Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=[O:17])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CC(C)(C=O)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C=O)c1cccc(O)c1
Yield: 56 %

Procedure:
A mixture of 38.9 g. (0.153 mole) of 2-(3-benzyloxyphenyl)-2-methylpropanal, 20 g. 5% Pd/C/50% water, 1.0 sodium bicarbonate and 150 ml. ethanol was shaken overnight under 55 psi of hydrogen. The reaction was filtered through diatomaceous earth, the filter cake washed with ethanol and the combined filtrate evaporated. The residue was reduced as above for another 8 hours. Another 10 g. portion of catalyst was added and the reaction continued overnight. The reaction was worked-up as above and the residue purified via column chromatography on 500 g. of silica gel eluted with 25% ether-hexane to yield 14 g. (56%) of the title compound as an oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C@H:12]([N:20]([CH2:35][C:36]([OH:38])=[O:37])[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][C:31]([F:34])([F:33])[F:32])(=[O:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([N:20]([CH2:35][C:36]([OH:38])=[O:37])[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][C:31]([F:33])([F:34])[F:32])(=[O:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](Cc1ccccc1)N(CC(=O)O)S(=O)(=O)c1ccccc1OC(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC[C@@H](Cc1ccccc1)N(CC(=O)O)S(=O)(=O)c1ccccc1OC(F)(F)F

Procedure:
To a solution of compound 31k (2.8 g, 5 mmol) in DCM (100 mL) was added TFA (20 mL). After the reaction was over, the solvents were removed by reduced pressure to give a white solid. The product was used in the next reaction step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10](=O)[NH:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[CH:17]=1.P(Cl)(Cl)([Cl:29])=O>CCN(C1C=CC=CC=1)CC>[Cl:29][C:10]1[C:9]2[C:14](=[CH:15][C:6]3[CH:5]=[C:4]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:3]([O:2][CH3:1])=[CH:17][C:7]=3[CH:8]=2)[N:13]=[CH:12][N:11]=1
Reactant: COc1cc2cc3c(=O)[nH]cnc3cc2cc1OCCN1CCOCC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: COc1cc2cc3c(Cl)ncnc3cc2cc1OCCN1CCOCC1
Temperature: 25 °C

Procedure:
A mixture of 0.3 g (0.844 mmol) of 7-methoxy-8-(2-morpholin-4-yl-ethoxy)-3H-benzo[g]quinazolin-4-one in 8 mL of phosphorus oxychloride and 1 mL of diethylaniline is refluxed for 15 minutes. After allowing to cool to room temperature, phosphorus oxychloride and diethylaniline are removed in vacuo. A 5 mL portion of toluene is added to the crude product mixture, and the solvents are again removed in vacuo. This step is repeated one more time. The product mixture is placed in an ice bath, and to this is added 10 mL of an ice-cooled solution of saturated sodium bicarbonate. This is extracted twice with a 95:5 mixture of methylene chloride/methanol, then with 1:1 tetrahydrofuran/ethyl acetate. The organic layers are combined, dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography, eluting with a solvent gradient of 98:2 to 4:1 methylene chloride/methanol, provided 0.229 g of 4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazoline as a yellow solid, mp 166-168° C.
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[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[S:29]1(=[O:35])(=[O:34])[CH2:33][CH2:32][CH2:31][NH:30]1>>[O:34]=[S:29]1(=[O:35])[CH2:33][CH2:32][CH2:31][N:30]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3S(C)(=O)=O)CC2)nc1C
Yield: 52.8 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (370 mg) described in Preparation Example 122 and isothiazolidine 1,1-dioxide (96 mg) and by the reaction and treatment in the same manner as in Example 4, the title compound (212 mg) was obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:21]=[C:10]3[C:11]4[CH:17]([CH2:18][CH2:19][NH2:20])[CH2:16][CH2:15][C:12]=4[CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30].C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]1([C:7]2[CH:21]=[C:10]3[C:11]4[CH:17]([CH2:18][CH2:19][NH:20][C:29](=[O:31])[CH3:30])[CH2:16][CH2:15][C:12]=4[CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCC1CCc2ccn3nc(-c4ccccc4)cc3c21
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCC1CCc2ccn3nc(-c4ccccc4)cc3c21
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
2-(2-Phenyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridin-9-yl)ethanamine (200 mg, 0.721 mmol) was dissolved in tetrahydrofuran (7 mL), triethylamine (201 μL, 1.44 mmol) and acetic anhydride (81.8 μL, 0.865 mmol) were added under ice-cooling, and the mixture was stirred for 15 min. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (195 mg, total yield from Reference Example 65, 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=C[C:29]=1[S:34]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])(=[O:36])=[O:35]>>[O:20]1[CH2:21][CH2:22][NH:23][C:24]2[N:25]=[CH:26][C:17]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[C:29]([S:34]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])(=[O:36])=[O:35])=[CH:28][CH:33]=[CH:32][CH:31]=4)=[CH:7][C:2]=3[F:1])=[CH:18][C:19]1=2
Reactant: CC1(C)OC(c2ccc(-c3cnc4c(c3)OCCN4)c(F)c2)OC1(C)C
Reactant: CCN(CC)S(=O)(=O)c1ccccc1Br
Product: CCN(CC)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc3c(c2)OCCN3)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using 7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine and 2-bromo-N,N-diethylbenzenesulfonamide. MS (ESI): mass calcd. for C23H24FN3O3S, 441.15; m/z found, 442.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.03-8.00 (m, 1H), 7.82 (d, J=1.0, 1H), 7.73-7.65 (m, 2H), 7.62-7.55 (m, 2H), 7.40-7.36 (m, 1H), 7.31 (s, 1H), 7.30-7.28 (m, 1H), 4.39-4.35 (m, 2H), 3.74-3.70 (m, 2H), 2.99 (q, J=7.1, 4H), 1.01 (t, J=7.1, 6H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([F:21])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25](I)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[C:27]([C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:7][C:8]=2[F:21])[CH:28]=1
Reactant: Fc1ccc(Cl)cc1I
Reactant: CCS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)c1ccc(-c2cc(Cl)ccc2F)c(F)c1
Temperature: 80 °C
Yield: 28 %

Procedure:
A solution of 2-(4-(ethylsulfonyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 45, 1.77 g, 5.64 mmol), 4-chloro-1-fluoro-2-iodobenzene (1.28 g, 5.00 mmol), and sodium carbonate (1.59 g, 15.00 mmol) in dioxane (40 mL) and water (10 mL) was degassed. Tetrakis(triphenylphosphine)palladium(0) (577 mg, 0.50 mmol) was added and the mixture was degassed twice more, and the reaction warmed to 80° C. for 2 hours. The reaction was cooled and diluted with EtOAc (50 mL) and water (50 mL), the layers separated and the aqueous extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4 and the solvent removed in vacuo. The crude was purified by silica gel column chromatography eluting with EtOAc:heptane 1:19 to 1:1 to give the title compound as a colourless oil 28% yield, 443 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:17].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])=[C:23](B(O)O)[CH:24]=1>>[C:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:21]3[CH:20]=[C:19]([Cl:18])[CH:24]=[CH:23][C:22]=3[O:28][CH3:29])=[C:3]([F:17])[CH:4]=2)(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)c(F)c1
Reactant: COc1ccc(Cl)cc1B(O)O
Product: COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)c2ccccc2)cc1F

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of example 5 step (i) and 5-chloro-2-methoxybenzene boronic acid.
Reaction SMILES: [OH:1][C@H:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[NH2:13].CC[O:17][P:18]([O:32]CC)([CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:19].CC(C)([O-])C.[Mg+2].CC(C)([O-])C.CN(C)C=O>O.C(Cl)CCl.C(Cl)(Cl)Cl.C(Cl)Cl.C(O)(=O)C>[P:18]([CH2:20][O:1][C@H:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[NH2:13])([OH:32])([OH:19])=[O:17]
Reactant: C[C@@H](O)Cn1cnc2c(N)ncnc21
Reactant: CCOP(=O)(COS(=O)(=O)c1ccc(C)cc1)OCC
Agent: CC(C)(C)[O-]
Agent: [Mg+2]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: C[C@H](Cn1cnc2c(N)ncnc21)OCP(=O)(O)O

Procedure:
Accordingly (R)-9-[2-(hydroxyl)propyl]adenine is condensed with Diethyl p-toluene sulfonyloxy methylphosphonate in presence of Magnesium tert-butoxide in a polar solvent preferably dimethylformamide at a temperature of 70° C. to 80° C. After the reaction completion the reaction mass is neutralized by adding an acid preferably acetic acid and the solvent is distilled off completely. The obtained crude is dissolved in a chlorinated hydrocarbon selected from Methylenedichloride, chloroform, and Ethylene dichloride and water is added. The reaction mixture is filtered to remove the salts and Methylenedichloride layer is separated. Methylenedichloride is distilled off completely to get (R)-9-[2-(phosphonomethoxy)propyl]adenine.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:13](=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([OH:29])[C:21]=2[CH2:30][CH2:31][CH3:32])[C:6]([CH3:12])=[C:7]([CH3:11])[C:8]=1[O:9]C.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:4]([CH3:34])=[C:5]([C:13](=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([OH:29])[C:21]=2[CH2:30][CH2:31][CH3:32])[C:6]([CH3:12])=[C:7]([CH3:11])[C:8]=1[OH:9]
Reactant: CCCc1c(OCCCCCC(=O)c2c(C)c(C)c(OC)c(OC)c2C)ccc(C(=O)O)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCc1c(OCCCCCC(=O)c2c(C)c(C)c(O)c(O)c2C)ccc(C(=O)O)c1O
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To 0.98 g (2.07 mmol) of 4-[[6-(3,4-dimethoxy-2,5,6-trimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid in 100 mL of methylene chloride cooled at -75° was added 7 mL (7 mmol) of 1M boron tribromide in methylene chloride. The reaction mixture was stirred at -75° for 30 minutes and then was kept at -20° for 18 hours. Workup as in Example 32 and recrystallization of the crude product from ether-hexane gave 0.51 g, mp 169°-170° of 4-[[6-(3,4-dihydroxy-2,5,6-trimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid.
Reaction SMILES: Cl.N[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[Cl:10].N([O-])=O.[Na+].[I-:15].[K+]>O>[Cl:10][C:4]1[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=1[I:15]
Reactant: Cc1ccc(N)c(Cl)c1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(I)c(Cl)c1
Temperature: -2 °C
Reaction time: 0.25 h
Yield: 111.3 %

Procedure:
250 ml of concentrated hydrochloric acid and 75 g of 4-amino-3-chlorotoluene (0.53 mol) are introduced onto 166 g of ice, and a solution of 40.3 g of sodium nitrite (0.583 mol) in 170 ml of water is then added dropwise at 0° C. After the solution has been stirred for 15 minutes, it is filtered through glass wool, and the solution, which has been cooled to -2° C., is added dropwise to a solution, warmed to room temperature, of 455 g of potassium iodide (2.74 mol) in 1 l of water together with a batch prepared analogously with 0.30 mol of 4-amino-3-chloro-toluene. After the reaction mixture has been stirred overnight, it is extracted three times with ether and the combined organic phases are washed twice with dilute sodium hydroxide solution, twice with dilute sodium bisulphite solution and with water. After drying over sodium sulphate, filtration and concentration, the residue of copper powder is distilled over a Vigreux column under 1 mm Hg. The fraction between 70° and 85° C. gives 149 g of a yellow oil [7% of theory, Rf =0.57 (hexane:ethyl acetate=9:1)].
Reaction SMILES: [NH:1]1[C:20](=[O:21])[C@H:7]([CH2:8][CH2:9][C:10](=[O:19])[O:11]CC2C=CC=CC=2)[NH:6][C:4](=[O:5])[C@@H:2]1[CH3:3]>C(O)C(F)(F)F.[Pd]>[NH:1]1[C:20](=[O:21])[C@H:7]([CH2:8][CH2:9][C:10](=[O:11])[OH:19])[NH:6][C:4](=[O:5])[C@@H:2]1[CH3:3]
Reactant: C[C@@H]1NC(=O)[C@H](CCC(=O)OCc2ccccc2)NC1=O
Agent: [Pd]
Solvent: OCC(F)(F)F
Product: C[C@@H]1NC(=O)[C@H](CCC(=O)O)NC1=O
Reaction time: 48 h

Procedure:
Cyclo-L-Ala-L-Glu(OBzl) (14.5 g, 0.05 mol) was dissolved in 200 ml of trifluorethanol and then 1.5 g of palladium black was added. Hydrogen was bubbled through the suspension and the mixture was stirred for 48 hours. The completion of the reaction was monitored by TLC. After the reaction was complete, the catalyst was filtered off and the solvent was evaporated in vacuum. The residual peptide was dissolved in 200 ml of distilled water and the impurities were extracted with 3×100 ml of EtOAc. The water phase was combined and evaporated in vacuum. The precipitate was washed with ether and hexane and then dried in air. The yield was 10.2 g (94%). Rf=0.2(CHCl3 EtOAc:MeOH:AcOH=6:3:1:0.1); Rf=0.5(CHCl3:EtOAc:MeOH: 32% Ac OH=6:3:1:0.1); HPLC data: retention time 6.7 min.
Reaction SMILES: C([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]1([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]1)[C:12](=[O:29])[N:13]2[CH2:18][C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][N:20]=1)C1C=CC=CC=1>C(O)(=O)C.[OH-].[OH-].[Pd+2].CO>[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]1([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]1)[C:12](=[O:29])[N:13]2[CH2:18][C:19]1[C:24]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=C1N(Cc2ncccc2C(F)(F)F)c2cccc(NCc3ccccc3)c2C12COc1cc3c(cc12)OCCO3
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cccc2c1C1(COc3cc4c(cc31)OCCO4)C(=O)N2Cc1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.1 %

Procedure:
A mixture of 4′-(benzylamino)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.251 g, 0.45 mmol) and palladium hydroxide on carbon (0.251 g, 20 dry wt %, contains −50% water, 0.18 mmol), methanol (20 mL), glacial acetic acid (1 drop, catalytic amount) was placed under an atmosphere of hydrogen (1 atm) and stirred at ambient temperature for 16 h. Further, palladium hydroxide on carbon (0.100 g, 20 dry wt %, contains −50% water, 0.072 mmol) and acetic acid (1 drop, catalytic amount) were added, the reaction mixture was again placed under an atmosphere of hydrogen (1 atm) and allowed to react at ambient temperature for 72 h. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate (50 mL). The filtrate was washed with water (100 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 0% to 25% gradient of ethyl acetate in dichloromethane, to yield 4′-amino-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.070 g, 33%) as a colorless solid: mp 243-245° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.68 (d, J=4.6 Hz, 1H), 8.25 (d, J=7.9 Hz, 1H), 7.58 (dd, J=7.7 Hz, J=5.0 Hz, 1H), 6.91 (dd, J=8.0 Hz, J=8.0 Hz, 1H), 6.54 (d, J=12.1 Hz, 1H), 6.33 (d, J=8.2 Hz, 1H), 6.08 (d, J=7.6 Hz, 1H), 5.14 (ABq, 2H), 4.71 (ABq, 2H), 4.52 (s, 2H), 4.17 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 178.0, 154.9, 152.6, 152.4, 144.7, 142.9, 142.8, 138.8, 134.2, 134.1, 129.4, 122.0, 118.6, 114.5, 112.8, 111.3, 99.0, 77.2, 64.5, 63.9, 57.2, 42.4; MS (ES+) m/z 469.9 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[N:14][C:8]=3[CH2:7][CH2:6][C:5]=2C=[N:3][C:2]=1N.Br.N1C(=[O:27])C=CC2C=1C=CCC=2.NC(N)=O.[OH-].[NH4+]>O>[N:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[N:14][C:8]=3[CH2:7][CH2:6][C:5]=2[O:27][C:2]=1[NH2:3]
Reactant: O=C1C=CC2=CCC=CC2=N1
Reactant: Nc1ncc2c(n1)-c1cccnc1CC2
Agent: Br
Agent: NC(N)=O
Agent: [NH4+]
Solvent: O
Product: Nc1nc2c(o1)CCc1ncccc1-2

Procedure:
A solution of 6-bromo-7,8-dihydro-5(6H- quinolinone, hydrobromide, 10.0 g (32.5 mmol), (Example 2), in 150 ml of hot water is refluxed with 6.0 g (100 mmol) of urea for 24 hours. After cooling, the solution is made basic with concentrated ammonium hydroxide and extracted with 2×250 ml of dichloromethane. The organic extract is concentrated and the residue is chromatographed (1% ammonium hydroxide, 99% ethyl acetate) to separate the two products, 4,5-dihydrooxazolo[4,5-f]quinolin-2-amine (Example 28) and 4,5-dihydrooxazolo[5,4-f]quinolin-2-amine (Example 27).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:5][CH:4]=1.[CH3:16][C:17]([N+:21]([O-:23])=[O:22])([CH3:20])[CH2:18]O.[OH-].[Na+].Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH3:16][C:17]([N+:21]([O-:23])=[O:22])([CH3:20])[CH2:18][NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:14][CH:15]=1
Reactant: CC(C)(CO)[N+](=O)[O-]
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: CC(C)(CNc1ccc(C(=O)CCC(=O)O)cc1)[N+](=O)[O-]
Yield: 87.5 %

Procedure:
A mixed solution containing 46 g of 3-(p-amino-benzoyl)propionic acid hydrochloride, 25 g of 2-methyl-2-nitro-1-propanol, 1 g of benzyl triethyl ammonium chloride, 17 g of sodium hydroxide and 40 ml of water was heated under reflux for 6 hours. Then, 12 g of 2-methyl-2-nitro-1-propanol was added, and the mixture was further heated under reflux for 18 hours. Then 20% HCl was added. The solution was acidified (pH 2). The crystals which precipitated were collected by filtration. The crystals were washed with water and recrystallized from tetrahydrofuran to give 51.6 g of 3-[4-(2-methyl-2-nitropropylamino)benzoyl]propionic acid.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:19]([CH3:24])([CH3:23])[CH2:18][CH2:17][C:16]([CH3:26])([CH3:25])[C:15]=4[CH:14]=3)[CH:11]=2)[CH:6]=[C:5]([C:27]([OH:29])=[O:28])[CH:4]=1.OC1C2C(=CC=C(C3C=CC4C(C)(C)CCC(C)(C)C=4C=3)C=2)C(C)=C(C(O)=O)C=1.CC1(C)C=CC(C)(C)C2C=C(C3C4CCCCC=4C=CC=3C(O)=O)C=CC1=2.CC1C2C(=CC(C3C=CC4C(C)(C)CCC(C)(C)C=4C=3)=CC=2)C=CC=1C(O)=O>>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:19]([CH3:23])([CH3:24])[CH2:18][CH2:17][C:16]([CH3:25])([CH3:26])[C:15]=4[CH:14]=3)[CH:11]=2)[CH:6]=[C:5]([C:27]([OH:29])=[O:28])[CH:4]=1
Reactant: COc1cc(C(=O)O)cc2ccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cc12
Agent: CC1(C)C=CC(C)(C)c2cc(-c3c(C(=O)O)ccc4c3CCCC4)ccc21
Agent: Cc1c(C(=O)O)cc(O)c2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)ccc12
Agent: Cc1c(C(=O)O)ccc2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)ccc12
Product: CC1(C)CCC(C)(C)c2cc(-c3ccc4cc(C(=O)O)cc(O)c4c3)ccc21

Procedure:
4-methoxy-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-naphtoic acid; 4-acetoxy-1-methyl-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-methyl naphthoate; 4-acetoxy-1-methyl-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-methyl naphthoate; 4-hydroxy-1-methyl-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-naphthoic acid; 4-hydroxy-1-methyl-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-methyl naphthoate; 4-mercapto-1-methyl-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-2-naphthoic acid; and 1-methyl-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-naphthoic acid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:44])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:34]([CH2:35][O:36]C3CCCCO3)=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[C:34]([CH2:35][OH:36])=[CH:33][N:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:44])[NH:20][C:9]=2[CH:10]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(methyl-propyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M27) (0.4 g, 0.64 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pale yellow solid (110 mg).
Reaction SMILES: Br[CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[OH:16])[O:12][C:11]([CH3:18])([CH3:17])[CH2:10][C:9]2=[O:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC)=O>[CH2:2]1[CH2:3][O:16][C:15]2[CH:14]=[C:13]3[C:8]([C:9](=[O:19])[CH2:10][C:11]([CH3:17])([CH3:18])[O:12]3)=[CH:7][C:6]=2[O:5]1
Reactant: BrCCBr
Reactant: CC1(C)CC(=O)c2cc(O)c(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1(C)CC(=O)c2cc3c(cc2O1)OCCO3
Temperature: 60 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a stirred mixture of 100 ml of methyl-ethyl-ketone and 2.6 ml (30 millimoles) of 1,2-dibromo ethane heated to 60° C. 4.2 g (20 millimoles) of 6,7-dihydroxy-2,2-dimethyl-4-chromanone and a suspension of 8.3 g (60 millimoles) of potassium carbonate and 0.5 g of potassium iodide in 100 ml of methyl-ethyl ketone are added dropwise within 3 hours. The reaction mixture is heated to boiling for 5 hours. The inorganic salt is filtered off, washed twice with 20 ml of acetone each and the solvent is removed. The residue is crystallized from 70% ethanol. Thus 3.75 g of the desired compound are obtained, yield 80%. Mp.: 118°-119° C.