Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:27][CH:28]([CH3:30])[CH3:29])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19]CC2C=CC=CC=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11].C([O-])=O.[NH4+].C(O)C>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:27][CH:28]([CH3:30])[CH3:29])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(C)c1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(O)cc2)c(C)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a round bottomed flask was added a stirrer bar, N-(2,4-dimethylphenyl)-N-(2-methylpropyl)-4-[(phenylmethyl)oxy]benzenesulfonamide (974 mg, 2.300 mmol), ammonium formate (725 mg, 11.50 mmol), palladium(II) hydroxide (20% on carbon) (164 mg, 0.230 mmol) and Ethanol (65 mL). A reflux condenser was placed on the top of the flask and the reaction mixture was heated to 90° C. under reflux with stirring overnight. A product peak was observed by LCMS analysis, but only partial conversion had been seen overnight. White crystals thought to be ammonium formate were observed on the side of the reflux condenser and consequently a further 5 equivalents of ammonium formate (725 mg, 11.50 mmol) were added to the reaction mixture. The temperature of the heater was raised to 95° C. after which the reaction mixture had reached boiling point. After a further 30 minutes of heating, another LCMS sample was taken, showing no change in the ratio of starting material:product. The reaction mixture was cooled for 5 minutes before the addition of another measure of palladium(II) hydroxide (20% on carbon) (164 mg, 0.230 mmol). The reaction mixture was then reheated to 95° C. for another 30 minutes after which full conversion to the product was observed. The reaction mixture was filtered through a 10 g Celite cartridge before concentrating in vacuo to give 727 mg of crude product. The crude mixture was diluted with ethyl acetate and washed with water, then brine. The organic phase was then concentrated in vacuo to give 663 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]N=1>C(O)C>[N:12]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:11]=1[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COC1=NCCCCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC1=NCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-tert-butoxycarbonyl-1,3-propanediamine (2 g; 11.48 mmol), described in Step a of Preparation A, in 1 ml of ethanol is added to a solution of 2-methoxy-4,5,6,7-tetrahydro-3H-azepine (1.46 g; 11.48 mmol; 1.7 ml) in 4 ml of absolute ethanol. After stirring for 8 hours at ambient temperature, the reaction mixture is concentrated to yield the expected product.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[C:10]([C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)[CH:11]=[CH:12][CH:13]=2)OC1.Br[C:22]1[N:26]2[N:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.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>[CH3:19][N:16]1[CH:17]=[CH:18][C:14]([C:10]2[CH:9]=[C:8]([C:22]3[N:26]4[N:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[N:30][C:25]4=[N:24][CH:23]=3)[CH:13]=[CH:12][CH:11]=2)=[N:15]1
Reactant: Cn1ccc(-c2cccc(B3OCC(C)(C)CO3)c2)n1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
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: C1CCOC1
Product: Cn1ccc(-c2cccc(-c3cnc4nc(C(F)(F)F)cnn34)c2)n1
Yield: 36 %

Procedure:
A mixture of 3-[3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl]-1-methyl-1H-pyrazole (from above), 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (300 mg, 1.1 mmol) and sodium carbonate (1.7 ml of a 2 N solution, 3.4 ml) in THF (7 ml) was degassed with nitrogen for 15 min. After this time tetrakis(triphenylphosphine)palladium(0) (130 mg, 0.11 mmol) was added and the mixture heated at reflux for 18 h. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (30 ml) and 1 N NaOH (2×30 ml). The organic phase was separated and washed with brine (30 ml), dried (MgSO4) and evaporated. The residue was chromatographed (silica gel, 2.5% MeOH/CH2Cl2) and the fractions containing the desired product were combined and evaporated. The residue was triturated with diethyl ether twice to afford the title compound (140 mg, 36%) as a colourless solid: 1H NMR (400 MHz, CDCl3) δ 3.99 (3H, s), 6.62 (1H, d, J 2.2 Hz), 7.43 (1H, d, J 2.2 Hz), 7.58 (1H, t, J 7.8 Hz), 7.89 (1H, dd, J 7.8, 1.2 Hz), 8.03 (1H, d, J 7.9 Hz), 8.51 (1H, t, J 1.5 Hz), 8.68 (1H, s), 8.80 (1H, s); MS (ES+) m/z 345 [M+H]+.
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:34])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C:30]([CH3:33])=[N:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[N:14][CH:15]=1.B(Br)(Br)Br.[Cl-].[NH4+]>C(Cl)Cl>[CH3:33][C:30]1[O:29][C:28]([C:25]2[NH:24][C:23]([C:21]3[CH:22]=[C:6]([CH:7]=[C:8]([O:9][C:10]4[CH:15]=[N:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=4)[CH:20]=3)[O:5][C@@H:4]([CH3:34])[CH2:3][OH:2])=[CH:27][CH:26]=2)=[N:32][N:31]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(-c3nnc(C)o3)[nH]2)c1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(O[C@@H](C)CO)c3)[nH]2)o1
Reaction time: 1 h
Yield: 61.2 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-2-(methylsulfonyl)pyridine (320 mg, 0.660 mmol) synthesized in Example 80 was dissolved in methylene chloride (10 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 1.00 mL, 1.00 mmol) was added dropwise at −78° C., and stirring was carried out at room temperature for 1 hour under nitrogen atmosphere. To this reaction solution, a saturated aqueous ammonium chloride solution (20 mL) was added, and extraction was carried out with methylene chloride (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=1%-3%) to afford the desired compound (190 mg, yield 61%) as a yellow solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:4][C:5]1[CH:40]=[CH:39][C:8]([C:9]([C:11]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]([C:23](=O)[C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([CH2:36][CH3:37])[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:26][CH:25]=3)=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=O)=[CH:7][CH:6]=1)[CH3:2].[H][H]>C1COCC1.[Pd]>[CH2:36]([CH:31]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:17]2[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:41][CH2:42][CH2:43][CH3:44])=[CH:40][CH:39]=3)=[CH:19][C:18]=2[C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1)[CH3:37]
Reactant: CCCCC(CC)Cc1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(CC(CC)CCCC)cc3)cc2C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCC(CC)Cc1ccc(Cc2cc(C(=O)O)c(Cc3ccc(CC(CC)CCCC)cc3)cc2C(=O)O)cc1

Procedure:
A mixture containing 20.0 grams of 2,5-bis(4-(2-ethylhexyl)benzoyl)terephthalic acid in 1500 mL of THF and 2.9 grams of 10% palladium on carbon (as a catalyst) was heated to 65° C. in an atmosphere of hydrogen at 275 kPa for 17 hours. The mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give 2,5-Bis(4-(2-ethylhexyl)benzyl)terephthalic acid.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[NH:15][S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[C:6]=2[CH2:5][CH2:4][CH2:3]1.O1CCCC1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[NH:15][S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCCc2c1[nH]c1c(NS(=O)(=O)c3cccs3)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cccc2c3c([nH]c12)C(O)CCC3)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
To a mixture of N-(1-oxo-2,3,4,9-tetrahydro-1H-carbazol-8-yl)thiophene-2-sulfonamide (0.50 g), tetrahydrofuran (20 mL) and methanol (2 mL) was added sodium borohydride (0.11 g) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (0.43 g, yield 86%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point>175° C. (decomposition).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH2:13][C:12]3([CH2:18][CH2:17][C:16](=[N:19][OH:20])[CH2:15][CH2:14]3)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH:24]1[CH2:29][CH2:28][O:27][C:25]1=[O:26]>C1COCC1>[O:26]=[C:25]1[CH:24]([O:20][N:19]=[C:16]2[CH2:17][CH2:18][C:12]3([O:11][N:10]=[C:9]([C:8]#[C:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:13]3)[CH2:14][CH2:15]2)[CH2:29][CH2:28][O:27]1
Reactant: O=C1OCCC1Br
Reactant: ON=C1CCC2(CC1)CC(C#Cc1ccccc1)=NO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OCCC1ON=C1CCC2(CC1)CC(C#Cc1ccccc1)=NO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of the compound of Example 46 (50 mg, 0.186 mmol) in THF (5 mL) was added sodium hydride (60% oil dispersion, 7.81 mg, 0.195 mmol) and the mixture was stirred at r.t. for 1 h. Afterwards, 2-bromo-gamma-butyrolactone (17.2 μL, 0.186 mmol) was added and the reaction was stirred overnight, quenched with water, extracted with EtOAc. The combined organic layers were washed with brine, evaporated to dryness in vacuo to afford a crude, which was purified by automated RP chromatography (Isolera®TM-Biotage; gradient buffer NH4HCO3-MeCN from 40-60 a 30-70. Yield: 32%
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:17]#[N:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][CH2:29][NH:30][CH3:31])=[CH:27][C:22]=2[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]([C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][N:30]([CH2:29][CH2:28][C:26]1[CH:25]=[CH:24][C:23]2[O:19][CH2:20][CH2:21][C:22]=2[CH:27]=1)[CH3:31])#[N:18]
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: CNCCc1ccc2c(c1)CCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc2c(c1)CCO2)CCC(C#N)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture containing 3-bromo-1-cyano-1,1-diphenylpropane (0.3 g -- see Preparation 4), N-[2-(2,3-dihydrobenzofur-5-yl) ethyl]-N-methylamine (0.177 g -- see Preparation 28), anhydrous potassium carbonate (0.276 g) and acetonitrile (25 ml) was heated under reflux for 48 hours. On cooling to room temperature, the mixture was concentrated in vacuo and the residue was partitioned between water (20 ml) and dichloromethane (40 ml). The layers were separated and the aqueous layer further extracted with dichloromethane (2×20 ml). The combined dichloromethane extracts were dried (Na2SO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing dichloromethane (50% up to 100%) and then with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield, 0.13 g.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9](=[O:21])[CH:8]=1)(=O)=O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[F:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:10]1[CH:11]=[CH:12][C:7]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:8][C:9]1=[O:21]
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)ccn1Cc1cccc(F)c1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccn(Cc3cccc(F)c3)c(=O)c2)cc1
Yield: 60.7 %

Procedure:
According to Scheme 13 Method C: The title compound was prepared from 1-(3-fluorobenzyl)-1,2-dihydro-2-oxopyridin-4-yl trifluoromethanesulfonate (1 eq, 0.28 mmol, 0.10 g) and 4-methoxyphenyl boronic acid (1.5 eq, 0.43 mmol, 65 mg) according to the procedure described for Example 1 Step 3. The crude product was purified by flash chromatography on silica gel using cyclohexane/AcOEt 70/30 as eluent to afford the title compound (0.17 mmol, 52 mg, 59%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[NH:8][C:7](=[O:14])[C:6]=1[CH2:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][C:17]=1[F:31])[CH2:2][CH2:3][CH3:4].Cl[CH2:33][O:34][CH3:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH2:33][O:34][CH3:35])[C:7](=[O:14])[C:6]=1[CH2:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][C:17]=1[F:31])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2c(F)cc(-c3ccccc3C#N)cc2F)c(=O)[nH]c2ncnn12
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1c(Cc2c(F)cc(-c3ccccc3C#N)cc2F)c(=O)n(COC)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A mixture of 4′-[(7-butyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]-3′,5′-difluorobiphenyl-2-carbonitrile (0.88 g), chloro(methoxy)methane (0.19 mL), potassium carbonate (0.58 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.77 g, 79%).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH:8]([O:10][C:11]([CH3:46])([CH3:45])[CH2:12][O:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([C:24]1N3C=C([C@@H](N4CC[C@H](N)C4)C(F)(F)F)C=CC3=NN=1)[CH:20]=[CH:19]2)=O.IC>O>[CH3:8][O:10][C:11]([CH3:46])([CH3:45])[CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([CH3:24])[CH:20]=[CH:19]2
Reactant: CC(C)(COc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc12)OC=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(C)(C)COc1cccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
To a mixture of sodium hydride (60% in mineral oil; 0.013 g, 0.32 mmol) in anhydrous dimethylformamide (1.4 mL, 0.22 mmol) was added dropwise a solution of 2-methyl-1-(2-methylquinolin-8-yloxy)propan-2-ol (Example 259; 0.050 g, 0.22 mmol) in anhydrous dimethylformamide (1.4 mL, 0.22 mmol). The mixture was allowed to stir at ambient temperature for 30 minutes before by addition of iodomethane (0.054 mL, 0.86 mmol), and the resultant mixture allowed to stir at ambient temperature for 12 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (2×40 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water) providing the title compound (0.038 g, 73%).
Reaction SMILES: I[Si](C)(C)C.C[O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[O:17]C)[CH:13]([CH3:19])[CH2:12][CH2:11]2.O>C(#N)C>[CH3:19][CH:13]1[C:14]2[C:10](=[CH:9][C:8]([OH:7])=[C:16]([OH:17])[CH:15]=2)[CH2:11][CH2:12]1
Reactant: COc1cc2c(cc1OC)C(C)CC2
Agent: C[Si](C)(C)I
Solvent: O
Solvent: CC#N
Product: CC1CCc2cc(O)c(O)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
Over 90 min at room temperature, 27.5 ml (202 mmol) of iodotrimethylsilane were added dropwise with stirring to a solution of 19.4 g (101 mmol) of 5,6-dimethoxy-1-methylindane in 150 ml of acetonitrile. The mixture was stirred for a further 2.5 d at room temperature, in the course of which, after 48 h, again 10 ml (73.5 mmol) of iodotrimethylsilane were added. The reaction mixture was then poured into 500 ml of water and the product was extracted twice, each time with 200 ml of ether. The combined extracts were washed with 100 ml of 40% sodium hydrogen sulfite solution, 100 ml of water and 50 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. After flash chromatography (pentane/ether, 2:1, Rf=0.28) on silica gel, 15.5 g (93%) of 1-methylindane-5,6-diol were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([CH2:8][CH2:9][C:10]([CH3:12])=[O:11])[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=1.C(OCC)(OCC)O[CH2:17][CH3:18].B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)C>[CH2:17]([O:11][C:10]1([CH3:12])[CH2:9][CH2:8][CH:7]2[C:2](=[CH2:1])[CH:3]1[CH2:4][CH2:5][C:6]2([CH3:14])[CH3:13])[CH3:18]
Reactant: CC(=O)CCC1C(C)=CCCC1(C)C
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: C=C1C2CCC(C)(OCC)C1CCC2(C)C
Temperature: 25 °C
Yield: 97.8 %

Procedure:
480 g (2.21 mol) of dihydro-α-ionone, 368 g (2.48 mol) of triethyl orthoformate and 480 ml of abs. ethanol are treated dropwise while stirring during 15 minutes with a solution of 34.5 g (0.31 mol) of boron trifluoride etherate in 500 ml of ethanol and the mixture is subsequently heated to an internal temperature of 46°-48° for 60 minutes. After cooling the reaction mixture to room temperature it is stirred with 600 ml of a 10% aqueous sodium hydroxide solution. After extraction with ether and evaporation of the organic phase there are obtained 668.7 g of a slightly yellow liquid which, after flash distillation in a vacuum, gives 480.5 g of crude product (b.p. 45°-73°, 0.07 mbar). After fractionation in a vacuum over a 20 cm Widmer column there are obtained 406.2 g (82.7% of theory) of a slightly yellowish colored liquid (b.p. 48°-67°, 0.06 mbar) which contains the desired bicyclo-nonane in an isomer ratio of exo:endo=2:1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([S:21][CH3:22])[N:15]=1.O>CN(C=O)C.C1COCC1>[Cl:13][C:14]1[CH:19]=[C:18]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:17]=[C:16]([S:21][CH3:22])[N:15]=1
Reactant: COc1ccc(CO)cc1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(Cl)nc(SC)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a solution of 4-methoxybenzyl alcohol (8.9 g, 65 mmol) in dry DMF (100 ml) was added a 60% suspension of sodium hydride (2.2 g, 55 mmol) in portions and the mixture was stirred for two hours at room temperature. The mixture was cooled in an ice bath and 4,6-dichloro-2-methylsulfanyl-pyrimidine (9.8 g, 50 mmol) in dry THF (20 ml) was added. The mixture was then stirred for 72 h at room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The organic phase was washed with water, dried with sodium sulphate and evaporated under reduce pressure. The residue was purified by silica gel chromatography eluted with hexane ethyl acetate which gave the title compound (9.1 g, 61%), (M+H)+296
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.C([Li])CCC.[CH2:13]([O:17][C:18]1[C:22](S(C)(=O)=O)=[N:21][S:20][N:19]=1)[CH2:14][CH2:15][CH3:16]>C1COCC1.CCCCCC>[CH2:13]([O:17][C:18]1[C:22]([O:7][CH:4]2[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]2)=[N:21][S:20][N:19]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOc1nsnc1S(C)(=O)=O
Reactant: CN1CCC(O)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCOc1nsnc1OC1CCN(C)C1

Procedure:
A solution of 1-methyl-3-pyrrolidinol (0.6 g, 0.0059 mol) in THF (20 mL) was treated with 1.6 M n-butyllithium in hexane (3.1 mL), 0.005 mol). To the solution was added 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1.0 g, 0.0042 mol) and the reaction heated to reflux overnight. The solvent was evaporated, the residue acidified with cold 1 N HCl, and the mixture extracted with ether. The aqueous fraction was made basic, extracted with EtOAc, and the extracts washed with water. The extracts were dried and the solvent evaporated to give a liquid. The HCl salt (0.7 g) crystallized from EtOAc, m.p. 157-158° C. (Compound 28).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([OH:16])[CH:10]=[CH:9][CH:8]=3.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([O:16][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[O:13][C:14]1[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:6]2=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1c2ccc(Cl)cc2oc2c(O)cccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ccc(Cl)cc2oc2c(OCc3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The 3-chloro-5-hydroxyxanthone (11 g.) in dimethylformamide (50 ml.) is added to a suspension of sodium hydride (1.5 g.) in dimethylformamide (100 ml.). The mixture is stirred at room temperature for 15 minutes and benzyl bromide (6 ml.) is added dropwise. The mixture is poured into water/ice (600 ml.), extracted with chloroform and the chloroform extract dired with MgS04. Evaporation of the solvent gives a light-brown solid which is recrystallised from ethanol to give 5-benzyloxy-3-chloroxanthone, m.p. 154° C.
Reaction SMILES: Cl.Cl[CH:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.[CH3:13][NH:14][CH3:15].[Cl-].[Na+].[OH-].[Na+]>>[CH3:13][N:14]([CH3:15])[CH:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: ClC1CCCc2cccnc21
Reactant: CNC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: CN(C)C1CCCc2cccnc21
Temperature: 25 °C

Procedure:
4.08 g of 8-chloro-5,6,7,8-tetrahydroquinoline hydrochloride of Example 1 were mixed with stirring for 75 minutes in 20 ml of a 40% aqueous solution of dimethylamine and the mixture was heated for 1 hour at 65° C.±2° C., then allowed to cool to ambient temperature. The reaction medium was saturated with sodium chloride and 0.3 ml of 2N sodium hydroxide were added. After extracting with ether, the extracts were washed with water, dried, and the solvent was eliminated under reduced pressure to obtain 3.35 g of N,N-dimethyl-5,6,7,8-tetrahydro-8-quinolinamine which was used as is for the following step.