Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28][CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28]/[CH:29]=[CH:30]/[C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Reactant: Brc1cccnc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4cccnc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 124, Step 1, using 1-{4′-[4-(1-hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-bromopyridine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7](CO)[CH:6]=[CH:5][N:4]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:12].O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[C:7]([Cl:12])[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#Cc1cc(CO)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: N#Cc1cc(Cl)ccn1
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a magnetically stirred solution of 9 grams (66 mm) of 2-cyano-4-hydroxymethylpyridine [Swan, et al. J. Chem. Soc., 3440 (1963)] contained in 300 mls of benzene is added 15.1 grams (72 mm) of phosphorous pentachloride. After stirring for 1/2 hour, ice and water are added followed by sodium bicarbonate. The organic layer is washed with water and evaporated. The residual oil is crystallized from petroleum ether, to yield 8.5 grams (83%) of 2-cyano-4-pyridyl chloride, m.p. -55°-56°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Yield: 66.4 %

Procedure:
The product was generated using general protocol D using dimethyl-5-hydroxyisophthalate (1.037 g, 4.93 mmol), 1-bromotetradecane (1.34 mL, 4.48 mmol), K2CO3 (2.48 g, XXmol), CH3CN (50 mL) yielded 1.21 g (60.2%) of a white solid. 1H NMR (CDCl3, 400 MHz) δ: 8.2607 (s, 1H, Ar—H), 7.7396 (s, 2H, Ar—H), 4.0315 (t, 2H, O—CH2, 3J=6.62 Hz), 3.9374 (s, 6H, COOCH3), 1.8046 (p, 2H, O—CH2—CH23J=6.82 Hz), 1.4660 (p, 2H, O—CH2—CH2—CH2, 3J=6.86 Hz), 1.2582 (m, 22H), 0.8809 (t, 3H, CH2—CH3, 3J=6.69 Hz
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][Si:5]([CH3:10])([CH3:9])[O:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1CCCCC1>[C:18]([S:1][CH2:2][CH2:3][CH2:4][Si:5]([O:6][CH2:7][CH3:8])([CH3:10])[CH3:9])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCO[Si](C)(C)CCCS
Solvent: CCN(CC)CC
Solvent: C1CCCCC1
Product: CCCCCCCC(=O)SCCC[Si](C)(C)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
Added dropwise at 5° C., under argon, to 3-mercaptopropyldimethylethoxysilane (34.0 g, 0.191 mol) in solution in triethylamine (19.2 g, 0.191 mol) and cyclohexane (400 ml) is octanoyl chloride (31.0 g, 0.191 mol) over 15 minutes at 8° C. The reaction medium is stirred for 15 hours at ambient temperature. The precipitate of triethylamine hydrochloride Et3N.HCl is filtered. The mixture obtained is purified by flash chromatography (eluent: petroleum ether, 500-600 ml). After evaporating the solvents under reduced pressure at 24° C., the S-octanoylmercaptopropylethoxydimethylsilane E with CAS number [1024594-66-8] (45.0 g, 0.148 mol) is obtained in the form of a colourless liquid with a yield of 78%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8]Cl)=[C:4]([O:10][CH3:11])[CH:3]=1.[Cl:12][C:13]1[C:14]([F:25])=[C:15]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)[C:16]([F:19])=[CH:17][CH:18]=1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][N:21]2[CH:22]=[CH:23][N:24]=[C:20]2[C:15]2[C:16]([F:19])=[CH:17][CH:18]=[C:13]([Cl:12])[C:14]=2[F:25])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)nnc1CCl
Reactant: Fc1ccc(Cl)c(F)c1-c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)nnc1Cn1ccnc1-c1c(F)ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6-chloro-3-chloromethyl-4-methoxy-pyridazine (58 mg, 0.3 mmol) and 2-(3-chloro-2,6-difluoro-phenyl)-imidazole (65 mg, 0.3 mmol) in DMF (6 mL) is added NaH (60% suspension in mineral oil, 14 mg). The mixture is stirred at room temperature overnight. The solvent is removed in vacuo and water (5 mL) and EtOAc (8 mL) is added. The layers are separated and the aqueous layer is extracted with EtOAc (8 mL). The combined extracts is washed with brine (8 mL) and dried (Na2SO4) and evaporated. Preparative TLC purification (5% MeOH in CH2Cl2) of the residue provides the title compound as a light yellow oil. H1 NMR δ (CDCl3) 7.48–7.56 (m, 1H), 7.15–7.20 (m, 2H), 7.02 (t, 1H, J=8.4 Hz), 6.87 (s, 1H), 5.27 (s, 2H), 3.764 (s, 3H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15](=[O:18])[CH:16]=[CH2:17])=[O:5])C.CS(C)=O.[OH-].[K+]>O.[OH-].[Na+]>[O:18]=[C:15]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH:6]1[C:4]([OH:5])=[O:3])[CH:16]=[CH2:17]
Reactant: C=CC(=O)N1c2ccccc2CC1C(=O)OCC
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=CC(=O)N1c2ccccc2CC1C(=O)O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 2,3-dihydro-1-(1-oxo-2-propenyl)-1H-indole-2-carboxylic acid ethyl ester (14.4 g.), 80% aqueous dimethyl-sulfoxide (200 ml.) and potassium hydroxide (86% pellets, 3.83 g.) was stirred under nitrogen atmosphere for 2.5 days at room temperature, then evaporated under reduced pressure on a rotary evaporator to give an oily residue. The residue was dissolved in water with the aide of a small amount of dilute sodium hydroxide solution. The aqueous solution was washed with ether twice, then made acidic by addition of dilute hydrochloric acid to pH ca. 2. The oil thus separated was extracted with ether three times. The combined ether extract was washed with water, then with saline, and dried over anhydrous magnesium sulfate. Evaporation of the ether on a rotary evaporator under reduced pressure gave a solid residue which melted at 158°-160°, and weighed 9.2 g. Recrystallization from ethyl acetate improved the melting point to 167°-169°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].S(Cl)(Cl)=O.[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1Br
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc(C(=O)c2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 4-bromo-3-methoxybenzoic acid (1.00 g, 4.33 mmol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed oh the pump. Benzene (20 mL, 0.2 mol) and aluminum trichloride (0.676 g, 5.07 mmol) were added to the reaction mixture. The reaction mixture turned yellow in color on addition of AlCl3. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:7]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([C:30]([F:41])([F:40])[F:29])[CH:36]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:7]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1cccc(Cl)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(C(F)(F)F)c3)ccc2n1-c1cccc(Cl)c1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(3-chlorophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (135 mg, 0.34 mmol, see step (b) Example 8) and 3-trifluoromethylphenylboronic acid (96 mg, 0.50 mmol). Yield 110 mg (60%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]([CH3:13])=[CH:11][C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=1.Cl[CH2:15][C:16]1[CH:26]=[CH:25][C:19]2[N:20]=[C:21]([S:23][CH3:24])[S:22][C:18]=2[CH:17]=1>CN(C=O)C>[CH3:3][C:4]1[C:12]([CH3:13])=[CH:11][C:7]2[N:8]([CH2:15][C:16]3[CH:26]=[CH:25][C:19]4[N:20]=[C:21]([S:23][CH3:24])[S:22][C:18]=4[CH:17]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1
Reactant: CSc1nc2ccc(CCl)cc2s1
Reactant: Cc1cc2nc[nH]c2cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cc(C)c(C)cc43)cc2s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.7 %

Procedure:
To a stirred mixture of anhydrous DMF (15 mL) and sodium hydride (60% dispersion in mineral oil, 105 mg, 2.63 mmol) at 0° C. under nitrogen, was added portionwise 5,6-dimethyl-1H-benzo[d]imidazole (215 mg, 1.4 mmol). The reaction mixture was stirred for 5 min. A solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (320 mg, 1.4 mmol) from Step 4 of Example 36 in anhydrous DMF (2 mL) was added dropwise. The reaction mixture was allowed to warm to rt and stir for 1 h. The reaction solution was poured into ice-water and extracted with EtOAc (50 mL×3). The combined organic layers were further washed with water (20 mL), then brine (20 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (450 mg, 96%) as a yellow solid which was not purified further. 1H NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.59 (s, 1H), 7.46 (s, 1H), 7.24-7.26 (m, 1H), 7.03 (s, 1H), 5.40 (s, 2H), 2.77 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H); LCMS (ESI) m/z 340 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1.[CH3:21][CH2:22][O:23][C:24]([C:26]([CH2:28][C:29]([CH3:31])=O)=O)=[O:25]>>[CH2:22]([O:23][C:24]([C:26]1[CH:28]=[C:29]([CH3:31])[N:18]([C:16]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH3:20])=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:17]=2)[N:19]=1)=[O:25])[CH3:21]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Product: CCOC(=O)c1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (4-chloro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine and ethyl acetopyruvate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1)CCC.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[C:18]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCCC1
Reactant: COc1ccc(Br)cc1[N+](=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+]
Solvent: C1COCCO1
Product: COc1ccc(C2=CCCCC2)cc1[N+](=O)[O-]
Yield: 74 %

Procedure:
To a stirred solution of 2.1 g (0.0091 Mol) 4-bromo-2-nitroanisole in 50 ml dioxane were added 1.05 g (0.00091 Mol) tetrakis(triphenylphosphine)palladium, 4.03 g (0.011 Mol) tri-n-butyl-(1-cyclohex-1-enyl)-stannane and 18.3 ml 2 M aqueous Na2CO3 solution. The mixture was heated for 16 h at reflux and then poured onto water. After extraction with dichloro methane, drying of the combined organic phases over sodium sulfate and evaporation of the solvent the crude material was subjected to column chromatography (ethyl acetate/hexane 1:10) to yield 1.57 g of 4-cyclohex-1-enyl-1-methoxy-2-nitro-benzene as a yellow liquid. EI-MS m/e (%): 233 ([M]+, 100).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:22]=[N:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:18]=2)[CH2:12]1)(C(C)(C)C)(C)C>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:23]1([C:20]2[N:21]=[CH:22][C:17]([N:13]3[CH2:14][CH2:15][CH2:16][CH:11]([CH2:10][CH2:9][OH:8])[CH2:12]3)=[N:18][C:19]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC1CCCN(c2cnc(-c3ccccc3)c(-c3ccccc3)n2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCC1CCCN(c2cnc(-c3ccccc3)c(-c3ccccc3)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of 1.20 g of 3-[2-(tert-butyldimethylsilyloxy)ethyl]-1-(5,6-diphenylpyrazin-2-yl)piperidine in 6 ml of tetrahydrofuran, 5.0 ml of 1M tetra-n-butylammonium fluoride in tetrahydrofuran was added. After stirring at room temperature for 2 hours, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.77 g of the desired compound as a pale yellow amorphous.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:9]2[C:8](=[O:31])[NH:7][C:6]1=[O:32])[CH:2]([CH3:4])[CH3:3].Cl.Cl[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:9]2[C:8](=[O:31])[N:7]([CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[C:6]1=[O:32])[CH:2]([CH3:4])[CH3:3]
Reactant: ClCc1cccnc1
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)Cn1c(=O)n(Cc2cccnc2)c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21

Procedure:
This compound was synthesized by the reaction of 7-isobutyl-2-(1-naphthylmethyl)-3-pyridin-4-yl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 3-(chloromethyl)pyridine hydrochloride using DBU as a base. Mass: 516.86 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[CH:43][N:42]=[N:41]2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[CH:43][N:42]=[N:41]2)[CH:35]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J41) (460 mg, 1.27 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K23) (364 mg, 1.27 mmol) according to the general procedure M. Obtained as a light brown oil (480 mg, 69%).
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:26][CH2:27][CH3:28])=[N:15]2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1.C(O)C>[C].[Pd].O1CCCC1>[CH2:27]([O:26][C:16]1[C:17]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][N:14]([CH2:13][C:12]2[CH:29]=[CH:30][C:9]([OH:8])=[C:10]([O:31][CH3:32])[CH:11]=2)[N:15]=1)[CH3:28]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccccc3)c(OC)c2)nc1OCC
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(O)c(OC)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A mixture of ethyl 3-[1-(4-benzyloxy-3-methoxybenzyl)-3-ethoxy-1H-pyrazol-4-yl]propionate (2.92 g), 5% palladium-carbon (6.00 g), ethanol (20 ml), and tetrahydrofuran (20 ml) was stirred at room temperature for one hour under a hydrogen atmosphere. After removal of the catalyst by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-(4-hydroxy-3-methoxybenzyl)-1H-pyrazol-4-yl]propionate (2.04 g, yield: 89%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: CCCCC[C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/C=C\CCCC(O)=O)[C@@H](O)[CH2:11][C@H:10]1[OH:24].C(OC(Cl)=O)C(C)C>C(N(CC)CC)C>[OH:25][C:6]1[CH:7]=[CH:8][C:9]([C:10](=[O:24])[CH3:11])=[CH:13][CH:14]=1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(O)cc1

Procedure:
Following the procedure of Example 1 but using 0.738 g. of PGF2 α , 0.306 ml. of triethylamine, 0.288 ml. of isobutylchloroformate, and 0.299 g. of p-hydroxyacetophenone, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-water (99:1) followed by ethyl acetate-acetonitrile (1:1). The residue obtained by concentration of selected fractions, 0.589 g. is crystallized from ethyl acetate diluted with an equal volume of hexane as the title compound, white free-flowing crystals, m.p. 85.3°-86.5° C. having Rf 0.4 (TLC on silica gel in ethyl acetate-acetonitrile (4:1)).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:3]=12.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][CH:40]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc1)nn2[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.075 g, 0.17 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)benzoyl chloride (0.025 mL, 0.17 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 4 hours, yielding the benzamide derivative (ESI-MS m/z [M+H]+ found 568.5, calculated 568.6). Boc-deprotection was completed through the addition of formic acid (5 mL) and concentrated HCl (0.5 mL) added dropwise directly to the reaction mixture. The reaction mixture was left stirring for 12 hours and then was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD70. ESI-MS m/z [M+H]+ found 468.5, calculated 468.2.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:23][CH2:24][CH3:25])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>CO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]([CH2:24][CH3:25])[CH2:28][CH2:27][C:26]([O:30][CH3:31])=[O:29])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)OC
Reactant: CCNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Solvent: CO
Product: CCN(CCC(=O)OC)Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)ethanamine (250 mg, 0.64 mmol, 1 equiv) was dissolved in CH3OH (1 mL). Then methyl acrylate (4 mL, 44 mmol, 70 equiv) was added to the mixture and stirred at r.t. for 16 h. The reaction was concentrated and purified by prep-TLC to give the title compound as a white solid (217 mg, 52%), (mobile phase:EA/PE=1:8). ESI-MS (M+1)+: 426.3, HPLC: 97.34%. 1H NMR (400 MHz, CDCl3) δ: 7.71˜7.60 (m, 3H), 7.44˜7.38 (m, 1H), 7.16˜7.09 (m, 2H), 4.30˜4.20 (m, 1H), 3.69 (s, 2H), 3.64 (s, 3H), 2.85 (t, 2H), 2.65˜2.46 (m, 4H), 2.31˜2.24 (m, 2H), 1.92˜1.85 (m, 2H), 1.49˜1.37 (m, 2H), 1.30˜1.10 (m, 3H), 1.05 (t, 3H), 0.89 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][NH2:37])[CH:32]=[CH:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][NH:37][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: NCCc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Product: Fc1cccc(CCNc2nccc(-c3cccc(NC4CCNCC4)c3)n2)c1

Procedure:
Intermediate 7 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 393. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.2 (d, 1H) 6.95-7.6 (m, 8H) 6.9 (m, 1H) 4.95 (m, 1H) 3.6-4.0 (m, 3H) 3.4 (m, 3H) 3.15 (m, 2H) 3.0 (m, 2H) 2.25 (m, 2H) 1.7 (m, 2H).