Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)[C:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](=[O:42])(=[O:41])[NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[N:32]2[C:40]3[C:35](=[N:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[N:33]2)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>C(Cl)Cl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][S:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]([CH3:15])([CH3:16])[CH2:13][OH:12])=[CH:18][CH:19]=2)(=[O:42])=[O:41])=[C:26]([N:32]2[C:40]3[C:35](=[N:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[N:33]2)[CH:27]=1
Reactant: COC(=O)C(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(CO)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Reaction time: 1 h

Procedure:
DIBAL-H (diisobutylaluminum hydride)(0.71 mL, 1.0 M solution in CH2Cl2) was added to 2-[4-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylsulfamoyl)-phenyl]-2-methyl-propionic acid methyl ester (synthesized according to general procedures F and G, 137 mg, 0.282 mmol) in CH2Cl2 (3 mL) at −78° C. After 1 hour, LCMS indicated a 2:1 ratio of the desired product and corresponding aldehyde intermediate. 1 N HCl (2 mL) was added to the reaction mixture, the flask was warmed to room temperature, and the solution was diluted with EtOAc (30 mL). The EtOAc layer was separated, dried (Na2SO4), and evaporated in vacuo. The resultant crude residue was treated with NaBH4 (30 mg, excess) in MeOH (3 mL) at room temperature for 10 minutes and directly purified by preparative HPLC to afford the title compound as a white powder: MS (ES) M+H expected 458.1, found 458.0.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([N+:26]([O-])=O)[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].[In].[Cl-].[NH4+]>C(O)C>[CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([NH2:26])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CN(C)CCNC(=O)c1cccc2nc3ccc4c([N+](=O)[O-])cccc4c3nc12
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: CCO
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4c(N)cccc4c3nc12
Yield: 100.3 %

Procedure:
A mixture of 4-nitro-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (176 mg), indium (154 mg) and saturated ammonium chloride solution (5 mL) in ethanol (20 mL) was heated to reflux for 3 hours. The reaction mixture was cooled, quenched with water and then filtered through celite. The filtrate was concentrated in vacuo, and the residue was treated with sodium bicarbonate solution, extracted into chloroform, dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a red solid (163 mg) 3-Amino-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared in an analogous manner from 3-nitro-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[C:5](Cl)[N:4]=1.[CH3:11][OH:12]>>[Cl:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[C:5]([O:12][CH3:11])[N:4]=1
Reactant: Nc1cc(Cl)nc(Cl)c1
Reactant: CO
Agent: [Na]
Product: COc1cc(N)cc(Cl)n1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.84 g (44.0 mmol) sodium in 40 mL MeOH was added 6.72 g (40.0 mmol) 2,6-dichloro-pyridin-4-ylamine. The reaction mixture was stirred at 150° C. for 30 min under microwave irradiation. The solvent was evaporated and ice water was added. The precipitate was filtered off, washed with water and dried.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][CH:17](O)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O>[CH3:15][N:14]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][C:10]2[O:9][N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[C:12]1=[O:13]
Reactant: CNC(=O)c1c(-c2ccccc2)noc1CC(O)c1ccccc1
Solvent: O
Product: CN1C(=O)c2c(-c3ccccc3)noc2CC1c1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To 550 ml. of polyphosphoric acid maintained at a temperature of 100° to 105° C. there is added 36.5 grams (0.114 moles) 3-phenyl-5-(β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide in portions. The mixture is then stirred at 100° for 5 hours and then poured onto 2 liters of ice and water. The resulting solid is filtered and purified by recrystallization to give 5-methyl-6,7-dihydro-3,6-diphenyl isoxazolo[4,5-c]pyridin-4-(5H)-one; m.p. 108° to 111° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH:16]=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][NH2:23].C(=O)(O)[O-].[Na+].CO>O>[CH3:21][O:22][N:23]=[CH:16][C:15]1[N:14]=[CH:13][N:12]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=3[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]=12
Reactant: CON
Reactant: CN1Cc2c(C=O)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CON=Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reaction time: 8 h

Procedure:
A suspension of 5.51 g (20 mmol) of 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde, 2.23 g (26.6 mmol) of O-methylhydroxylamine hydrochloride and 75 ml of water is treated dropwise at room temperature with a solution of 7.67 g (26.6 mmol) of sodium bicarbonate in 65 ml of water. 40 ml of methanol are added thereto and the mixture is stirred at 70° for 8 hours. The mixture is then poured into 700 ml of water, the suspension is suction filtered and the filter residue is dissolved in methylene chloride. The solution is dried over magnesium sulphate and evaported. By chromatography on silica gel while eluting with ethyl acetate and recrystallization from ethyl acetate there is obtained 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3carboxaldehyde O-methyl oxime of melting point 173°-174°.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[C:30]([CH:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)#[N:31]>>[C:30]([CH:32]1[CH2:37][CH2:36][CH:35]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:34][CH2:33]1)#[N:31]
Reactant: N#CC1CCC(=O)CC1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CCC(N2CC(NC(=O)CNc3noc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-cyano-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[C:8]([CH3:32])=[C:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[NH2:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39]>CCCCCC.C(OCC)(=O)C>[OH:39][CH2:38][C:37]([NH:36][C:5]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:4])([CH3:41])[CH3:40]
Reactant: CC(C)(N)CO
Reactant: Cc1c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)NC(C)(C)CO)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Yield: 49 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 142 and 2-amino-2-methyl-1-propanol, the title compound was synthesized in the same manner as in Example 143. Yield: 49%. Melting point: 181-182° C. (hexane-ethyl acetate).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([OH:27])[C:24]([C:28]([OH:30])=[O:29])=[CH:23][N:22]=2)=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C)C=O.ClCCl>[O:1]=[C:2]1[NH:6][CH:5]([C:7]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:26]=[C:25]([OH:27])[C:24]([C:28]([OH:30])=[O:29])=[CH:23][N:22]=3)=[CH:19][CH:20]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C1CCC(C(=O)O)N1
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCC(C(=O)Nc2ccc(-c3ncc(C(=O)O)c(O)n3)cc2)N1
Reaction time: 1.67 h
Yield: 72.2 %

Procedure:
A suspension of 3.87 g (30 mmol) of 5-oxo-DL-proline, 2.3 ml (30 mmol) of dimethylformamide, and 50 ml of dichloromethane is stirred at 0°-5° C. and 2.2 ml (30 mmol) of thionyl chloride is added. Stirring is continued at 0°-5° C. for 1.67 hrs and a solution of 4.62 g (20 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid, 3.1 ml (22 mmol) of triethylamine and 60 ml of dimethylformamide is added. The reaction mixture is stirred at 0°-5° C. for 3 hrs and at room temperature overnight. The solid is filtered, washed with dichloromethane, methanol, and ether, and dried to give 4.94 g of 2-[4-((5-oxo-DL-prolyl)-amino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid.
Reaction SMILES: C(OC1C(=O)N=C(CC2(C3C=CC=CC=3)CCCC2)N2CCN(C3CC3)C(=O)C=12)C1C=CC=CC=1.[CH:36]1([N:41]([CH2:71][CH2:72]O)[C:42]([C:44]2[C:49]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[C:48]([OH:58])[N:47]=[C:46]([CH2:59][C:60]3([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[CH2:64][CH2:63][CH2:62][CH2:61]3)[N:45]=2)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH2:51]([O:50][C:49]1[C:48](=[O:58])[N:47]=[C:46]([CH2:59][C:60]2([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[CH2:64][CH2:63][CH2:62][CH2:61]2)[N:45]2[CH2:72][CH2:71][N:41]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[C:42](=[O:43])[C:44]=12)[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CCCC1
Agent: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CC1
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CCCC1
Yield: 47.3 %

Procedure:
This compound was prepared following the same method as described for 9-benzyloxy-2-cyclopropyl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (286) from 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopentyl-(2-hydroxyethyl)-amide (289) (175 mg, 0.34 mmol). The product was obtained as an off-white sticky solid (80 mg, 47.31%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:8](=[O:12])(=O)(O)[OH:9]>>[CH:6]1[C:1]([OH:7])=[CH:2][CH:3]=[C:4]([S:8]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)(=[O:12])=[O:9])[CH:5]=1
Reactant: O=S(=O)(O)O
Reactant: Oc1ccccc1
Product: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
To practice the process of this invention, phenol, sulfuric acid and a solvent are placed into a reactor, and the mixture is heated at a temperature of about 130° ~ about 220° C. The water resulting from the progress of the reaction is removed by refluxing a mixture of the solvent and water, separating off the water alone in the course of reflux and returning the solvent to the reactor. The solvent to be returned can be partly drawn off from the reaction mixture. When the dehydration reaction has been almost completed, the solvent is substantially completely removed from the system. The solvent is readily removable by distillation suitably reducing the internal pressure of the reactor. The dry solid residue obtained is dissolved in an aqueous solution of alkali, and the solution is treated with active carbon to remove small amounts of colored impurities and then neutralized with an inorganic acid such as H2SO4, HCl, etc. to obtain 4,4'-dihydroxydiphenylsulfone crystals, separating by filtration from the filtrate which contains phenol sulfonic acid as a by-product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[N:13][C:14]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH3:29][C:30]([CH3:32])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH:30]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[N:13][C:14]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1)([CH3:32])[CH3:29]
Reactant: CC(C)=O
Reactant: FC(F)(F)c1cccc(Nc2ncc3ccc(OC4CCNCC4)cc3n2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CCC(Oc2ccc3cnc(Nc4cccc(C(F)(F)F)c4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 7-(piperidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)quinazolin-2-amine in DCM was added acetone (10 eq), a few drops of acetic acid and sodium triacetoxy borohydride (4 eq). The reaction mixture was stirred for 16 h at ambient temperature. The reductive amination went to completion to give 7-(1-isopropylpiperidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)quinazolin-2-amine. The mixture was then purified on prep HPLC to give 7-(1-isopropylpiperidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)quinazolin-2-amine. ES/MS m/z 431 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH:25]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=6)[CH2:24][O:23][C:22]5=[O:32])=[N:17][C:16]=34)=[CH:8][CH:7]=2)=[N:2]1>C(O)C>[NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([N:21]5[C@H:25]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=6)[CH2:24][O:23][C:22]5=[O:32])=[N:17][C:16]=34)=[CH:10][CH:11]=2)=[N:2]1
Reactant: O=C1OCC(c2ccccn2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1
Solvent: CCO
Product: O=C1OC[C@@H](c2ccccn2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1

Procedure:
Racemic 3-(3-(4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(pyridin-2-yl)oxazolidin-2-one (Example 69) was dissolved in hot ethanol (10 mg/3 mL) and 1.5 mL of the solution injected (8 injections total) onto a 2.2 cm×250 mm Chiral Tech OD-H column using 35% ethanol/65% hexanes as eluent with a 21 mL/minute flow rate. Peak 2 was isolated to give (R)-3-(3-(4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(pyridin-2-yl)oxazolidin-2-one (19.8 mg). LCMS (APCI+) m/z 425 [M+H]+.
Reaction SMILES: C(O[C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])C.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][C:21]=1[NH:30][NH2:31]>C1(C)C=CC=CC=1>[C:16]([O:15][C:13]([N:8]1[CH2:9][CH2:10][C:11]2[NH:31][N:30]([C:21]3[CH:22]=[N:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:20]=3)[C:4](=[O:5])[C:6]=2[CH2:7]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NNc1cnc2ccccc2n1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2[nH]n(-c3cnc4ccccc4n3)c(=O)c2C1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (500 mg, 1.84 mmol; Tetrahedron 1994, 50, 515) in toluene (10 mL) was added quinoxalin-2-yl-hydrazine (295 mg, 1.85 mmol; Heterocycles 1985, 23, 2603). This mixture was stirred at reflux overnight, cooled to room temperature, concentrated, and purified by flash column chromatography (25→75% ethyl acetate/hexanes) to give 600 mg (89%) of the title compound of Example 75, Step A as a light orange solid. 1H NMR (CDCl3, 250 MHz, 5:1 mixture of tautomers) δ 11.94 (br s, 0.83H), 10.16 (s, 0.17H), 9.57 (s, 0.83H), 8.13 (dd, 1H), 7.91-7.69 (c, 3H), 4.45 (s, 1.66H), 4.33 (s, 0.34H), 3.79-3.72 (c, 2H), 2.82-2.72 (c, 2H), 1.52 (s, 9H); MS (APCI) 368 (MH+).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[OH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:13][C:12]=1[C:27](OCC)=[O:28]>C1C=CC=CC=1>[OH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:13][C:12]=1[C:27]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:28]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2ccccc2c1O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(Nc1ccccn1)c1nc(-c2ccccc2)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
To a stirred slurry of 1.14 g of sodium hydride (as a 50% oil dispersion) in 100 ml of benzene was added 2.25 g of 2-aminopyridine. After stirring at room temperature for 15 minutes the slurry was treated with a solution of 2.25 g of 4-hydroxy-1-phenyl-3-isoquinolinecarboxylic acid, ethyl ester in 50 ml of benzene. After refluxing for one hour, the reaction mixture was cooled to room temperature, quenched with water, and extracted with three 100 ml aliquots of hot tetrahydrofuran. The organic layer was dried over magnesium sulfate, filtered, and evaporated to yield 1.7 g (65%) of 4-hydroxy-1-phenyl-N-(2-pyridyl)-3-isoquinolinecarboxamide. Recrystallization from dichloromethane afforded the analytical sample, m.p. 228°-230° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:6][C:5]=1[N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([O-])=O>[Pd].C1(C)C=CC=CC=1.CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)=[CH:6][C:5]=1[N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Oc3ccccc3)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Oc3ccccc3)cc2)ccc1N
Yield: 89.9 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[2-nitro-5-(4-phenoxyphenoxy)phenyl]-N-methylcarbamate (8.6 g), palladium on carbon (10%, 0.6 g) and toluene/methanol=16/3 (190 ml) and the reaction mixture was purified to give the title compound (7.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH2:13][N:14](C)[C:15](=O)OC(C)(C)C)=[N:7][C:6]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH2:13][NH:14][CH3:15])=[N:7][C:6]=12
Reactant: CN(CCNc1ccn2ncc(Br)c2n1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCNc1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
The tert-butoxycarbonyl was removed by dissolving 600 mg (1.62 mmol) of tert-butyl (2-((3-bromopyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)(methyl)carbamate in 4 mL of DCM, and then adding 4 mL TFA, stirring for 0.5 hr at rt, and concentrating the mixture to afford the TFA-salt of the desired product in 100% yield (622 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[S:36])([CH3:27])[CH3:26]>O1CCCC1>[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([NH:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:23])[F:24])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[S:36])([CH3:27])[CH3:26]
Reactant: CC(C)c1ccccc1N=C=S
Reactant: NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: C1CCOC1
Product: CC(C)c1ccccc1NC(=S)NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
To a solution of (4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine (0.066 g, 0.20 mmol) in tetrahydrofuran (4.0 mL), 1-isopropyl-2-isothiocyanatobenzene (0.048 g, 0.27 mmol) was added. The reaction mixture was stirred in a pre-heated heating block at 80° C. for 4 hours. The reaction mixture was adsorbed onto Celite® and purified via reverse phase chromatography using 5-100% acetonitrile/water as eluent to afford the title compound as a white solid (0.070 g, 68%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.30 (s, 1H), 8.07 (dd, J=9.4, 7.3 Hz, 4H), 7.81 (s, 1H), 7.68-7.58 (m, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.36 (d, J=7.7 Hz, 1H), 7.29 (t, J=7.5 Hz, 1H), 7.21 (dd, J=13.2, 6.1 Hz, 2H), 4.78 (s, 2H), 3.11 (s, 1H), 1.15 (d, J=6.9 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 512 ([M+H]+).
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1C(O)=O)([O-])=O.[N+:16]([C:19]1[CH:39]=[C:38]([N+:40]([O-])=O)[CH:37]=[CH:36][C:20]=1[C:21]([O:23][CH:24]1[CH:30]([OH:31])[C:29]([CH3:33])([CH3:32])[CH2:28][C:27](=[O:34])[C:26]([CH3:35])=[CH:25]1)=[O:22])([O-])=O.[N+](C1C=C([N+]([O-])=O)C=CC=1C(OC1C(C)(C)CC(=O)C(C)=CC1O)=O)([O-])=O>CCCCCC.C(OCC)(=O)C>[NH2:16][C:19]1[CH:39]=[C:38]([NH2:40])[CH:37]=[CH:36][C:20]=1[C:21]([O:23][CH:24]1[CH:30]([OH:31])[C:29]([CH3:33])([CH3:32])[CH2:28][C:27](=[O:34])[C:26]([CH3:35])=[CH:25]1)=[O:22]
Reactant: CC1=CC(OC(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])C(O)C(C)(C)CC1=O
Agent: CC1=CC(O)C(OC(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])C(C)(C)CC1=O
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1=CC(OC(=O)c2ccc(N)cc2N)C(O)C(C)(C)CC1=O
Yield: 26 %

Procedure:
Saishin N (3.68 g, 20 mM) was treated with 2,4-dinitrobenzoic acid (6.79 g, 32 mM) according to the procedures described in Example 20, forming a mixture of 4-(2,4-dinitrobenzoyloxy)-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one and (per acyl transfer reaction) 5-(2,4-dinitrobenzoyloxy)-4-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one, and then the mixture was reduced at the nitro groups according to the procedures described in Example 19 and fractionated by silica gel column chromatography using hexane-ethyl acetate (3:2) as an eluent. The first eluted portion was crystallized from a mixed solution of ethyl acetate and hexane to obtain 1.65 g (26%) of 4-(2,4-diaminobenzoyloxy)-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU242) as a brown powder. Melting point: 154° to 156° C.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH2:27])[CH:21]=1)([O-:19])=[O:18]>>[O:13]=[C:11]1[NH:10][C:9](=[O:14])[C:8](=[CH:7][C:6]2[CH:15]=[CH:16][C:3]([C:1]3[NH:27][C:22]4[CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:25]=[CH:24][C:23]=4[N:26]=3)=[CH:4][CH:5]=2)[S:12]1
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4ccc([N+](=O)[O-])cc4[nH]3)cc2)S1

Procedure:
2-[4-[(2,4-Dioxothiazolidin-5-ylidene)methyl]phenyl]-5-nitrobenzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 4-nitro-1,2-phenylenediamine by following General Procedure 2.