Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH3:11])=[C:6]([O:12][CH3:13])[N:5]=[C:4]([C:14]([OH:16])=[O:15])[CH:3]=1.[H][H].[CH3:19]O>[Pd]>[CH3:19][O:16][C:14]([C:4]1[CH:3]=[CH:2][C:7]([CH2:8][CH2:9][CH2:10][CH3:11])=[C:6]([O:12][CH3:13])[N:5]=1)=[O:15]
Reactant: [H][H]
Reactant: CO
Reactant: CCCCc1c(Cl)cc(C(=O)O)nc1OC
Agent: [Pd]
Product: CCCCc1ccc(C(=O)OC)nc1OC

Procedure:
2.43 g (0.01 mol) of 4-chloro-5-n-butyl-6-methoxy-2-picolinic acid dissolved in 50 ml of methanol are hydrogenated in the presence of 300 mg of 5% strength palladium on charcoal. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated to dryness. Distillation of the residue in a bulb tube in a high vacuum at 120° yields 2-methoxycarbonyl-5-butyl-6-methoxy-pyridine of the formula ##STR14##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:11][C:12]([OH:16])([CH3:15])[C:13]#[CH:14]>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][C:12]([OH:16])([CH3:15])[C:13]#[C:14][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCCc1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCc1ccc(C#CC(C)(C)O)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 60.7 %

Procedure:
60 g of 1-bromo-4-propylbenzene, 38 g of 3-methyl-1-butyn-3-ol, 1.3 g of triphenylphosphine and 0.7 g of bis(triphenylphosphine) palladium(II) chloride were dissolved in 260 ml of triethylamine in nitrogen atmosphere, and 0.2 g of copper(I) iodide was added thereto. This was stirred for one hour at room temperature and for 5 hours at 90° C. The crystals as precipitated were filtered out and, after triethylamine was removed by distillation, extracted with chloroform. These were washed two times with 10% hydrochloric acid and two times with water, and chloroform was removed by distillation. The residue was purified by silicagel-chloroform column chromatography to obtain 37 g of 3-methyl-1-(4'-propylphenyl)-1-butyn-3-ol.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:15]#[N:16])[C:9]=2[C:11]([F:14])([F:13])[F:12])[NH:4][C:3]=1[CH3:17].Cl[CH2:19][C:20]1[N:24]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=2)[O:22][N:21]=1>>[F:31][C:29]1[CH:30]=[C:25]([C:23]2[O:22][N:21]=[C:20]([CH2:19][N:4]3[C:5]4[C:10](=[C:9]([C:11]([F:13])([F:12])[F:14])[C:8]([C:15]#[N:16])=[CH:7][CH:6]=4)[C:2]([F:1])=[C:3]3[CH3:17])[N:24]=2)[CH:26]=[C:27]([F:32])[CH:28]=1
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Reactant: Cc1[nH]c2ccc(C#N)c(C(F)(F)F)c2c1F
Product: Cc1c(F)c2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(F)cc(F)c2)n1

Procedure:
Synthesized as described in Example 23 from 3-fluoro-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole: MS (ES) m/z 437 (M+1).
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH:27]1[CH2:36][C:35](=[O:37])[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1>>[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH:27]1[CH2:36][CH:35]([OH:37])[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1
Reactant: O=C1CC(c2cccc(F)c2F)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: Oc1ccc2c(c1)C(O)CC(c1cccc(F)c1F)O2

Procedure:
2-(2,3-Difluorophenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 2.91 g of 2-(2,3-difluorophenyl)-6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.88 (s, 1H), 7.45-7.36 (m, 2H), 7.28 (m, 1H), 6.89 (d, 1H, J 2.8 Hz), 6.61 (d, 1H, J 8.7 Hz), 6.55 (dd, 1H, J 8.7, 2.8 Hz), 5.49 (bs, 1H), 5.40 (dd, 1H, J 11.8, 1.4 Hz), 4.90 (m, 1H), 2.28 (m, 1H), 1.99 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([S:20][C:21]3[S:22][CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:25]=3)[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].[OH-].[Na+].O.Cl>C(O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([S:20][C:21]3[S:22][CH:23]=[C:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:25]=3)[CH2:17][CH2:18][CH3:19])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:32][CH2:33][C:34]([OH:36])=[O:35]
Reactant: CCCC(Sc1nc(-c2ccccc2)cs1)c1ccc(COc2ccc(CCC(=O)OCC)c(F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC(Sc1nc(-c2ccccc2)cs1)c1ccc(COc2ccc(CCC(=O)O)c(F)c2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of ethyl 3-{2-fluoro-4-[(4-{1-[(4-phenyl-1,3-thiazol-2-yl)thio]butyl}benzyl)oxy]phenyl}propanoate (0.130 g, 0.236 mmol) in a mixture of ethanol (0.5 mL) and tetrahydrofuran (1 mL) was added 2N aqueous sodium hydroxide solution (0.25 mL) and the mixture was stirred at 50° C. for 3 hr. Water was added to the reaction mixture, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-70:30) to give the title compound (0.119 g, yield 97%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][C:6]=1[CH3:16].[OH-].[Na+]>C(O)C.O>[OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[CH3:16]
Reactant: CCOC(=O)c1ccc(OCC(C)(C)O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1OCC(C)(C)O
Temperature: 40 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A mixture of 1-chloro-2-methyl-propan-2-ol (10 mL), 4-hydroxy-3-methyl-benzoic acid (2.0 g, 13.15 mmol), potassium carbonate (7.3 g, 52.71 mmol), water (6 mL) and ethanol (60 mL) was heated at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and partitioned between 1N NaOH and EtOAc and the layers were separated. The organic layer was washed with 1N NaOH (2×10 mL) and the combined aqueous layers were washed with EtOAc. The combined organic layers were dried and concentrated in vacuo to give ethyl 4-(2-hydroxy-2-methyl-propoxy)-3-methyl-benzoate. The ester was dissolved in ethanol (15 mL) and water (2 mL), sodium hydroxide (1.1 g, 26.30 mmol) was added and the reaction mixture was stirred at 40° C. for 4 hours. The reaction mixture was poured into 1N NaOH solution and extracted with ether (2×10 mL). The aqueous layer was acidified to pH 2-3 using 6N HCl solution and extracted with EtOAc (3×10 mL). The organics were separated and washed with brine solution. The organic layer was dried (Na2SO4) and concentrated in vacuo and the resulting material was triturated with ether to give 4-(2-hydroxy-2-methyl-propoxy)-3-methyl-benzoic acid (2.2 g, 75%) as a white solid. ESI-MS m/z calc. 224.1. Found 225.5 (M+1); Retention time: 1.06 minutes (3 min run) 1H NMR (400 MHz, DMSO) δ 7.75 (dd, J=8.5, 2.0 Hz, 1H), 7.73-7.70 (m, 1H), 6.96 (d, J=8.6 Hz, 1H), 4.67 (s, 1H, OH), 3.76 (s, 2H), 2.20 (s, 3H), 1.22 (s, 6H).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:18]2[C:17](=[O:19])[O:16][C:15]([CH2:20][C:21]#[N:22])=[CH:14][C:13]=2[CH:12]=[C:11]([O:23][CH3:24])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].[F-].[CH2:28]([N+](CCCC)(CCCC)CCCC)CCC.CI>C(Cl)Cl>[Si:1]([O:8][C:9]1[C:18]2[C:17](=[O:19])[O:16][C:15]([CH:20]([C:21]#[N:22])[CH3:28])=[CH:14][C:13]=2[CH:12]=[C:11]([O:23][CH3:24])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)c2c(=O)oc(CC#N)cc2c1
Agent: [F-]
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: ClCCl
Product: COc1cc(O[Si](C)(C)C(C)(C)C)c2c(=O)oc(C(C)C#N)cc2c1
Temperature: 0 °C
Yield: 155.2 %

Procedure:
2.50 g (7.24 mmol) of the 8-tert-butyldimethylsilyloxy-3-cyanomethyl-6-methoxy-1-oxo-1H-2-benzopyran obtained in Example 5 was dissolved in 80 ml of methylene chloride. 100 ml of a 1M aqueous solution of sodium hydroxide was added thereto, and the resulting mixture was cooled to 0° C. While this mixture was being vigorously stirred, 584 mg (1.81 mmol) of tetrabutylammonium fluoride and then 10 ml of methylene chloride containing 0.92 ml (14.47 mmol) of methyl iodide were added thereto, followed by stirring at 0° C. for 1 hour. Moreover, 10 ml of methylene chloride containing 0.92 ml (14.47 mmol) of methyl iodide was added thereto, followed by stirring for 30 minutes. After completion of the reaction, the methylene chloride layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [using 130 g of Wako Gel C-200 and hexane/ethyl acetate (5:1)]. Thus, 1.01 g of the title compound was obtained in a 39% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[CH3:23][C:24]1[N:29]=[C:28]([CH2:30]O)[CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.O1CCCC1>[CH3:30][C:28]1[N:29]=[C:24]([CH2:23][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Cc1cccc(CO)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 41.1 %

Procedure:
To a mixture of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.23 g, 0.79 mmol), 6-methyl-2-pyridinemethanol (0.13 g, 1.07 mmol) and triphenylphosphine (0.30 g, 1.14 mmol) in benzene (10 mL) under nitrogen was slowly added a solution of diethyl azodicarboxylate (0.22 g, 1.27 mmol) in tetrahydrofuran (6 mL). The resulting mixture was stirred at ambient temperature for 16.5 h. The solvents were removed under reduced pressure, and the residue was taken up into 2 M sodium carbonate (50 mL) and extracted with dichloromethane (3×30 mL). The combined organic solution was washed with brine (50 mL), dried with sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with hexanes/ethyl acetate (2:1) gave 1′-[(6-methylpyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.13 g, 41%) as a colorless solid: mp 183-185° C. (hexanes/diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.56 (dd, J=7.8, 7.5 Hz, 1H), 7.23-7.16 (m, 2H), 7.10-7.00 (m, 3H), 6.90 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.32 (s, 1H), 5.23 (d, J=15.9 Hz, 1H), 4.958 (d, J=9.0 Hz, 1H), 4.956 (d, J=15.9 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.23-4.18 (m, 2H), 4.15-4.11 (m, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.8, 158.2, 155.4, 154.7, 144.8, 142.2, 138.4, 138.2, 132.3, 129.0, 124.0, 123.7, 122.9, 121.2, 118.8, 111.8, 109.8, 99.6, 80.3, 64.7, 64.1, 58.3, 45.7, 24.1; MS (ES+) m/z 401.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1.N.[BH3-]C#[N:18].[Na+].Cl>CO>[ClH:1].[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:18])[CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCN(c2cncc(Cl)n2)CC1
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CO
Product: NC1CCN(c2cncc(Cl)n2)CC1
Reaction time: 60 h

Procedure:
To a solution of 17.1 g (81 mmol) 6-chloro-2-(4-oxopiperidino)pyrazine in 250 ml methanol which has been saturated with gaseous NH3 is added 62.4 g (0.81 mol) NH4OAc and 5.0 g (80 mmol) NaCNBH3. After stirring at 20°-25° C. for 60 hours, the MeOH is removed in vacuo. Water is added to the residue, and the pH is adjusted to 14. The product is extracted into ethyl acetate which is dried and concentrated. Chromatography of the residue over silica gel, eluting with 5% MeOH/CHCl3 saturated with NH3, gives the product base which is converted to the hydrochloride salt with ethanolic HCl. Recrystallization from water/acetone affords the desired product, m.p. 291° C. (dec.).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([CH3:17])=[N:14]2)=[CH:9][CH:8]=1)[CH3:5].[Se](=O)=[O:19]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][C@H:4]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([CH:17]=[O:19])=[N:14]2)=[CH:9][CH:8]=1)[CH3:5]
Reactant: O=[Se]=O
Reactant: COC[C@@H](C)Oc1ccc2ccc(C)nc2c1
Solvent: C1COCCO1
Solvent: O
Product: COC[C@@H](C)Oc1ccc2ccc(C=O)nc2c1
Yield: 46.7 %

Procedure:
To a solution of (R)-7-(1-methoxypropan-2-yloxy)-2-methylquinoline (0.22 g, 0.96 mmol) in dioxane (7 mL) and water (0.07 mL) was added selenium dioxide (0.13 g, 1.2 mmol) and the resultant mixture heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-20% ethyl acetate/hexanes) to afford the title compound (0.11 g, 46%).
Reaction SMILES: FC1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]2([O:19][CH2:20][CH:21]2[CH2:23][CH2:22]2)[CH:16]([F:18])[F:17])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1.[CH2:35]([Cl:37])Cl>>[Cl:37][C:35]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]([O:19][CH2:20][CH:21]4[CH2:23][CH2:22]4)([CH:16]([F:18])[F:17])[C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][N+:8]=3[O-:32]
Reactant: Fc1ccc2c(c1)C(OCC1CC1)(C(F)F)c1cccnc1N2
Reactant: ClCCl
Reactant: O=C(OO)c1cccc(Cl)c1
Product: [O-][n+]1cccc2c1Nc1ccc(Cl)cc1C2(OCC1CC1)C(F)F
Temperature: 23 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
Method FF: To a 10.0 mL round bottom equipped with a magnetic stirrer, and nitrogen inlet was added 7-fluoro-9-cyclopropylmethoxy-9-difluoromethyl-4-azaacridine (1.4 g, 4.15 mmol) and anhydrous CH2Cl2 (50 mL). MCPBA (1.23 g, 4.64 mmol) was added in portions and stirred at 23° C. for 4 h. The reaction mixture was diluted with CH2Cl2, washed with sat. NaHCO3 solution (3×100 mL), brine and dried (MgSO4). Concentration afforded a yellow residue which was purified by column chromatography (SiO2, 1% Et3N-EtOAc) to afford 1.03 g of 7-Chloro-5-cyclopropylmethoxy-5-difluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine 1-oxide as a light green solid (mp 185-186° C., 70% yield).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[N+:24]([O-:26])=[O:25])=[N:14][NH:15][CH:16]=1>N1C=CC=CC=1>[O:4]([C:2]([C:16]1[NH:15][N:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[N+:24]([O-:26])=[O:25])[C:12]=1[Cl:11])=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1c(Cl)cccc1-c1n[nH]cc1Cl
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)c1[nH]nc(-c2cccc(Cl)c2[N+](=O)[O-])c1Cl
Reaction time: 8 h

Procedure:
1.0 ml of phenyl chloroformate is added, in small portions, to a solution, cooled to 0° C., of 1.3 g of 4-chloro-3-(2-nitro-3-chlorophenyl)pyrazole in 20 ml of pyridine. Stirring is continued for 8 hours at room temperature. The reaction mixture is concentrated to dryness under reduced pressure and taken up in 100 ml of an H2O ethyl acetate (1/1) mixture. The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residual solid is purified by recrystallisation from diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16].[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1>>[ClH:1].[CH2:13]([NH:17][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:20]2[C:19]([CH3:18])=[CH:23][C:22]([CH3:24])=[N:21]2)[N:11]=1)[CH2:14][CH2:15][CH3:16]
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CCCCN
Reactant: Cc1cc(C)[nH]n1
Product: CCCCNc1nc(-n2nc(C)cc2C)nc2ccccc12
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, butylamine and 3,5-dimethylpyrazole. Mp. 98.4° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=1)[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CO>[CH3:3][CH:2]([C:4]1[C:12]2[C:7]([NH:8][CH:9]=[N:10][C:11]=2[N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:18]2)=[N:6][CH:5]=1)[CH3:1]
Reactant: CC(C)c1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCC(NC(=O)c4ccccc4)CC3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cnc2[nH]cnc(N3CCC(NC(=O)c4ccccc4)CC3)c1-2
Reaction time: 2 h

Procedure:
To a solution of N-{1-[5-(1-methylethyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide D9 (140 mg) in THF (2 mL) and MeOH (1 mL) was added cesium carbonate (272 mg, 0.834 mmol) and the mixture stirred for 2 hours. LCMS showed a small amount of starting material so the reaction was stirred for a further 2 hours. The mixture was then partitioned between EtOAc (20 mL) and water (20 mL) and the organic phase washed with water (20 mL) and brine (20 mL) before it was dried (MgSO4), filtered and the solvent removed in vacuo. The crude product was purified by MDAP. The compound-containing fractions were concentrated and dried in a vacuum oven to give E20 (23 mg) as a white solid, 1H NMR (d6-DMSO) δ 11.62 (1H, s), 8.39 (1H, d), 8.26 (1H, s), 7.88 (2H, d), 7.52 (1H, t), 7.46 (2H, t), 7.09 (1H, s), 4.05 (1H, m), 3.90 (2H, d), 3.16 (1H, septet), 3.00 (2H, t), 1.94 (2H, d), 1.77 (2H, ddd), 1.28 (6H, d), MS(ES+) 364 [M+H]+.
Reaction SMILES: C1(CNCC2C=C(C3C=[C:15]4[C:19](=[C:20](C(N)=O)C=3)[NH:18][CH:17]=[C:16]4C3CCN(S(CC)(=O)=O)CC3)C=NC=2)CC1.[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39]([C:44]2[CH:45]=[C:46]([CH:50]=O)[CH:47]=[N:48][CH:49]=2)[O:38]1.CC1CCCN1.[BH3-]C#N.[Na+]>>[CH3:20][CH:19]1[CH2:15][CH2:16][CH2:17][N:18]1[CH2:50][C:46]1[CH:47]=[N:48][CH:49]=[C:44]([B:39]2[O:38][C:37]([CH3:52])([CH3:36])[C:41]([CH3:43])([CH3:42])[O:40]2)[CH:45]=1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: CC1CCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC1CCCN1Cc1cncc(B2OC(C)(C)C(C)(C)O2)c1

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), 2-methylpyrrolidine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 25 mg of crude 3-[(2-methyl-1-pyrrolidinyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. The crude 3-[(2-methyl-1-pyrrolidinyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 6 mg of the title compound (16%).
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH:6]3[CH2:7]C([CH2:10][C:4]([CH3:12])([CH2:5]3)[CH2:3]1)[CH2:9]2.C(Cl)Cl.[C:16](=[O:19])(O)[O-].[Na+].[OH:21]OS([O-])=O.[K+]>O>[OH:21][C:6]12[CH2:11][C:2]3([CH3:9])[CH2:3][C:4]([CH3:12])([CH2:10][C:16]([OH:19])([CH2:1]3)[CH2:7]1)[CH2:5]2
Reactant: O=C([O-])O
Reactant: O=S([O-])OO
Reactant: CC12CC3CC(C1)CC(C)(C3)C2
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC12CC3(C)CC(O)(C1)CC(O)(C2)C3
Temperature: 0 °C

Procedure:
1,3-Dihydroxy-5,7-dimethyladamantane was synthesized in a similar manner as described for 1,3,5,7-tetrahydroadamantane. Into a 4-neck flask immersed in a cooling bath and equipped with a low-temperature condenser (-20° C.), an air-driven, well-sealed mechanical stirrer, a solid addition funnel, and a thermocouple, there were charged 4.5 grams, 1,3-dimethyladamantane (Aldrich, 99%+), 100 ml methylene chloride, 96 grams sodium bicarbonate, 100 ml double distilled water. Upon stirring and cooling the mixture to 0° C., 100 grams TFP were added and the temperature of the mixture went to 10° C. After the mixture was cooled down again to 0° C., 100 grams OXONE were added in the course of an hour. The reaction mixture was stirred at -5° C. for additional 20 hours (overnight). The TFP was recovered by distilling the reaction mixture at a pot temperature of 50° C. into a receiver immersed in DryIce/acetone. The remainder mixture was filtered by suction over Celite as a filter aid. The filtrate was yellow and contained two phases (aqueous and organic). It was rotavapped to dryness. The dry solid was extracted with ethanol and filtered. Crude product was obtained by evaporating off the ethanol which contained more than 95% 1,3-dihydroxy-5,7-dimethyladamantane. The brownish crude product was purified by crystallization from ethanol/methylene chloride mixture to a GC pure product with a molecular weight of 196 gram/mole (by GC-MS). Calculated for C12H20O2 :196.28 gram/mole
Reaction SMILES: [CH3:1][C:2]([O:26]C1CCCCO1)([CH3:25])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][CH:15]2OCC3C=CC=CC=3O2)=[CH:9][CH:8]=1.[C:33]([OH:36])(=O)[CH3:34].[CH2:37]1[CH2:41][O:40][CH2:39][CH2:38]1>O>[OH:40][CH2:39][C:38]1[CH:37]=[CH:41][C:15]([CH:14]=[CH:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:26])([CH3:1])[CH3:25])=[CH:12][CH:11]=2)=[CH:34][C:33]=1[OH:36]
Reactant: CC(=O)O
Reactant: C1CCOC1
Reactant: CC(C)(CCCCc1ccc(C=CC2OCc3ccccc3O2)cc1)OC1CCCCO1
Solvent: O
Product: CC(C)(O)CCCCc1ccc(C=Cc2ccc(CO)c(O)c2)cc1

Procedure:
In a manner similar to Example 8(k), by reacting 2 g (4.3 mmol) of 2,2-dimethyl-7-(2-{4-[5-methyl-5-(tetrahydropyran-2-yloxy)hexyl]phenyl}vinyl-4H-benzo[1,3]dioxin in a solution of 50 ml of acetic acid+25 ml of THF+12.5 ml of water, after purification on a silica column (ethyl acetate 50-heptane 50), a white powder (m=44 mg; Y=3%) is obtained. m.p.=163-5° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH:13]=[CH2:14].[CH3:22]C(C)=O>>[OH:11][C:3]1[C:2]([CH3:1])=[C:8]2[C:6](=[C:5]([CH3:9])[C:4]=1[CH3:10])[O:7][C:12]([O:15][CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][CH2:14]2
Reactant: CC(C)=O
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(=O)c1ccccc1
Product: COC1(c2ccccc2)CCc2c(C)c(O)c(C)c(C)c2O1

Procedure:
Trimethylhydroquinone was reacted with acrylophenone by the procedure of Example 1 to give (±)-6-hydroxy-2-methoxy-2-phenyl-5,7,8-trimethylchroman as a white solid, m.p. 190.5°-192.5° from acetone-30°-60° petroleum ether.
Reaction SMILES: C(O[C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Br:18])=[CH:15][N:16]=2)[C:11](=[O:19])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[C:20]([N:28]=C=O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[Br:18][C:14]1[CH:13]=[C:12]2[C:17](=[N:16][CH:15]=1)[N:8]([C:6]([NH:28][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])[CH2:9][CH2:10][C:11]2=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2cc(Br)cnc21
Reactant: O=C=NC(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=O)N1CCC(=O)c2cc(Br)cnc21)c1ccccc1
Temperature: 50 °C
Yield: 100.2 %

Procedure:
A mixture of 6-bromo-4-oxo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (228 mg, 1.00 mmol) and benzoyl isocyanate (207 mg, 1.41 mmol, 90%) in 5 mL CH2Cl2 is heated at 50° C. for 2 hrs. The mixture is concentrated to give 375 mg of N-(6-bromo-4-oxo-3,4-dihydro-2H-[1,8]naphthyridine-1-carbonyl)-benzamide which is carried on without purification.