Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:7])[C:3]([O:5]C)=[O:4].O.[OH-].[Li+]>C1COCC1.CO>[CH3:7][C:2]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)Sc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Sc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
Methyl 2-methyl-2-(phenylthio)propanoate (1.126 g, 5.35 mmol) was dissolved in THF (15 mL) and methanol (5 mL). That solution was treated with an aqueous solution of lithium hydroxide monohydrate (1.12 g, 26.8 mmol in 5 mL of water). The reaction mixture was stirred at rt overnight. The volatiles were removed and the remaining aqueous solution was acidified with a 1 N HCl solution to pH 2. Ethyl acetate was added and the layers were separated. The organic layer was dried over MgSO4, filtered and concentrated to provide the desired carboxylic acid as a white solid (1.020 g, 97.1% yield).
Reaction SMILES: NC[C@@H]1C[C@H](O)C1.CS([O:12][C@H:13]1[CH2:16][C@@H:15]([CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH2:14]1)(=O)=O.[F:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[C:32]([F:40])[C:33]=1[CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O.O>[F:27][C:28]1[CH:29]=[C:30]([CH:31]=[C:32]([F:40])[C:33]=1[CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[O:12][C@H:13]1[CH2:16][C@H:15]([CH2:17][N:18]([CH3:19])[C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14]1
Reactant: Oc1cc(F)c(CN2CCCC2)c(F)c1
Reactant: CN(C[C@H]1C[C@@H](OS(C)(=O)=O)C1)C(=O)OC(C)(C)C
Agent: NC[C@H]1C[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C[C@H]1C[C@H](Oc2cc(F)c(CN3CCCC3)c(F)c2)C1)C(=O)OC(C)(C)C
Temperature: 92.5 °C

Procedure:
A mixture of intermediate 6, cis-3-{[(tert-butoxycarbonyl)(methyl)-amino]methyl}cyclobutyl methanesulfonate (2 g, 6.9 mmol), intermediate 21, 3,5-difluoro-4-(pyrrolidin-1-ylmethyl)phenol (3.47 g, 13.8 mmol) and Cs2CO3 (4.5 g, 13.8 mmol) in DMSO (20 mL) was heated at 90-95° C. for 4 h under vigorous stirring in a flow of argon, then cooled. Water (40 ml) and EtOAc (40 ml) were added, and the layers were separated. The water layer was extracted with ether (20 ml), the combined organic layers were washed with 1N NaOH (3×25 mL), brine, dried with Na2SO4, and evaporated to give the title compound (2.8 g, 98%) as a yellow oil. LC/MS data: 411.6, 412.6 (M+H) (calculated for C22H32F2N2O3 410.51). 1H NMR-data (DMSO-d6): 6.50-6.61 (m, 2H, Ar—H); 4.79-4.87 (m, 1H); 3.55 (s, 2H, CH2); 3.32 (d, 2H, J=8.1 Hz, CH2); 2.78 (s, 3H, NCH3); 2.52-2.62 (m, 1H); 2.38-2.50 (m, 4H); 2.20-2.28 (m, 2H); 2.05-2.17 (m, 2H); 1.58-1.73 (m, 4H); 1.41 (s, 9H, Boc).
Reaction SMILES: N1C=C[CH:4]=[CH:3][CH:2]=1.[NH2:7][C@H:8]([C:11]([OH:13])=[O:12])[CH2:9][SH:10].C([O-])(O)=[O:15].[Na+]>C(Cl)Cl>[NH2:7][C@H:8]([C:11]([OH:13])=[O:12])[CH2:9][S:10][O:15][CH2:2][CH:3]=[CH2:4]
Reactant: N[C@@H](CS)C(=O)O
Reactant: c1ccncc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOSC[C@H](N)C(=O)O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
The 3″-amide of L-Cys(Oallyl) was prepared following the general description of Example 5. To this 3″-amide (50 mg) and pyridine (44 μL) in CH2Cl2 (0.25 mL) at −50° C. was added neat (CF3SO2)2O(13 μL) dropwise down the side of the flask to pre-cool it. After the addition was complete, the solution was stirred at −78° C. for 10 min, then allowed to warm to 0° C. in an ice bath. The solution was aged for 7.5 h at 0° C. and L-cysteine ally ester (26 mg) in CH2Cl2 (0.1 mL) was added. The solution was allowed to warm to room temperature and was aged overnight. The solution was poured into saturated NaHCO3(aq), extracted with CH2Cl2 and dried (Na2SO4). The solution was filtered, concentrated under reduced pressure and pure 7,24-bis-O-triethylsilyl protected title compound was obtained following PTLC on silica gel (1×1000 μm plate) using 3/7 acetone/hexanes as eluant. The pure product thus obtained was characterized by 1H NMR.
Reaction SMILES: [Cl:1]C1C=C(C2C=CC=CC=2C(F)(F)F)N=C(N)C=1[N+]([O-])=O.[H-].[Na+].[C:24]([C:28]1[C:29]([Cl:37])=[C:30]([C:34](O)=[O:35])[N:31]([CH3:33])[N:32]=1)([CH3:27])([CH3:26])[CH3:25].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[C:24]([C:28]1[C:29]([Cl:37])=[C:30]([C:34]([Cl:1])=[O:35])[N:31]([CH3:33])[N:32]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)O
Reactant: Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (87.5 mg, 0.275 mmol, prepared as described in STEP B above) in THF (10 mL) was treated with NaH (33.1 mg, 0.826 mmol, 60% dispersion in oil), and the mixture was allowed to stir at room temperature for 1 h. Simultaneously, a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (77.6 mg, 0.358 mmol, prepared as described in Example B above) in DCM (10 mL) was treated with oxalyl chloride (31.2 μL, 0.358 mmol), and DMF (2 drops), and the mixture was stirred at room temperature for 1 h. Volatile components were removed in vacuo, to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carbonyl chloride as a solid. The solid was taken up in anhydrous THF (6 mL) and this acid chloride solution was then added to the sodium anilide solution, as prepared above, and the resulting mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted twice with EtOAc (40 mL and 25 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on an 8-g SEPRA Si 35 SPE column (Flow rate=10 mL/min; Eluent=EtOAc-hexanes, 1:19 for 15 min, then 1:19 to 1:3 over 40 min) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide as a colorless glassy solid. Mass Spectrum (LCMS, ESI pos.): Calculated for C21H18N5O3Cl2F3: 516.2 (M+H); Measured: 516.2.
Reaction SMILES: C([N:8]([C@@H:10]([C:20]#[CH:21])[CH2:11][O:12][Si](C(C)(C)C)(C)C)[CH3:9])(OC(C)(C)C)=O.[F:22][C:23]1[C:24](I)=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:33]\[C:34]1[NH:35][CH:36]=[CH:37][C:38]=1[O:39][CH3:40]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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>[F:22][C:23]1[C:24]([C:21]#[C:20][C@H:10]([NH:8][CH3:9])[CH2:11][OH:12])=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:33]\[C:34]1[NH:35][CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: C#C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN[C@@H](C#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2)CO
Reaction time: 2 h

Procedure:
Using Method C above, (S)-2-(N-Boc-N-methylamino)-1-(tert-butyldimethylsilyloxy)-but-3-yne (190 mg, 0.61 mmol) (Example 115C above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80 IC for 5.5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 40-100% EtOAc in hexanes gradient. The resulting intermediate was dissolved directly in 6 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.5 mL of H2O at 0 °C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-[3-methylamino-4-hydroxy-1-butynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 32 mg, 42%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[Cl:24].[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[Cl:24][C:3]1[CH:4]=[C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:7][C:2]=1[N:27]1[CH2:28][CH2:29][O:25][C:26]1=[O:30]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(Cl)c3)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)c(Cl)c3)CC2)c(C)c1
Yield: 57.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-3-chlorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (815 mg) described in Preparation Example 3 and oxazolidin-2-one (174 mg), the title compound (478 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])([CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:3][C:4]#[CH:5].[CH2:15]([SnH:19]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18].N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])/[CH:5]=[CH:4]/[CH2:3][C:2]([CH3:1])([O:10][Si:11]([CH3:13])([CH3:14])[CH3:12])[CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:25][CH2:26][CH3:27]
Reactant: C#CCC(C)(CCC=C)O[Si](C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: C=CCCC(C)(C/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
A mixture of 30 g. of 4-methyl-4-trimethylsilyloxy-oct-1-yn-7-ene, 58.66 g. of tri-n-butylstannane and 200 mg. of azobisisobutyronitrile is placed in a bath at 95° C. and stirred under argon. The mixture is heated at 140° C. for one hour and then at 140° C. under vacuum for 1.5 hours. The mixture is distilled via a Kugelrohr at 140° C., 0.06 mm to give the product as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: COC(=O)c1ccc(-c2nc3c(O)cccc3s2)cc1
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(-c2nc3c(OC(C)=O)cccc3s2)cc1

Procedure:
The methyl 4-(4-hydroxybenzothiazol-2-yl)benzoate (2.5 g) obtained in Example 4 was added to 30 ml of acetic anhydride, and the mixture was refluxed for 2 hours. After the reaction, the reaction mixture was dried under reduced pressure. The residue was washed with a small amount of cyclohexane, and recrystallized from cyclohexane and ethyl acetate to give 2.3 g of methyl 4-(4-acetoxybenzothiazol-2-yl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]=[C:9]=[S:10])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[F:12][C:13]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=1>CN(C=O)C>[ClH:1].[F:12][C:13]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:9]2[S:10][C:2]3[C:7]([N:8]=2)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=3)[CH:17]=1
Reactant: Nc1cc(Oc2c(F)cccc2F)ccn1
Reactant: Cc1ccc(N=C=S)c(Cl)n1
Solvent: CN(C)C=O
Product: Cc1ccc2nc(Nc3cc(Oc4c(F)cccc4F)ccn3)sc2n1
Product: Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
A mixture of 2-chloro-3-isothiocyanato-6-methylpyridine (0.0831 g, 0.450 mmol) and 4-(2,6-difluorophenoxy)pyridin-2-amine (0.100 g, 0.450 mmol) in DMF (2 mL) was stirred at 80° C. for 3 hours and then at 120° C. overnight. The reaction was cooled and partitioned between ethyl acetate and 2N NaOH. The organic layer was washed with water and brine, dried, and concentrated. The crude material was purified via MPLC (Biotage) eluting with 3:2 hexane:ethyl acetate. The isolated product was dissolved in ether (5 mL), followed by the addition of 1N HCl in ether (3 mL) and then hexanes (4 mL). The resulting solids were filtered and washed with hexanes to provide the desired product (0.095 g, 51.9% yield) as a white powder: 1H NMR (d6-DMSO) δ 2.64 (s, 3H), 6.71 (s, 1H), 6.81 (d, 1H), 7.38-7.53 (m, 4H), 8.05 (d, 1H), 8.36 (d, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)=[O:7].[Br:18][C:19]1[C:20](Cl)=[N:21][C:22]([Cl:25])=[N:23][CH:24]=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[Br:18][C:19]1[C:20]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[O:7])=[N:21][C:22]([Cl:25])=[N:23][CH:24]=1
Reactant: NCCCNC(=O)Nc1cccc([N+](=O)[O-])c1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCCNc1nc(Cl)ncc1Br)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1.6 g (6.7 mmol) of 1-(3-amino-propyl)-3-(3-nitro-phenyl)-urea in 30 ml of acetonitrile is mixed with a solution of 1.6 g (7.0 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 10 ml of acetonitrile. 2.0 ml of triethylamine is added, and it is stirred for 90 minutes at room temperature. It is diluted with ethyl acetate (150 ml) and washed with citric acid (10%), saturated NaHCO3 solution as well as saturated NaCl solution, dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate 1:1). 1.7 g (4.0 mmol, corresponding to 60% of theory) of the product is obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br.Br[CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.O>CO>[N:1]([CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[N+:2]=[N-:3]
Reactant: BrCCCC1CCNCC1
Reactant: [N-]=[N+]=[N-]
Agent: Br
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NCCCC1CCNCC1

Procedure:
Sodium azide (1 g) was added to a mixture of 4-(3'-bromopropyl)-piperidine hydrobromide (2 g), water (7 ml) and methanol (7 ml). The pH of the mixture was adjusted to 6.3, and the resulting solution was refluxed for 2 hours. After cooling, methanol was evaporated, 30 percent aqueous sodium hydroxide was added and the mixture was extracted several times with ether. The ether extracts were dried and evaporated to leave the desired compound as an oil. The IR-spectrum (CHCl3) showed strong bands at 2925, 2100 and 1450 cm-1.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([C:13]3[CH:34]=[CH:33][C:16]4[C:17]([N:20]5[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]5)=[N:18][O:19][C:15]=4[CH:14]=3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl>CO.O1CCOCC1>[NH3:4].[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([C:13]3[CH:34]=[CH:33][C:16]4[C:17]([N:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)=[N:18][O:19][C:15]=4[CH:14]=3)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)noc2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCNCC3)noc2c1
Product: N
Reaction time: 18 h

Procedure:
A solution of 1,1-dimethylethyl 4-(6-{5-[(cyclopropylamino)carbonyl]-2methylphenyl}-1,2-benzisoxazol-3-yl)-1-piperazinecarboxylate (Intermediate 26) in methanol (1 ml) was treated with a solution of hydrogen chloride in dioxan (4N, 1 ml) then stirred at room temp. for 18 h. The solvent was evaporated and the residue was re-dissolved in methanol and applied to an SCX cartridge (1 g). Elution with methanol followed by methanol:0.88 ammonia (99:1) gave the title compound as a white solid (0.016 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([NH:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]2)[N:14]=[CH:13]3)[CH2:3][CH2:2]1.[C:26](Cl)(=[O:28])[CH3:27].CCN(CC)CC.CO>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([NH:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]2)[N:14]=[CH:13]3)[CH2:5][CH2:6]1
Reactant: N[C@H]1CC[C@H](Nc2ncc3cccc(OC4CCOCC4)c3n2)CC1
Reactant: CC(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CC[C@H](Nc2ncc3cccc(OC4CCOCC4)c3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trans-N-[8-(tetrahydro-2H-pyran-4-yloxy)quinazolin-2-yl]cyclohexane-1,4-diamine (0.3 g, 0.876 mmol) and acetyl chloride (0.0825 g, 1.05 mmol) in CH2Cl2 (10 mL) was added Et3N (0.106 g, 1.05 mmol). The resulting mixture was stirred at room temperature overnight. TLC (DCM:MeOH=10:1) showed the reaction was complete. CH2Cl2 (30 mL) was added to the solution. The solution was washed with H2O (3×20 mL) and brine (30 mL), dried over Na2SO4 and concentrated in vacuo to give crude solid, which was washed with ethyl acetate to give the title compound (0.180 g, 54.5%) as a white solid. 1H NMR (CDCl3, 400 Hz): 8.875 (s, 1H), 7.255 (d, 2H), 7.132 (d, 1H), 7.050 (t, 1H), 5.245 (d, 1H), 5.133 (d, 1H), 4.002 (m, 2H), 3.869 (m, 1H), 3.709 (m, 1H), 3.507 (m, 2H), 2.178 (d, 2H), 1.979 (t, 4H), 1.893 (m, 5H), 1.249 (m, 4H).
Reaction SMILES: Cl.[N+]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7](OC)[CH:6]=1)([O-])=O.N[C:15]1C=CC(C(N)=O)=CC=1.[N:24]([O-:26])=[O:25].[Na+]>O>[N+:24]([C:10]1[CH:5]=[CH:6][C:7]([CH3:15])=[C:8]([NH2:11])[CH:9]=1)([O-:26])=[O:25]
Reactant: O=N[O-]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1N

Procedure:
24.3 Parts of 20 degrees Baume hydrochloric acid was slurried with 15.2 parts of 4-nitro-1-amino-2-methoxybenzene and 1.33 parts of 4-aminobenzamide in 210 parts of water. The mixture was iced to 0° C. and reacted with 7.3 parts of sodium nitrite to form a solution of the diazonium salt of 4-nitro-2-amino-1-methylbenzene and the diazonium salt of 4-aminobenzamide.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:14]C)[CH:8]=[CH:9][C:10]=2[O:12]C)[N:5]=[CH:4][CH:3]=1.O.[N+]([O-])([O-])=O.[NH4+].[Ce]>CC#N>[Br:1][C:2]1[C:11]2[C:10](=[O:12])[CH:9]=[CH:8][C:7](=[O:14])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(OC)c2c(Br)ccnc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1C=CC(=O)c2c(Br)ccnc21
Reaction time: 0.5 h

Procedure:
100 mg (0.373 mmol) of 4-bromo-5,8-dimethoxyquinoline are dissolved in 8 mL of CH3CN and 4 mL of water at room temperature. 0.6 g (1.11 mmol) of cerium ammonium nitrate (CAN) is added and the mixture is stirred for 30 min. After evaporating off the CH3CN on a rotary evaporator, 100 mL of water are added and the medium is extracted with CHCl3 (3 times 100 mL). After drying the organic phases over MgSO4 and evaporating off the solvent on a rotary evaporator, 83 mg of quinone are obtained in the form of a pinkish powder.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:8](=[O:14])O[C:6]1=[O:15])[CH:2]([CH3:4])[CH3:3].C([C:18](CC)([C:22]([O-:24])=[O:23])C([O-])=O)C.[H-].[Na+].CN(C)[C:31](=O)[CH3:32]>>[OH:14][C:8]1[C:9]2[CH:13]=[CH:12][S:11][C:10]=2[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6](=[O:15])[C:18]=1[C:22]([O:24][CH2:31][CH3:32])=[O:23]
Reactant: CC(C)Cn1c(=O)oc(=O)c2ccsc21
Reactant: CC(=O)N(C)C
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(O)c2ccsc2n(CC(C)C)c1=O
Temperature: 110 °C
Yield: 74 %

Procedure:
To a solution of crude 1-isobutyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (2.0 g) in N,N-dimethylacetamide (30 mL) were added diethylmalonate (2.13 g, 13.3 mmol) and sodium hydride (0.32 g, 13.3 mmol). The resulting mixture was heated at 110° C. for 4 h, cooled to room temperature, concentrated to dryness and dissolved in water. This aqueous solution was washed with ethyl acetate, acidified with concentrated hydrochloric acid and followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated. The residue was purified on a silica gel flash chromatography column eluted with 10% ethyl acetate-hexane to afford the title compound as a slightly yellow oil (1.95 g, 74% yield for Steps C and D combined). 1H NMR (400 MHz, CDCl3): δ 7.32 (d, 1H), 6.90 (d, 1H), 4.49 (q, 2H), 3.90 (d, 2H), 2.49 (m, 1H), 1.46 (t, 3H), 0.98 (d, 6H); MS: m/e 296 (M+H+).
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[CH2:3][CH:4]1[C:7]2([CH2:10][CH2:9][CH2:8]2)[CH2:6][C:5]1=[O:11].ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[Cl:12][C:2]([Cl:1])([Cl:13])[CH2:3][CH:4]1[O:22][C:5](=[O:11])[CH2:6][C:7]21[CH2:8][CH2:9][CH2:10]2
Reactant: O=C1CC2(CCC2)C1CC(Cl)(Cl)Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1CC2(CCC2)C(CC(Cl)(Cl)Cl)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.42 g (0.01 mol) of the 1-(2',2',2'-trichloroethyl)spiro(3.3)heptan-2-one produced according to Example 10 is placed into 30 ml of methylene chloride, and 2 g (0.012 mol) of m-chloroperbenzoic acid is added. The reaction mixture is subsequently stirred for 48 hours at room temperature (21°-26° C.), filtered, and then washed with methylene chloride. The filtrate is washed with cold (0°-5° C.) sodium carbonate solution and cold (0°-5° C.) water, dried over sodium sulphate and concentrated by evaporation. The residue is recrystallised from diethyl ether/n-hexane to yield 5-(2',2',2'-trichloroethyl)-6-oxaspiro(3.4)octan-7-one of the formula ##STR14## as white crystals, m.p. 86.5°-87.5° C.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH3:17])=[CH:13][CH:14]=2)[C:9]1=[O:18])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH3:17])=[CH:13][CH:14]=2)[C:9]1=[O:18]
Reactant: CC=CCC1Cc2ccc(C)cc2C1=O
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 1.33 h
Yield: 82 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 80 minutes while stirring through a solution, cooled to -70°, of 16.3 g of (RS)-2-(2-buten-1-yl)-6-methyl-1-indanone in 300 ml of anhydrous dichloromethane and 60 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 8.95 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 300 ml of dichoromethane and, after the addition of 40 ml of water and 40 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 200 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 100 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 200 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. The crude product obtained was recrystallized from diethyl ether/hexane. 12.7 g (82%) of (RS)-2-(2-oxoethyl)-6-methyl-1-indanone were obtained as a light yellow solid with m.p. 53°-54°.