Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2]CCO[AlH2-]OCCOC.[Na+].[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][S:20][CH:21]([CH3:27])[C:22](OCC)=O)=[CH:15][CH:14]=1>O1CCCC1>[OH:2][CH:19]([S:20][CH:21]([CH3:27])[CH3:22])[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: COCCO[AlH2-]OCCOC
Reactant: CCOC(=O)C(C)SCc1ccncc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)SC(O)c1ccncc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Red-al [70% solution of sodium bis(2-methoxyethyl)aluminum hydride in benzene, 1.2 g., 1.1 ml., 5.86 mmoles] was cooled under nitrogen in an ice bath. A solution of ethyl 2-(4-pyridylmethylthio)propionate in 10 ml. of dry tetrahydrofuran was added dropwise over 10 minutes. The mixture was then heated and gently refluxed for 1 hour and then stirred at room temperature for approximately 16 hours. The reaction mixture was poured into 40 ml. of ice cold 1 N HCl and salts removed by filtration. The filtrate was made basic with sodium bicarbonate and the product extracted into ethyl acetate (four times with 50 ml. aliquots). The combined ethyl acetate extracts were dried (by wash with saturated sodium chloride and then over anhydrous sodium sulfate) and concentrated to yield 4-(1-hydroxy-2-propylthiomethyl)pyridine (oil; approximately 200 mg.; pnmr/CDCl3 /TMS/τ: 8.6 (d, 3H), 7.2 (s, broad, 1H), 6.3 (m, 5H), 2.7 (d, 2H), 1.5 (d, 2H); m/e calcd: 183; found: 183, 152, 118, 92, 65; ir (film): 3.1, 6.25, 7.1, 9.25, 12.25μ). To further purify the product, it was taken up in chloroform, treated with activated carbon and concentrated to an oil (194 mg.).
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][CH2:8][C@H:9]([NH:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)=[O:26])[C:10](=[O:23])[NH:11][C:12]([CH3:22])([CH3:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(C)(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:30]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27]([C:25]([NH:24][C@H:9]([C:10](=[O:23])[NH:11][C:12]([CH3:22])([CH3:21])[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:8][CH2:7][C:6]([OH:39])=[O:5])=[O:26])=[CH:32][CH:31]=1
Reactant: CC(C)(Cc1ccc(F)cc1)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Cc1ccc(F)cc1)NC(=O)[C@H](CCC(=O)O)NC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
To a suspension of Compound 5 (100 g) in toluene (325 ml) were added trifluoroacetic acid (TFA, 313 g) at 5 to 20° C. The resulting solution was stirred at ambient temperature until the reaction was completed (4 to 6 h). TFA was removed by vacuum distillation, the solution diluted with ethyl acetate, washed with aqueous potassium acetate, and crystallization was affected by adding heptane to afford Compound 6 as white solid (82.7 g, yield 92%; Purity—99.8% (HPLC area %); Strength—98.0%; ee—99.0%). NMR data: 1.37, 1.45-s, 6H, CH3; 2.10-m, 2H, CH2; 2.35-2.60-m, 2H, CH2; 2.80-3.10-d, 2H, CH2; 4.80-q, 1H, CH; 6.80-7.80-m, 13H, Ph; 7.90-s, 2H, NH.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:33][C@@H:34]1[CH2:38][NH:37][CH2:36][C@H:35]1[NH:39]C(=O)OC(C)(C)C>>[NH2:39][C@H:35]1[C@H:34]([F:33])[CH2:38][N:37]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:17])[F:18])=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:36]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H]1F
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Product: N[C@@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C[C@H]1F

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and tert-butyl (trans-4-fluoropyrrolidin-3-yl)carbamate to afford an off-white powder. HPLC (Condition 4) tR=4.58 min, UPLC-MS (Condition 3) tR=0.83 min, m/z=467 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.01 (br. s, 1H) 3.20-3.39 (m, 3H) 3.47 (d, J=10.56 Hz, 2H) 3.55-3.82 (m, 1H) 4.76-4.94 (m, 1H) 6.41 (br. s, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.79-7.90 (m, 3H) 8.06 (s, 1H) 8.73 (br. s, 1H) 10.22 (s, 1H) 12.91-13.15 (m, 1H).
Reaction SMILES: [OH-].[K+].[C:3]([OH:19])(=[O:18])/[CH:4]=[CH:5]/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[C:3]([OH:19])(=[O:18])/[CH:4]=[CH:5]/[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCC/C=C/C=C/C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCC=C/C=C/C(=O)O
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 90.5 %

Procedure:
To the trans-2-tridecenal (1.7 g) dissolved in methylene chloride (80 ml) was added (carbomethoxymethylene)triphenyl phosphorane (4.0 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-pentadecadienoic acid (2.1 g). Potassium hydroxide (2.0 g) was dissolved in a mixed solvent of ethanol-water (1:1), and the methyl ester of trans,trans-2,4-pentadecadienoic acid (2.1 g). After the mixture was stirred at 60° C. for 40 minutes, it was cooled, adjusted to a weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans, trans-2,4-pentadecadienoic acid (1.9 g). The product was dissolved in N,N-dimethylformamide (DMF, 50 ml ), and para-nitrophenol (1.2 g) and N,N'-dicyclohexylcarbodiimide (1.7 g) were added. The mixture was stirred for 12 hours. After the reaction, precipitates produced were removed by filtration, DMF was removed by distillation, and the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-pentadecadienoic acid (1.3 g). To the active ester (600 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (750 mg) and triethylamine (1.2 ml). The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK285 in the yield of 530 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15](C)[C:16](=O)OCC3C=CC=CC=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][CH2:11][CH:12]([NH:15][CH3:16])[CH2:13][CH2:14]2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(N2CCC(N(C)C(=O)OCc3ccccc3)CC2)ccn1
Solvent: CO
Product: CNC1CCN(c2ccnc(OC)c2)CC1
Reaction time: 3 h
Yield: 99 %

Procedure:
Benzyl 1-(2-methoxypyridin-4-yl)piperidin-4-yl(methyl)carbamate (250 mg, 0.704 mmol, 1.0 eq.) was dissolved in MeOH (20 ml) and degassed with argon. Pd/C (75 mg) was then added and hydrogenation was carried out for 3 hours. After monitoring by TLC, the reaction mixture was filtered over Celite and washed with MeOH (2×20 ml) and the filtrate was concentrated under reduced pressure. The crude product was used in the next stage without being purified further. Yield: 99% (155 mg, 0.701 mmol)
Reaction SMILES: [CH3:1][S:2]([OH:5])(=O)=O.[CH2:6]([N:9]([CH2:22][CH2:23][CH3:24])[CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[C:13](SC)[CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[CH2:7][CH3:8].I([O-])(=O)(=O)=O.[Na+].[NH4+].[OH-]>O>[CH2:22]([N:9]([CH2:6][CH2:7][CH3:8])[CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[C:13]([S:2]([CH3:1])=[O:5])[CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[CH2:23][CH3:24]
Reactant: CCCN(CCC)C1CCc2cccc(SC)c2C1
Reactant: CS(=O)(=O)O
Agent: [NH4+]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(S(C)=O)c2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.8 %

Procedure:
To a solution of water (60 mL) which contains methanesulfonic acid (0.16 mL, 2.33 mMol) was added 2-dipropylamino-8-methylthio-1,2,3,4-tetrahydronaphthalene (630 mg, 2.33 mMol). To this solution was added a solution of sodium metaperiodate (550 mg, 2.57 mMol) in water (10 mL), and the reaction mixture was stirred for two days at room temperature. The reaction mixture was made basic (NH4OH) and extracted with dichloromethane. The organic extracts were combined, dried (Na2SO4) and concentrated in vacuo to give the crude title compound as a light yellow oil. Purification by flash chromatography (3% methanol in dichloromethane+tr. NH4OH) gave the desired product (580 mg, 85%) as a colorless oil. The fumarate salt was formed. Recrystallization (ethanol/diethyl ether) gave a colorless, crystalline solid which was found to be extremely hygroscopic. Drying in a vacuum dessicator (60° C., 18 hours) gave a colorless glass (260 mg, m.p.=63° C.).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]([NH:19][C:20](=[O:51])[CH2:21][CH:22]([C:41]2[CH:50]=[CH:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)[CH2:23][NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]([NH:19][C:20](=[O:51])[CH2:21][CH:22]([C:41]2[CH:50]=[CH:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)[CH2:23][NH:24][S:25]([C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(NC(=O)CC(CNS(=O)(=O)c2ccc(Oc3ccccc3)cc2)c2ccc3ccccc3c2)cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1ccc(NC(=O)CC(CNS(=O)(=O)c2ccc(Oc3ccccc3)cc2)c2ccc3ccccc3c2)cc1O
Yield: 71.9 %

Procedure:
A solution of 63 (0.023 g, 0.032 mmol) in methanol (1 ml) was stirred in presence of ammonium formate (0.089 g) and 10% Pd/C (0.023 g), under H2, at room temperature for 2 days. The solution was then filtered through a celite bed and the solvent removed under reduced pressure to afford ester 64 (0.014 g, 0.0230 mmol, 70%) as yellow solid, which was used in the next step without further purification.
Reaction SMILES: [C@@H:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:36]=[CH:37][CH:38]=1)[CH2:11][N:12]1[C:16](=[O:17])[C:15]2([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[N:14]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:13]1)=[O:7])([CH2:3][CH3:4])[CH3:2].Cl>O1CCOCC1>[O:17]=[C:16]1[C:15]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:14]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:13][N:12]1[CH2:11][C:10]1[CH:9]=[C:8]([CH:38]=[CH:37][CH:36]=1)[C:6]([O:5][C@H:1]([CH2:3][CH3:4])[CH3:2])=[O:7]
Reactant: CC[C@H](C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C

Procedure:
To (S)-tert-butyl 3-(3-(sec-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.072 g, 0.14 mmol) was added 4M solution of HCl in dioxane (1.5 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated in vacuo to obtain (S)-sec-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[C:11]3[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:4][C:3]=2[O:2]1>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[CH:11]3[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Solvent: CO
Product: CCOC(=O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
Ethyl(RS)-1,3-di-(3,4-Methylenedioxyphenyl)indene-2-carboxylate (163 mg, 0.38 mmol) was placed in MeOH (0.05 ml), and to this was added SmI2 (10 ml of 0.1M solution in THF, 1.0 mmol). The resulting mixture was stirred under an argon atmosphere overnight, at which time thin layer chromatographic analysis indicated that the reaction was incomplete. Additional SmI2 (5 ml of 0.1M solution in THF, 0.5 mmol) was added, and stirring was continued for 2 h. The reaction mixture was partitioned between Et2O and 5% aqueous Na2S2O3. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to afford the title compound as a colorless, glassy solid (120 mg, 75%).
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:11]=[CH:10]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C[AlH]CC(C)C)C.Br[C:55]1[CH:62]=[CH:61][CH:60]=[CH:59][C:56]=1[C:57]#[N:58].N1C2C(=CC=CC=2)C=C1>C1COCC1.CCCCCC.[Cl-].[Na+].O.[Cl-].[Cl-].[Zn+2].C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2].CCOCC>[C:57]([C:56]1[CH:59]=[CH:60][CH:61]=[CH:62][C:55]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:17]([CH3:18])[CH3:19])[CH:20]([CH3:21])[CH3:22])[CH:11]=[CH:10]2)#[N:58]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Reactant: N#Cc1ccccc1Br
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(-c3ccccc3C#N)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
sec-Butyllithium (41 mmole, 31.5 ml) was added dropwise over 10 minutes to 5-bromo-1-triisopropylsilylindole (40 mmoles, 14.0 g) in 400 ml THF at -78° C. The solution was stirred for 15 minutes. A solution of anhydrous ZnCl2 in 50 ml THF was added. The solution was warmed to 0° C. and stirred for 40 minutes. In a separate flask nickel acetylacetonate (1.5 mmole, 0.385 g) and triphenylphosphine (6.0 mmoles, 1.60 g) were dissolved in 20 ml of THF and cooled to -78° C. DIBAL mmole, 1.5 ml of 1.0M solution in hexane) was added. The solution was stirred for 10 minutes. 2-Bromobenzonitrile (39.9 mmoles, 7.26 g) was added. After stirring for minutes, the indole solution was added over a 10 minute period. The mixture was allowed to warm to room temperature, stirred for 2 hours, and then added to ether and brine. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The product was chromatographed over silica gel eluted with 0-15% ether in hexane to yield 7.83 g of 5-(2-cyanophenyl)-1-triisopropylsilylindole. (MS)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:7]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)[C:14]=2[CH3:23])[CH:7]=1)[CH3:2]
Reactant: Cn1cc(Br)cn1
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)Cc1cccc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and 4-bromo-1-methylpyrazole.
Reaction SMILES: [C:1]1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[N:18]12CCC[N:25]=[C:24]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2.CC1N=C(CO)C=CC=1>C1(C)C=CC=CC=1.CO.[OH-].[OH-].[Pd+2]>[CH3:1][C:24]1[N:25]=[C:20]([CH2:19][NH2:18])[CH:21]=[CH:22][CH:23]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: Cc1cccc(CO)n1
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cccc(CN)n1
Reaction time: 8 h
Yield: 119.1 %

Procedure:
Diphenylphosphoryl azide (DPPA) (0.74 mL, 0.9 g, 3.4 mmol, 1.2 eq) and 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU) (0.508 mL, 0.52 g, 3.4 mmol, 1.2 eq) were added to a stirred solution of the (6-methylpyridin-2-yl)methanol (0.35 g, 2.8 mmol, 1 eq) in 7 mL anh. toluene under Ar. After stirring overnight, the solvent was removed in vacuo. Purification via flash chromatography yielded 0.47 g (3.2 mmol, 113% yield of the crude product. The crude was dissolved in 5 mL MeOH. Pd(OH)2 (20% by wt. on carbon, 0.040 g) was added, and the mixture was stirred vigorously under H2 overnight. The mixture was filtered through Celite, and the filter cake rinsed with MeOH. The solvent was removed in vacuo yielding 0.4948 g of crude (6-methylpyridin-2-yl)methanamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15](O)[CH:14]([Br:20])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>CCOC(C)=O.CCCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16]([CH:15]=[C:14]([Br:20])[CH2:13][CH2:12]2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1c2ccc(OCc3ccccc3)cc2CCC1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: BrC1=Cc2ccc(OCc3ccccc3)cc2CC1
Temperature: 25 °C
Yield: 57 %

Procedure:
The intermediate, 6-(benzyloxy)-2-bromo-1,2,3,4-tetrahydronaphthalen-1-ol, was heated to reflux with p-toluenesulfonic acid monohydrate (0.916 g, 0.00482 mol) in toluene (300 mL, 3 mol) with a Dean-Stark tube for 1 hour, cooled to r.t., washed with saturated NaHCO3, water, brine, dried over anhydrous Na2SO4, filtered, evaporated in rotavapor to give a crude oil. Chromatograph with EtOAc:hexane (0:100 to 10:90) gave a solid product (17.29g, 57%). 1H NMR (CHLOROFORM-d) δ: 7.30-7.49 (m, 5H), 6.85-6.96 (m, 1H), 6.76 (m, 3H), 5.06 (s, 2H), 2.87-3.00 (m, 2H), 2.67-2.83 (m, 2H). MS (M+1): 316.0.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].C[O:19][C:20]([CH:22]1[C:27](=O)[CH2:26][CH2:25][CH2:24][S:23]1)=O.Cl>C(O)C>[OH:10][C:9]1[C:8]2[C:27]3[CH2:26][CH2:25][CH2:24][S:23][C:22]=3[C:20](=[O:19])[O:12][C:7]=2[CH:6]=[C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])[CH:11]=1
Reactant: COC(=O)C1SCCCC1=O
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Agent: Cl
Solvent: CCO
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SCCC3
Reaction time: 48 h

Procedure:
A solution of 14.2 g. (0.06 mole) of 5-(3-methyl-2-octyl)resorcinol and 11.1 g. (0.063 mole) of methyl-3-oxo2,3,4,5-tetrahydro-6H-thiopyran-2-carboxylate in 90 ml. of absolute ethanol was cooled in an ice-salt bath and saturated with anhydrous hydrogen chloride. After standing for 2 days at room temperature, the ethanol was removed on a rotary evaporator. The residue was dissolved in ether, washed with sodium bicarbonate solution and dried over sodium sulfate. Evaporation of the solvent gave 28.0 g. of residue which was chromatographed using Florisil (60-100 mesh) and graded methanol/chloroform solvent mixtures. A total of 10 g. of crude solid was obtained from the 1% methanol/chloroform fractions. The material was recrystallized twice from ethyl acetate/hexane to give 8.5 g. (40%) colorless crystals, m.p. 131°-133°. The proposed structure was confirmed by IR and nmr.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([O:36][CH3:37])=[CH:8][C:9]([O:34][CH3:35])=[C:10]([CH:12]=[CH:13][C:14]([CH:16]3[C:21](C)(C)[C:20]([O:24][CH3:25])=[C:19](C(C)(C)C)[C:18]([O:30][CH3:31])=[C:17]3O[SiH3])=[O:15])[CH:11]=2)=[CH:4][C:3]2[CH:38]=[CH:39][CH:40]=[CH:41][C:2]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:60]1CCCC1>>[S:1]1[C:5]([C:6]2[C:7]([O:36][CH3:37])=[CH:8][C:9]([O:34][CH3:35])=[C:10]([CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[C:20]([O:24][CH3:25])[C:19]([OH:60])=[C:18]([O:30][CH3:31])[CH:17]=3)=[O:15])[CH:11]=2)=[CH:4][C:3]2[CH:38]=[CH:39][CH:40]=[CH:41][C:2]1=2
Reactant: COC1=C(O[SiH3])C(C(=O)C=Cc2cc(-c3cc4ccccc4s3)c(OC)cc2OC)C(C)(C)C(OC)=C1C(C)(C)C
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=CC(=O)c1cc(OC)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of 3-[5-(benzo[b]thien-2-yl)2,4-dimethoxyphenyl]-1-(4-tert-butyldimethyl-siloxy-3,5-dimethoxyphenyl)-2-propen-1-one, from Ex-59B, (0.135 g, 0.228 mmol) in tetrahydrofuran (2 mL) was added tetrabutylammonium fluoride (0.061 g. 0.228 mmol), and the mixture was stirred at room temperature for two hours. Upon quenching with water, the mixture was extracted with dichloromethane. The organic phase was dried and evaporated. Silica gel chromatography (hexane/ethyl acetate, 1:1) gave 0.05 g (46%) of the desired 3-[5-(benzo[b]thien-2-yl)2,4-dimethoxyphenyl]-1-(4-hydroxy-3,5-dimethoxy-phenyl)-2-propen-1-one product as a yellow solid, m.p. 85-105° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:19]4([CH3:24])[O:23][CH2:22][CH2:21][O:20]4)[CH:15]=3)[CH:10]=2)=O)[CH:2]=1.C(O)COCCOCCO.NN.[OH-].[K+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:19]4([CH3:24])[O:20][CH2:21][CH2:22][O:23]4)[CH:15]=3)[CH:10]=2)[CH:2]=1
Reactant: CC1(c2ccc3cc(C(=O)c4cccnc4)ccc3c2)OCCO1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: CC1(c2ccc3cc(Cc4cccnc4)ccc3c2)OCCO1
Temperature: 160 °C
Yield: 62 %

Procedure:
A mixture of 270 mg of 2-(3-pyridylcarbonyl)-6-(2-methyl-1,3-dioxolan-2-yl)naphthalene, 7 ml of triethylene glycol, 1 ml of anhydrous hydrazine and 500 mg of potassium hydroxide were heated at 160° C. for 30 minutes. The temperature was then raised to 210° C. for 1 hour. The mixture was cooled, poured into water and extracted with methylene chloride. The organic layer was dried over sodium sulfate, the solvent removed under reduced pressure and the residue chromatographed on silica gel to give 160 mg of 2-(3-pyridylmethyl)-6-(2-methyl-1,3dioxolan-2-yl)naphthalene as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:23][C:11]=2[N:12](CC2C=CC(OC)=CC=2)[N:13]=1>ClCCCl.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:23][C:11]=2[NH:12][N:13]=1
Reactant: CCOC(=O)c1cc2c(-c3ccc(F)cc3F)nn(Cc3ccc(OC)cc3)c2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCOC(=O)c1cc2c(-c3ccc(F)cc3F)n[nH]c2s1
Temperature: 100 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Ethyl 3-(2,4-difluorophenyl)-1-(4-methoxybenzyl)-1H-thieno[2,3-c]pyrazole-5-carboxylate (1.0103 g, 2.358 mmol) was dissolved in a mixture of 1,2-dichloroethane (11.79 ml) and trifluoroacetic acid (11.79 ml) at 25° C. in a sealed heavy-walled reaction vessel. The reaction mixture was heated to 100° C. and allowed to stir for 2 h. The reaction was stopped, cooled to room temperature, and concentrated under reduced pressure. The residue was taken up in ethyl acetate (20 mL), washed with saturated aqueous sodium bicarbonate (1×15 mL) and saturated aqueous sodium chloride (1×15 mL), dried (sodium sulfate), and concentrated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 120 g column) on a CombiFlash purification system eluting with ethyl acetate-hexanes (0-60%). The title compound (719.0 mg, 2.332 mmol, 99% yield) was recovered as a white solid. LC-MS [M+1]=309.3.