Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:9][N:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=12)=O.S(O)(O)(=O)=O.[N:33]1([C:38](=[NH:40])[NH2:39])[CH2:37][CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN1CCCC1=O.O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:8]2[C:7]([C:5]3[CH:4]=[CH:3][N:39]=[C:38]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[N:40]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:19])[F:18])=[CH:15][N:10]3[N:9]=2)=[CH:25][CH:24]=1
Reactant: N=C(N)N1CCCC1
Reactant: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: Fc1ccc(-c2nn3cc(C(F)(F)F)ccc3c2-c2ccnc(N3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propen-1-one (100 mg, 0.27 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was added 1-pyrrolidinecarboximidamide sulfate (111 mg, 0.53 mmol), and potassium carbonate (73 mg, 0.53 mmol). The mixture was heated at reflux for 8 hours. Upon cooling to room temperature, ether was added followed by water. The organics were washed with brine, and the aqueous layer was extracted with ether. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica (6:1 hexanes-ethyl acetate) to give 2-(4-fluorophenyl)-3-[2-(1-pyrrolidinyl)-4-pyrimidinyl]-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine (80 mg, 71%) as a foam. 1H NMR (CDCl3): δ 8.86 (s, 1 H), 8.61 (d, 1 H), 8.19 (m, 1 H), 7.67 (m, 2 H), 7.46 (d, 1 H), 7.19 (m, 2 H), 6.31 (m, 1 H), 3.70 (m, 4 H), 2.08 (m, 4 H); 19F NMR (CDCl3) δ −62.68, −112.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH3:23][C:24]1[C:28]([CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:27]([CH3:36])[NH:26][C:25]=1[CH:37]=O>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:37]\[C:25]1[NH:26][C:27]([CH3:36])=[C:28]([CH2:29][N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[C:24]=1[CH3:23])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCOCC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCOCC1

Procedure:
5-(2,6-Dichlorophenylmethanesulfonyl)-1,3-dihydro-indol-2-one was condensed with 3,5-dimethyl-4-morpholin-4-ylmethyl-1H-pyrrole-2-carbaldehyde to give 2.0 g of the titled compound as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[Cl:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([O:13][CH3:14])[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[N:11]2
Reactant: CCOC(=O)Cl
Reactant: COc1nc2ccc(Cl)cc2nc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 95 %

Procedure:
3-Amino-6-chloro-2-methoxyquinoxaline (629 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 803 mg of the titled compound (yield, 95%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]=[CH:17][N+:18]([O-])=O.OS(O)(=O)=O>C1COCC1>[F:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][CH2:17][NH2:18]
Reactant: COc1ccc(C=C[N+](=O)[O-])c(F)c1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(CCN)c(F)c1

Procedure:
LiAlH4 (3.5 equivalents) was suspended in THF and brought to reflux. 2-fluoro-4-methoxy-1-(2-nitro-vinyl)-benzene (1 equivalent) was dissolved in THF and added dropwise to the LiAlH4. The reaction was allowed to proceed at reflux overnight. The reaction was then cooled in an ice bath and H2SO4 was added dropwise. The reaction was extracted with ether. The ether fractions were discarded. The aqueous layer was adjusted to pH 12 with 5% NaOH and extracted with ether (3×). Combined ether fractions were washed with brine and dried over Na2SO4. Solvent was removed to yield 2-(2-fluoro-4-methoxy-phenyl)-ethylamine as an oil, which was used without further purification.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[OH-].[Na+].C(N1C2C=CC=CC=2C2C1=CC=CC=2)CCCCCC>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:28]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CCCCCCCCCCCCCCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CCCCCCCn1c2ccccc2c2ccccc21
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCn1c2ccccc2c2ccccc21

Procedure:
N-Tetradecylcarbazole was prepared from carbazole (59.27 g, 0.35 mol), 1-bromotetradecane (100 g, 0.36 mol, commercially available from Aldrich, Milwaukee, Wis.), benzyltriethyl ammonium chloride (4.00 g, 0.018 mol), 50% aqueous NaOH (200 g), and toluene (400 ml) according to the procedure described for N-heptylcarbazole. The product was obtained as 120 g of a brown liquid (93% yield). Upon standing at room temperature overnight, the liquid solidified.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH:11]([CH3:15])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:28])[O:18][CH2:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:17]([O:18][CH2:19][C:20]2[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)=[O:28])[CH:11]([CH3:15])[CH2:10]1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CC(CNC(=O)OC(C)(C)C)CCN1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1CC(CNC(=O)OC(C)(C)C)CCN1C(=O)OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture comprising tert-butyl((2-methylpiperidin-4-yl)methyl)carbamate (step 2) (1.15 g, 5.04 mmol) and 3,5-dichlorobenzyl carbonochloridate (1.327 g, 5.54 mmol) in DCM (15 ml) was treated with aq. saturated sodium bicarbonate (0.504 ml, 5.04 mmol) and stirred at room temperature for 18 hours. The organic portion was separated and the aqueous phase extracted with DCM (2×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. Further purification by chromatography on silica, eluting in 0-20% 2M ammonia in MeOH in DCM afforded the title compound;
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[F:22][C:23]([F:28])([F:27])[C@@H:24]1[CH2:26][O:25]1>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]([C@@H:9]2[CH2:10][N:11]([CH2:26][C@H:24]([OH:25])[C:23]([F:28])([F:27])[F:22])[CH2:12][CH2:13][O:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Clc1cccc([C@@H]2CNCCO2)c1
Reactant: FC(F)(F)[C@@H]1CO1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O[C@@H](CN1CCO[C@H](c2cccc(Cl)c2)C1)C(F)(F)F
Temperature: 50 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
To a solution of (R)-2-(3-chloro-phenyl)-morpholine hydrochloride (45 mg, 192 μmol) and triethylamine (134 μL, 961 μmole) in 4 mL of acetonitrile was added (S)-2-(trifluoromethyl)oxirane (43.1 mg, 384 μmol). The mixture was stirred at 50° C. for 3 h, followed by evaporation in vacuo to afford (S)-3-((R)-2-(3-chlorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol (59.5 mg), which was used directly for next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH:10]=[C:11]2[C:16](=O)[C:15](=[CH:18][C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=3[CH3:28])[CH2:14][O:13][CH2:12]2)=[C:5]([CH3:29])[CH:4]=1.[NH2:30][C:31]1[S:32][CH2:33][CH2:34][N:35]=1>C(Cl)(Cl)Cl.CCO>[CH3:27][O:26][C:22]1[C:23]([CH3:25])=[CH:24][C:19]([CH:18]2[N:35]3[CH2:34][CH2:33][S:32][C:31]3=[N:30][C:16]3[C:11](=[CH:10][C:6]4[CH:7]=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:29])[CH2:12][O:13][CH2:14][C:15]2=3)=[C:20]([CH3:28])[CH:21]=1
Reactant: COc1cc(C)c(C=C2COCC(=Cc3cc(C)c(OC)cc3C)C2=O)cc1C
Reactant: NC1=NCCS1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc(C)c(C=C2COCC3=C2N=C2SCCN2C3c2cc(C)c(OC)cc2C)cc1C
Yield: 46.9 %

Procedure:
A stirred solution of tetrahydro-3,5-bis[(4-methoxy-2,5-dimethylphenyl)methylene]-4H-pyran-4-one (3.0 g, 7.6 mmole) and 2-amino-2-thiazoline (1.0 g, 9.7 mmole) in 75 ml of CHCl3 is heated at reflux temperature for 72 hours. After cooling, the solution is filtered to remove a small amount of insoluble material. The solvent is evaporated to give an oily residue. A solution of this material in 25 ml of EtOH yields 1.7 g of light yellow solid, m.p. 195°-197°. Crystallization from 20 ml of 10% DMF/MeOH gives 1.3 g (35%) of cream colored solid, m.p. 196°-198°.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Cl)=[C:6]([CH3:10])[CH:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[OH:15].[SH:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C>[CH3:1][C:2]1[C:7]([CH2:8][S:16][CH2:17][CH2:18][OH:19])=[C:6]([CH3:10])[CH:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[OH:15]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CSCCO

Procedure:
This material was prepared according to the procedure of Example III using 2,4-dimethyl-3-chloromethyl-6-t-butylphenol (160.8 g, 0.71 m), 2-mercaptoethanol (52.5 g, 0.71 m), potassium carbonate (110.4 g, 0.8 m), potassium iodide (5.0 g), and methyl isobutyl ketone (500 ml). Work-up afforded a dark colored oil. This material can be distilled under a very good vacuum. The nmr spectrum was consistent with the desired structure.
Reaction SMILES: [BH4-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([C:12](=[O:28])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]2)=[CH:4]1>C(O)C>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([CH:12]([OH:28])[CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH2:18][CH2:19]2)=[CH:4]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(=O)c2coc3ccccc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(CC(O)c2coc3ccccc23)CC1

Procedure:
1.2 g of sodium borohydride are added in portions to a solution of 7.7 g of the product obtained in Step A in 100 ml of ethanol. After 1 hour's reaction, the solution is evaporated, taken up in water, extracted with ethyl acetate, dried and then concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethanol: 95/5) enables the expected product to be isolated.
Reaction SMILES: O.O.O=[Al]O[Si](O[Si](O[Al]=O)=O)=O.[P:14](=[O:18])([OH:17])([OH:16])[OH:15].[N+:19]([O-:22])([O-:21])=[O:20].[Ce+3:23].[N+:24]([O-:27])([O-:26])=[O:25].[N+:28]([O-:31])([O-:30])=[O:29]>O>[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[N+:19]([O-:22])([O-:21])=[O:20].[Ce+3:23].[N+:24]([O-:27])([O-:26])=[O:25].[N+:28]([O-:31])([O-:30])=[O:29]
Reactant: O=P(O)(O)O
Agent: O=[Al]O[Si](=O)O[Si](=O)O[Al]=O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+3]
Solvent: O
Product: O=P([O-])([O-])[O-]
Reaction time: 0.5 h

Procedure:
A clay/phosphate/cerium nitrate solution was prepared (according to the general teachings of U.S. Pat. No. 5,190,902) by adding 1403 grams of Theile RC-32® kaolin clay slurry to 591 milliliters of water in a high speed mixer. To this mixture, 192 grams of phosphoric acid was then added. To the resulting system, 440 grams of cerium nitrate solution was added. The slurry formulation was then spray dried and the resulting particles calcined at 650° C. for 30 minutes in a muffle furnace. The calcined particles were then mixed with magnesium oxide in a 50/50 weight percent ratio and the resulting material analyzed by a TGA test that showed a SOx absorption rate of 0.21% per minute for the end product material.
Reaction SMILES: I[C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:15]4)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.C([N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1)(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+].CO>O1CCOCC1.CCOC(C)=O.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].C(Cl)Cl>[C:23]1([CH2:22][C:21]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:9]4[C:4]5[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:40]6[CH:41]=[N:37][NH:38][CH:39]=6)[C:3]=5[S:11][CH:10]=4)=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:29])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ncc(I)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1ncc(-c2cn[nH]c2)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A mixture of 7-iodo-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-4-amine (101 mg, 0.198 mmol), 1-Boc-pyrazol-4-boronic acid pinacol ester (88 mg, 0.299 mmol), and PdCl2(dppf)-CH2Cl2 adduct (9 mg, 0.011 mmol) in 1,4-Dioxane (2.0 mL) and saturated aqueous sodium bicarbonate (0.6 mL, 0.600 mmol) was degassed with Nitrogen for 10 minutes in a microwave vial. The vial was then capped and the mixture was stirred at 120° C. in the microwave for 30 min. LCMS showed complete conversion to the de-Boc product. The mixture was cooled, poured into water (15 mL), and extracted with ethyl acetate (2×15 mL). The extracts were washed with brine (1×15 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 24 g SiO2, 50%-100% EtOAc in hexanes gradient over 15 minutes, then EtOAc for 5 minutes, then 0-10% MeOH in EtOAc over 20 minutes) to give 3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]-7-(1H-pyrazol-4-yl)thieno[3,2-c]pyridin-4-amine (50 mg, 0.105 mmol, 53.3% yield) as a light gray solid. LC/MS (ES) m/z=452 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.24 (t, J=8.34 Hz, 2H), 3.89 (s, 2H), 4.26 (t, J=8.46 Hz, 2H), 5.40 (br. s., 2H), 7.22-7.30 (m, 2H), 7.30-7.40 (m, 5H), 7.48 (s, 1H), 7.95 (br. s., 1H), 8.06 (s, 1H), 8.12-8.21 (m, 2H), 13.10 (br. s., 1H).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:27]=3[C:20]([C:21]3[C:26]=2[C:25]=1[CH:24]=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]4[C:28]([O:30]CC(C)C)=[O:29])=[O:7])C(C)C.[OH-].[K+:36]>CCO>[CH:19]1[C:20]2=[C:27]3[C:12]([C:11]4[C:26]5[C:25](=[CH:24][CH:23]=[CH:22][C:21]2=5)[C:8]([C:6]([O-:7])=[O:5])=[CH:9][CH:10]=4)=[CH:13][CH:14]=[CH:15][C:16]3=[C:17]([C:28]([O-:30])=[O:29])[CH:18]=1.[K+:36].[K+:36]
Reactant: CC(C)COC(=O)c1ccc2c3cccc4c(C(=O)OCC(C)C)ccc(c5cccc1c52)c43
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1ccc2c3cccc4c(C(=O)[O-])ccc(c5cccc1c52)c43
Yield: 81.8 %

Procedure:
3,9-Perylenedicarboxylic acid diisobutyl ester (500 mg, 1.1 mmol, 1 eq) was suspended in 200 mL EtOH, and 1 M aq. KOH (7 mL, 3.3 mmol, 3 eq) was added. The reaction mixture was refluxed for 16 h. The precipitate was filtered off and washed with EtOH as well as DCM to provide the title compound as a yellow powder (369 mg, 0.9 mmol, 80%). 1H NMR (400 MHz, MeOD, 333K) δ 6.87-6.82 (m, 2H, PDA aromatic H), 6.76 (dd, J=9.7, 7.5 Hz 4H, PDA aromatic H), 6.17 (d, J=7.7 Hz 4H, PDA aromatic H), 5.99 (ddd, J=8.6, 7.6, 1.2 Hz 4H, PDA aromatic H). HRMS (ESI): calcd. mass for C22H11O4−: ([M−H]−) 339.0663. found: 339.0653.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([C:6]1[C:15]([OH:16])=[CH:14][C:9]2C(C#N)=[CH:11][C:8]=2[CH:7]=1)=[O:5].[C:22]([OH:25])(=[O:24])[CH3:23]>Cl>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([C:6]1[C:15]([OH:16])=[CH:14][C:9]2[C:23]([C:22]([OH:25])=[O:24])=[CH:11][C:8]=2[CH:7]=1)=[O:5]
Reactant: CC(=O)O
Reactant: N#CC1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Agent: Cl
Product: O=C(O)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10.65 g of 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carbonitrile are suspended in a mixture of 100 ml of concentrated hydrochloric acid and 100 ml of acetic acid and stirring is carried out for 4 hours at 100°. The whole is left to cool to room temperature, filtered with suction, washed thoroughly with water, left to dry in the air and recrystallised from trichloromethane/hexane with the addition of a small amount of methanol. 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid is obtained having a melting point of 202°-203°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:7]=1I.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.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.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:7]=1[C:25]1[CH:26]=[CH:27][C:22]([C:21]([F:32])([F:31])[F:20])=[CH:23][CH:24]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1cc(Cl)c(I)c(OCC2CC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)c(OCC2CC2)c1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A mixture of compound ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate (5.1 g, 14 mmol), 4-trifluoromethylphenylboronic acid (3.36 g, 17 mmol), CsF (0.28 g, 1.84 mmol) and Pd (PPh3)4 (0.410 g, 0.4 mmol) in 75 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled to RT and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over NaSO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate (4.6 g) as a yellow oil. 1H-NMR (CDCl3, 200 MHz): 0.41 (m, 2H), 0.62 (m, 2H), 1.22 (t, 3H), 1.23 (m, 1H), 3.58 (s, 2H), 3.89 (d, 2H), 4.17 (q, 2H), 6.96 (m, 2H), 7.31 (s, 1H), 7.64 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]2[C:29]([O:31][C:32](=O)[C:20]=12)=[O:30]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[C:32](=[O:31])[C:20]3[CH:19]=[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[CH:22][C:21]=3[C:29]2=[O:30])=[O:8])=[CH:17][CH:18]=1
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccccc2N2C(=O)c3cc4ccccc4cc3C2=O)cc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
A pressure tube was charged with N1-(4-methoxybenzoyl)-1,2-benzenediamine (1.00 g, 4.13 mmol), 2,3-napthalenedicarboxylic anhydride (820 mg, 4.13 mmol), and tetrahydrofuran (16 mL). The resultant slurry was then placed in a bath heated to 110° C. for 16 h. After cooling to ambient temperature and standing for 3 h, the mixture was further cooled to −10° C. for 20 h. The resulting solid was collected by filtration and washed with cold ethyl acetate. The solid was then pulverized and dried under vacuum at 50° C. for 20 h to yield 1.45 g (83%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C3CCCCO3)[CH:10]=2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][OH:32])[CH:27]=[CH:28][CH:29]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][OH:32])[CH:25]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CCO)c1
Reactant: Clc1ncc(Cl)c(Nc2cccc(OC3CCCCO3)c2)n1
Product: OCCc1cccc(Nc2ncc(Cl)c(Nc3cccc(O)c3)n2)c1
Yield: 65 %

Procedure:
The desired compound was prepared according to the procedure of Example D5, step B, using 2,5-dichloro-N-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidin-4-amine and 2-(3-aminophenyl)ethanol [Bioorg. Med. Chem. 2005, 13, 6703-6712] as the starting materials in 65% yield. LCMS for C18H18ClN4O2 (M+H)+: m/z=357.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])[N:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])[N:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cccc(OCc3nc(-c4ccccc4)oc3C)n2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2cccc(OCc3nc(-c4ccccc4)oc3C)n2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]-1H-pyrazol-4-yl]propionate (652 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (522 mg, yield: 85%). This was recrystallized from ethanol-hexane. Melting point: 144–145° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].I[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1>C(N(CC)CC)C.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.[Cu]I>[CH3:2][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)[CH3:3]
Reactant: C#Cc1ccc(C(C)C)cc1
Reactant: CC(C)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(C#Cc2ccc(C(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
The crude 4-isopropylphenylacetylene was dissolved in triethylamine (100 mL). 4-iodoisopropylbenzene (12.3 g, 50 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.70 g, 1 mmol), and copper(I) iodide (1.5 g) were added. The reaction was stirred at room temperature for 2 days, heated to reflux for 1 hour, cooled, diluted with hexanes, and filtered. The filtrate was evaporated under reduced pressure. The residue was filtered through a pad of silica gel with hexanes, and the solvent was evaporated to give 11.40 g (87%) of 1,2-bis(4-(2-propyl)phenyl)acetylene.