Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:19]=[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CC#N>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:19]=[C:9]2[N:10]=[C:11]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Reactant: C1CNCCN1
Solvent: CC#N
Product: Nc1nc(N2CCNCC2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C

Procedure:
18 mmol of 2-furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (prepared as described in Caulkett et al., J. Chem. Soc. Perkin Trans I. 801-808 (1995)) was suspended in 50 mL of CH3CN along with 5 eq. of piperazine. The reaction mixture was stirred under reflux for 2 hours. It was then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in CH2Cl2 and washed with H2O, brine, dried with Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by chromatography (95% CH2Cl2, 4% MeOH, 1% Et3N) to afford 2-furan-2-yl-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine. 1H NMR (DMSO-d6) δ 8.2 (br s, 2H), 7.85 (d, J=1.0 Hz, 1H), 7.07 (d, J=3.6 Hz, 1H), 6.68 (dd, J=3.6 Hz. 1.0 Hz, 1H), 3.20-2.75 (m, 8H) ppm. MS: m/z=287 [M+H]+.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:15][C@@H:14]([C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)=[O:17])[C:13]1([CH3:30])[CH3:29])=O)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:11][C@H:12]1[CH2:15][C@@H:14]([C:16]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:23]2)=[O:17])[C:13]1([CH3:29])[CH3:30]
Reactant: CCOC(=O)C1CCN(C(=O)[C@@H]2C[C@H](NC(=O)OCc3ccccc3)C2(C)C)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(C(=O)[C@@H]2C[C@H](N)C2(C)C)CC1
Reaction time: 8 h

Procedure:
To a solution of ethyl 1-((1R,3S)-3-(benzyloxycarbonylamino)-2,2-dimethylcyclobutanecarbonyl)piperidine-4-carboxylate (step 1, 1.30 g) in ethyl acetate (50 ml), Pd/C (100 mg) was added carefully under argon atmosphere. Then the reaction mixture was stirred for overnight under hydrogen conditions. After completion of the reaction (monitored by TLC), diluted with ethyl acetate, filtered on celite, washed with ethyl acetate. The combined organic extracts were concentrated under reduced pressure to give crude product which was preceded for next step without further purification and analysis.
Reaction SMILES: [CH2:1]([NH-:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]=[C:10]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](O)=[O:12].C(N)C1C=CC=CC=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.C(N(CC)CC)C>[CH2:1]([NH:8][C:11](=[O:12])[C:10](=[O:9])[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH-]Cc1ccccc1
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: NCc1ccccc1
Product: O=C(CCc1ccccc1)C(=O)NCc1ccccc1

Procedure:
Prepare the benzylamide of 2-oxo-4-phenylbutyric acid by dissolving 3.0 g of this acid, 2.4 ml of benzylamine, and 4.7 ml of diphenylphosphorylazide in 60 ml of cold dimethylformamide and adding dropwise 2.6 ml of triethylamine in DMF, holding the temperature at about -10° C. for 2.5 hours. Store overnight at room temperature, strip off the DMF in vacuo, and partition the residue between water and ethyl acetate. Chromatograph the contents of the organic layer on silica gel, eluting with ethyl acetate:hexane 1:4. Evaporate the solvent from the product fractions to obtain 2.2 g of crystalline N-benzyl-2-oxo-4-phenylbutyramide. Couple 1.26 g of this with 0.19 g of L-Ala-L-Pro using 0.125 g of sodium cyanoborohydride in ethanol in the manner described in Example 44. Purify the crude product by gel filtration (LH-20) to obtain the mixture of diastereoisomers of N-(1-benzylaminocarbonyl-3-phenylpropyl)-L-alanyl-L-proline. The nmr spectrum (CDCl3) shows a doublet at 1.1 ppm (3H) a close pair of singlets at 7.3 (10H), and complex absorption at 1.6-2.3 (6H), 2.3-2.9 (2H), 2.9-3.8 (4H) and 4.0-4.6 (3H). The mass spectrum of silylated material shows prominent peaks at m/e=509 (monosilyl derivative) and 581 (disilyl derivative).
Reaction SMILES: [ClH:1].[NH2:2][NH:3][C:4](=[NH:7])[NH:5][NH2:6].O.[CH3:9][C:10]1([CH3:19])[CH2:15][C:14](=O)[CH2:13][C:12]([CH3:18])([CH3:17])[NH:11]1>C(O)C>[ClH:1].[CH3:9][C:10]1([CH3:19])[CH2:15][C:14](=[N:2][NH:3][C:4]([NH:5][N:6]=[C:14]2[CH2:13][C:12]([CH3:18])([CH3:17])[NH:11][C:10]([CH3:19])([CH3:9])[CH2:15]2)=[NH:7])[CH2:13][C:12]([CH3:18])([CH3:17])[NH:11]1
Reactant: N=C(NN)NN
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1(C)CC(=NNC(=N)NN=C2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of diaminoguanidine hydrochloride (6.28 grams; 0.05 mole) and 2,2,6,6-tetramethyl-4-piperidone monohydrate (17.3 grams; 0.10 mole) in 200 mls. of ethanol 2B was refluxed for a period of 15 hours while stirring. The resulting slurry was cooled to 25° C. and the solid was separated to obtain 10.0 grams of crude 1,3-bis[(2,2,6,6-tetramethyl-4-piperidylidene)amino]guanidine hydrochloride. Recrystallization of the crude hydrochloride from ethanol 2B gave 8.9 grams of white solid, m.p. 210°-220° C. (dec).
Reaction SMILES: I.[CH3:2][O:3][C:4]([C:6]1[C:7]2[C:8]([CH2:15]N(C)C)=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:5].S(OC)(OC)(=O)=O.C[O-].[Na+].[N+:29]([CH:32]([CH3:34])[CH3:33])([O-:31])=[O:30]>CO.C(OCC)(=O)C.[NH4+].[Cl-]>[CH3:2][O:3][C:4]([C:6]1[C:7]2[C:8]([CH2:15][C:32]([CH3:34])([N+:29]([O-:31])=[O:30])[CH3:33])=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:5]
Reactant: CC(C)[N+](=O)[O-]
Reactant: COC(=O)c1cccc2[nH]cc(CN(C)C)c12
Agent: C[O-]
Agent: I
Agent: [Cl-]
Solvent: COS(=O)(=O)OC
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2[nH]cc(CC(C)(C)[N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 0° C. solution of 3-dimethylaminomethyl-1H-indole-4-carboxylic acid methyl ester hydroiodide (19 g, 52.7 mmol) in 75 ml of methanol and 75 ml of 2-nitropropane is treated with dimethyl sulfate (10 ml, 105.5 mmol) and solid sodium methoxide (6.3 g, 110.6 mmol) sequentially. The resulting mixture is allowed to warm to ambient temperature, and, after stirring overnight, the reaction mixture is diluted with ethyl acetate (300 ml) and saturated aqueous NH4Cl solution (500 ml). The aqueous layer is extracted with ethyl acetate (200 ml), and the combined organic layers are dried over Na2SO4 and concentrated in vacuo to give 3-(2-methyl-2-nitropropyl)-1H-indole-4-carboxylic acid methyl ester in quantitative yield.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:22])[CH:18]=3)[N:13]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]=2[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[NH2:8][C@@H:9]1[CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:22])[CH:18]=3)[N:13]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]=2[CH2:11][CH2:10]1
Reactant: CCOC(=O)Cn1c2c(c3cc(F)ccc31)C[C@@H](NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)Cn1c2c(c3cc(F)ccc31)C[C@@H](N)CC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of (S)-ethyl 2-(3-((tert-butoxycarbonyl)amino)-6-fluoro-3,4-dihydro-1H-carbazol-9(2H)-yl)acetate (8.2 g, 0.021 mol) in dry DCM (50 ml) was added dropwise 4N HCl in dioxane (52.5 ml, 0.21 mol). The resulting reaction mixture was stirred at 0° C. for 2 h and then at rt for 5 h. The reaction mixture was concentrated in vacuo and the resulting solid was dissolved in EtOH (70 ml) and was added at 0° C. 3N HCl in EA (7 ml). The reaction mixture was stirred at reflux overnight. After cooling to rt, the reaction mixture was concentrated in vacuo to afford the title compound as a beige powder.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=1.CO.[OH-].[Na+]>C1COCC1>[C:21]1([C:18]2[CH:19]=[CH:20][C:14]3[O:13][C:12]([C:8]4[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:27])=[O:2])[CH:11]=[CH:10][CH:9]=4)=[N:16][C:15]=3[CH:17]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C=Cc1cccc(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C=Cc1cccc(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Reaction time: 2 h

Procedure:
The ester (33) (41 mg, 0.12 mmol) was hydrolysed using Method C, except that MeOH (3 mL), THF (3 mL) and 1M NaOH (5 mL) were used, and the reaction was stirred for 2 hours. Yield: 21 mg, 53%; LC-MS tr 1.74 min; HPLC Purity: 96%; MS (ES+) m/z 342 (M+H); 1H NMR (400 MHz; DMSO): δ 6.7 (d, 1H), 7.4 (t, 1H), 7.45-7.55 (t, 2H), 7.70-7.80 (m, 5H), 7.9 (d, 1H), 8.05 (d, 1H), 8.10 (s, 1H), 8.30 (d, 1H), 8.50 (s, 1H), 12.55 (br. s, 1H)
Reaction SMILES: ClC(N(C)C)=C.[CH3:7][O:8][C@H:9]([CH3:13])[C:10]([OH:12])=O.[NH2:14][C:15]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([NH:33][C:34]([NH:36][C:37]3[N:41]([C:42]4[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=4)[N:40]=[C:39]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:38]=3)=[O:35])=[CH:25][CH:24]=2)[CH:18]=[CH:17][N:16]=1.CCN(C(C)C)C(C)C.N>C(Cl)Cl.CO.CCCC(C)C.CCOC(C)=O>[C:49]([C:39]1[CH:38]=[C:37]([NH:36][C:34](=[O:35])[NH:33][C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([O:22][CH2:21][C:19]3[CH:18]=[CH:17][N:16]=[C:15]([NH:14][C:10](=[O:12])[C@H:9]([O:8][CH3:7])[CH3:13])[CH:20]=3)=[CH:24][CH:25]=2)[N:41]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:40]=1)([CH3:52])([CH3:51])[CH3:50]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(N)c3)c3ccccc23)cc1
Reactant: CO[C@H](C)C(=O)O
Agent: C=C(Cl)N(C)C
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCC(C)C
Product: CO[C@H](C)C(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
1-Chloro-N,N-dimethylethenamine (38 μL, 0.36 mmol) was added to a stirred solution of (R)-2-methoxypropionic acid (37 mg, 0.36 mmol) in DCM (1.0 mL) and the resulting solution was stirred at RT for 1 hr. The solution was added dropwise to a stirred mixture of 1-(4-((2-aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate A) (75 mg, 0.14 mmol) and DIPEA (75 μL, 0.43 mmol) in DCM (2.0 mL) at 0° C. Stirring was continued for a further 48 hr. The mixture was poured in to 1% NH3 in MeOH (20 mL) and stirred for 1 hr, and evaporated in vacuo to give a yellow residue. Column chromatography (12 g, 20-50% EtOAc in iso-hexane) gave (R)—N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-methoxypropanamide (Example 5) as a light pink solid (39 mg, 43%): m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, d), 1.30 (3H, s), 2.39 (3H, s), 3.31 (3H, s), 4.02 (1H, q), 5.39 (2H, s), 6.35 (1H, s), 7.02 (1H, d), 7.29 (1H, dd), 7.35 (2H, m), 7.45 (2H, m), 7.56-7.64 (3H, m), 7.93 (1H, m), 8.30-8.37 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 10.09 (1H, s).
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:60][CH2:61][N:62]([CH3:64])[CH3:63]>CN(C=O)C.CCOCC>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:60][CH2:61][N:62]([CH3:64])[CH3:63])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: CN(C)CCCl
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCN(C)C)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF was added potassium carbonate (4.4 eq.) and 2-chloro-N,N-dimethylethanamine hydrochloride (2.5 eq.). The reaction was heated to 80° C. and stirred for 4 hr. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with 5% aqueous potassium carbonate solution, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 2%→5% [2 M NH3 in MeOH] in DCM) to afford the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:23][O:24][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.COCCOC>[CH2:17]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2([C:5]3[CH:6]=[CH:7][C:2]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)=[CH:3][C:4]=3[O:24][CH2:23]2)[C:9]1=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: OB(O)c1cccnc1
Reactant: CCCCCN1C(=O)C2(COc3cc(Br)ccc32)c2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Product: CCCCCN1C(=O)C2(COc3cc(-c4cccnc4)ccc32)c2ccccc21
Yield: 95.8 %

Procedure:
A mixture of 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.08 g, 0.19 mmol), pyridine-3-boronic acid (0.05 g, 0.41 mmol), palladium acetate (0.002 g, 0.07 mmol), tri-O-tolylphosphine (0.0015 g, 0.005 mmol), 2 M sodium carbonate (1.00 mL) and 1,2-dimethoxyethane (9.00 mL) was heated at reflux for 16 hours under N2. The solvent was evaporated and the black residue was extracted with ethyl acetate (4×15.0 mL). The combined organics was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 4/1) to give the title compound (0.07 g, 67% yield) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.60 (br, 1H), 7.85 (d, 1H), 7.45-7.24 (m, 3H), 7.20-7.10 (m, 2H), 7.12-6.98 (m, 2H), 6.95 (d, 1H), 6.81 (d, 1H), 5.05 (d, 1H), 4.78 (d, 1H), 3.89-3.64 (m, 2H), 1.80-1.68 (m, 2H), 1.43-1.34 (m, 4H), 0.92 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.9, 161.6, 149.5, 147.3, 142.6, 139.9, 136.4, 135.6, 133.4, 130.1, 129.2, 124.9, 121.7, 119.5, 110.3, 109.7, 107.7, 80.1, 57.8, 42.3, 28.8, 27.1, 22.3, 14.85; MS (ES+) m/z 385.5 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:16][C:15](=[O:17])[O:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.[N+:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[NH:16][C:15](=[O:17])[O:14][C:8]4([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[C:6]=3[CH:7]=2)[CH:24]=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=C1Nc2ccc(Br)cc2C2(CCCCC2)O1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: O=C1Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc2C2(CCCCC2)O1

Procedure:
Prepared from 6-bromo-spiro[4H-3,1-benzoxazine-4,1′-cyclohexane]-2(1H)-one and 3-nitrophenyl boronic acid according to Procedure A. Off-white solid: mp 245-246° C. 1H-NMR (CDCl3) δ 8.39 (t, 1H, J=1.9 Hz), 8.20 (dd, 1H, J=8.2, 1.4 Hz), 8.11 (s, 1H, D2O exchangeable), 7.86 (d, 1H, J=8.0 Hz), 7.62 (t, 1H, J=8.1 Hz), 7.50 (dd, 1H, J=8.2, 1.9 Hz), 7.39 (d, 1H, J=1.8 Hz), 6.93 (d, 1H, J=8.2 Hz), 2.25 (d, 2H, J=12.7 Hz), 1.60-1.99 (m, 7H), 1.31-1.42 (m, 1H); MS (EI) m/z 337 ([M−H]−, 100%). Anal. Calc. For C19H18N2O4.0.35H2O: C, 66.21; H, 5.47, N, 8.13. Found: C, 66.22; H, 5.43; N, 7.86.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:21][S:22]([C:25]2([CH2:28][CH2:29][CH2:30][O:31]CC3C=CC=CC=3)[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[C:12]2[O:20][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[C:15]=1[CH3:16].B(Cl)(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:21][S:22]([C:25]2([CH2:28][CH2:29][CH2:30][OH:31])[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[C:12]2[O:20][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[C:15]=1[CH3:16]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CCCOCc3ccccc3)CC2)c2n(c1=O)CCO2
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CCCO)CC2)c2n(c1=O)CCO2
Temperature: 0 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
1-(3-Benzyloxy-propyl)cyclopropanesulfonic acid [7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-8-yl]-amide (0.23 g, 0.352 mmol) in DCM (10 mL) was reacted with 1M BCl3 (0.12 g, 1.056 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 3 hours. Purification by column chromatography on silica gel (4% MeOH in CHCl3) afforded 70 mg of the product (36% yield).
Reaction SMILES: [CH3:1][Li].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]2[CH:12]([O:13]2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(OCC)C.[Cu]I>[C:3]([O:7][C:8]([N:10]1[CH2:11][C@@H:12]([CH3:1])[C@H:14]([OH:13])[CH2:15]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: [Li]C
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Agent: [Cu]I
Solvent: CCOCC
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
Cool down a suspension of copper (I) iodide (1 g, 5.5 mmol) in dry diethyl ether (13 mL) under nitrogen to −10° C. with a saturated aqueous sodium chloride/ice bath and add methyllithium (1.6 M in diethyl ether, 6.8 mL, 10.9 mmol) dropwise to maintain the temperature at −10° C. Stir for 20 min at this temperature and add a solution of 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (430 mg, 2.32 mmol) in dry diethyl ether (5 mL). Stir for 1 h at −10° C. then add water (5 mL) dropwise and dichloromethane (5 mL), filter the resulting mixture through a pad of Celite® and wash thoroughly with dichloromethane. Separate the aqueous and organic phases and extract with 30:70 isopropanol:chloroform and wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give trans-3-hydroxy-4-methylpyrrolidine-1-carboxylic acid tert-butyl ester which can be used without further purification (360 mg, 77%). 1H NMR (300 MHz, CDCl3) δ 3.84-3.91 (1H, m), 3.48-3.62 (2H, m), 3.10-3.23 (1H, m), 2.88-3.02 (1H, m), 1.98-2.12 (1H, m), 1.39 (9H, s), 0.95 (3H, d, J=6.97 Hz), MS (ES): m/z=224 [M+Na].
Reaction SMILES: C[O:2][C:3]1[C:10]([O:11]C)=[CH:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:4]=1[CH:5]=[O:6].Br>C(O)(=O)C>[OH:2][C:3]1[C:10]([OH:11])=[CH:9][C:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1cc(-c2ccccc2)cc(C=O)c1OC
Agent: Br
Solvent: CC(=O)O
Product: O=Cc1cc(-c2ccccc2)cc(O)c1O
Yield: 52.1 %

Procedure:
A mixture of 21 (0.63 g; 2.6 mmol), 48% aqueous hydrobromic acid (15 mL) and acetic acid (12 mL) was stirred under nitrogen at reflux overnight. The suspension was decanted from dark solid and evaporated. The residue was taken up in boiling dichloromethane (three lots of 50 mL), filtered hot and evaporated giving 22 as pale brown solid (0.290 g):
Reaction SMILES: N1C=CN=C1.C1CCN2C(=NCCC2)CC1.[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:27][C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:29]=1[C:40]1[CH:45]=[CH:44][N:43]=[CH:42][N:41]=1>C1COCC1>[F:39][C:36]1[CH:37]=[CH:38][C:33]([C:30]2[C:29]([C:40]3[CH:45]=[CH:44][N:43]=[CH:42][N:41]=3)=[C:28]([NH:27][C:24](=[O:25])[CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:32][N:31]=2)=[CH:34][CH:35]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1onc(-c2ccc(F)cc2)c1-c1ccncn1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccccc1)Nc1onc(-c2ccc(F)cc2)c1-c1ccncn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.9 %

Procedure:
Imidazole 0.43 g and DBU 1.9 g were dissolved in 40 mL of THF. Under cooling with ice, 0.97 g of phenylacetyl chloride was dropped into the solution, followed by 20 minutes' stirring at room temperature. Then 40 mL of a THF solution containing 0.8 g of 5-amino-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole was dropped into the system and stirred at room temperature for 6 hours. From the reaction solution the solvent was distilled off under reduced pressure and water was added to the residue, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and from which the solvent was distilled off under reduced pressure. Thus obtained residue was purified on 40 g silica gel column chromatography (eluent, chloroform:methanol=100:1) and washed with ether to provide 0.77 g of the title compound (yield: 66%) in the form of colorless crystal.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])C1C=CC=CC=1>[Pd]>[CH3:14][N:11]1[CH2:12][CH2:13][NH:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1
Reactant: CCOC(=O)C1CN(C)CCN1Cc1ccccc1
Agent: [Pd]
Product: CCOC(=O)C1CN(C)CCN1
Yield: 81.8 %

Procedure:
Ethyl 1-benzyl-4-methylpiperazine-2-carboxylate (11.54 g, 44 mmol) was reacted with Pd—C (10%, 1 g) according to the procedure as described in Example 34, Step C to give the title compound as colorless oil (6.2 g, 82%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C#N)c1
Reaction time: 0.02 h
Yield: 112.1 %

Procedure:
40% Methanolic Triton B (0.06 mL, 0.13 mM) was added to a solution of the 9-[(3-cyanophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (34.1 mg, 0.1 mM) in 5 mL DMF at room temperature. After 1 minute, tert-butyl bromoacetate (40 mg, 0.2 mM) was added and the resultant mixture stirred at room temperature for 24 h. The mixture was diluted with ethyl acetate, washed four times with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with hexane to afford 51 mg (100%) of the {9-[(3-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (CDCl3) δ 7.55 (d, 1H, J=8 Hz), 7.5-7.2 (m, 7H), 6.95 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.3 (br s, 1H), 6.1 (br s, 1H), 5.5 (s, 2H), 4.8 (s, 2H), and 1.5 (s, 9H). IR (KBr, cm−1) 2228, 1748, and 1669. MS (ES) m/e 455, 456.