Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:15]=[C:14]3[C:10]([NH:11][CH:12]=[N:13]3)=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22]CC4C=CC=CC=4)[CH:17]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CO.C1COCC1.[Pd]>[N:1]1([C:7]2[N:15]=[C:14]3[C:10]([NH:11][CH:12]=[N:13]3)=[C:9]([C:16]3[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: c1ccc(COc2cccc(-c3nc(N4CCOCC4)nc4nc[nH]c34)c2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1cccc(-c2nc(N3CCOCC3)nc3nc[nH]c23)c1
Yield: 75.4 %

Procedure:
To a solution of compound A (45 mg, 0.116 mmol) in methanol (10 mL) and THF (10 mL) was added 50 mg of 10% Pd/C. The mixture was degassed for three times with N2, and hydrogenated under H2 atmosphere over night. After removing Pd/C by filtration, the reaction was evaporated and the residue purified by prep-TLC (PE:EA=1:2) to give 1 (26 mg, 75%). 1H-NMR (300 MHz, DMSO-d6): δ=3.73-3.76 (m, 8H), 6.89-6.92 (m, 1H), 7.30-7.35 (m, 1H), 8.19 (s, 1H), 8.23 (m, 2H), 9.59 (s, 1H). LC-MS [M+H]+: 298.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][CH2:11][CH2:12][C:13]([OH:15])=O>C(Cl)(Cl)Cl>[O:15]=[C:13]1[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]=2[S:10][CH2:11][CH2:12]1
Reactant: O=C(O)CCSc1cc2ccccc2[nH]1
Solvent: ClC(Cl)Cl
Product: O=C1CCSc2[nH]c3ccccc3c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 88.5 g (0.4 mol) of 3-(2-indolylthio)propionic acid and 300 g of polyphosphate ester in 3.5 liters of chloroform is stirred for 16 hours at room temperature and under a nitrogen atmosphere. The mixture is diluted with 3 liters of ice-cold water, the organic phase is separated after settling has occurred and the aqueous phase is extracted with chloroform. The organic phases are combined, washed with 10% strength aqueous sodium bicarbonate solution and then with water, dried and concentrated on a water bath under vacuum. The residue is recrystallized in ethanol, the crystals obtained are removed and the filtrate is concentrated.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH2:9][CH2:10][CH3:11].[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][C:26](=[O:28])[CH:25]=[C:24]([OH:29])[CH2:23]2)=[CH:18][CH:17]=1)[CH3:15]>O1CCCC1>[C:8]([C:25]1[C:26](=[O:28])[CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([CH2:14][CH3:15])=[CH:21][CH:20]=2)[CH2:23][C:24]=1[OH:29])(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(=O)Cl
Reactant: CCc1ccc(C2CC(=O)C=C(O)C2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)C1=C(O)CC(c2ccc(CC)cc2)CC1=O
Reaction time: 8 h

Procedure:
51 g (0.51 mol) of triethylamine and--with ice cooling--54 g (0.51 mol) of butyryl chloride are dripped into a solution of 110 g 0.51mol) of the 5-(4-ethylphenyl)-3-hydroxy-2-cyclohexen-1-one, obtained in accordance with the foregoing instructions, in 500 ml of tetrahydrofuran. After 8 hours at room temperature, the mixture is filtered and the precipitate is washed with tetrahydrofuran. The filtrate is concentrated, the residue is taken up in 500 ml of ethyl acetate and 6.2 g of 4-N,N-dimethylaminopyridine is added. The homogeneous solution is kept for 40 hours at room temperature, is then concentrated and the residue is taken up in 10% strength potassium hydroxide solution. The undissolved constituents are separated off, and the filtrate is acidified to pH 1. The product which precipitates out is filtered off and dried under reduced pressure.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([S:15](Cl)(=[O:17])=[O:16])[CH:6]=1)(=[O:3])[CH3:2].[CH:19]12[CH2:25][CH:22]([NH:23][CH2:24]1)[CH2:21][S:20]2.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([S:15]([N:23]2[CH2:24][CH:19]3[CH2:25][CH:22]2[CH2:21][S:20]3)(=[O:17])=[O:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(S(=O)(=O)Cl)cc2ccccc12
Reactant: C1SC2CNC1C2
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(S(=O)(=O)N2CC3CC2CS3)cc2ccccc12
Yield: 35.3 %

Procedure:
4-Acetoxy-2-naphthalenesulfonyl chloride (375 mg, 2.50 mmol) and 2-thia-5-azabicyclo[2.2.1]heptane (711 mg, 2.50 mmol) were combined in CHCl3 (20 ml) and pyridine (20 ml) and the mixture was stirred at room temperature for 15 hr. At this time the solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc and 1N aq HCl. The EtOAc was then washed with saturated aq NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography using 3% acetone in CHCl3 to provide of the pure product as a white foam (321 mg, 35% yield): 1H NMR (CDCl3) δ 1.60-1.79 (2H, m, CH2), 2.48 (3H, s, CH3CO), 2.98 (1H, dd, J=7.78, 2.44 Hz, 1/2 CH2), 3.18 (1H, d, J=10.21 Hz, 1/2 CH2), 3.51 (2H, br m, CH2), 3.67 (1H, d, J=9.48 Hz, CH), 4.70 (1H, s, CH), 7.61-7.70 (3H, m, ArH), 7.94-8.05 (m, 2H, ArH, 8.28 (s, 1H, ArH).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)[CH:20]=1)(C)(C)C>C(Cl)(Cl)Cl>[N:21]1([C:19]2[CH:20]=[C:15]([NH2:14])[CH:16]=[N:17][CH:18]=2)[CH:22]=[CH:23][CH:24]=[CH:25]1
Reactant: CC(C)(C)OC(=O)Nc1cncc(-n2cccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Nc1cncc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
TFA (1 ml) was added to a chloroform (1 ml) solution containing tert-butyl(5-(1H-pyrrol-1-yl)pyridin-3-yl)carbamate (36 mg) obtained in the 1st step, followed by stirring at room temperature for 1 hour. Then, the solvent was distilled away under reduced pressure and the residue was added to a mixture of chloroform, water, and a 1M sodium hydroxide aqueous solution, followed by extraction with chloroform. The resultant was dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and a light brown solid of 5-(1H-pyrrol-1-yl)pyridin-3-amine (23 mg) was thus obtained.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N+:9]([C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([F:24])([F:23])[F:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:11])=[O:10]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 16 h
Yield: 97.1 %

Procedure:
4-Bromo-2-nitroaniline (10.1 g, 46.7 mmol), 2-trifluoromethylphenylboronic acid (1.3 eq., 11.5 g, 60.7 mmol), and (dppf)PdCl2.DCM (0.05 eq., 1.91 g, 2.34 mmol) were placed in a 500 mL round-bottom flask equipped with a magnetic stir bar. The vial was evacuated and backflushed with Ar, and DME (180 mL) and 2M aq Na2 CO3 (60 mL) were added via syringe. The flask was capped tightly, and the reaction was stirred at 90° C. for 16 h. The reaction was cooled to RT, diluted with EtOAc, and washed sequentially with water and brine. The organic extract was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was dry-loaded onto 25 g of SiO2 and purified by column chromatography using an 80-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:7, v/v over 20 min, yielding 12.8 g (97%) of the desired compound. 1H-NMR (400 MHz, CDCl3) δ: 8.11 (d, J=2.0 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.54-7.62 (m, J=7.6 Hz, 1H), 7.44-7.53 (m, J=7.8 Hz, 1H), 7.36 (dd, J=8.6, 1.3 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2=[C:15]3[C:20](=[N:21][C:22]4=[CH:23][CH:24]=[CH:25][C:12](=[C:13]24)[O:11][CH2:10][C:9]1=O)[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>O1CCCC1>[CH2:1]([N:8]1[C:14]2=[C:15]3[C:20](=[N:21][C:22]4=[CH:23][CH:24]=[CH:25][C:12](=[C:13]24)[O:11][CH2:10][CH2:9]1)[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COc2cccc3nc4c(c(c23)N1Cc1ccccc1)CCCC4
Agent: B
Solvent: C1CCOC1
Product: c1ccc(CN2CCOc3cccc4nc5c(c2c34)CCCC5)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 1-benzyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.71 g) in dry tetrahydrofuran (200 ml) was added borane in tetrahydrofuran (1M, 65 ml). The reaction mixture was stirred at room temperature overnight, quenched with 5% hydrochloric acid (500 ml), and stirred for an additional 2.5 hrs. The reaction mixture was cooled (0° C.), basified with 10% sodium hydroxide solution (500 ml), and extracted with ethyl acetate (800 ml). The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. Recrystallization of the residue from methanol yielded 3.05 g (68%) of product, mp 132°-133° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[N:30]=[C:29](Cl)[CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:27]3[CH:28]=[CH:29][N:30]=[C:25]([Cl:24])[N:26]=3)[CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2cccc(O)c2)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(-c2cccc(Oc3ccnc(Cl)n3)c2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of [2-(3′-hydroxy-biphenyl-4-yl)-ethyl]-carbamic acid tert -butyl ester (552 mg), 2,4-dichloropyrimidine (189 mg) and potassium carbonate (252 mg) in DMF (10 ml) is stirred at rt for 20 h. This mixture is quenched with brine and extracted twice with EtOAc. The combined organic phases are dried over sodium sulfate, the solvent is evaporated and the resulting crude product is purified on silica (60 g) with cyclohexane/EtOAc 80/20 to afford pure {2-[3′-(2-chloro-pyrimidin-4-yloxy)-biphenyl-4-yl]-ethyl}carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:6]2=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:4]=1[CH:23]([CH2:29][CH2:30][CH3:31])[C:24]([O:26]CC)=[O:25])[CH3:2].[OH-].[Na+]>CO.C(O)C>[CH2:1]([C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:6]2=[C:5]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:4]=1[CH:23]([CH2:29][CH2:30][CH3:31])[C:24]([OH:26])=[O:25])[CH3:2]
Reactant: CCCC(C(=O)OCC)c1c(CC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCC(C(=O)O)c1c(CC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 90 °C
Yield: 67.4 %

Procedure:
To a suspension of ethyl 2-[2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.322 g; 0.739 mmol) in a mixture methanol-ethanol (2:1) (22.5 mL) was added a solution of sodium hydroxide 5% (18 mL; 22.5 mmol) and the reaction mixture was heated at 90° C. for 4 h. The organic volatiles were removed under reduced pressure and the remaining basic solution was acidified until pH 2 with a solution of hydrochloric acid 1N. The aqueous layer was extracted with ethyl acetate, the organics were combined, dried over sodium sulphate and concentrated under reduced pressure to furnish 0.203 g (68%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:23][C@H:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:31][C@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](Nc1c([N+](=O)[O-])c(Cl)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
The method described in Part A of Example 4 was used to treat 2,4-dichloro-3-nitroquinoline (19.4 g, 78.5 mmol) in DMF (100 mL) with triethylamine (32 mL, 0.235 mol) and (S)-(−)-α-methylbenzylamine (11.5 g, 94.2 mmol) with the modification that the reaction was allowed to warm to room temperature and stirred for two hours. After the isolated precipitate was washed with water, it was dried under high vacuum overnight to provide 25.1 g of 2-chloro-3-nitro-N-[(1S)-1-phenylethyl]quinolin-4-amine as an orange solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[CH:19](=O)[CH2:20][CH:21]([CH3:23])[CH3:22]>C1(C)C=CC=CC=1.C(O)(C)C.C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[CH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CC(C)CC=O
Reactant: CCOCc1nc2cnc3ccccc3c2n1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2cnc3ccccc3c2n1N=CCC(C)C
Reaction time: 15 h
Yield: 99.8 %

Procedure:
A solution of 2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (1.00 g, 4.13 mmol) in 20 mL of toluene and 5 mL of isopropanol was treated with isovaleraldehyde (0.94 mL, 8.76 mmol) and pyridinium p-toluenesulfonate (0.052 g, 0.21 mmol) and the reaction mixture was heated to reflux under an atmosphere of nitrogen. After 15 h, the reaction mixture was concentrated under reduced pressure to yield a brown oil. The oil was dissolved in CHCl3 and washed with water (2×) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(3-methylbutylidene)amine (1.28 g) as a dark orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccoc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccoc1
Yield: 87.4 %

Procedure:
1.5 g of ethyl 2-[2-(4-chlorophenyl)-5-(3-furyl)-4-oxazolyl]acetate, 40 ml of methanol, 5 ml of water and 1.5 g of potassium hydroxide are treated in the same manner as described in Example 16. 1.2 g of 2-[2-(4-chlorophenyl)-5-(3-furyl)-4-oxazolyl]acetic acid are thereby obtained. Yield: 87.6%
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:20](=[O:24])[N:21]([CH3:23])[CH3:22])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.O>[C:29]([O:28][C:26]([NH:25][CH:19]([C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:33])=[O:2])=[CH:7][CH:8]=2)=[CH:14][CH:15]=1)=[O:27])([CH3:31])([CH3:30])[CH3:32]
Reactant: COC(=O)CCc1ccc(Oc2ccc(C(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
Amide 32 (3.6 g, 7.9 mmol) was dissolved in THF (40 mL) and diluted with water (40 mL). Lithium hydroxide (0.76 g, 31.0 mmol) was added and the reaction mixture was stirred at room temp for about 2 h. The THF was evaporated and the resulting aqueous layer was acidified with 2.0 M HCl and extracted into EtOAc (2×100 mL). The organic layer was washed with water (1×150 mL) and brine (1×200 mL), dried and concentrated to yield the desired acid compound 33 (3.4 g, 97%). 1H NMR (400 MHz, DMSO-d6): 12.2 (br, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.93 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 5.50 (d, J=8.0 Hz, 1H), 2.90 (s, 3H), 2.84 (s, 3H), 2.81 (t, J=7.6 Hz, 2H), 2.53 (t, J=7.6 Hz, 2H), 1.37 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19]C(=O)OC(C)(C)C)[CH:5]=[C:6]([F:18])[C:7]=1[C:8]1[S:9][C:10]2[C:11](Cl)=[N:12][CH:13]=[CH:14][C:15]=2[N:16]=1.[CH3:27][C:28]1[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[CH:29]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:19][C:4]1[CH:5]=[C:6]([F:18])[C:7]([C:8]2[S:9][C:10]3[C:11]([NH:34][C:30]4[CH:29]=[C:28]([CH3:27])[N:33]=[CH:32][N:31]=4)=[N:12][CH:13]=[CH:14][C:15]=3[N:16]=2)=[C:2]([Cl:1])[CH:3]=1
Reactant: Cc1cc(N)ncn1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc3nc(-c4c(F)cc(N)cc4Cl)sc23)ncn1
Temperature: 150 °C
Yield: 10.3 %

Procedure:
A mixture of tert-butyl N-[3-chloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-5-fluoro-phenyl]carbamate (56 mg, 0.135 mmol), 6-methylpyrimidin-4-amine (44 mg, 0.40 mmol), Pd2(dba)3 (6.2 mg, 0.00676 mmol), XantPhos (7.8 mg, 0.0135 mmol) and Cs2CO3 (88 mg, 0.27 mmol) in 1,4-Dioxane (2 mL) was heated at 150° C. in a microwave reactor for 20 min, The mixture was filtered through Celite, washed with EtOAc, concentrated. The crude product was purified by reverse phase HPLC to give the title compound (5.4 mg, 10% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.61 (s, 1H), 8.39 (d, J=5.6 Hz, 1H), 7.75 (d, J=5.6 Hz, 1H), 7.58 (s, 1H), 6.66 (s, 1H), 6.49 (dd, J=12.7, 2.0 Hz, 1H), 6.34 (s, 2H), 2.38 (s, 3H). LCMS (Method B): RT=3.43 min, m/z 387.0 [M+H+].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+].C(OCC=C)C=C>C1(C)C=C(C)C=C(C)C=1>[CH2:15]([C:7]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=1[OH:12])[CH:14]=[CH2:13]
Reactant: CC(C)(C)c1cc(Cl)ccc1O
Reactant: C=CCBr
Agent: C=CCOCC=C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1cc(C)cc(C)c1
Product: C=CCc1cc(Cl)cc(C(C)(C)C)c1O

Procedure:
Treatment of 2-tert-butyl-4-chlorophenol (12.73 g, 0.070 mol) with allyl bromide (10.01 g, 0.083 mol) and potassium carbonate (38.11 g, 0.276 mol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 gave 2-allyl-6-tert-butyl-4-chlorophenol. Treatment of the phenol with 3-chloroperoxybenzoic acid (35.90 g, 0.146 mol, 77%) followed by potassium carbonate (28.18 g, 0.204 mol) generally according to the procedure described for Intermediate 9 provided (±)-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of the alcohol with with p-toluenesulfonyl chloride (10.27 g, 0.054 mol) generally according to the procedure described for Intermediate 10 afforded 13.84 g (51%) (±)-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 74-77° C.; Anal. calcd. for C20H23ClO4S C, 60.83; H, 5.87. Found C, 60.79; H, 5.80.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=O.[OH-].[K+].[C:14]1(=O)[CH2:19][CH2:18]C[CH2:16][CH2:15]1>C(O)C>[CH2:7]1[C:6]2[C:11](=[N:1][C:16]3[C:2]([CH:4]=2)=[CH:18][CH:19]=[CH:14][CH:15]=3)[CH2:10][CH2:9][CH2:8]1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: O=C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2nc3c(cc2c1)CCCC3
Temperature: 310 °C
Reaction time: 10 h

Procedure:
A solution of isatin (40 g. 0.272 mol) in 30% aqueous potassium hydroxide (160 ml., 1.5 mol.) was added to a solution of cyclohexanone (69.7 g. 0.712 mol.) in ethanol (300 ml.) and the mixture heated at reflux with stirring for 10 hours. The ethanol was removed in vacuo and the residue dissolved in water (400 ml.) and extracted with ether (3 × 50 ml.). The aqueous phase was acidified with acetic acid and the resultant solid was washed with water, dried and heated at 310° C in a Wood's metal bath for 35 minutes. The cooled melt was diluted with 2N HCl (200 ml.) and extracted with chloroform (2 × 200 ml.) and the extracts discarded. The aqueous phase was adjusted to pH 9.0 with sodium carbonate and extracted with ethyl acetate (4 × 100 ml.) The combined extracts were washed with brine, dried and the solvent removed and the residual oily solid recrystallised from (bp 40°-60°) petrolum ether to give 1,2,3,4-tetrahydroacridine as colourless needles (38 g.). A sample (1 g.) was dissolved in anhydrous ether and treated with ethereal hydrogen chloride. The resultant solid was removed and recrystallised from isopropanol to give 1,2,3,4-tetrahydroacridine hydrochloride quarter hydrate as colourless needles m.p. 232° C. (Found C,70.2; H,6.5; N,5.9, C13H13N.HCl. 1/4H2O requires: C,69.7; H, 6.5; N, 6.2%).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:27]([CH2:28][CH2:29][C@:11]12[CH3:12])[C@:24]1([CH2:25][OH:26])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][C@@H:23]1[CH3:30])[CH:18]=[CH:17]3.[CH3:32][Cu]C.[Li].[Cl-].[NH4+].C1C=CC=CC=1>O1CCCC1>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[OH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:27]([CH2:28][CH2:29][C@:11]12[CH3:12])[C@:24]1([CH2:25][OH:26])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][C@@H:23]1[CH3:30])[CH2:18][C@H:17]3[CH3:32]
Reactant: C[C@H]1CC(=O)C=C2C=C[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Reactant: C[Cu]C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H]1CC2=CC(=O)C[C@H](C)[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 17β,19-dihydroxy-1α-methyl-4,6-androstadien-3-one diacetate in anhydrous tetrahydrofuran is added slowly to an ice cold ethereal solution of lithium dimethylcopper prepared as in the preceding Example. Stirring is continued for 30 minutes and the mixture is poured onto a saturated aqueous ammonium chloride solution. Benzene is added and the mixture filtered through a bed of diatomaceous earth. The organic layer is washed with aqueous ammonium chloride, water, dried over magnesium sulfate and evaporated to dryness. The residue is stirred at room temperature with aqueous methanolic hydrochloric acid for 1 hour and then poured onto ice water. The gum is extracted with ether, washed with water, dried over magnesium sulfate and the ether removed. The residue is chromatographed on silica gel and eluted with benzene. The eluant is recrystallized from hexane to give 17β,19-dihydroxy-1α,7α-dimethyl-4-androsten-3-one diacetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22]CC2C=CC=CC=2)[CH:17]=1>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=1
Reactant: COC(=O)Cc1c(C(=O)c2cccc(OCc3ccccc3)c2)[nH]c2cc(Cl)ccc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c(C(=O)c2cccc(O)c2)[nH]c2cc(Cl)ccc12
Reaction time: 2.5 h
Yield: 24 %

Procedure:
A mixture of methyl[6-chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetate (Example 177, 0.37 g, 0.85 mmol) and 10% palladium-charcoal (80 mg) in ethyl acetate-methanol (5:1, 30 ml) was stirred under hydrogen atmosphere for 2.5 h. The mixture was filtered thorough a pad of Celite and the filtrate was concentrated. The solids were washed with dichloromethane (10 ml) to afford 70mg (24%) of the title compound as white solids.