Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](O)=O)=[CH:3][N:2]=1.[C:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([NH2:23])=[C:19]([NH2:22])[CH:20]=2)[C:15]([CH3:25])([CH3:24])[CH2:14]1)(=[O:12])[CH3:11].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[C:10]([N:13]1[C:21]2=[CH:20][C:19]3[NH:22][C:7]([C:4]4[CH:5]=[CH:6][N:1]=[N:2][CH:3]=4)=[N:23][C:18]=3[CH:17]=[C:16]2[C:15]([CH3:25])([CH3:24])[CH2:14]1)(=[O:12])[CH3:11]
Reactant: O=C(O)c1ccnnc1
Reactant: CC(=O)N1CC(C)(C)c2cc(N)c(N)cc21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC(=O)N1CC(C)(C)c2cc3nc(-c4ccnnc4)[nH]c3cc21

Procedure:
To 75 g. polyphoshoric acid are added 3.1 g. pyridazine-4-carboxylic acid, 5.0 g. (23 mmole) 1-acetyl-5,6-diamino-3,3-dimethylindoline (Example 2b) and 22 g. phosphorus pentoxide and heated to 150°-160° C. for 7 hours. The reaction mixture is poured on to ice, rendered ammoniacal, extracted with dichloromethane and the extract evaporated to give 3.6 g. (51% of theory) of the title compound in the form of a dark solid; m.p. 225°-260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[O:27][C:23]=2[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:30]=[CH:29][C:24]4[NH:25][C:26](=[O:28])[O:27][C:23]=4[CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(Cl)cc2)CC1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Product: O=C(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(Cc2ccc(Cl)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-chloro-benzyl)-piperidin-1-yl]-oxo-acetic acid and 6-amino-3H-benzoxazol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 215° C. (isopropanol)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:5]=[CH:6][CH:7]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2cccc3[nH]ccc23)c1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To the suspension of 4-(3-chloro-phenyl)-1H-indole (1.52 g, 6.68 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (81 mL) was added pyridinium tribromide (90% purity from Aldrich, 7.12 g, 20.0 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (30 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (1.55 g, 95%) as a tan solid
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:19])[CH2:12][N:13]([OH:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][C:4]=1[Br:20]>>[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH:11]([OH:19])[CH2:12][N:13]([OH:18])[C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:5][C:4]=1[Br:20]
Reactant: CC(C)(C)N(O)CC(=O)c1cc(Br)c(N)c(C#N)c1
Agent: Cl
Product: CC(C)(C)N(O)CC(O)c1cc(Br)c(N)c(C#N)c1

Procedure:
m.p. of the hydrochloride: 221°-222° C., was prepared from 4'-amino-3'-bromo-5'-cyano-2-(hydroxy-tert.butylamino)-acetophenone analogous to Example 48.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]12([N:14]=[C:15]=[S:16])[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2>CCO>[C:4]12([NH:14][C:15](=[S:16])[NH:2][NH2:3])[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2
Reactant: NN
Reactant: S=C=NC12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: CCO
Product: NNC(=S)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A solution of 1.5 g (0.03 mol) of hydrazine hydrate in 50 ml of EtOH was treated with 3.86 g (0.02 mol) of 1-adamantyl isothiocyanate, and stirred for one hour at room temperature. The product was collected and washed two times with EtOH, affording 4.33 g (96%) of 4-(1-adamantyl)-3-thiosemicarbazide, mp 206°-207° C. This thiosemicarbazide is disclosed in Chemical Abstracts, 70:11223 (1969); and in U.S. Pat. No. 3,406,180.
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[CH:19](O)[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[CH2:16][S:15](=[O:26])(=[O:25])[C:14]=2[CH:27]=1)=[O:9].[H][H]>C(O)(=O)C.[Pd]>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[CH2:16][S:15](=[O:25])(=[O:26])[C:14]=2[CH:27]=1)=[O:9]
Reactant: [H][H]
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)Cc1ccccc1C2O
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)Cc1ccccc1C2
Temperature: 25 °C

Procedure:
Pd/C (0.015 g, 10% w/w) and catalytic amount of perchloric acid was added to a solution compound of Example 203 (0.11 g, 0.3 mmol) in acetic acid (60 ml). The reaction mixture was subjected to hydrogenation at 100 psi of hydrogen at 65° C. for 6.5 h. The reaction mixture was cooled to 25° C. and filtered through high flow bed. The filtrate was concentrated, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water, brine, concentrated and purified using flash chromatography (silica gel, ethyl acetate and pet ether) to obtain the title compound. Yield: 0.05 g (47%); 1H NMR (CDCl3): δ 3.8 (s, 2H, CH2), 3.9 (s, 3H, CH3), 4.32 (s, 2H, CH2), 7.38 (m, 5H, Ar), 8.09 (d, 1H, Ar), 8.61 (s, 1H, Ar); MS: m/e (CI+) 303 (M+1).
Reaction SMILES: [C:1]([N:4]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([F:33])=[C:21]([CH:32]=2)[O:22][CH2:23][CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28]C)=[O:27])=[O:16])[C@@H:7]([CH3:34])[CH2:6]1)(=[O:3])[CH3:2].[Li+].[OH-]>CO.C1COCC1>[C:1]([N:4]([C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([F:33])=[C:21]([CH:32]=2)[O:22][CH2:23][CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([OH:28])=[O:27])=[O:16])[C@@H:7]([CH3:34])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCOc1cc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)c(OCCC(C)(C)C(=O)O)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of Methyl 4-(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-fluorophenoxy)-2,2-dimethylbutanoate in MeOH/THF (1 mL/1 mL) was added excessive LiOH (1N aqueous solution). The reaction mixture was stirred at r.t. for overnight. The reaction was quenched by adding 6N HCl to PH 2. The mixture was concentrated under reduced pressure to remove MeOH and THF. DCM was added. The reaction mixture was washed with brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to afford pure product.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21](Br)=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[C:25]1=[O:33]>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:26]4[C:25](=[O:33])[N:24]([CH3:23])[CH:29]=[CH:28][CH:27]=4)=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cn1cccc(B(O)O)c1=O
Reactant: CC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Product: CC(C)OC(=O)N1CCN(c2ccn3ncc(-c4cccn(C)c4=O)c3n2)CC1

Procedure:
Prepared similarly to the preparation of example 5.6.9 from 4-(3-bromo-pyrazolo[1,5-a]pyrimidin-5-yl)-piperazine-1-carboxylic acid isopropyl ester and (1-methyl-2-oxo-1,2-dihydropyridin-3-yl)boronic acid to provide a yellow powder as a free base, mp. 206-207° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (d, J=6.32 Hz, 6 H) 3.53 (s, 7 H) 3.70-3.82 (m, 4 H) 4.83 (spt, J=6.23 Hz, 1H) 6.37 (t, J=6.82 Hz, 1 H) 6.78 (d, J=7.83 Hz, 1 H) 7.55 (dd, J=6.57, 1.26 Hz, 1 H) 8.64 (dd, J=7.20, 1.14 Hz, 1 H) 8.72 (d, J=7.83 Hz, 1 H) 8.96 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) δ ppm 21.97, 37.39, 42.84, 44.11, 68.16, 96.94, 100.56, 105.49, 122.80, 132.49, 135.00, 136.42, 144.40, 144.56, 154.29, 155.46, 160.29. LRMS (ESI) m/z 397.1 [(M+H)]+, calc'd for C20H24N6O3: 396.45.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C@@:7]1([OH:36])[C@H:12]([NH:13][CH3:14])[C@@H:11]([OH:15])[C@@H:10]([O:16][C@@H:17]2[C@@H:22]([OH:23])[C@H:21]([O:24][C@H:25]3[O:30][C:29]([CH2:31][NH2:32])=[CH:28][CH2:27][C@H:26]3[NH2:33])[C@@H:20]([NH2:34])[CH2:19][C@H:18]2[NH2:35])[O:9][CH2:8]1.F[C:38](F)(F)[C:39](O)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.P(=O)(O)(O)O.[N+]([O-])(O)=O.C(=O)C.C([BH3-])#N.[Na+]>O.C(O)(=O)C>[CH3:38][CH2:39][NH:35][C@H:18]1[C@H:17]([O:16][C@H:10]2[O:9][CH2:8][C@@:7]([OH:36])([CH3:6])[C@H:12]([NH:13][CH3:14])[C@H:11]2[OH:15])[C@@H:22]([OH:23])[C@H:21]([O:24][C@H:25]2[O:30][C:29]([CH2:31][NH2:32])=[CH:28][CH2:27][C@H:26]2[NH2:33])[C@@H:20]([NH2:34])[CH2:19]1
Reactant: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3OC(CN)=CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Reactant: O=C(O)C(F)(F)F
Agent: CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCN[C@@H]1C[C@H](N)[C@@H](O[C@H]2OC(CN)=CC[C@H]2N)[C@H](O)[C@H]1O[C@H]1OC[C@](C)(O)[C@H](NC)[C@H]1O

Procedure:
in the procedure of above Example 1A instead of adding 1 N sulfuric acid to the solution of sisomicin in water until it reaches a pH of about 5, other acids may be used, such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, phosphoric acid, or nitric acid. The acidified aqueous solution is then treated with acetaldehyde and sodium cyanoborohydride and the resultant product is purified as described above, whereby is obtained 1-N-ethylsisomicin.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([O:15][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To an ice-cooled solution of Boc-D-Trp-OH (8.61 g) in DMF (100 ml) were added benzyl bromide (7.19 g) and diisopropylethylamine (4.02 g). The solution was stirred for two hours at the same temperature and overnight at room temperature. After evaporation, the residue was extracted with ethyl acetate. The organic layer was washed successively with water, sodium hydrogencarbonate solution, 0.5 hydrochlolic acid, and sodium chloride solution, and dried over magnesium sulfate. Evaporation gave Boc-D-Trp-OBzl (10.6 g) as a crystalline mass.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].C([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)N2CCNCC2)cc1Cl

Procedure:
50 mg 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to Boc-piperazine via Procedure G. The organic layer was evaporated to dryness and treated with TFA. After 1 h the TFA was removed and the crude was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(piperazine-1-carbonyl)benzamide. MS (Q1) 455 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([O:18][C:19]1[CH:24]=[CH:23][C:22](N)=[CH:21][N:20]=1)=[CH:12][CH:11]=3)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[Cu][C:33]#[N:34].[C-]#N.[K+]>O.Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:33]#[N:34])=[CH:21][N:20]=1)=[CH:12][CH:11]=3)=[O:4]
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ccc(Oc3ccc(N)cn3)cc12
Reactant: N#C[Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [C-]#N
Solvent: O
Product: COC(=O)c1cc2c(cn1)[nH]c1ccc(Oc3ccc(C#N)cn3)cc12

Procedure:
A suspension of 1.7 g of amino derivative (Example 24) in 10 ml of water and 2.5 ml of hydrochloric acid (37%) is combined dropwise at -5° C. with a solution of 0.4 g of NaN2 in 1.5 ml of water, then stirred for another hour at 0°-5° C. By adding sodium carbonate, solution is then adjusted to pH 5.5-6 and poured into a mixture, preheated to about 60° C., of 0.5 g of copper (I) cyanide and 1.6 g of potassium cyanide in 10 ml of water. After the reaction is completed, the cooled-off solution is extracted with dichloromethane, the organic phase is washed with water and concentrated. The residue is purified over silica gel, thus obtaining 1.12 g (65%).
Reaction SMILES: [CH2:1]([C:5]1([CH2:18][C:19](=[O:21])[CH3:20])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=O)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>CCO.O>[CH2:1]([C:5]12[CH2:18][C:19](=[O:21])[CH:20]=[C:6]1[C:7]1[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CC(C)=O)CCc2cc(OC)ccc2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCC12CCc3cc(OC)ccc3C1=CC(=O)C2

Procedure:
A solution of crude 2-butyl-6-methoxy-2-(2-oxopropyl)-3,4-dihydro-1(2H)-naphthalenone (888 mg, ˜3 mmol) in EtOH (15 mL) was treated with freshly prepared 2N KOH in EtOH (1.5 mL, 3 mmol). The resulting solution was placed under a N2 atmosphere and heated at reflux for 17 hours. After cooling, the mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The extracts were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40S (4×7 cm) silica gel column, eluting with 1000 mL portions of 19:1 and 10:1 hexane-EtOAc. The product-containing fractions were evaporated under vacuum to provide 3a-butyl-7-methoxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.NN.[OH-].[Na+]>Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Agent: Cl
Agent: NN
Agent: [Na+]
Product: O=C1Cc2ccc(Br)cc2N1
Temperature: 125 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
To 6-bromo-1H-indole-2,3-dione (15 g) was added hydrazine (66 ml), and the mixture was stirred at 125° C. for 2 hours. After the reaction was complete, to the mixture was added 6N aqueous HCl solution (60 ml), and the mixture was stirred at 60° C. for 2 hours. After the reaction was complete, the mixture was neutralized with 3N aqueous NaOH solution, and the mixture was extracted with ethyl acetate. This ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to give the title compound (9.1 g) as a red crystal.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH2:22][C:23](O)=[O:24]>>[CH2:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:19])[N:2]([NH:1][C:23](=[O:24])[CH2:22][C:21]([CH3:20])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[N:11]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: Nn1nc(Cc2ccccc2)c2ccccc2c1=O
Product: CC(C)(CC(=O)Nn1nc(Cc2ccccc2)c2ccccc2c1=O)c1ccccc1

Procedure:
The product of Example 139A and 3-methyl-3-phenylbutanoic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.31 (s, 1H), 8.31 (dd, J=7.8, 1.4 Hz, 1H), 7.96-8.01 (m, 1H), 7.90 (ddd, J=8.0, 7.2, 1.5 Hz, 1H), 7.85 (ddd, J=7.8, 7.2, 1.4 Hz, 1H), 7.44-7.47 (m, 2H), 7.25-7.35 (m, 6H), 7.17-7.23 (m, 2H), 4.30-4.30 (bs, 2H), 2.61 (s, 2H), 1.48 (s, 6H); LC/MS (APCI) M/Z 412 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:18])[CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)C#N)[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+]>Br>[CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:18])[CH2:9][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C(=O)C(C#N)c2ccccc2)ccn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(=O)Cc2ccccc2)ccn1
Yield: 25.6 %

Procedure:
3-(2-Methyl-pyridin-4-yl)-3-oxo-2-phenyl-propionitrile (1.02 g, 4.3 mmol) was suspended in HBr (48%, 10 mL) and heated to reflux overnight. The mixture was poured onto ice (20 g), was made alkaline (pH=11) by addition of NaHCO3 (satd.), and extracted with ethyl acetate. The combined organic layers were combined and dried (Na2SO4). After evaporation of the solvent, the title compound (233 mg, 26%) was isolated from the residue by column chromatography (silica gel, heptane:ethyl acetate=100:0-50:50). 1H NMR (300 MHz, DMSO-D6) □ 8.66 (1H, d), 7.78 (1H, s), 7.69 (1H, d), 7.35-7.24 (5H, m), 4.43 (2H, s), 2.57 (3H, s); MS (m/e)=212.1 [MH+].
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Product: COc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1

Procedure:
The product is prepared according to the procedure described in Example 9, using 300 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 and 1.254 ml of 3-methoxyaniline in place of the 2-fluoroaniline. 56 mg of N-(3-methoxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=2[Cl:27])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][C:9]=3[NH:8][C:7](=[O:18])[C:6]=12.[Cl-].[Ca+2].[Cl-]>C(O)C>[NH2:1][C:2]1[N:3]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=2[Cl:27])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([NH2:15])=[CH:10][C:9]=3[NH:8][C:7](=[O:18])[C:6]=12
Reactant: COc1ccc(Cl)c(-n2nc3c(c2N)c(=O)[nH]c2cc([N+](=O)[O-])ccc23)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: COc1ccc(Cl)c(-n2nc3c(c2N)c(=O)[nH]c2cc(N)ccc23)c1
Yield: 65.1 %

Procedure:
A mixture of 3-amino-2-(2-chloro-5-methoxyphenyl)-7-nitro-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (0.50 g), 90% calcium chloride (0.40 g), reduced iron (1.0 g) and 90% ethanol (30 ml) was heated under reflux for 3 hours, and 90% calcium chloride (0.10 g) and reduced iron (0.27 g) was added thereto. The reaction mixture was heated under reflux for additional 8 hours. The reaction mixture was cooled and the insoluble materials were filtered off through Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with a 5% sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residual solid was washed with diisopropyl ether, and dried to obtain the target compound (0.30 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:21]=[CH:20][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.C([Li])CCC.[CH2:41]([C@H:48]1[CH2:52][O:51][C:50](=[O:53])[NH:49]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O1CCNC1=O>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([N:49]3[C@@H:48]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH2:52][O:51][C:50]3=[O:53])=[O:19])=[CH:20][CH:21]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: N#Cc1ccc(-c2ccc(OCCCC(=O)O)cc2)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-c2ccc(OCCCC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
To a -70° C. solution in THF (100 mL) of 4-[4-(4-cyanophenyl)phenoxy]butanoic acid (1.00 g, 3.66 mmol), prepared as in Example 3, was added triethylamine (0.64 mL, 4.62 mmol) and pivaloyl chloride (0.49 mL, 3.91 mmol). The reaction mixture was stirred for 15 minutes at -70° C., 45 minutes at 0° C., and then was cooled back to -70° C. In a separate flask, n-butyllithium (2.5M in hexanes, 2.56 mL, 6.40 mmol) was added via syringe to a -78° C. a solution in THF (50 mL) of (S)-(-)-4-benzyl-2-oxazolidinone. The oxazolidinone anion solution was then added to the mixed anhydride solution via cannula. The reaction mixture was then warmed slowly to ambient temperature and stirred overnight. The reaction mixture was quenched with aqueous 1M HCl and extracted with ethyl ether. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting white solid was azeotroped with ethyl ether and purified by chromatography on silica gel (2% methanol-dichloromethane) to give N-[4-(4-(4-cyanophenyl)phenoxy)butanoyl]-(S)-(-)-4-benzyl-2-oxazolidinone (1.30 g, 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:13]3[S:14][CH:15]=[CH:16][N:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Cl-].[NH4+].C([O-])(O)=O.[Na+]>O1CCOCC1.O.O.[Zn]>[N:21]1[CH:20]=[CH:19][C:18]([C:17]2[C:10]([C:6]3[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=3)=[N:11][N:12]3[CH:16]=[CH:15][S:14][C:13]=23)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccc(-c2nn3ccsc3c2-c2ccncc2)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cccc(-c2nn3ccsc3c2-c2ccncc2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
6-(3-Nitrophenyl)-7-pyridin-4-yl-pyrazolo[5,1-b]thiazole (410 mg, 1.272 mmol) was dissolved in a 3:1 dioxane/water mixture (8 mL). Zinc powder (333 mg, 5.094 mmol, 4 eq) and ammonium chloride (680 mg, 12.72 mmol, 10 eq) were added and the mixture was stirred at 100° C. for 2 hours. It was then diluted with water, made basic by addition of saturated aqueous NaHCO3 and extracted with ethyl acetate (3×20 mL). Combined organic layers were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (DCM/MeOH 97:3) to give 255 mg (68%) of 3-(7-pyridin-4-yl-pyrazolo[5,1-b]thiazol-6-yl)-phenylamine as white solid.