Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:44][N:43]=[C:42]([CH:45]=[CH2:46])[CH:41]=1)CCC.O>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[S:44][N:43]=[C:42]([CH:45]=[CH2:46])[CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cc([Sn](CCCC)(CCCC)CCCC)sn1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1cc(-c2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1
Yield: 68.6 %

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (75 mg, 0.150 mmol), 5-(tributylstannyl)-3-vinylisothiazole (90 mg, 0.225 mmol) and tetrakis(triphenylphosphine)palladium(0) (87 mg, 0.075 mmol) in toluene (4.0 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to give the title compound as a yellow solid (59.2 mg, 69%). ESI-MS m/z [M+H]+ calc'd for C27H34FN5O6S, 576. found, 576.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:30])[NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([C:24]4([CH3:29])OCC[O:25]4)[CH2:20][CH2:19]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>O>[C:24]([CH:21]1[CH2:20][CH2:19][CH:18]([NH:17][C:16](=[O:30])[O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:23][CH2:22]1)(=[O:25])[CH3:29]
Reactant: CC1(C2CCC(NC(=O)OCC3c4ccccc4-c4ccccc43)CC2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)C1CCC(NC(=O)OCC2c3ccccc3-c3ccccc32)CC1

Procedure:
13.10 g (32 mmol) of 9H-fluoren-9-ylmethyl[4-(2-methyl-[1,3]dioxolan-2-yl)cyclohexyl]carbamate (cis/trans mixture) and 1.30 g of p-toluenesulfonic acid are refluxed in 25 mL of water and 500 mL of acetone for 16 hours with stirring. Then the reaction mixture is concentrated by evaporation and the residue is dissolved in ethyl acetate and extracted with water. The organic phase is dried and evaporated to dryness. The residue is extracted with diisopropylether and suction filtered. Yield: 7.77 g (89%) of cis compound; NMR: LH201628.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.OC(C(F)(F)F)=O.[NH2:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]([OH:38])=[O:37].C[O-].[Na+]>CCO>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([S:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]([OH:38])=[O:37])=[O:7]
Reactant: CC(C)(CN)C(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 26.7 %

Procedure:
A mixture of 4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (60 mg, 0.17 mmol) (prepared according to WO 2004108681), 3-amino-2,2-dimethyl-propionic acid TFA salt (157 mg, 0.68 mmol) and NaOMe (73 mg, 1.36 mmol) in EtOH (2 mL) was heated at 150° C. in a microwave reactor for 6 h. The solvent was evaporated, and the residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-30% EtOAc/hexanes+2% AcOH) to give 18 mg of the title compound as a yellow solid. MS: (+) m/z 397.11 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH2:18][CH3:19])[CH:12]=1>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:8][CH3:9])=[C:13]([CH2:18][CH3:19])[CH:12]=1
Reactant: CCc1cc(Br)ccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)cc1CC
Reaction time: 20 h
Yield: 71.8 %

Procedure:
Potassium carbonate (3.3 g, 23.6 mmol) followed by iodoethane (0.63 mL, 7.9 mmol) were added to a solution of 4-bromo-2-ethyl-phenol (1.6 g, 7.9 mmol) in DMF (10 mL). The mixture was stirred for 20 hours and then partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The crude yellow oil was purified by flash column chromatography (hexanes) to give the desired product (1.3 g, 72%).
Reaction SMILES: [CH3:1][CH:2]1[NH:4][CH2:3]1.[OH-].[Na+].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>O1CCCC1>[CH3:1][CH:2]1[N:4]([C:12]([C:11]2[CH:15]=[CH:16][C:8]([Cl:7])=[CH:9][CH:10]=2)=[O:13])[CH2:3]1
Reactant: CC1CN1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1CN1C(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of propyleneimine (12.3 mL) in tetrahydrofuran (160 mL) was added to 1N aqueous sodium hydroxide solution. To this mixture was added dropwise 4-chlorobenzoyl chloride (25 g) at 0C. After completion of dropwise addition, the mixture was stirred for further 30 min. The reaction mixture was extracted with ethyl acetate. The extract was dried, and the solvent was evaporated to give the title compound (24.9 g, yield 89%). oil.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:46]([O:47][Si](C(C)(C)C)(C)C)[CH:41]6[CH:42]([O:43][CH2:44][CH3:45])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:55]([CH3:57])[CH3:56])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:46]([OH:47])[CH:41]6[CH:42]([O:43][CH2:44][CH3:45])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:55]([CH3:56])[CH3:57])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
Compound (27) was mixed with in 70 μl of 1M tetrabutylammonium fluoride-tetrahydrofuran solution and stirred at room temperature. After 80 minutes, the reaction solution was mixed with 15 ml of ethyl acetate and washed with 10 ml of sodium phosphate buffer (10 mM, pH 5.97) and then with 10 ml of water twice. After the washing, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered for removal of solids and concentrated in vacuo to give a crude reaction product. The reaction product was further subjected to silica gel column chromatography (Kieselgel 60, Merck, 1.5φ×15 cm) and eluted with n-hexane-ethyl acetate (3:1) to give 21.2 mg of compound (28) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH:6]([OH:24])[CH2:7][NH:8][CH:9]([CH3:23])[CH2:10][C:11]1[CH:22]=[CH:21][C:14]([CH:15]([OH:20])[C:16](OC)=[O:17])=[CH:13][CH:12]=1.Cl.[NH2:31][C:32]([NH2:34])=N.[Na]>CO>[NH2:31][C:32]1[O:20][CH:15]([C:14]2[CH:21]=[CH:22][C:11]([CH2:10][CH:9]([NH:8][CH2:7][CH:6]([OH:24])[C:5]3[CH:25]=[CH:26][CH:27]=[C:3]([C:2]([F:1])([F:28])[F:29])[CH:4]=3)[CH3:23])=[CH:12][CH:13]=2)[C:16](=[O:17])[N:34]=1
Reactant: N=C(N)N
Reactant: COC(=O)C(O)c1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CC(Cc1ccc(C2OC(N)=NC2=O)cc1)NCC(O)c1cccc(C(F)(F)F)c1
Yield: 29.3 %

Procedure:
To a solution of methyl 4-[2-[(3-trifloromethyl-β-hydroxyphenethyl)amino]propyl]mandelate (1.5 g) and guanidine hydrochloride (0.35 g) in methanol at room temperature was added a solution of sodium (0.084 g) in methanol. The solution was heated under reflux for 2 h., cooled, filtered and the solvent removed in vacuo. The residue was partitioned between ethyl acetate, and water, the organic layer separated, dried (magnesium sulphate), and evaporated to an oil which was chromatographed on silica. Elution with chloroform:methanol (95:5) gave 2-amino 5-[4-[2[(3-trifluoromethyl-β-hydroxyphenethyl)amino]propyl]phenyl]oxazol-4-one (0.45 g) as a 40:60 mixture of diastereoisomers, m.p. 152°-164° C. (acetone).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14][CH2:15][OH:16])[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=[O:19].OS(O)(=O)=O.O=[Cr](=O)=O.C(Cl)Cl>CC(C)=O>[C:1]1([C:7]2([CH2:13][CH2:14][C:15]([OH:19])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCC1(c2ccccc2)CCCCO1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=C(O)CCC1(c2ccccc2)CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-phenyltetrahydro-2H-pyran-2-yl)propan-1-ol (640 mg, 2.91 mmol) in acetone (10 mL) at 0° C. was added 4.15 mL of 0.7 M Jones reagent, and the mixture was stirred for 30 mins at 0° C. and for 1 hr at room temperature. It was added to CH2Cl2 and washed with water twice. The extract was dried over Na2SO4 and evaporated to give an oily residue. The residue was purified by Combiflash (40 g silica gel) eluting with 4:6 EtOAc-hexane to 3-(2-phenyltetrahydro-2H-pyran-2-yl)propanoic acid (346 mg). LC/MS: m/e 235.21 (M+H)+.
Reaction SMILES: [NH3:1].[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[O:19][C:20]([C:23](Cl)=[O:24])=[CH:21][CH:22]=2)=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[O:19][C:20]([C:23](=[O:24])[NH2:1])=[CH:21][CH:22]=2)=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
With simultaneous introduction of ammonia, a solution of 0.8 g (2.4 mmol) of 1-benzyl-3-(5-chlorocarbonyl-2-furyl)indazole in 10 ml of THF was added dropwise to 25 ml of a saturated solution of ammonia in THF. After 45 min, the mixture was poured into ice-water and extracted with ethyl acetate, and the organic phase was washed with 1 N hydrochloric acid, dried and concentrated using a rotary evaporator. The crude product was recrystallized from isopropanol. This gave 0.29 g (38%) of the title compound. m.p.: 259° C.
Reaction SMILES: [O:1]([C:8]1[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)C.CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]([C:8]1[O:12][C:11]([C:13]([NH:28][C:24]2[CH:23]=[C:22]([CH:21]=[CH:20][C:19]([OH:29])=[O:18])[CH:27]=[CH:26][CH:25]=2)=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(Oc2ccccc2)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)C=Cc1cccc(NC(=O)c2ccc(Oc3ccccc3)o2)c1

Procedure:
5-phenoxy-2-furoic acid (3) (213 mg, 1.05 mmol) was coupled to aniline (2) (200 mg, 1.05 mmol) using Method B, except that DIPEA (270 mg, 2.09 mmol) and DMF (2 mL) were used to give the title compound. Yield: 178 mg, 96%; LC/MS tr 1.65 min; HPLC Purity: 95%; MS (ES+) m/z 378 (M+H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:15]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[C:11]([OH:13])[C:10]([Cl:15])=[N:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cncc(O)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cnc(Cl)c(O)c1
Temperature: 80 °C
Yield: 49.7 %

Procedure:
The compound of Example 52A (400 mg, 2.05 mmol) was dissolved in DMF (2 mL) and N-chlorosuccinimide (328 mg, 2.46 mmol) was added. The mixture was heated to 80° C. overnight, concentrated and purified by column chromatography to give the chloro pyridine (234 mg, 50%). MS (DCI) m/z 230, 232 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:9]=3[N:10]([CH2:18][CH2:19]4)[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[C:1]1([CH:7]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]3[CH2:18][CH2:19][C:20]4=[CH:21][CH:22]=[CH:23][C:8]2=[C:9]34)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2=Nc3ccccc3N3CCc4cccc2c43)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc(C2Nc3ccccc3N3CCc4cccc2c43)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred mixture, under N2, of 23.0 g of 1,2-dihydro-6-phenylindolo[1,7-ab][1,5]benzodiazepine in 200 ml of absolute ethanol is cooled to 0°-5° C. Sodium borohydride is then added in small portions and at such a rate as to keep the reaction temperature less than 5° C., and to minimize foaming. About 3 g. are required to discharge the initial blue-purple color, and another 1 g. is added to insure complete reduction. The mixture is then stirred 1 hour at 0° C. and 1 hour at room temperature. Water is added, the product is filtered, washed repeatedly with water, and dried to give 6-phenyl-1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepine, m.p. 161°-164° C.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH:16]([CH2:18][CH:19]=[O:20])[C:15](=[O:21])[C:14]([CH3:22])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:23]COC)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl>CO.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][CH:16]([CH2:18][CH:19]=[O:20])[C:15](=[O:21])[C:14]([CH3:22])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:23])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(CC=O)C2
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCC12Cc3cc(O)ccc3C1=C(C)C(=O)C(CC=O)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
A solution of (2RS,9aSR)-9a-butyl-7-methoxymethoxy-4-methyl-2-(2-oxoethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (85 mg) in methanol (1 mL) was diluted with 2N HCl (0.36 mL, 0.72 mmol). The resulting mixture was stirred at room temperature for 30 minutes followed by heating in an oil bath at 80° C. for 40 minutes. On cooling to room temperature, crystals formed. The mixture was diluted with EtOAc and washed with 5% NaHCO3 and 1N HCl. The aqueous washes were back-extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by PLC on a 0.1×20×20 cm silica gel GF plate, using 2:1 hexanes-EtOAc as developing solvent, to afford (2RS,9aSR)-9a-butyl-7-hydroxy-4-methyl-2-(2-oxoethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (50 mg).
Reaction SMILES: [CH:1]1[C:6]2[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][C:5]=2[CH:4]=[CH:3][C:2]=1[C:17](=[O:19])[CH3:18].[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O>C(Cl)Cl.O>[N+:20]([C:3]1[C:2]([C:17](=[O:19])[CH3:18])=[CH:1][C:6]2[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][C:5]=2[CH:4]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccc2c(c1)OCCOCCOCCO2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc2c(cc1[N+](=O)[O-])OCCOCCOCCO2
Temperature: 0 °C
Yield: 36.1 %

Procedure:
1-(6,7,9,10,12,13-Hexahydro-5,8,11,14-tetraoxa-benzocyclododecen-2-yl)-ethanone (200 mmol, 51.3 g) dissolved in DCM (750 ml) and the mixture cooled to 0° C. Nitric acid (90%, 300 mmol, 14 ml) was added dropwise to the cooled solution over 20 minutes. Sulfuric acid (96.2%, 300 mmol, 8.75 ml) was then added dropwise over 40 minutes at 0° C. Additional nitric acid (200 mmol, 9.4 ml) was added dropwise over 20 minutes. The reaction mixture was diluted with water (300 ml) and wash with water (3×200 ml), Sat. NaHCO3 (4×200 ml, or until neutral). The organic layer was dried over Na2SO4 and concentrated. The crude mixture was recrystallized with DMF to give 22.5 g of the nitro product. The DMF layer was concentrated and recrystallized with ethyl acetate to give additional 8.75 g of the product. The ethyl acetate layer was concentrated and purified on silica column using 20% EtOAc/hexanes to give another 4.75 g of the product. Total yield is 36 g, (−60%). 1HNMR (400 MHz, DMSO) δ 7.82 (s, 1H), 7.61 (s, 1H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H), 2.71 (s, 3H). LC/MS Calcd for (M+H)−312.3. found 312.5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33]>>[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CC(C)(C)CN
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Product: CC(C)(C)CNc1cccc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)c1

Procedure:
Compound is formed by reacting 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide with 2,2-dimethylpropylamine under conditions described in general procedure B. 1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.22 (m, 1H), 7.86 (m, 1H), 7.56 (m, 2H), 7.41 (d, 1H, J=8.4), 7.28 (s, 1H), 7.21 (d, 2H, J=5.7), 6.87 (m, 1H), 5.70 (m, 1H), 4.32 (t, 2H, J=5.7), 3.62 (t, 4H, J=4.8), 2.89 (t, 4H, J=5.4), 2.58 (t, 4H, J=4.8), 1.48 (t, 1H, J=14.1), 0.97 (s, 9H). MS: 462.2 (M+1).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].CC[O-].[Na+].Cl.[CH2:21]([C:25]1[NH:26][CH:27]=[C:28]([CH2:30]Cl)[N:29]=1)[CH2:22][CH2:23][CH3:24]>C(O)C>[CH2:21]([C:25]1[NH:26][CH:27]=[C:28]([CH2:30][C:5]([NH:4][C:1](=[O:3])[CH3:2])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:29]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCc1nc(CCl)c[nH]1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(CC(NC(C)=O)(C(=O)OCC)C(=O)OCC)c[nH]1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-n-Butyl-4-hydroxymethylimidazole (33.3 g) is dissolved in methanol (50 ml), and thereto is added 18% hydrogen chloride-methanol solution (160 ml), and the mixture is evaporated under reduced pressure to remove the solvent. To the resulting residue is added toluene (150 ml), and thereto is added dropwise thionyl chloride (52 ml) under ice-cooling. The mixture is stirred at 50° C. for two hours, and concentrated to dryness under reduced pressure to give 2-n-butyl-4-chloromethylimidazole hydrochloride (58.3 g) as oil. Separately, diethyl N-acetylaminomalonate (140.8 g) is added to a solution of sodium ethylate (44 g) in ethanol (500 ml) with ice-cooling under argon atmosphere, and the mixture is stirred at 0° C. for 15 minutes. To the mixture is added dropwise a solution of 2-n-butyl-4-chloromethylimidazole hydrochloride obtained above in ethanol (250 ml), and the mixture is stirred at room temperature overnight. The mixture is evaporated under reduced pressure to remove the solvent, and to the resulting residue are added ethyl acetate (1 liter) and saturated aqueous ammonium chloride solution (500 ml). The aqueous layer is extracted with ethyl acetate, and the extract is combined with the organic layer, and evaporated. To the resulting residue is added 10% hydrochloric acid, and the mixture is neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate to give 2 n butyl-4-{2-acetylamino-2,2-bis(ethoxycarbonyl)ethyl}imidazole (56.8 g) as powder.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C@@H:3]([NH:5][CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:9])[CH3:4].C([O-])([O-])=O.[K+].[K+].Cl[C:26]([O:28][CH3:29])=[O:27]>C(Cl)Cl>[CH3:18][C:2]([CH3:17])([CH3:1])[C@@H:3]([N:5]([CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:9])[C:26](=[O:27])[O:28][CH3:29])[CH3:4]
Reactant: C[C@H](NCCC(=O)c1ccc(F)cc1)C(C)(C)C
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)N(CCC(=O)c1ccc(F)cc1)[C@@H](C)C(C)(C)C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of (S)-3-(3,3-dimethylbutan-2-ylamino)-1-(4-fluorophenyl)propan-1-one (2.00 g, 7.97 mmol) and K2CO3 (3.30 g, 23.9 mmol) in CH2Cl2 (100 mL) was added methyl chloroformate (2.25 g, 23.9 mmol) dropwise at 0° C., and the reaction mixture was stirred at it overnight. The solution was filtered, and the filtrate was concentrated to give the crude product, which was purified by chromatography to afford (S)-methyl 3,3-dimethylbutan-2-yl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (2.0 g, 81%). 1H NMR (CDCl3): 0.92 (s, 9H), 1.12-1.21 (d, 3H), 3.02-3.11 (m, 1H), 3.27-3.49 (m, 1H), 3.66 (s, 3H), 3.98-4.23 (m, 1H), 7.06-7.17 (m, 2H), 7.92-8.08 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:10]([O:18][CH3:19])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:20](OC(=O)C)(=[O:22])[CH3:21].O1CCOCC1>O>[C:20]([NH:1][C:2]1[C:11]([O:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)=[C:10]([O:18][CH3:19])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(OC)c(OC2CCCC2)c1N
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(OC)c(OC2CCCC2)c1NC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of methyl 2-amino-3-(cyclopentyloxy)-4-methoxybenzoate (5.54 g, 20.9 mmol), acetic anhydride (21.0 mL, 222 mmol), and dioxane (35 mL) was heated at 40° C. under N2 for 17 h and then allowed to cool to rt. Water (10 mL) was added, and after 15 min of stifling, the reaction was concentrated to give methyl 2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate: MS (ESI): 307.9.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:15]=2[N:16]=[C:17]([C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[O:23]1[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:15]=3[N:16]=2)=[CH:20][CH:21]=[N:22]1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: CCc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3-nitrobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.