Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH:11]([OH:14])[CH2:12][CH3:13])=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:22]1[N:27]=[C:26]([CH3:28])[C:25]([CH2:29][N:30]([CH3:41])[C@@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][CH2:33][CH2:32]2)=[C:24]([O:42][CH:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)[CH:23]=1>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>[CH:43]1([O:42][C:24]2[C:25]([CH2:29][N:30]([CH3:41])[CH:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:34][CH2:33][CH2:32]3)=[C:26]([CH3:28])[N:27]=[C:22]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=3[CH:11]([OH:14])[CH2:12][CH3:13])[CH:23]=2)[CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: Cc1nc(Cl)cc(OC2CCCC2)c1CN(C)[C@H]1CCCc2ccccc21
Reactant: CCC(O)c1c(F)cccc1B(O)O
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+]
Product: CCC(O)c1c(F)cccc1-c1cc(OC2CCCC2)c(CN(C)C2CCCc3ccccc32)c(C)n1
Temperature: 100 °C

Procedure:
3-Fluoro-2-(1-hydroxypropyl)phenylboronic acid (81 mg, 0.43 mmol), Na2CO3 (126 mg, 1.2 mmol) and Pd(PPh3)4 (10 mg) are added to a degassed solution (toluene 5 mL, H2O 21.6 mL and EtOH 0.8 mL) of (S)-(6-chloro-4-cyclopentyloxy-2-methyl-pyridin-3-ylmethyl)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (prepared as described in Example 43) (150 mg, 0.39 mmol) at room temperature. The mixture is heated to 100° C. for 14 hours. The organic layer is separated and the aqueous layer is extracted with DCM (2×10 mL). The combined organic layers are washed with brine, dried, and evaporated in vacuo to give crude product. The crude product is purified by PTLC and eluted with 2% MeOH in DCM to give 1-[2-(4-cylopentyloxy-6-methyl-5-{[methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amino]-methyl}-pyridin-2-yl)-6-fluoro-pheny]-propan-1-ol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Li:10]CCCC>CCCCCCC>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Li:10]
Reactant: COc1ccccc1Br
Reactant: [Li]CCCC
Solvent: CCCCCCC
Product: [Li]c1ccccc1OC
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromoanisole (11.2 g, 60.08 mmol) in heptane (150 mL) was slowly added n-BuLi (1.6 M in hexenes, 36.7 mL). White precipitate formed. The slurry was stirred for 0.5 hrs and was filtered. The solid was washed with pentane and was dried under vacuum. The yield was 6.5 g (94%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(-c2ccccn2)c2ccccc2c1=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2ccccn2)c2ccccc2c1=O

Procedure:
The product from Example 18A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.78 (ddd, J=4.8, 1.7, 0.9, 1H), 8.46-8.30 (m, 2H), 7.99 (dddd, J=16.4, 15.3, 7.5, 1.6, 3H), 7.80 (dt, J=7.8, 1.0, 1H), 7.59 (ddd, J=7.6, 4.8, 1.1, 1H), 7.23-7.09 (m, 3H), 3.79 (s, 2H); MS (APCI) M/Z 393 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[NH:4].[C:14]1([C:20]2[CH:21]=[C:22]([C:29](OC)=O)[S:23][C:24]=2[C:25]([F:28])([F:27])[F:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O-]CC.[Na+]>>[C:14]1([C:20]2[CH:21]=[C:22]([C:29]3[O:1][N:2]=[C:3]([C:5]4[CH:6]=[C:7]5[C:11](=[CH:12][CH:13]=4)[NH:10][CH:9]=[CH:8]5)[N:4]=3)[S:23][C:24]=2[C:25]([F:28])([F:26])[F:27])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N=C(NO)c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Agent: CC[O-]
Agent: [Na+]
Product: FC(F)(F)c1sc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1-c1ccccc1
Temperature: 120 °C
Yield: 29.9 %

Procedure:
D1 (174 mg) and methyl 4-phenyl-5-(trifluoromethyl)-2-thiophenecarboxylate (286 mg) were combined, treated with sodium ethoxide (21% wt in EtOH, 411 ul) and heated to 120° C. in a microwave reactor for 30 minutes. LCMS analysis showed the reaction was incomplete so microwave heating was continued for a further two periods of 30 minutes. The reaction mixture was then cooled to RT, quenched with H2O (2 ml) and evaporated to dryness under reduced pressure to give the crude product (411 mg) as a brown solid. The crude residue was purified on a 40+S Biotage cartridge, eluting with a 0 to 50% mixture of Et2O in petroleum ether. This gave the title compound (122 mg) as an off-white solid. δH (CDCl3, 400 MHz): 6.68 (1H, s), 7.30 (1H, t), 7.41-7.55 (6H, m), 7.92 (1H, s), 7.99 (1H, d), 8.36 (1H, br. s), 8.50 (1H, s). MS (ES): C21H12F3N3OS requires 411; found 410 (M−H+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([F:22])[CH:11]=1.Cl>C(Cl)Cl>[C:5]([C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][C:12]=2[F:22])=[CH:21][CH:20]=1)(=[O:7])[CH3:6]
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2ccc(Br)cc2F)cc1
Temperature: 0 °C
Yield: 82.2 %

Procedure:
A reaction vessel was charged with 113 g of anhydrous aluminum chloride and 600 ml of methylene chloride. To the mixture was added dropwise 113 g of acetyl chloride with stirring at a temperature not higher than 0° C., and was then added dropwise a solution of 100 g of 4-bromo-2-fluoro-biphenyl in 400 ml of methylene chloride. The mixture was reacted with stirring for 7 hours while gradually bringing it back to room temperature. The reaction liquid was poured into ice and diluted hydrochloric acid. The methylene chloride layer was washed successively with water, an aqueous solution of sodium hydrogen carbonate and water, and then dried over Glauber's salt. The solvent was then distilled off and the residue was recrystallized from acetone to give 96 g (82.2%) of 4-acetyl-2'-fluoro-4'-bromobiphenyl.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:12]([O-])([OH:14])=[O:13].N([O-])=O.[Na+]>C(OCC)(=O)C>[N+:12]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[OH:11])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
Commercially available 4-t-butyl phenol (30 g, 0.2 mole) was dissolved in 200 mL ethyl acetate in a 600-mL round-bottomed flask fitted with a mechanical stirrer, and cooled to 0° C. The mixture was treated with nitric acid (13 mL, in 13 mL water) dropwise over 10 min and then a catalytic amount of NaNO2. After 45 min the reaction was washed with excess 1N HCl and the organic layer was dried over MgSO4 and stripped to yield 37 g of 2-nitro-4-t-butyl phenol. This nitrophenol (37 g, 0.19 mole) was dissolved in 100 mL ethyl acetate and placed into a Parr bottle with a teaspoon of 10% Pd/C. The mixture was: placed on a hydrogenator under 50 psi hydrogen with agitation for 1 hr. The catalyst was filtered off through celite, and the ethyl acetate was stripped off under vacuum. The material crystallized with the addition of about 200 mL heptane to give 25.6 g of the corresponding amine (2-amino-4-t-butyl phenol).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]([NH:18][CH3:19])=[O:17])=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:6](F)[CH:5]=1>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3[C:15](=[CH:14][N:13]=[CH:12][CH:11]=3)[C:16](=[O:17])[N:18]([CH3:19])[C:6]=2[CH:5]=1
Reactant: CNC(=O)c1cnccc1-c1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)c2cnccc2c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 108.3 %

Procedure:
Sodium hydride (80 mg, 3.32 mmol) was taken in THF (1 mL) and cooled to 0° C. To the suspension, 4-(4-chloro-2-fluorophenyl)-N-methylnicotinamide (440 mg, 1.66 mmol) in THF (1 mL) was added dropwise and the temperature was maintained at 0° C. for 30 min. The reaction mixture was then warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with ice and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (1×5 mL) dried (Na2SO4) and concentrated under reduced pressure to afford 8-chloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (440 mg, 1.798 mmol) as a light brown oil. LC/MS (ESI) m/e 245.1 [(M+H)+, calcd for C13H10ClN2O 245.1]; LC/MS retention time (method C): tR=1.79 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](Br)=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[SH:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][CH2:15][S:14][C:4]1[S:3][C:2]([NH2:1])=[N:6][CH:5]=1)[CH3:21]
Reactant: Nc1ncc(Br)s1
Reactant: CCOC(=O)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCSc1cnc(N)s1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 2-amino-5-bromothiazole (50 g, 192 mmol) in DMF (300 mL) were added potassium carbonate (53 g, 384 mmol) and ethyl 3-mercaptopropionate (25.8 g, 192 mmol). The reaction mixture was stirred at room temperature for 36 h. The mixture was partitioned between water (500 mL) and ethyl acetate (500 mL) and the isolated water phase was extracted with ethyl acetate (250 mL). The combinde organic phases were washed with water (250 mL) and 10% aqueous sodium hydrogencarbonate (250 mL), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo to give 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. Yield: 19.6 g (44%). 1H-NMR (CDCl3): δ 7.07 (s, 1H); 4.15 (q, 2H); 2.88 (t, 2H); 2.61 (t, 2H); 1.26 (t, 3H); HPLC-MS: m/z: 233 (M+1).
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:19])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[I-].[Na+].[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[F:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:41][CH2:40][N:39]([CH2:2][CH:3]([CH3:19])[CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:38][CH2:37]2)=[CH:34][CH:35]=1
Reactant: CC(CCl)CN1c2cccc3cccc(c23)S1(=O)=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(CN1CCN(c2ccc(F)cc2)CC1)CN1c2cccc3cccc(c23)S1(=O)=O
Temperature: 20 °C
Yield: 20.1 %

Procedure:
The experiment is carried out as in Example 56, starting with 2-(3-chloro-2-methylpropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (10.4 g), triethylamine (5.1 cc), sodium iodide (5.4 g) and 4-(4-fluorophenyl)piperazine (6.5 g) in toluene (130 cc). The mixture is heated at boiling point for 16 hours, then cooled to a temperature of about 20° C. After purification by flash chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane and then ethyl acetate as eluants, and recrystallization from boiling acetonitrile (20 cc), 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]-2-methylpropyl}naptho[1,8-cd]isothiazole 1,1-dioxide (3.1 g) is obtained m.p. 133° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)=[CH:17][CH:16]=2)=[CH:21][CH:20]=1
Reactant: NCCc1ccncc1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(c2ccc(C(=O)NCCc3ccncc3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.3 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (150 mg, 0.60 mmol) in 30 mL of DCM were added 2-(pyridin-4-yl)ethanamine (110 mg, 0.9 mmol), HATU (274 mg, 0.72 mmol) and DIEA (232 mg, 1.80 mmol) at room temperature. Then the reaction mixture was stirred at room temperature overnight. The solution was washed with sat NaHCO3 (2×20 mL), brine (20 mL), then dried over anhydrous sodium sulfate, concentrated under reduce pressure to give crude N-(2-(pyridin-4-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (250 mg) and used without further purification. LC-MS: 353 [M+H]+, tR=1.22 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:26]1[C:31]([C@H:32]([OH:35])[CH2:33][NH2:34])=[CH:30][C:29]([OH:36])=[C:28]([OH:37])[CH:27]=1>>[OH:36][C:29]1[CH:30]=[C:31]([C@@H:32]([OH:35])[CH2:33][NH:34][CH:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:15]=[CH:14][C:13]([NH:12][S:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)(=[O:10])=[O:11])=[CH:18][CH:17]=3)[CH2:20][CH2:21]2)[CH:26]=[CH:27][C:28]=1[OH:37]
Reactant: NC[C@@H](O)c1ccc(O)c(O)c1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-methoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 218) and L-norepinephrine according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.55 (m, 2 H), 1.90–2.05 (m, 2 H), 2.50–3.00 (m, 5 H), 3.50–3.75 (m, 2 H), 3.79 (s, 3 H), 4.50–4.65 (m, 1 H), 6.60 (d, J=8.0 Hz, 1 H), 6.68 (d, J=8.0 Hz, 1 H), 6.76–6.80 (m, 3 H), 6.88 (d, J=9.0 Hz, 2 H), 7.04 (d, J=7.8 Hz, 2 H), 7.61 (d, J=7.8 Hz, 2 H), 8.85 (s, 1 H); MS (ES) m/z: 513.9 (MH+); HRMS Calcd. for C26H32N3O6S (MH+): 514.2011. Found: 514.2000.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](I)[CH:6]=1.C(N(CC)CC)C.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[OH:1][CH2:2][C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc(C#C[Si](C)(C)C)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
tert-Butyl [(1S)-2-hydroxy-1-(3-iodobenzyl)ethyl]carbamate (1.0 g, 2.6 mmol), copper(I) iodide (0.020 g, 0.11 mmol), bis(triphenylphosphine)palladium(II) chloride (0.074 g, 0.11 mmol), tetrahydrofuran (7 mL), and triethylamine (0.41 mL, 2.9 mmol) were combined. The reaction mixture was stirred under N2 for 5 min. (Trimethylsilyl)acetylene (1.1 mL, 8.0 mmol) was then added. The reaction mixture was stirred at 65° C. for 1 h, then evaporated under vacuum. The residue was purified by combi-flash chromatography to give 0.84 g (91% yield) of the desired product as light brown solid. LC-MS found: 248.0 (M−Boc+H)+.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([CH2:13][OH:14])[O:4]1.[H-].[Na+].[CH3:17]I.O>O1CCCC1>[CH3:1][O:2][C@H:3]1[C@H:7]2[C@H:6]([O:10][C:9]([CH3:12])([CH3:11])[O:8]2)[C@@H:5]([CH2:13][O:14][CH3:17])[O:4]1
Reactant: CI
Reactant: CO[C@@H]1O[C@H](CO)[C@H]2OC(C)(C)O[C@@H]12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
A stirred solution of [(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol (J. Heterocycl. Chem., 13 1966, 485) (43.1 g, 0.21 mol) in dry tetrahydrofuran (400 ml), at 0° C. and under an atmosphere of nitrogen, was carefully treated with sodium hydride, (7.7 g of an 80% dispersion in mineral oil, 0.26 mol). The resultant mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was cooled to 0° C. and a solution of methyl iodide (15.8 m, 0.25 mol) in dry tetrahydrofuran (30 ml) added slowly. The resultant mixture was stirred for a further 30 min at 0° C. and then at room temperature for 24 hr. Water (1000 ml) was added carefully and the mixture extracted with diethyl ether (3×500 ml). The combined organic extracts were washed with brine, dried with anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent system of diethyl ether:pentane (1:4), to afford the title compound as an oil (36.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH2:19]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:20][C:21]#[CH:22]>>[CH:23]1([CH2:19][CH2:20][C:21]#[C:22][C:2]2[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Reactant: C#CCCC1CCCC1
Product: O=C(NCCC(O)c1cccc(C#CCCC2CCCC2)c1)C(F)(F)F

Procedure:
Sonogashira reaction of 25 with but-3-ynyl-cyclopentane yielded N-(3-(3-(4-cyclopentylbut-1-ynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as a dark brown oil. Yield (690 mg, 69%): 1H NMR (400 MHz, CDCl3) δ 7.22-7.57 (m, 4H), (m, 1H), 3.65-3.72 (m, 1H), 3.36-3.45 (m, 1H), 2.41 (t, J=8.0 Hz, 2H), 2.37 (bs, 1H), 1.90-1.97 (m, 3H), 1.80-1.82 (m, 2H), 1.54-1.59 (m, 4H), 1.51-1.53 (m, 2H), 1.12-1.15 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Br:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([Br:9])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1cc(Br)nc(Br)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])Nc1cc(Br)nc(Br)c1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
2,6-dibromo pyridin-4-ylamine (11 g, 43.6 mmol) was dissolved in 100 mL of sulfuric acid at room temperature and then cooled at −5° C. 6 mL of nitric acid was added dropwise keeping the temperature between −10° C. to −5° C. and the mixture was stirred at −5° C. for 30 minutes. The mixture was then poured onto 400 mL of crushed ice. The solid formed was filtered off then dissolved in EtOAc. The residual water was removed and the organic layer was washed with 300 mL of brine, dried over magnesium sulfate and the solvent was removed in vacuo to give 12.5 g of the title product as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH:9]=[CH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:20](=[O:21])[N:19]([CH3:18])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:3][CH:4]=2)=[O:17])[CH:12]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(C=Cc1cccnc1)c1ccc(O)cc1
Product: CN(C(=O)Oc1ccc(C(=O)C=Cc2cccnc2)cc1)c1ccccc1

Procedure:
The title product was prepared from 1-(4-hydroxy-phenyl)-3-pyridin-3-yl-prop-2-en-1-one and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (56%, off-white solid). HPLC-MS: m/z=359.0 (M+1); Rt: 3.27 min.
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=O)[CH3:17]>C1(C)C=CC=CC=1>[CH2:1]([C:2]1[CH:3]=[CH:4][C:5]([N:6]=[C:1]([CH3:9])[C:2]2[CH:8]=[CH:7][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1)[C:9]1[CH:15]=[CH:14][C:12]([N:13]=[C:16]([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccccc1
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(Cc2ccc(N=C(C)c3ccccc3)cc2)cc1)c1ccccc1

Procedure:
A mixture of 4,4'-methylenedianiline (198 g; 1 mole), acetophenone (240 g; 2 moles) and a catalytic amount of stannous chloride was refluxed in toluene (3L) for 30 hours using a Dean-Stark trap. The theoretical amount of water was removed from the system. The toluene was then removed under vacuum.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:29]2[S:30][CH:31]=[C:32]([CH:34]=O)[N:33]=2)[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26]>C1COCC1.C(OCC)(=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:29]2[S:30][CH:31]=[C:32]([CH:34]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:33]=2)[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26]
Reactant: COc1cc(-c2nc(C=O)cs2)cc(OC)c1OC
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1csc(-c2cc(OC)c(OC)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
THF (5 mL) was added to sodium hydride (55% dispersion in mineral oil, 162 mg) under an argon atmosphere, and a solution of ethyl diethylphosphonoacetate (832 mg) in THF (2 mL) was added dropwise to the mixture at −10° C. After 30 minutes, a solution of 2-(3,4,5-trimethoxyphenyl)thiazole-4-carboaldehyde (942 mg) in THF (8 mL) was slowly added to the resultant mixture, and the mixture was warmed to room temperature over 30 minutes and then stirred for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate. After concentrating the reaction mixture under reduced pressure, the resultant crude crystals were recrystallized from ethyl acetate-hexane to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[CH3:10][C:11]([CH3:13])=O>>[Cl:9][C:4]1[CH:3]=[C:2]([N:1]=[C:11]([CH3:13])[CH3:10])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: CC(C)=O
Product: CC(C)=Nc1ccc(O)c(Cl)c1

Procedure:
4-amino-2-chloro-phenol Compound 13a was refluxed with acetone to provide 2-chloro-4-isopropylideneamino-phenol Compound 13b in quantitative yield. MS (ESI) m/z: 185 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:16])=[C:7]([CH:15]=1)[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])=[CH2:2].I[C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:16][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH:2][C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[CH:15][C:7]=1[C:8]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[O:9]
Reactant: C=Cc1ccc(O)c(C(=O)OCC(C)C)c1
Reactant: O=S(=O)(Nc1ccccn1)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O

Procedure:
Palladium (II) acetate (0.15 g, 0.67 mmol) was added to a stirred solution of isobutyl 5-ethenyl-2-hydroxybenzoate (6.6 g, 30 mmol) and 4-iodo-N-2-pyridinylbenzenesulfonamide (10.8 g, 30 mmol) in dimethylacetamide (40 ml) and tributylamine (10 ml, 42 mmol) at 95° C. After 100 min. the solution was filtered and evaporated at 50°-60° C. (bath temp.) until solid material appeared. The mixture was diluted with isopropanol (0.5 l) and chilled in a freezer. The product was filtered off to yield 7.1g (52%).