Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH3:19])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]([F:44])([F:43])[O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][NH:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[CH:5]=[C:4]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:3]=[C:2]([C:37]3[CH:36]=[CH:35][C:34]([O:33][C:32]([F:31])([F:43])[F:44])=[CH:39][CH:38]=3)[N:7]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: CNS(=O)(=O)c1ccc(Nc2cc(N3CCCC3)cc(Cl)n2)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CNS(=O)(=O)c1ccc(Nc2cc(N3CCCC3)cc(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 34 %

Procedure:
To a solution of 4-(6-chloro-4-pyrrolidin-1-yl-pyridin-2-ylamino)-N-methyl-benzenesulfonamide (100 mg, 0.27 mmol) in 1,4-dioxane (8 mL) was added 1N sodium carbonate solution (0.3 mL) and tetrakis(triphenylphosphine)palladium(0) (15.8 mg, 0.013 mmol), followed by 4-trifluoromethoxyphenyl boronic acid (67.2 mg, 0.32 mmol). The resulting reaction mixture was refluxed for 8 hours, after which time water was added (100 mL) to the reaction mixture, and the product was extracted with ethyl acetate (100 mL×3). The organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum. The resulting product was purified by column chromatography using 230-400 mesh silica gel (20:80 acetone:petroleum ether) to afford the desired compound pale yellow solid (46 mg, yield 34%.).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:15](=O)[CH2:16][C:17](=O)[CH3:18])[C:9]2[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:8]1=2)=[O:6])([CH3:3])[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.[NH2:56][NH2:57]>CCO>[F:35][C:32]([F:34])([F:33])[C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=1)[CH2:21][N:14]([C:15]1[CH:16]=[C:17]([CH3:18])[NH:57][N:56]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:6])[C:8]2[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:9]1=2
Reactant: CC(=O)CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)ccc21
Reactant: NN
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CCO
Product: Cc1cc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C2CCCN(C(=O)OC(C)C)c3cc(Cl)ccc32)n[nH]1
Temperature: 0 °C
Yield: 21.2 %

Procedure:
Add cold (ice bath) absolute EtOH (1 mL) slowly to a cooled 0° C. stirred mixture of (+/−)-5-[(3,5-bistrifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester (118 mg, 0.20 mmol) and phosphorus pentoxide (511 mg, 3.6 mmol). Then, add hydrazine hydrate (0.062 mL, 2.0 mmol) dropwise while keeping the mixture cooled at 0° C. Heat at 100° C. overnight in a sealed tube. Cool down the mixture and remove the solvents under reduce pressure. Partition the residue between water and dichloromethane. Separate the layers, and dry organic phase over anhydrous magnesium sulfate, filter and concentrate in vacuo. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, and then by a SCX cartridge to afford the title compound (25 mg, 21%). MS (ES+): 589 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]([C:33](=[O:35])[NH2:34])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:32])[CH2:22][CH2:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(C)(C)C>ClCCl>[NH2:14][C@@H:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:32])[CH2:22][CH2:23][C:24](=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:33]([NH2:34])=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)CCC(=O)c1ccccc1)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)[C@@H](N)CCCCNC(=O)CCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
Trifluoroacetic acid (25 ml) was added to a solution of [(1S)-1-carbamoyl-5-(4-oxo-4-phenylbutyrylamino)pentyl]carbamic acid tert-butyl ester (0.56 g, 1.38 mmol) in dichloromethane (25 ml). The reaction mixture was stirred for 1 h at room temperature. The solvent was removed. The crude product was purified by HPLC on a RP-18 column, using a gradient of 20-45% acetonitrile in water, containing 0.1% of trifluoracetic acid as buffer to give 92 mg of the title compound with a purity of approx. 85%, which was used for the further experiments.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23][CH2:24][C:25]([OH:27])=O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].FC(F)(F)C(O)=O.[NH2:35][C@@H:36]1[C:43](=[O:44])[N:42]2[C@@H:37]1[S:38][CH2:39][C:40](/[CH:48]=[C:49]1/[C:50](=[O:62])[N:51]([CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([OH:61])[CH:56]=3)[CH2:52][CH2:53]/1)=[C:41]2[C:45]([OH:47])=[O:46]>CN(C)C(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23][CH2:24][C:25]([NH:35][C@@H:36]2[C:43](=[O:44])[N:42]3[C@@H:37]2[S:38][CH2:39][C:40](/[CH:48]=[C:49]2/[C:50](=[O:62])[N:51]([CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[C:57]([OH:61])[CH:56]=4)[CH2:52][CH2:53]/2)=[C:41]3[C:45]([OH:47])=[O:46])=[O:27])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(SCC(=O)O)cc1OC
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cccc(O)c4)C3=O)CS[C@H]12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: COc1ccc(SCC(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4\CCN(Cc5cccc(O)c5)C4=O)CS[C@H]23)cc1OC

Procedure:
With 121.1 mg (0.75 mmol) 1,1,-carbonyldiimidazole, 170.6 mg (0.75 mmol) 2-(3,4-dimethoxyphenylthio)acetic acid and 250.0 mg (0.62 mmol) (E)-(6R,7R)-7-amino-3-[1-(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia- 1-aza-bicyclo[4.2.0]oct-2-ene2-carboxylic acid trifluoroacetate in 4 ml N,N-dimethylacetamide. The resulting solid was purified by column chromatography on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:7](O)=[O:8])[CH2:3][C:4](O)=[O:5].[NH2:11]C(N)=O>O>[CH3:1][C:2]1([CH3:10])[CH2:3][C:4](=[O:5])[NH:11][C:7]1=[O:8]
Reactant: NC(N)=O
Reactant: CC(C)(CC(=O)O)C(=O)O
Solvent: O
Product: CC1(C)CC(=O)NC1=O
Temperature: 160 °C
Reaction time: 10 h
Yield: 89.7 %

Procedure:
The mixture of 10 g of 3,3-dimethylsuccinic acid and 102.7 g of urea was stirred for 10 hours at 160° C. Into the reaction mixture was added water at 100° C., and the mixture was cooled to near room temperature. The mixture was extracted with ethyl acetate three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 7.8 g of 3,3-dimethylpyrrolidin-2,5-dione.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[N:7]([CH:8]=[CH:9][CH:10]=2)[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1)=O.[NH2:17][OH:18].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[OH:18]/[N:17]=[CH:1]/[C:3]1[C:11]2[N:7]([CH:8]=[CH:9][CH:10]=2)[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(C=O)c2cccn12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(/C=N/O)c2cccn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 8-formylindolizine-5-carboxylate (100 mg, 0.46 mmol) and NH2OH.HCl (48 mg, 0.69 mmol) in THF (10 mL) and H2O (3 mL) at rt was added NaOAc (75 mg, 0.92 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was extracted with EA (2×20 mL). The organic layers was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was used in next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:11]([N:18]=[C:19]=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19](=[O:20])[NH:1][CH2:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(C)(C)CN
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)C(C)(C)CNC(=O)NCc1ccccc1
Yield: 60.4 %

Procedure:
According to the procedure described in the synthesis method of Compound V-3, ethyl 3-amino-2,2-dimethylpropanoate (2.90 mg, 20 mmol) was reacted with benzyl isocyanate (1.24 ml, 10 mmol) to obtain the title compound (1.68 g, 30%).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[O:9][N:8]=1.BrBr.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1ON=C(CCC[Br:43])C=1>>[Br:43][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[O:9][N:8]=1
Reactant: Cc1cc(CCCBr)no1
Reactant: Cc1cc(CCCCCO)no1
Agent: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(CCCCCBr)no1
Yield: 77 %

Procedure:
3-(5-Bromopentyl)-5-methylisoxazole [XXVII; R9 =CH3, Hal=Br] was prepared by reacting 3-(5-hydroxypentyl)-5-methylisoxazole with bromine and triphenylphosphine according to the procedure of part (f) above, and was obtained in 77% yield as an oil, b.p. 140°-150° C. (0.05 mm).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[CH:23]=[CH2:24].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C>[C:27]([O:26][C:22](=[O:25])[CH:23]=[CH:24][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C=Cc1ccc(-c2ccc(OC(=O)OC(C)(C)C)cc2)cc1
Reaction time: 24 h
Yield: 93.9 %

Procedure:
To 7.4 g (21.2 mmol) of 4-(tert-butoxycarbonyloxy)-4′-bromobiphenyl synthesized in the Example 9, were added 2.85 g (22.2 mmol) of tert-butyl acrylate, 10 ml of triethylamine, 30 ml of acetonitrile, 50 mg (2.22×10−1 mmol) of palladium acetate [Pd(OAc)2], and 116 mg (4.42×10−1 mmol) triphenylphosphine. The reaction system was purged with argon, and the reaction was conducted for 24 hours with heating and refluxing. The reaction mixture was poured into 500 ml of an iced water, and hydrochloric acid was added to the resultant mixture with stirring. The solid formed by stirring was collected by filtration, washed with water, dried, and recrystallized from methanol to give 7.9 g (19.9 mmol) of tert-butyl-4-(4′-tert-butoxycarbonyloxyphenyl)cinnamate.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3].P(Cl)(Cl)(Cl)=O.[Cl:20][C:21]([Cl:26])(Cl)[C:22](Cl)=[O:23]>CCOCC.[Cu].[Zn]>[Cl:20][C:21]1([Cl:26])[C:22](=[O:23])[CH2:3][CH:2]1[CH2:1][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(CC1CC(=O)C1(Cl)Cl)C(=O)OCC
Temperature: 25 °C

Procedure:
To a stirred suspension of Cu.Zn (1.771 g, 13.73 mmol) and diethyl 2-allylmalonate (1.084 mL, 5.49 mmol) in anhydrous Et2O (20 mL) at reflux was added a solution of phosphorus oxychloride (1.127 mL, 12.09 mmol) and 2,2,2-trichloroacetyl chloride (1.357 mL, 12.09 mmol) in Et2O (10 mL) dropwise through an addition funnel over 2 h. The resulting mixture was then heated at reflux overnight. After cooling to room temperature, the mixture was filtered through CELITE® and washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel column chromatography (80 g, EtOAc/hexane=0-50%) to afford Preparation 7A (1.59 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[N:9]=2)[NH:4][CH:3]=1.P(Br)(Br)[Br:16].O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:16][C:11]1[C:2]([Cl:1])=[CH:3][N:4]=[C:5]2[C:10]=1[N:9]=[C:8]([O:13][CH3:14])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]cc(Cl)c(=O)c2n1
Reactant: BrP(Br)Br
Agent: COc1ccc2ncc(Cl)c(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ncc(Cl)c(Br)c2n1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 3-chloro-6-(methyloxy)-1,5-naphthyridin-4(1H)-one (3-chloro-6-(methoxy)-1,5-naphthyridin-4-ol, for a synthesis see WO2004058144, Example 1(a)) (43 g, 204.8 mmol) in N,N-dimethylformamide (500 ml) at 0° C. was added phosphorous tribromide dropwise (23.3 ml, 245.8 mmol). The reaction mixture was then stirred at 10° C. for 0.5 hour and then at 25° C. for 1 hour. The mixture was then poured onto 1600 ml of water and basified to pH 7 with potassium carbonate. The solid formed was filtered off, washed with water and dried in vacuo to afford the desired compound (51 g, 91%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13](=[O:25])[C@H:14]([CH2:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19])[NH2:15].[Cl:26][C:27]1[CH:35]=[C:34]([C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=2)=[O:37])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[C:34]([C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=2)=[O:37])[CH:33]=[CH:32][C:28]=1[C:29]([NH:15][C@H:14]([C:13]([O:12][CH3:11])=[O:25])[CH2:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19])=[O:30]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC(=O)[C@@H](N)CNC(=O)c1cccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 70.2 %

Procedure:
Diisopropylethylamine (7.00 g, 64.2 mmol) was added to a solution of 3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester hydrochloride (Example 301; 7.00 g, 26.4 mmol), 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]-carbonyl]benzoic acid (Example 26; 7.00 g, 22.9 mmol), and HBTU (13.00 g, 34.3 mmol) in DMF (75 mL). The solution was allowed to stir at room temperature for 4 days, and it was then concentrated to remove most of the DMF. Ethyl acetate (200 mL) was added, followed by water (200 mL) and 1 M HCl (100 mL). The layers were separated; the ethyl acetate layer was evaporated, and the residue was chromatographed (50-100% ethyl acetate/hexanes) to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (8.30 g, 70%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=[C:28]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc(-c5ccccc5)nc5ccccc45)cc3CC[C@@H]12
Yield: 63.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 4-chloro-2-phenylquinazoline (111 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80-100% ethyl acetate/hexanes eluent gradient) to give 112 mg (63%) of the title compound as an off white solid. mp 185°-193°. FDMS: m/e=465. α[D]589 =+49.59 (c=0.57, chloroform).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[ClH:6].[CH3:7][C:8]1[CH:9]=[C:10]([CH:26](O)[CH2:27][NH+:28]=[C:29]([NH2:31])[NH2:30])[CH:11]=[C:12]([CH3:25])[C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C.CCOCC>[ClH:3].[Cl:6][CH:26]([C:10]1[CH:9]=[C:8]([CH3:7])[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[C:12]([CH3:25])[CH:11]=1)[CH2:27][NH:28][C:29]([NH2:31])=[NH2+:30]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C(O)C[NH+]=C(N)N)cc(C)c1OCc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc(C(Cl)CNC(N)=[NH2+])cc(C)c1OCc1ccccc1[N+](=O)[O-]
Reaction time: 24 h
Yield: 75.3 %

Procedure:
Phosphoryl Chloride (3.3 mL,3.54 mmol) was added to a solution of 14 (40.2 mg, 0.10 mmol) in DMF (1 ml). Following stirring under N2 for 24 hrs, the cmde product was isolated by diluting with Et2O. The product was then purified by recrystillization from CHCl3Et2O/EtOH. Giving pure compound 15 (31.2 mg, 74%) as an off-white solid: 1H NMR (270 MHz, MeCN d3) δ8.14(d, 1H, I=8.2 Hz, ArNO2), 8.07(d, J=8.2 Hz, 1H, ArNO2), 7.81 (t, J=8.2 Hz, 1H, ArNO2), 7.59(t, J=8.2 Hz, 1H, ArNO2), 7.49(t, J=5.2 Hz, 1H, RCH2NH), 7.19(s, 2H, Ar-H), 5.20.(s, 2H, ArOCH2 Ar(NO2)), 5.04(m, 1H, ArCH(OH)), 3.71(m, 2H, CH2—NH), 2.24(s, 6H, ArCH) 13C NMR (67.5 MHz, MeOHd4) δ157.4, 156.1, 147.4, 134.1, 133.7, 133.4, 131.5, 128.8, 128.5, 127.9, 124.5, 70.1, 60.3, 48.3, 15.2;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2oc(-c3ccc(F)cc3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc2oc(-c3ccc(F)cc3)nc12
Yield: 80.7 %

Procedure:
A mixture of 1.1 g (4.0 mmol) methyl 2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate 9ee and 3.7 mL of 3N aqueous NaOH in 10 mL of THF was refluxed overnight. After cooling the reaction mixture was poured into water and acidified with conc. HCl. The resulting solid was filtered and dried to give 830 mg (79%) of 2-(4-fluorophenyl)-benzo[d]oxazole-4-carboxylic acid, 9ff. MS m/z (M+H+) 258.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][C:7]([Cl:12])([Cl:11])[C:8](Cl)=[O:9]>>[Cl:6][C:7]([Cl:12])([Cl:11])[C:8]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:9]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: c1cc[nH]c1
Product: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Yield: 79.2 %

Procedure:
2-(Trichloroacetyl)pyrrole was prepared from pyrrole (12.5 g, 186 mmol) and trichloroacetyl chloride (36.5 g, 200 mmol) according to the method of Bailey et al, Org. Synth., 1971, 100. In this manner the title compound (31.3 g, 80%) was obtained as a cream solid, m.p. 73-74° C. (lit. m.p. 73-75° C.). 1H n.m.r. d 9.30, broad s, 1H; 7.39, m, 1H; 7.17, m, 1H; 6.40, dt, J 3.9 and 2.4 Hz, 1H. (see also J. Org. Chem., 1972, 37, 3618; 1993, 58, 7245).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=O)[CH3:25].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][NH2:34].O>C(O)C.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=[N:34][NH:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=1)[CH3:25]
Reactant: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=O)c2cc1OC
Reactant: NNc1ccccn1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CCO
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=NNc3ccccn3)c2cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethylphenyl]-1-ethanone (compound 38) (30 mg) was dissolved in ethanol (1 ml) to prepare a solution. (2-Pyridyl)hydrazine (28 mg) was added to the solution, and the mixture was stirred at 60° C. overnight. Ytterbium triflate (1 mg) was added to the reaction solution, and the mixture was stirred at 60° C. for 5 days. The reaction solution was cooled to room temperature, water was then added to the cooled solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using hexane-acetone to give the title compound (13 mg, yield 39%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][CH:11]([C:16]1[CH:20]=[C:19]([CH:21]=O)[O:18][N:17]=1)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:31]C(O)=O>O>[CH2:37]([O:36][C:30](=[O:35])[CH:31]=[CH:21][C:19]1[O:18][N:17]=[C:16]([CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:23])[CH2:12][CH:13]([CH3:14])[CH3:15])[CH:20]=1)[CH3:38]
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)c1cc(C=O)on1
Reactant: CCOC(=O)CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1cc(C(CC(C)C)NC(=O)OCc2ccccc2)no1
Temperature: 550 °C
Yield: 95.5 %

Procedure:
A stirred mixture of [1-(5-formyl-isoxazol-3-yl)-3-methyl-butyl]-carbamic acid benzyl ester (407 mg, 1.3 mmol), pyridine (10 ml) and ethyl hydrogen malonate (255 mg, 1.9 mmol) was warmed to 550° C. After 2 days the mixture was cooled to room temperature, poured into water and extracted into EtOAc (3×). The combined organics were washed with 1N HCl, water, and brine; dried over NaSO4, filtered and concentrated under reduced pressure to give 480 mg of a yellow oil. Purification by Flash 40(small) chromatography eluting with 1:3 EtOAc/hexane gave 220 mg of the title compound as a light yellow oil. MS [M+1]+387.
Reaction SMILES: C[N:2]([CH3:19])/[CH:3]=[CH:4]/[C:5](=O)[CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[NH2:20][C:21]1[NH:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)[C:22]=1C#N>CC(O)=O>[O:16]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:17])[N:7]1[CH2:6][C:5]1[N:25]2[N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)[C:22]([C:21]#[N:20])=[C:19]2[N:2]=[CH:3][CH:4]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: CN(C)/C=C/C(=O)CN1C(=O)c2ccccc2C1=O
Solvent: CC(=O)O
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(CN3C(=O)c4ccccc4C3=O)ccnc12
Temperature: 120 °C
Yield: 39.1 %

Procedure:
A mixture of (E)-2-(4-(dimethylamino)-2-oxobut-3-enyl)isoindoline-1,3-dione (600 mg, 2.33 mmol) and 5-amino-3-(4-phenoxy phenyl)-1H-pyrazole-4-carbonitrile (642 mg, 2.33 mmol) in 20 mL of HOAc was stirred and heated to 120° C. for 15 hr. The mixture was concentrated and suspended in 30 mL of solvent (PE/EA=4/1). The mixture was filtered and the solid was purified by pre-TLC (DCM/EA=50/1) to give 430 mg (40%) of 7-((1,3-dioxoisoindolin-2-yl)methyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile as a solid. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J=4.4 Hz, 1H), 8.05 (d, J=8.8 Hz, 2H), 7.96-7.90 (m, 1H), 7.88-7.85 (m, 2H), 7.50 (d, J=4.4 Hz, 1H), 7.46-7.37 (m, 2H), 7.21-7.09 (m, 5H), 5.32 (s, 2H). MS (ESI) m/e [M+1]+ 472.1.