Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](C)[CH:3]([CH3:22])[CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]#[N:7].Cl[C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26]>C1(C)C=CC=CC=1>[C:6]([C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH:3]([N:2]([CH3:1])[C:25](=[O:26])[O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])[CH3:22])#[N:7]
Reactant: COc1cccc(C(C#N)(CC(C)N(C)C)c2ccccc2)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cccc(C(C#N)(CC(C)N(C)C(=O)OCC(Cl)(Cl)Cl)c2ccccc2)c1
Temperature: 25 °C

Procedure:
The product of Step 2 (38 g) was dissolved in toluene (400 mL). To this, 2,2,2-trichloroethyl chloroformate (90 mL) was added. The reaction mixture was heated to reflux under Argon purging for 3 hr. The reaction mixture was allowed to cool to 25° C. and concentrated under vacuum to give ˜200 g crude material. Purification was performed as follows on the BIOTAGE® AB ISOLERA™ flash chromatography system. Crude product (50 g) was loaded on a SNAP cartridge containing 340 g silica gel and eluted using a gradient of acetone and hexane. Fractions containing product were pooled and evaporated under vacuum. Yield of purified product (combined runs): 42 g. 1H NMR (CDCl3): 1.2 δ (3H, —CH—CH3 of isopropyl), 2.8 δ (6H, —N—(CH3)), 2.5, 2.6, 3.1 δ (1H, 1H, 1H —CH2-CH—CH3 of isopropyl), 3.8 δ (3H, —OCH3), 6.8-7.5 δ (9H, phenyl rings). Mass spectrometry: m/z=469 (M+H), 486 (M+H2O)
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[O:18]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH:5]1[CH2:6][CH2:7][CH:2]([N:19]2[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:25])[CH2:20]2)[CH2:3][CH2:4]1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(N3C(=O)c4ccccc4C3=O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 2-(4-oxo-cyclohexyl)-isoindole-1,3-dione (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:27])[C:11]([C:17]1[CH:24]=[C:23]([CH3:25])[C:20]([C:21]#[N:22])=[C:19]([CH3:26])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:27])[C:11]([C:17]1[CH:18]=[C:19]([CH3:26])[C:20]([C:21]#[N:22])=[C:23]([CH3:25])[CH:24]=1)([OH:16])[C:12]([F:15])([F:13])[F:14]
Reactant: COc1ccc(C(C)C(O)(c2cc(C)c(C#N)c(C)c2)C(F)(F)F)c(Cl)c1
Agent: BrB(Br)Br
Product: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cc(C)c1C#N

Procedure:
In analogy to Example 1, step 4, 4-[2-(2-chloro-4-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-2,6-dimethyl-benzonitrile was reacted with BBr3 to give the title compound as a colorless foam. MS (m/e, ISP neg. ion)=382.1 [M−H+].
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][S:25]([CH2:28][CH2:29][CH2:30][CH3:31])(=[O:27])=[O:26])=[C:20]([O:32][CH3:33])[CH:19]=2)[CH:12]=[CH:11][C:10]=1/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:28]([S:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][CH2:15][C:13]2[CH:12]=[CH:11][C:10]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:9]([OH:8])[CH:14]=2)=[CH:19][C:20]=1[O:32][CH3:33])(=[O:27])=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: [H][H]
Reactant: CCCCS(=O)(=O)Oc1ccc(C/C=C/c2ccc(/C=C/C(=O)OC)c(OCc3ccccc3)c2)cc1OC
Agent: [Pd]
Solvent: CO
Product: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)OC)c(O)c2)cc1OC
Yield: 93.8 %

Procedure:
78 mg (10% mass equivalent) of 10% palladium-on-charcoal are added to a solution of 780 mg (1.4 mmol) of methyl(E)-3-(2-benzyloxy-4-{(E)-3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propenyl}phenyl)acrylate in 8 ml of methanol. The reaction mixture is placed under an atmospheric pressure of hydrogen at room temperature for 16 hours and then filtered through Celite and rinsed with dichloromethane. The solvents are evaporated off and the residue is then purified by chromatography on a column of silica eluted with a 60/40 heptane/ethyl acetate mixture. 610 mg (94%) of methyl 3-(4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-2-hydroxyphenyl)propanoate are obtained in the form of a colorless oil.
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]=[C:18]2[CH:25]=O>>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]=[C:18]2[CH2:25][NH:6][CH3:5]
Reactant: Cn1cc(C=O)c2cc(F)ccc21
Reactant: COC(=O)CNc1ccc(Br)cn1
Product: CNCc1cn(C)c2ccc(F)cc12
Yield: 35 %

Procedure:
According to the procedure of Preparation 11 (c), except substituting 5-fluoro-1-methyl-1H-indole-3-carboxaldehyde (0.3 g, 1.69 mmole) for the 1,3 dimethyl-1H-2-carboxaldehyde, the title compound (0.11 g, 35%) was prepared as a viscous oil: MS (ES) m/e 193 (M+H)+.
Reaction SMILES: [Mg].[CH2:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH:14]=[O:15]>C(OCC)C.II>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[OH:15])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: ClCc1ccccc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: OC(Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
Into a 1000 ml three necked flask equiped with a reflux condenser and an addition funnel was placed 8.8 g of magnesium turnings (0.36 mole) and 400 ml of diethyl ether. After activation of the magnesium with 0.02 g of iodine, the mixture was heated to reflux and a solution of 44 g (0.35 mole) of benzyl chloride in ethyl ether was added at a rate to maintain the reflux. When the reaction had subsided, a solution of 50 g (0.29 mole) of 3,4-dichlorobenzaldehyde in 75 ml of diethyl ether was added at a rate to maintain reflux. After 15 minutes, the reaction was quenched with water and acidified with dilute hydrochloric acid. The organic layer was washed with brine, dried, and concentrated in vacuo yielding 75 g of 3,4-dichlorophenyl benzyl carbinol which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([SH:19])[N:3]=1.[CH3:20][NH:21][C:22](=[O:25])[CH2:23]Br.C([O-])(O)=O.[Na+].C(Cl)Cl.CO>CN(C)C=O.O.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:19][CH2:23][C:22]([NH:21][CH3:20])=[O:25])[C:5]([C:17]#[N:18])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: CNC(=O)CBr
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CNC(=O)CSc1nc(N)c(C#N)c(-c2ccc(O)cc2)c1C#N

Procedure:
At room temperature (RT), 53.6 mg (0.2 mmol) of 2-amino-4-(4-hydroxyphenyl)-6-sulfanyl-3,5-pyridinedicarbonitrile and 45.6 mg (0.3 mmol) of N-methylbromoacetamide are stirred in 0.5 ml of dimethylformamide (DMF) together with 33.6 mg (0.4 mmol) of NaHCO3 for 4 hours. Thin-layer chromatography (TLC) (CH2Cl2/CH3OH 10:1) shows complete conversion. The entire mixture is diluted with water and ethyl acetate (EA) and the EA phase is dried with MgSO4 and concentrated under reduced pressure. The residue crystallizes from methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[N:13]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:14](=O)[O:15]CC.[H-].[Na+].Cl>C(O)C>[Br:8][C:6]1[CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:3]2[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=3)[C:14](=[O:15])[NH:1][C:2]=2[CH:7]=1
Reactant: CCOC(=O)N(Cc1cccc(C(F)(F)F)c1)c1c(N)cc(Br)cc1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c2cc(Br)cc(C(F)(F)F)c2n1Cc1cccc(C(F)(F)F)c1
Yield: 106.2 %

Procedure:
To a solution of ethyl 2-amino-4-bromo-6-(trifluoromethyl)phenyl[3-(trifluoromethyl)benzyl]carbamate (257.8 mg) in ethanol (10 ml) was added sodium hydride (60%) (48.7 mg). The reaction mixture was heated at reflux for 1.5 hours. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (247.7 mg, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15](S(N)(=O)=O)=[CH:14][CH:13]=1)=[O:8].ClC1C=C(C(O)=O)C(O)=CC=1.COC(=O)C1C=C(Cl)C=CC=1OC.C(N)CC1C=CC=CC=1>>[CH2:10]([NH:9][C:7](=[O:8])[C:6]1[CH:22]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:23][CH3:24])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(N)(=O)=O)cc1
Agent: COC(=O)c1cc(Cl)ccc1OC
Agent: NCCc1ccccc1
Agent: O=C(O)c1cc(Cl)ccc1O
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccccc1

Procedure:
A process for preparing p-(2-{5-chloro-2-methoxybenzamido}ethyl)-benzene sulfonamide which comprises the steps of methylating 5-chlorosalicylic acid to methyl-5-chloro-2-methoxybenzoate, treating methyl-5-chloro-2-methoxybenzoate with phenethylamine to obtain N-phenethyl-5-chloro-2-methoxybenzamide, subjecting said N-phenethyl-5-chloro-2-methoxybenzamide to chlorosulfonation and aminolysis to yield p-(2-{5-chloro-2-methoxybenzamido}ethyl)-benzene sulfonamide.
Reaction SMILES: C[O:2][C@:3]1([C@@H:22]2[CH2:26][S:25][C:24](=[O:27])[N:23]2CC2C=CC(OC)=CC=2)[CH2:18][C@H:17]2[CH2:19][C@@H:5]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][C:13]([CH3:21])=[CH:14][C:15](=[O:20])[NH:16]2)[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[OH:2][C@:3]1([C@@H:22]2[CH2:26][S:25][C:24](=[O:27])[NH:23]2)[CH2:18][C@H:17]2[CH2:19][C@@H:5]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][C:13]([CH3:21])=[CH:14][C:15](=[O:20])[NH:16]2)[O:4]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)N3)O2)cc1
Agent: C/C1=C/C(=O)N[C@@H]2C[C@@H](CCC/C=C\CC1)O[C@@](O)([C@@H]1CSC(=O)N1)C2
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)N3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Product: CC1=CC(=O)N[C@@H]2C[C@@H](CCCC=CCC1)O[C@@](O)([C@@H]1CSC(=O)N1)C2

Procedure:
Application of the method shown in Example 46, with the modification that (1R,4Z,8Z,13R,15R)-15-methoxy-15-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-5-methyl-14-oxa-2-aza-bicyclo[11.3.1]heptadeca-4,8-dien-3-one was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound, together with the 8E-isomer.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.I[C:22]1[NH:26][N:25]=[CH:24][CH:23]=1.C(Cl)Cl>O1CCOCC1.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]>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:22]1[NH:26][N:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Ic1ccn[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(-c2ccn[nH]2)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 41.1 %

Procedure:
To methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 800 mg, 2.9 mmol) in dioxane (30 mL) was added 5-iodo-1H-pyrazole (674 mg, 3.5 mmol), and Pd(dppf)Cl2.DCM (237 mg, 0.29 mmol). The mixture was degassed with argon and stirred for 10 minutes then an aqueous potassium carbonate solution (2 M, 8 mL) was added. The mixture was heated at 90° C. for 18 h, then cooled and diluted with EtOAc and filtered through Celite®. The filtrate was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2; 0-30% EtOAc in hexanes) to yield 258 mg (41%) of the title compound as a solid. m/z (ES+) 217 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14](O)=[O:15])=[CH:5][CH:4]=1)[CH3:2].CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH2:14][OH:15])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2sccc2C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1ccc(-c2sccc2CO)cc1
Temperature: 0 °C

Procedure:
Into a 100-mL 3-necked round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 2-(4-ethylphenyl)thiophene-3-carboxylic acid (0.46 g, 1.98 mmol), anhydrous ether (18 mL). This was followed by the addition of a solution of LiAlH4 (1 M in THF, 2.7 mL, 2.7 mmol) in tetrahydrofuran dropwise with stirring at 0° C. The resulting solution was stirred for 2.0 h at 25° C. The reaction progress was monitored by LCMS/TLC (ethyl acetate/petroleum ether=1:6). The reaction was then quenched by the addition of 10 mL of water and 5 mL of 2N HCl. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 0.46 g (100%) of (2-(4-ethylphenyl)thiophen-3-yl)methanol as a white oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:3]=1.B(O)(O)[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[S:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl-].CC1C=C(C)C=C(C)C=1[N+]1C=CN(C2C(C)=CC(C)=CC=2C)C=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[S:27]1[CH:26]=[C:25]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:3]=2)[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]1=2
Reactant: OB(O)c1csc2ccccc12
Reactant: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(Cl)nc21
Agent: [Pd]
Agent: Cc1cc(C)c(-n2cc[n+](-c3c(C)cc(C)cc3C)c2)c(C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(-c3csc4ccccc34)nc21
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A flame-dried schlenk flask was charged with 4-(2-(2-chloro-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol (0.62 mmol), thianaphthene-3-boronic acid (0.94 mmol), pd2(dba)3 (0.062 mmol), Cs2CO3 (1.25 mmol) and 1,3-bis(2,4,6-trimethylphenyl) imidazolium chloride (0.125 mmol). The flask was evacuated and backfilled with N2 and anhydrous 1,4-dioxane (2 mL) was added. The flask was sealed and the reaction mixture was stirred at 80° C. for 24 hours. The reaction mixture was concentrated and purified directly by column chromatography on silica gel, eluting with hexane/EtOAc (20:1 to 1:4) to afford the title compound as a yellowish solid.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8](=[O:25])[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17]([NH:19]C(OCC)=O)=[S:18])[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4]>O.CCO>[C:3]([O:7][C:8](=[O:25])[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17]([NH2:19])=[S:18])[CH2:12][CH2:11]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)NC(=S)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(N)=S)CC1
Reaction time: 0.5 h

Procedure:
7.4 ml of 4M NaOH are added to a suspension of 1.69 g of [trans-4-(3-ethoxycarbonyl-thioureido)cyclohexyl]carbamic acid tert-butyl ester in 10 ml of H2O and 15 ml of EtOH. The mixture obtained is kept at 90° for 30 minutes at RT. The precipitate formed is filtered and washed with diethylether. (trans-4-Thioureido-cyclohexyl)-carbamic acid tert-butyl ester is obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([C:19]2[CH:24]=[CH:23][C:22](Br)=[C:21]([CH2:26][C:27]3[CH:36]=[CH:35][C:30]4[O:31][CH2:32][CH2:33][O:34][C:29]=4[CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2].[CH:42]1(P(C2CCCCC2)C2CCCCC2)CCCC[CH2:43]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(B(O)O)C>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([C:19]2[CH:24]=[CH:23][C:22]([CH2:42][CH3:43])=[C:21]([CH2:26][C:27]3[CH:36]=[CH:35][C:30]4[O:31][CH2:32][CH2:33][O:34][C:29]=4[CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(c2ccc(Br)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCB(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc(C2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Yield: 146.9 %

Procedure:
To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (10.0 g, 15.74 mmol) in toluene (200 mL) was added tricyclohexylphosphine (1.76 g, 6.29 mmol), a solution of potassium phosphate tribasic (13.3 g, 62.9 mmol) in water (15 mL), and ethylboronic acid (3.4 g, 47.2 mmol. The reaction mixture was degassed for 45 min then palladium (II) acetate (529 mg, 2.3 mmol) was added. After refluxing overnight, the reaction mixture was cooled to room temperature, and water was added. The resulting mixture was extracted with ethyl acetate, (2×200 mL), washed with water and brine, then dried over sodium sulfate, concentrated and purified by column chromatography to furnish acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (5.4 g).
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[NH:7][CH:8]=[O:9].[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11]>CN(C=O)C.C(N(CC)CC)C.[Cu]I.C1(P([Pd](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][Si:12]([C:10]#[C:11][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[NH:7][CH:8]=[O:9])([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: O=CNc1ccsc1I
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1sccc1NC=O
Yield: 95.3 %

Procedure:
The product from step A (37.8 g) was dissolved in a mixture of DMF (500 ml) and triethylamine (50 ml). CuI (1.4 g) and bis(triphenylphosphino)palladiumdichloride (5.2 g) were added under nitrogen and after 15 minutes ethinyl trimethylsilane (22 g) was added dropwise. After 6 hours the solvents were removed under vacuum and the residue was chromatographed on silica gel (hexane:ethyl acetate 2:1) to yield 2-(trimethylsilylethinyl)-3-formamido-thiophene (31.78 g) (m.p. 87-93° C.).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16](Cl)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O.C(#N)C>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH:16]2[C:17]3[C:12](=[CH:11][C:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])=[CH:19][CH:18]=3)[CH2:13][CH2:14][CH2:15]2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)CCCC2Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C2CCCc3cc(S(=O)(=O)c4ccccc4)ccc32)CC1
Yield: 44.9 %

Procedure:
6-Benzenesulfonyl-1-chloro-1,2,3,4-tetrahydro-naphthalene (0.6 g, 1.96 mmol), piperazine 1-carboxylic acid tert-butyl ester (0.65 g, 3.5 mmol), sodium iodide (0.1 g) and potassium carbonate (0.5 g) were added to 50 mL of acetonitrile, and the reaction mixture was refluxed for 120 hours. The reaction mixture was cooled and diluted with 200 mL of water. The aqueous mix was extracted twice with 200 mL of EtOAc, and the combined organic layers were washed with water, brine, and dried over MgSO4. Solvent was removed under reduced pressure, and the resulting oil was eluted through silica gel (medium pressure chromatography) eluting with EtOAc/Hexanes 20%/80%. Removal of solvent under reduced pressure afforded 0.4 g (0.88 mmol, 45%) of 4-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butyl ester as an oil. MS: 458 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[C:12]([O:18][CH3:19])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[C:12]([O:18][CH3:19])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
87.65 g (1.01 mol) of manganese dioxide were added to a solution of 29.30 g of (4-t-butyldimethylsilyloxymethyl-2-methoxyphenyl)methanol [prepared as described in step (i) above] in 150 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, 41.2 g (0.474 mol) of manganese dioxide were added, with stirring, to the mixture. The reaction mixture was then stirred at 30° C. for 1.5 hours and heated under reflux for 1 hour with stirring, after which it was filtered. The filtrate was freed from the solvent by distillation under reduced pressure, to give 27.29 g (a quantitative yield) of the title compound as an oily substance.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].[CH3:12][C:13](C)=[O:14].C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)(=O)C>C(Cl)Cl.CO>[C:13]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][OH:1])(=[O:14])[CH3:12]
Reactant: OCCOc1ccccc1O
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)Oc1ccccc1OCCO
Reaction time: 3 h

Procedure:
2-(2-Hydroxyethoxy)phenol (308 g; 2 mol) was taken up in a 5 L Erlnmeyer flask fitted with mechanical stirrer. Anhydrous acetone (4 L, dried over K2CO3), and potassium carbonate powder (290 g; 2.1 mol) were added, and the mixture was stirred vigourously. Acetic anhydride (207 mL; 2.2 mol) was added from an additional funnel slowly over a period of 1 hour. Stiiring was continued for 3 hours. TLC (CH2Cl2/MeOH: 9:1, v/v) showed disapperence of starting material. The reaction mixture was filtered, solid washed thoroughly with acetone (1 L). The combined fractions was concentrated and purified by chromatography eluting with hexane and ethyl acetate (0% to 35% EtOAc; v/v). The product was obtained as a colorless viscous oil. Yield 258-264 gms (70-72%)