Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].N[C@@H]1CCCC[C@H]1N.[NH:32]1[CH2:36][CH2:35][CH2:34][C:33]1=[O:37]>O1CCOCC1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:32]3[CH2:36][CH2:35][CH2:34][C:33]3=[O:37])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCN1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1Cc2ccc(N3CCCC3=O)cc2C1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
Lit. J. Am. Chem. Soc. 2001, 123, 7727-7729. To a stirred suspension of 0.58 mmol 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) in 4 ml dioxane were added 0.12 mmol copper(I) iodide, 1.74 mmol potassium carbonate, 0.17 mmol trans-1,2-diaminocyclohexane and 2.90 mmol 2-pyrrolidone and the reaction mixture was stirred at 140° C. for 16 h. The mixture was then cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid. MS (m/e): 247.3 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH:5]=[O:6].ClC1C=C(C=CC=1OCC)C=[O:19]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[C:5]([OH:19])=[O:6]
Reactant: CCCOc1ccc(C=O)cc1Br
Reactant: CCOc1ccc(C=O)cc1Cl
Product: CCCOc1ccc(C(=O)O)cc1Br
Yield: 86 %

Procedure:
When the product of Step A was substituted for 3-chloro-4-ethoxybenzaldehyde in Example 49, Step A, the identical process afforded the title compound in 86% yield. 1H-NMR (DMSO-d6) 0.98 (tr, 3H, J=7.32 Hz); 1.68-1.79 (m, 2H); 4.06 (tr, 2H, J=6.39 Hz); 7.14 (d, 1H, J=8.7 Hz); 7.87 (dd, 1H, J=2.07, 8.61 Hz); 8.01 (d, 1H, J=2.04 Hz); 11.2 (broad s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].CCOCC>C(Cl)Cl>[O:1]=[CH:2][CH2:3][CH2:4][NH:5][C:6](=[O:11])[C:7]([F:9])([F:10])[F:8]
Reactant: O=C(NCCCO)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-(3-hydroxypropyl)trifluoroacetamide (1.6 g, 9.3 mmol) in anhydroud DCM (10 mL) cooled to 0° C. was added a solution of Dess-Martin periodinane (30 mL of 15 wt % in DCM; 14 mmol). Stirring was continued at 0° C. for 10 min, then the mixture was allowed to warm to room temperature and stirring was continued for 2 h. The mixture was poured onto a biphasic mixture of saturated aqueous NaHCO3 (60 mL) and Et2O (60 mL) and stirred vigorously for 20 min. The forming precipitate was eliminated by filtration and the layers separated. The aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried (MgSO4), filtrated, and evaporated. The product was purified by column chromatography (Hex:EtOAc 3:2) to provide N-(3-oxopropyl)trifluoroacetamide as a viscous liquid in a yield of 0.82 g (52%). The product decomposes at room temperature and was used within 24 h of preparation. 1H-NMR (500 MHz, CDCl3): δ=2.84 ppm (t, J=6.0 Hz, 2H), 3.64 ppm (dt, J=6.0, 6.0 Hz, 2H), 6.98 ppm (bs, 1H), 9.81 ppm (s, 1H); 13C-NMR (500 MHz, CDCl3): δ=33.36, 42.58, 115.74 ppm (q, J=1144 Hz), 157.42 ppm (q, J=146.5 Hz), 200.85 ppm.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[N:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1ccccc1N1CCOCC1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccccc2N2CCOCC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 2-morpholin-4-yl-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)ccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 97.4 %

Procedure:
4-Bromo-2-nitro-phenol (Aldrich, 2.18 g, 10 mmol) was treated with K2CO3 (Aldrich, 2.76 g, 20 mmol) in DMF (Aldrich, 100 mL) at ambient temperature for 20 min. Benzyl chloride (Aldrich, 1.52 g, 12 mmol) was added. The mixture was stirred at 100° C. for 6 h. It was then poured into ice/water (200 mL) and stirred at ambient temperature for 10 hours. The white solid was filtered and dried to give the title compound (3.0 g, yield, 100%). 1H NMR (300 MHz, CDCl3) δ 5.23 (s, 2 H), 7.01 (d, J=9.2 Hz, 1 H), 7.31-7.49 (m, 5 H), 7.58 (dd, J=9.0, 2.5 Hz, 1 H), 7.98 (d, J=2.7 Hz, 1 H) ppm. MS (DCl/NH3): 325 (M+H)+, 327 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23].C(OCC)C>CC(C)=O.O>[Cl:23][CH2:22][CH2:21][CH2:20][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:6][CH2:5]1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: ClCCCN1CCN(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
In 5 ml of acetone, 853 mg of 2-piperazin-1-ylquinoline as synthesized in Step 7-1-A was dissolved and to which 160 mg of sodium hydroxide as dissolved in 5 ml of water was added. Into the mixed liquid 0.5 ml of 1-bromo-3-chloropropane was dropped, followed by stirring for an overnight at room temperature. After addition of diethyl ether, the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, and the organic layer was dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (chloroform:methanol=50:1) to provide 1.10 g (95%) of 2-[4-(3-chloropropyl)piperazin-1-yl]quinoline.
Reaction SMILES: C([O:4][C:5]1[C:12]([Br:13])=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][C:6]=1[Br:14])(=O)C.O.NN.O.Cl>C1COCC1.CO>[Br:13][C:12]1[CH:11]=[C:8]([CH:7]=[C:6]([Br:14])[C:5]=1[OH:4])[CH:9]=[CH2:10]
Reactant: C=Cc1cc(Br)c(OC(C)=O)c(Br)c1
Agent: Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=Cc1cc(Br)c(O)c(Br)c1

Procedure:
10 g of 4-acetoxy-3,5-dibromostyrene are dissolved in 50 ml THF and 25 ml methanol, 12 g hydrazine hydrate (80% aqueous solution) is added, and the cloudy mixture is then converted into a clear solution by adding 3 ml of water. After 40 minutes it is acidified with a semi-concentrated HCl to pH2 and extracted twice with ether, the ether phase is washed twice with water and dried over sodium sulfate, and the ether is removed with a rotary evaporator at room temperature under aspirator vacuum. 8.5 g of crude product remain, from which 6.45 g of white crystals (mp 74° C.) are obtained by recrystallization from petroleum ether.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=O)[C:8]([OH:19])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1([NH2:27])[CH2:26][CH2:25][CH2:24]1>>[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:19])=[C:7]([CH2:20][NH:27][C:23]2([CH3:22])[CH2:26][CH2:25][CH2:24]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(Cl)c(Cl)c2)c1
Reactant: CC1(N)CCC1
Product: CC1(NCc2cc(C(C)(C)C)cc(-c3ccc(Cl)c(Cl)c3)c2O)CCC1

Procedure:
5-(tert-Butyl)-3′,4′-dichloro-3-(((1-methylcyclobutyl)amino)methyl)-[1,1′-biphenyl]-2-ol was prepared as a white solid using the procedure described in Example 5 from 5-(tert-butyl)-3′,4′-dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde (from Example 19, Step 1) and 1-methylcyclobutylamine.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C@H:18]2[C@H:23]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[CH:31]=3)=[O:26])[CH:22]3[CH2:36][CH2:37][N:19]2[CH2:20][CH2:21]3)[CH:12]=1.C(OCC)(=O)C>C(O)C>[C:6]([C@H:4]([C@@H:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C@H:18]2[C@H:23]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[CH:31]=3)=[O:26])[CH:22]3[CH2:36][CH2:37][N:19]2[CH2:20][CH2:21]3)[CH:12]=1
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: O=C(N[C@@H]1C2CCN(CC2)[C@H]1Cc1cccnc1)c1cc2ccccc2o1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Temperature: 25 °C

Procedure:
Tartaric acid (25.6 mg, 0.173 mmol) was added to a solution of (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide (125 mg, 0.346 mmol) in hot ethanol (1 mL). The resulting solution was slowly cooled to ambient temperature. No solids precipitated, so the solution was concentrated to give a white foam. Attempts to crystallize in isopropanol failed. The foam was dissolved in methanol and another half-equivalent of tartaric acid (25.6 mg, 0.173 mmol) was added. The mixture was concentrated to give a white foam, which would not crystallize from mixtures of methanol and isopropanol. The concentrated material (mixture of solid and gummy liquid) was then slurried in ethyl acetate (1 mL), producing a white solid. This was isolated by filtration (ethyl acetate wash) and drying in a vacuum oven (18 h at 40° C.), to give 141 mg (79.7% yield) of the mono stoichiometry salt (NMR), mp 136-140° C. Chiral LC analysis gave a purity of 98.1% (270 nm). 1H NMR (300 MHz, D2O) δ 8.50 (s, 1H), 8.01 (d, 1H), 7.86 (d, 1H), 7.75 (d, 1H), 7.56 (m, 2H), 7.38 (t, 1H), 7.32 (s, 1H), 7.21 (t, 1H), 4.34 (s, 2H, tartaric acid), 4.26 (d, 1H), 3.95 (m, 1H), 3.64 (m, 2H), 3.15-3.55 (m, 4H), 1.90-2.30 (m, 5H).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCCP(O)(O)=O.[CH3:26][N:27]1[C:32]2=[CH:33][N:34]([CH2:43][CH2:44][CH2:45][C:46]([OH:48])=O)[C:35]([C:36]3[CH:37]=[C:38]([CH3:42])[CH:39]=[CH:40][CH:41]=3)=[C:31]2[C:30](=[O:49])[N:29]([CH3:50])[C:28]1=[O:51]>CN(C=O)C.C(OCC)(=O)C>[CH3:26][N:27]1[C:32]2=[C:33]3[N:34]([C:35]([C:36]4[CH:37]=[C:38]([CH3:42])[CH:39]=[CH:40][CH:41]=4)=[C:31]2[C:30](=[O:49])[N:29]([CH3:50])[C:28]1=[O:51])[CH2:43][CH2:44][CH2:45][C:46]3=[O:48]
Reactant: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CCCC(=O)O)c1
Agent: CCCP(=O)(O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCCC3=O)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of T3P® (1-propylphosphonic acid cyclic anhydride 50% solution in DMF) (1.0M, 329 μL, 0.56 mmol) was added to solid 4-(1,3-dimethyl-2,4-dioxo-5-m-tolyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)butanoic acid (step 2) (200 mg, 0.56 mmol), giving a paste. DMF (1 mL) was added and a solution formed. The solution was stirred at room temperature for 1 hour and at 100° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with sat. sodium bicarbonate (1×5 mL) and brine (3×5 mL). The organic phase was dried with magnesium sulfate and the solvent was removed under vacuum to give the title compound.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)Cl.[CH2:17]([O:19][C:20]([C:22]1([NH2:31])[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21])[CH3:18].CCN(C(C)C)C(C)C>CC(O)C.C(Cl)Cl>[CH2:17]([O:19][C:20]([C:22]1([NH:31][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][CH:1]([CH3:2])[CH3:3])[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21])[CH3:18]
Reactant: CC(C)Sc1ccccc1C(=O)O
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2ccccc2SC(C)C)Cc2ccccc2C1
Reaction time: 0.08 h

Procedure:
A 30 mL reaction vial is charged with 2-isopropylsulfanylbenzoic acid (430 mg, 2.19 mmol) and dry DCM (7 mL). A stirring bar is added. Stirring is initiated. After dissolution is complete, the HTBU (831 mg, 2.19 mmol) is added. After 5 min, 2-amino-indane-2-carboxylic acid ethyl ester. (450 mg, 2.19 mmol) is added followed by DIPEA (0.96 mL, 5.48 mmol). The reaction is allowed to stir for 3 days. Analysis by tlc of the reaction mixture (silica, 5% iPrOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are transferred to a separatory funnel and diluted with EtOAc (50 mL). This is washed consecutively with dilute aqueous HCl (3%, 25 mL), saturated aqueous NaHCO3 (25 mL) and brine (25 mL), and then dried over MgSO4, filtered and evaporated in vacuo to provide 0.87 g of light yellow solid. This material is dissolved in 10 mL of DCM. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 50% EtOAc in heptanes over 10 column volumes. 17 mL fractions of eluent are collected. Fractions 32 through 40 are combined and evaporated in vacuo. This provides white solid material (0.69 g, 82%).
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:19][C:20]4[N:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][CH:21]=4)[S:16][C:17]=3[CH3:18])[CH:10]=[N:9]2)=CC=1.C(Cl)Cl.CO>C(O)(C(F)(F)F)=O>[CH3:18][C:17]1[S:16][C:15]([NH:19][C:20]2[N:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][CH:21]=2)=[N:14][C:13]=1[C:11]1[CH:12]=[N:8][NH:9][CH:10]=1
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4cccc(C#N)n4)sc3C)cn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1sc(Nc2cccc(C#N)n2)nc1-c1cn[nH]c1
Yield: 13 %

Procedure:
According to Scheme 4 Step 2: A solution of 6-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-methylthiazol-2-ylamino)picolinonitrile (0.69 mmol, 277 mg) in TFA (4 mL) was microwaved for 7 minutes at 100° C. After evaporation of the solvent, the resulting residue was neutralized with a saturated solution of Na2CO3. The compound precipitated and after filtration, the solid was washed with water and dried. The solid was finally triturated in Et2O, DCM and MeOH to yield 6-(5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-ylamino)picolinonitrile (90 μmol, 25 mg, 12%) as a beige solid.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[Na].[C:6]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[CH3:7]>>[C:6]([CH:9]([C:10](=[O:12])[CH3:11])[CH2:3][CH2:2][C:1]#[N:4])(=[O:8])[CH3:7]
Reactant: C=CC#N
Reactant: CC(=O)CC(C)=O
Agent: [Na]
Product: CC(=O)C(CCC#N)C(C)=O

Procedure:
4,4-Diacetylbutyronitrile was prepared by addition of acrylonitrile to the sodium salt of acetyl acetone according to the procedure of Johnson et al, J.Chem.Soc (C), 1969, 176.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:15]=[C:16]([CH:33]2[S:38][CH2:37][CH2:36][CH2:35][S:34]2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.[I:44][C:45]1[CH:52]=[CH:51][C:48]([CH:49]=[O:50])=[CH:47][CH:46]=1>C1COCC1>[CH2:1]([O:13][C:14]1[CH:15]=[C:16]([C:33]2([CH:49]([C:48]3[CH:51]=[CH:52][C:45]([I:44])=[CH:46][CH:47]=3)[OH:50])[S:34][CH2:35][CH2:36][CH2:37][S:38]2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=Cc1ccc(I)cc1
Reactant: CCCCCCCCCCCCOc1ccc(C2SCCCS2)cc1OCCCCCCCCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(C2(C(O)c3ccc(I)cc3)SCCCS2)cc1OCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
A solution of 2-(3,4-bis-dodecyloxy-phenyl)-[1,3]dithiane (12.0 g, 21.1 mmol) in 120 mL of dry THF in a Schlenk tube was cooled down to −78° C. Under N2 atmosphere, n-BuLi (9.4 mL of 2.5 M solution in hexanes, 23.4 mmol) was added dropwise to the mixture. After stirring at 0° C. for 1 h, the reaction mixture was cooled down to −78° C. and 4-iodobenzaldehyde (3.72 g, 16.0 mmol) in 100 mL of dry THF was added dropwise. The resulting mixture was allowed to warm up to room temperature and stirred at room temperature overnight. The reaction was quenched with H2O and THF was removed under reduced pressure. The resulting slurry was extracted with CH2Cl2 and the organic layer was washed with H2O and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The product was purified by column chromatography (silica gel, hexanes:dichloromethane=3:2, 1:1, then 2:3 (v/v)) to give light yellow oil (8.3 g, 65%). 1H NMR (300 MHz, CDCl3, δ): 7.44 (d, J=8.2 Hz, 2H), 7.23 (dd, J=8.5 Hz, 2.5 Hz, 1H), 7.02 (d, J=2.5 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 6.61 (d, J=8.5 Hz, 2H), 4.84 (s, 1H), 3.98 (t, J=6.6 Hz, 2H), 3.73 (m, 2H), 3.00 (s, 1H), 2.69 (m, 4H), 1.66-1.94 (m, 6H), 1.20-1.51 (m, 36H), 0.86 (t, J=6.7 Hz, 6H). 13C{1H} NMR (75 MHz, CDCl3, δ): 148.40, 148.31, 136.96, 135.88, 130.04, 128.93, 122.95, 115.99, 112.55, 93.82, 80.51, 69.29, 69.05, 66.33, 32.00, 29.78, 29.72, 29.55, 29.45, 29.32, 29.29, 27.41, 27.02, 26.12, 24.80, 22.78, 14.24. LRMS-EI (m/z): [M−H2O]+ calcd for C41H63IO2S2, 778.3; found, 778.5.
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:10]1[N:11]=[C:12]([NH2:14])[S:13][C:9]=1[CH2:8][CH2:7]2.[C:18]1([C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:10]1[N:11]=[C:12]([NH:14][S:30]([C:27]3[CH:26]=[CH:25][C:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:29][CH:28]=3)(=[O:32])=[O:31])[S:13][C:9]=1[CH2:8][CH2:7]2
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COc1ccc2c(c1)CCc1sc(N)nc1-2
Agent: Br
Product: COc1ccc2c(c1)CCc1sc(NS(=O)(=O)c3ccc(-c4ccccc4)cc3)nc1-2

Procedure:
The title compound was prepared from 7-methoxy4,5-dihydronaphto[1,2-D][1,3]thiazol-2-amine hydrobromide and 4-phenylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (17.0 mg) with purity >80%. MS (pos) m/z 449.2.
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.CS(N)(=O)=O.C([Si]([O:71]/[C:72](/[C:75]1[CH:80]=[CH:79][C:78]([O:81][CH2:82][C:83]2[CH:88]=[CH:87][C:86]([O:89][CH3:90])=[CH:85][CH:84]=2)=[CH:77][CH:76]=1)=[CH:73]\[CH3:74])(C)C)(C)(C)C.S([O-])([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.O>[OH:22][C@H:73]([CH3:74])[C:72]([C:75]1[CH:80]=[CH:79][C:78]([O:81][CH2:82][C:83]2[CH:88]=[CH:87][C:86]([O:89][CH3:90])=[CH:85][CH:84]=2)=[CH:77][CH:76]=1)=[O:71]
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccc(OC)cc2)cc1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CS(N)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(COc2ccc(C(=O)[C@@H](C)O)cc2)cc1
Yield: 89 %

Procedure:
Ad-mix-β (28.0 g) and methanesulfonamide (1.90 g, 20 mmol) were suspended in t-butanol (100 mL) and water (100 mL), then the compound (7.7 g, 20 mmol) synthesized in the above (2) was added under stirring with cooling with ice. The reaction solution was stirred for 15 hours with cooling with ice, then sodium sulfite (20 g, 0.16 mol) was added, and further stirred at room temperature for 1 hour. The reaction solution was poured in water, extracted with chloroform, and the organic layer was washed with saturated ammonium chloride and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting pale yellow solid was washed with diisopropyl ether and n-heptane to obtain the entitled compound (5.1 g, 89%) as a milky white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6](NC)[CH:5]([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][N:15](C4CCCCO4)[C:12]3=[CH:13][N:14]=2)[CH2:4][C:3]1=[O:30].FC(F)(F)C(O)=O>>[CH3:1][N:2]1[CH2:6][C:5]([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][NH:15][C:12]3=[CH:13][N:14]=2)=[CH:4][C:3]1=[O:30]
Reactant: CNC1C(c2cc3c(-c4ccccc4)nn(C4CCCCO4)c3cn2)CC(=O)N1C
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(c2cc3c(-c4ccccc4)n[nH]c3cn2)=CC1=O
Temperature: 105 °C
Reaction time: 72 h
Yield: 16.4 %

Procedure:
A mixture of 1-methyl-5-(methylamino)-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyrrolidin-2-one (34.3 mg, 0.084 mmol) and trifluoroacetic acid (3 mL) in a sealed high-pressure tube was stirred at 105° C. for 3 days. The reaction was cooled to RT and trifluoroacetic acid was removed via rotary evaporator. The resultant oil was diluted with ethyl acetate (30 mL). The organic layer was washed with aqueous saturated sodium bicarbonate solution (2×), water and brine, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by reverse phase HPLC to give 259 as white solid (4.0 mg, 16.3%). 1H NMR (400 MHz, DMSO) δ 9.13 (s, 1H), 8.43 (s, 1H), 8.11 (d, J=7.5 Hz, 2H), 7.56 (t, J=7.6 Hz, 2H), 7.47 (d, J=7.3 Hz, 1H), 6.82 (s, 1H), 6.68 (s, 1H), 4.61 (s, 2H), 2.99 (s, 3H). LC/MS: m/z 291.0 [M+1]
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([O:1][CH:2]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][CH:20]=2)[CH2:3][O:4][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[CH:7][N:6]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: CC(C)(C)c1ccc(C(O)COc2ncnc3ccccc23)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC(COc2ncnc3ccccc23)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 4 h

Procedure:
A 15 ml round bottom flask is charged with 4-(2-hydroxy-2-(4-tert-butylphenyl) ethoxy) quinazoline (0.25 g, 0.77 mmol) is dissolved in pyridine (5 ml). p-Toluenesulfonyl chloride (0.15 g, 0.79 mmol) is then added to it and the mixture stirred for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using silica gel (ethyl acetate/hexanes)to give the product.