12][CH2:11][O:10]2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(c2ccc(I)cc2)OCCO1
Yield: 99.1 %

Procedure:
1-(4-Iodophenyl)ethanone (15.0 g, 61 mmol) and ethylene glycol (7.17 g, 122 mmol) in toluene (120 mL) were treated with TsOH—H2O (0.290 g, 1.52 mmol). The flask was equipped with a Dean-Stark apparatus and condenser and heated to reflux for about 4 h. The mixture was cooled and concentrated under reduced pressure to give a material. The material was dissolved in EtOAc (120 mL) then washed with saturated aqueous NaHCO3 (25 mL) then saturated aqueous NaCl (30 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give 2-(4-iodophenyl)-2-methyl-1,3-dioxolane (17.54 g, 99%): LC/MS (Table 2, Method a) Rt=2.80 min; MS m/z 291 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=Cc1cccc(Br)c1F
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1cccc(Br)c1F
Temperature: -78 °C

Procedure:
To a solution of 3-bromo-2-fluorobenzaldehyde (0.150 g, 0.739 mmol) in THF (3.21 mL) cooled to −78° C. was added (4-fluorophenyl)magnesium bromide (0.443 mL, 0.887 mmol). The reaction mixture was maintained at −78° C. for at least 1 hr, then allowed to warm to room temperature slowly over 2 hr. The reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with CH2Cl2 and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×). Organics were combined, dried over Na2SO4, filtered, and concentrated to afford the title compound as a yellow residue.
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][C@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl.F[CH2:38][C:39](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=CC(OC4CCNCC4)=CN=3)=CC=2)C=1)(C)[CH2:40]F>>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][C@H:29]4[CH2:33][CH2:32][N:31]([CH:39]([CH3:40])[CH3:38])[CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(O[C@H]4CCNC4)cn3)cc2)no1
Agent: Cl
Product: CC(C)N1CC[C@H](Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)C1
Yield: 94 %

Procedure:
(S)-N-(4-(3-(5-tert-Butylisoxazol-3-yl)ureido)phenyl)-5-(1-isopropylpyrrolidin-3-yloxy)picolinamide (50 mg, 94%) was prepared using a procedure analogous to that described in Example 20, substituting (S)-N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(pyrrolidin-3-yloxy)picolinamide hydrochloride from Step 1 of this example for N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 20. LC-MS (ESI) m/z 507 (M+H)+.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:9]([N:10]([CH3:33])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][O:7][CH2:6]1)=[O:4].[OH-].[Li+]>C1COCC1.CO.O>[CH3:33][N:10]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)=[CH:18][CH:19]=1)(=[O:12])=[O:13])[CH:9]1[CH2:8][O:7][CH2:6][CH:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)C1COCC1N(C)S(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)C3COCC3C(=O)O)cc2)c2ccccc2n1

Procedure:
A solution of 4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-furan-3-carboxylic acid methyl ester (0.160 g, 0.3 mmol) and lithium hydroxide (0.082 g,. 3.4 mmol) in THF:methanol:water (3: 2:2 mL) was stirred at 25° C. for 19 h. The solution was then washed with ethyl acetate (2×30 mL) and the aqueous layer was acidified with 2N HCl to pH ˜2. The aqueous layer was washed with ethyl acetate (3×40 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to produce 4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-furan-3-carboxylic acid as a crude solid (0.160 g, 100%). MS: 457 (M+H)+
Reaction SMILES: [OH:1][CH:2]1[CH2:19][CH2:18][C@@:17]2([CH2:20][OH:21])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH:10]=[CH:11]2)=[CH:3]1>CCCCCC.[O-2].[O-2].[Mn+4]>[OH:21][CH2:20][C@@:17]12[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[CH:11]=[CH:10][CH2:9]4)[CH2:6][CH2:5][C:4]1=[CH:3][C:2](=[O:1])[CH2:19][CH2:18]2
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(O)CC[C@]3(CO)[C@H]1CC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(CO)[C@H]1CC2

Procedure:
3,19-Dihydroxyandrosta-4,16-diene (21) is treated with manganese dioxide (MnO2, c) in hexane. The mixture is filtered and evaporated to give the crude product. Purification yields the enone (22).
Reaction SMILES: COC1C=CC(C[N:8]([C:16]2[S:17][C:18]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[N:27][CH:26]=[CH:25]4)=[C:19]([Cl:21])[N:20]=2)C(=O)OC(C)(C)C)=CC=1>CC(O)=O>[Cl:21][C:19]1[N:20]=[C:16]([NH2:8])[S:17][C:18]=1[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[N:27][CH:26]=[CH:25]2
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc(Cl)c(-c3ccc4cnccc4c3)s2)cc1
Solvent: CC(=O)O
Product: Nc1nc(Cl)c(-c2ccc3cnccc3c2)s1
Temperature: 120 °C
Yield: 85.7 %

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 4-methoxybenzyl(4-chloro-5-(isoquinolin-6-yl)thiazol-2-yl)carbamate (1.5 g, 3.12 mmol) and AcOH. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc.,) at 120° C. for 5 minutes. Excess AcOH was removed under high vacuum. The residue was dissolved in DCM and washed with saturated NaHCO3 (50 mL) and saturated sodium chloride. This intermediate was synthesized in the same manner as described previously and water dried over Na2SO4, filtered and concentrated in vacuo to provide 4-chloro-5-(isoquinolin-6-yl)thiazol-2-amine (0.7 g, 81% yield), m/z (%): 263.2 (100%, M++H).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH:6]([C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1)=[O:7]>S(=O)(=O)(O)O>[CH:6]([C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][C:13]=1[N+:1]([O-:4])=[O:2])=[O:7]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1cccc(C=O)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
A solution of potassium nitrate (6.2 g, 61 mmol) in sulfuric acid (30 mL) was added dropwise to stirred solution of N-(3-formylphenyl)acetamide (10.0 g, 61 mmol) in sulfuric acid (120 mL) maintained at 5° C. After 2 hours, the reaction mixture was poured onto ice water (500 mL) and filtered to give N-(3-formyl-4-nitrophenyl)acetamide (6.2 g, 48%) mp 131°-135° C., used without further purification.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:23]1([NH:29]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-n2ccc(=O)c(C(=O)C=CN(C)C)n2)cc1
Reactant: NNc1ccccc1
Solvent: CO
Product: COc1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)cc1
Yield: 17 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-methoxyphenyl)pyridazin-4(1H)-one (crude 640 mg, 2.14 mmol) in 20 mL of methanol was added phenylhydrazine (347 mg, 3.21 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(4-methoxyphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (127 mg, 17% for two steps) as a yellow solid.