Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][NH:28][C:29](=[NH:40])[C:30]1[CH:35]=[CH:34][C:33]([S:36](=[O:39])(=[O:38])[NH2:37])=[CH:32][CH:31]=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:27][N:28]=[C:29]([C:30]4[CH:35]=[CH:34][C:33]([S:36]([NH2:37])(=[O:38])=[O:39])=[CH:32][CH:31]=4)[N:40]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:4]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)cc1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) (188 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (ethyl acetate/MeOH/hexane) as a light yellow solid (179 mg, 65%). MS (ISN) 552.8 [(M−H)−]; mp 275° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]([F:60])([F:59])[C:14]1[CH:15]=[C:16]([C@H:24]([N:26]([CH3:58])[C:27]([N:29]2[CH2:49][CH2:48][C@:32]3([N:36]([C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])[CH:35]([OH:47])[CH2:34][CH2:33]3)[CH2:31][C@@H:30]2[C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][C:51]=2[CH3:57])=[O:28])[CH3:25])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.O>C(Cl)Cl>[F:60][C:13]([F:12])([F:59])[C:14]1[CH:15]=[C:16]([C@H:24]([N:26]([CH3:58])[C:27]([N:29]2[CH2:49][CH2:48][C@:32]3([N:36]([C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])[C:35](=[O:47])[CH2:34][CH2:33]3)[CH2:31][C@@H:30]2[C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][C:51]=2[CH3:57])=[O:28])[CH3:25])[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=1
Reactant: Cc1cc(F)ccc1[C@H]1C[C@]2(CCC(O)N2C(=O)OCc2ccccc2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CCC(=O)N2C(=O)OCc2ccccc2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a suspension of Pyridinium chlorochromate (PCC) (66.5 mg, 0.307 mmol) in DCM (2 ml) was added a solution of phenylmethyl(5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-hydroxy-1,8-diazaspiro[4.5]decane-1-carboxylate (Intermediate 32, 107 mg) in DCM (2 ml) and the reaction mixture was left stirring at rt for 1 hr. Further pyridinium chlorochromate (PCC) (66.5 mg, 0.307 mmol) was added and the reaction mixture was left stirring overnight. To the mixture were added H2O and further DCM. The two phases were separated and the organic one was washed two times with water and filtered through a phase separator tube. The crude obtained after evaporation was purified by Flash Chromatography (20 g cartridge; eluting from 2:1 to 1:1 Cy:EtOAc). Relevant fractions were collected and the solvent removed in vacuo obtaining the title compound (86 mg) as a white solid; UPLC: Rt=0.95 mins, m/z=694 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.CO.[OH-].[Na+].O>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(Cl)nc2)C1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a solution of 1,1-dimethylethyl(4RS,5SR)-5-(6-chloro-3-pyridyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate (600 mg, 1.31 mmol) in methanol (3.1 ml) was added 0.5N sodium hydroxide methanol solution (3.1 ml, 1.55 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added water (50 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (321 mg, 57%).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:16][C@H:17]([C:26]([NH:28][C@@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22]C=1.ClC(OCC(C)C)=O>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:16][C@H:17]([C:26]([NH:28][C@@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:27])[CH2:18][C:19]1[CH:20]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5]
Reactant: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](N)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 70 %

Procedure:
Condensation of ZPheOH (7.5 g.) and HDPheOMe (5.4 g.) by the mixed anhydride method using isobutyl chloroformate gave ZPhe-DPheOMe in 66% yield. Debenzyloxycarbonylation of ZPhe-DPheOMe (6.9 g.) by hydrogenation with palladium catalyst gave HPhe-DPheOMe in 100% yield. Condensation of BocProOH (3.23 g.) and HPhe-DPheOMe (4.9 g.) by the mixed anhydride method using isobutyl chloroformate gave BocPro-Phe-DPheOMe in 70% yield. Hydrazinolysis of BocPro-Phe-DPheOMe (5.0 g.) gave BocPro-Phe-DPheNHNH2 in 84% yield.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[NH:14][C:15]4[N:16]([N:20]=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)[N:22]=4)[C:17](=[O:19])[CH:18]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[NH:14][C:15]4[N:16]([N:20]=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)[N:22]=4)[C:17](=[O:19])[CH:18]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1
Reactant: CC(=O)n1ncc2cc(-c3cc(=O)n4nc(-c5ccccn5)nc4[nH]3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=c1cc(-c2ccc3[nH]ncc3c2)[nH]c2nc(-c3ccccn3)nn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(1-acetyl-1H-indazol-5-yl)-2-(pyridin-2-yl)-4H,7H-[1,2,4]triazolo[1,5-α]pyrimidin-7-one (120 mg, crude) in methanol (10 ml) was added a solution of potassium carbonate (48 mg, 0.35 mmol) in water (1 ml), and the reaction was stirred overnight at room temperature. The resulting solution was concentrated and diluted with water (5 ml). The solids were collected by filtration to give a crude product, which was purified by Flash-Prep-HPLC to afford 5-(1H-indazol-5-yl)-2-(pyridin-2-yl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a brown solid (36.9 mg, 12% 2 steps).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH3:5].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11]>[OH-].[Na+]>[CH2:13]([O:12][C:10]([NH:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH3:5])=[O:11])[CH3:14]
Reactant: CCC[C@@H](N)C(=O)O
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC[C@@H](NC(=O)OCC)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
D-Norvaline (10.0 g, 85.3 mmol) was dissolved in aqueous sodium hydroxide (4M, 25 mL). Ethyl chloroformate (10.6 mL, 111 mmol) and aqueous sodium hydroxide (4M, 25 mL) was added over 15 min. at 0° C. The reaction mixture was warmed to room temperature and stirred at this temperature for 4 h. The reaction mixture was washed with diethyl ether three times and then acidified with aqueous hydrochloric acid (2M). The product was extracted with diethyl ether three times. The combined organic phases were dried over magnesium sulphate and concentrated in vacuo to yield the title compound in quantitative yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[S:26]([O:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:4]1)([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: COC(=O)C1(CO)CN(C(=O)OC(C)(C)C)CCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C1(COS(=O)(=O)c2ccc(C)cc2)CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
E3 (3.2 g, 11.62 mmol) was dissolved in pyridine (75 mL), p-toluenesulfonyl chloride (2.66 g, 13.95 mmol) was added in 4 portions in ca. 10 minutes and the solution was stirred for 15 h at RT. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was washed with 1 N HCl and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by flash column chromatography (heptane:EtOAc 100:0 to 40:60) yielding the title compound (4.0 g, 80%). MS (ES) C19H27NO8S requires: 429. found: 452.1 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@:5]1([CH3:18])[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@:5]1([CH3:18])[C@H:9]([O:10][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@]1(C)[C@H](O)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@]1(C)[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of (2S,3R)-3-Hydroxy-2-methylpyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester-2-methyl ester (25A) (362 mg, 1.39 mmol) in CH2Cl2 (4 mL) was added imidazole (284 mg, 4.17 mmol) then tert-butydimethylsilyl chloride (1.05 g, 6.95 mmol). After stirring overnight, the reaction was partitioned between H2O and CH2Cl2. The CH2Cl2 layer was washed with 1M H3PO4 (2×) and brine, dried (MgSO4), then filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 30% EtOAc/hexane to yield the title compound (456 mg) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[C:9](=[CH2:12])[C:10]#[N:11].[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH3:1][CH:2]1[CH2:6][C:5]([CH3:7])([CH3:8])[CH2:4][CH:3]1[CH:9]([CH3:12])[C:10]#[N:11]
Reactant: C=C(C#N)C1CC(C)(C)CC1C
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(C#N)C1CC(C)(C)CC1C

Procedure:
A solution containing 1 equivalent of 2-(2,4,4-trimethyl-cyclopentyl)acrylonitrile 5 in toluene and 5% by weight of 5% palladium-on-charcoal is placed in an autoclave, under 20 bar of hydrogen, at 40° C. At the end of the reaction, the autoclave is purged with nitrogen and the solution is filtered through celite. The filtrate is concentrated. The crude product, obtained in the form of four diastereomers in proportions of 8:18:22:52, is purified by distillation.
Reaction SMILES: [CH2:1]([CH:5]1[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:17])[CH2:2][CH2:3][CH3:4].N12CCCN=C1CCCCC2.[CH:29]([C:31]([CH3:33])=[O:32])=[CH2:30]>O1CCCC1>[CH2:1]([C:5]1([CH2:30][CH2:29][C:31](=[O:32])[CH3:33])[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:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CCc2cc(OC)ccc2C1=O
Reactant: C=CC(C)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC1(CCC(C)=O)CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of 2-butyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone (230 mg, 1 mmol) in anhydrous tetrahydrofuran (THF, 0.5 mL) was placed under a N2 atmosphere and treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.037 mL, 0.25 mmol) followed by methyl vinyl ketone (MVK, 0.104 mL, 1.25 mmol). The mixture was stirred at room temperature for 19 hours and then heated at 60° C. for 80 minutes. Additional MVK (0.104 mL, 1.25 mmol) was added and the mixture was stirred at 60° C. for 2.5 hours. Additional DBU (0.037 mL, 0.25 mmol) was then added and the mixture was stirred at 60° C. for 70 minutes. After cooling to room temperature, the mixture was concentrated under a stream of N2 and the residue was purified by preparative layer chromatography on three 0.1×20×20 cm silica gel GF plates (Analtech, Newark, Del.), developing with 5% EtOAc in CH2Cl2. The UV visible product band was eluted with EtOAc and the eluant was evaporated under vacuum to provide 2-butyl-6-methoxy-2-(3-oxobutyl)-3,4-dihydro-1(2H)-naphthalenone as an oil.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2]1.[H-].[Na+].Cl[CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27]>CN(C=O)C>[CH3:29][N:28]([CH3:30])[C:26](=[O:27])[CH2:25][N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH2:1][CH2:2][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH2:5][C:6]1=2
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
tert-Butyl 1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.100 g, 0.349 mmol) was dissolved in DMF (1.0 mL) under N2 at rt. NaH (0.0450 g, 1.13 mmol, 3.22 equiv., 60% dispersion) was added and the mixture was stirred at rt for 30 min. 2-Chloro-N,N-dimethylacetamide (86 μL, 0.102 g, 0.838 mmol, 2.4 equiv.) was added, and the reaction mixture was stirred at rt for 24 h. The reaction mixture was poured over ice, then extracted with EtOAc (2×). The organic extracts was washed first with water, then with brine and dried over MgSO4. The organic extracts was filtered and concentrated to yield a crude product (0.148 g). The crude product was chromatographed (SiO2 18 g, eluted with 3:1 toluene:acetone) to give tert-butyl 6-[2-(dimethylamino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.116 g) in 90% yield. 1H NMR (300 MHz, CDCl3) δ 1.50, 2.87-2.95, 3.01, 3.00-3.07, 3.13, 3.68-3.80, 4.85, 7.07-7.19, 7.47-7.51; MS (ESI+) for C21H29N3O3 m/z 372.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[C:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:29]=[C:28]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])[CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC(=O)c1cccc(-c2ccc3c(c2)C(C)(C)CC3=O)c1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3-acetyl phenyl boronic acid according to the procedure described in example 21. MS (ESI) m/z 279; HRMS: calcd for C19H18O2+H+, 279.13796; found (ESI, [M+H]+), 279.1374.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.O>CO>[CH3:1][O:2][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: C[O-]
Reactant: Cc1ccc(CCl)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCc1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of NaOMe (1.6 g, 29.63 mmol) in dry MeOH (40 mL) under inert atmosphere was added 4-chloromethyl-1-methyl-2-nitro-benzene (5.0 g, 26.94 mmol). The reaction mixture was stirred at room temperature for 16 h. Water was added and EtOH was removed under reduced pressure. The crude product was extracted with DCM (2 times) and the organic layer was washed with water, then with a saturated solution of NaCl, dried over MgSO4 and concentrated to give intermediate II-l as yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.94 (s, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 4.48 (s, 2H), 3.41 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[CH3:13][C@H:14](N)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@H:14]([CH3:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)ccc2C1
Reactant: C[C@H](N)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](C1=Cc2ccc(Cl)cc2CC1)c1ccccc1

Procedure:
To a stirred solution of 6-chloro-2-tetralone (1.0 equiv., 100.0 mmol., 18.06 g) in toluene (300 ml) was added (S)-(-)-α-methylbenzylamine (1.0 equiv., 100.0 mmol., 12.9 ml). The mixture was heated at reflux for 3 hrs with the azeotropic removal of water (Dean-Stark). The cooled reaction mixture was concentrated in vacuo to give the enamine, (S)-6-chloro-2-(α-methylbenzyl)-3,4-dihydronaphthalene, as a purple oil. The oil was taken up in chloroform (150 ml) and saturated aqueous sodium bicarbonate was added (150 ml). The vigorously stirred mixture was treated with acryloyl chloride (1.05 equiv., 105.0 mmol., 8.5 ml) dropwise over 5 min. The reaction mixture was allowed to stir at ambient temperature for 20 min., then diluted with chloroform and the layers separated. The aqueous layer was extracted with chloroform (1×). The combined organics were washed with brine (1×), dried (Na2SO4), and concentrated in vacuo to give 37.9 g of a black oil. The crude oil was subjected to HPLC on silica gel (gradient elution with hexanes increasing to 25% ethyl acetate/hexanes) to give 19.03 g of a purple oil which was further purified by flash chromatography on silica gel (elution with 20% ethyl acetate/hexanes) to give 17.96 g, 53% yield of the title compound as a brown glass which was homogeneous by HPLC analysis (reverse phase, C18, mobile phase: 60% acetonitrile/0.5% aqueous ammonium acetate buffer),thin layer chromatography (Silica gel, Rf =~0.5, developed with 40% ethyl acetate/hexanes), and 300 MHz 1H NMR analysis. FDMS: m/e=337. α[D]589 =-24.75 (c=1.0, CHCl3).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[CH3:29][O-:30].[Na+]>CO>[CH3:29][O:30][CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1nc(-c2c(-c3ccccc3)noc2C)cn1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To a solution of 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (50 mg, 0.13 mmol) in methanol (1 mL) was added a solution of sodium methoxide (5.4 M in MeOH, 23.5 μL, 0.13 mmol) and the resulting mixture stirred at room temperature overnight. The mixture was then poured onto water and extracted with ethyl acetate. The combined organic layers were then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 80:20) afforded the title compound (27 mg, 55%) which was obtained as a yellow solid. MS: m/e=391.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[H-].[Na+].Cl[C:16]1[N:24]=[C:23]2[C:19]([N:20]=[C:21]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]([OH:36])([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[N:22]2[CH3:25])=[C:18]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[N:17]=1>CN(C=O)C.O>[CH3:1][O:2][CH2:3][C:4]1[N:5]([C:16]2[N:24]=[C:23]3[C:19]([N:20]=[C:21]([CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([C:33]([OH:36])([CH3:35])[CH3:34])[CH2:29][CH2:28]4)[N:22]3[CH3:25])=[C:18]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)[N:17]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: COCc1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1cc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Temperature: 180 °C
Yield: 18.9 %

Procedure:
To a solution of 2-(methoxymethyl)-1H-indole (57 mg, 0.35 mmol) in DMF (2 mL) was added sodium hydride (60% dispersion, 15 mg, 0.38 mmol) at 0° C. The mixture was stirred at 0° C. for 10 minutes before the addition of 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (120 mg, 0.29 mmol). The mixture was then heated in the microwave at 180° C. for 15 minutes. The reaction mixture was then diluted with water. The mixture was extracted with three times with EtOAc. The combined extracts were washed with water, dried over Na2SO4, filtered and concentrated. The crude product was then purified by flash chromatography (0-100% gradient EtOAc-heptane) followed by RP-HPLC to give 127 (29.2 mg, 19%). LCMS: M+H+=534.3. 1H-NMR (400 MHz, DMSO-d6): δ 8.18 (d, 1H), 7.57 (d, 1H), 7.20 (t, 1H), 7.12 (t, 1H), 6.66 (s, 1H), 4.98 (s, 2H), 4.25 (s, br, 4H), 4.02 (s, 1H), 3.81 (s, 3H), 3.77 (m, 4H), 3.72 (s, 2H), 2.90 (d, 2H), 1.99 (m, 2H), 1.67 (m, 2H), 1.21 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[N+:15]([O-])=O)[CH:2]([CH3:4])[CH3:3]>CO.[Pd]>[NH2:15][C:7]1[CH:8]=[C:9]([C:12](=[O:14])[CH3:13])[CH:10]=[CH:11][C:6]=1[NH:5][CH2:1][CH:2]([CH3:3])[CH3:4]
Reactant: CC(=O)c1ccc(NCC(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(=O)c1ccc(NCC(C)C)c(N)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 31.6 g (134 mM) of 1-[4-(isobutylamino)-3-nitrophenyl]-ethanone in 400 ml of methanol are added 3.2 g of 10% palladium-on-charcoal. The reaction medium is then placed under a hydrogen atmosphere at ambient pressure with vigorous stirring for 1 hour. The reaction medium is filtered through Celite and the solvent is evaporated off under vacuum to give 27.6 g of 1-[3-amino-4-(isobutylamino)phenyl]ethanone in quantitative yield, in the form of an oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:8](=O)[C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[O:5][C:4]=2[C:3](=[O:15])[O:2]1.[H][H]>C(O)(=O)C.[Pd].C(OCC)(=O)C>[CH2:1]1[C@H:9]2[C@H:4]([O:5][C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[CH2:8]2)[C:3](=[O:15])[O:2]1
Reactant: [H][H]
Reactant: O=C1OCc2c1oc1ccccc1c2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1OC[C@@H]2Cc3ccccc3O[C@H]12
Yield: 67.1 %

Procedure:
A suspension of 1H-furo[3,4-b][1]benzopyran-3,9-dione (6.1 g) in glacial acetic acid (300 ml) was hydrogenated over 10% palladium on charcoal (1 g) until hydrogen uptake ceased. The catalyst was filtered off and the solvent evaporated from the filtrate to give an oil. The oil was dissolved in ethyl acetate and the solution washed with aqueous sodium bicarbonate and brine. The organic layer was separated, dried (MgSO4) and the solvent evaporated. Crystallisation of the residue from ethyl acetate/ether gave the title compound (3.85 g) m.p. 107°-111°.