Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([NH:15][CH2:16][C:17]2[C:25]3[C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=[N:21][C:20]=3[NH:19][CH:18]=2)([CH3:14])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:11]1([N:15]2[CH2:16][C:17]3=[CH:18][NH:19][C:20]4[C:25]3=[C:24]([CH:23]=[CH:22][N:21]=4)[C:26]2=[O:27])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC1(NCc2c[nH]c3nccc(C(=O)O)c23)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude 3-((1-(tert-butoxycarbonyl)-4-methylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid obtained in Example 4 was dissolved in DCM (3 mL) and TFA (1 mL) and allowed to stir at room temperature for 1 h. The solution was concentrated in vacuo and purified via preparative HPLC 5% to 20% B in A and gave 21 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 8.74 (s, 1H), 8.42 (m, 1H), 7.59 (m, 1H), 7.43 (m, 1H), 5.05 (s, 2H), 3.29-3.33 (m, 2H), 3.22-3.23 (m, 2H), 2.93-2.97 (m, 2H), 2.20-2.26 (m, 2H), 3.17 (s, 3H). [M+H] found 271.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC1(C)[O:28][C@H:27]([CH2:29][N:30]2[C:34]([CH3:35])=[C:33](B3OC(C)(C)C(C)(C)O3)[C:32]([CH3:45])=[N:31]2)[CH2:26][O:25]1.C([O-])([O-])=O.[K+].[K+].O.[ClH:54].CCOCC>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.O1CCOCC1>[Cl:22][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:33]3[C:32]([CH3:45])=[N:31][N:30]([CH2:29][C@@H:27]([OH:28])[CH2:26][OH:25])[C:34]=3[CH3:35])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12].[ClH:54]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(Br)cc12
Reactant: Cc1nn(C[C@@H]2COC(C)(C)O2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3c(C)nn(C[C@@H](O)CO)c3C)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (100.0 mg, 0.2606 mmol), 1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (175 mg, 0.521 mmol), Pd(PPh3)4 (15.1 mg, 0.0130 mmol), K2CO3 (108 mg, 0.782 mmol) and 4:1 dioxane:H2O (10 mL, 100 mmol) was heated to 95° C. for 5 h. After cooling to rt, 2 M of HCl in H2O (1.3 mL, 2.6 mmol) was added, and the mixture was heated to 40° C. for 2 h. The organic solvent was removed in vacuo, and the material was extracted with DCM and sat. NaHCO3. The organic layer was purified via column chromatography, eluting with 3-5% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo, redissolved in MeOH, and 2.0 M of HCl in Et2O (1 mL, 2 mmol) was added at rt. The solution was stirred for 30 min, and concentrated in vacuo to afford the title compound as an HCl salt. 1H NMR (400 MHz, CD3OD): δ=1.79 (d, J=7.1 Hz, 3H), 2.00-2.07 (m, 3H), 2.17 (s, 3H), 3.51-3.59 (m, 2H), 3.63 (br. s., 3H), 3.98-4.09 (m, 2H), 4.12-4.19 (m, 1H), 5.09 (q, J=6.8 Hz, 1H), 6.88 (dd, J=9.1, 4.3 Hz, 1H), 7.07 (t, J=8.8 Hz, 1H), 7.30 (s, 1H), 7.35 (d, J=1.3 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H). MS (ES+): m/z=473.07/475.06 (100/50) [MH+]. HPLC: tR=3.13 min (polar—5 min, ZQ3).
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:18])[C:6]([CH3:17])([CH3:16])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH2:9]([O:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]([OH:18])=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(C)(C)COCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(COCc1ccccc1)C(=O)O
Yield: 32 %

Procedure:
A solution of potassium hydroxide (1.8 g, 338 mmol) and 3-benzyloxy-2,2-dimethyl-propionic acid methyl ester in ethanol (50.0 mL) is refluxed for 24 h. The solvent is removed under reduced pressure, the crude is diluted with water and extracted with ethyl acetate. The water phase is acidified with 1N aq. HCl (pH ˜2-3) and extracted with ethyl acetate. The combined organic layers are washed with water and brine; the organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2.5 g of 3-benzyloxy-2,2-dimethyl-propionic acid as a brown solid that is used in the next step without any further purification. Yield: 32%, over two steps; m/z 209 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]23[CH2:14][CH:13]2[CH2:12][O:11]C(=O)[NH:9]3)[CH:7]=1.O.[OH-].[Li+]>C(O)C.O.[Cl-].[Na+].O>[NH2:9][C:8]1([C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:16])[CH2:14][CH:13]1[CH2:12][OH:11]
Reactant: O=C1NC2(c3cc(Br)ccc3F)CC2CO1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC1(c2cc(Br)ccc2F)CC1CO
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of (1SR,6RS)-1-(5-bromo-2-fluoro-phenyl)-4-oxa-2-aza-bicyclo[4.1.0]heptan-3-one (intermediate B7A) (1.48 g, 5.17 mmol) and lithium hydroxide monohydrate (LiOH.H2O) (2.17 g, 52 mmol) in ethanol (EtOH) (2.5 ml) and water (12.5 ml) was stirred at 100° C. for 16 h. Poured into ice water, added brine, extracted twice with tert-butyl methyl ether (TBME), washed organic layer with brine, dried over sodium sulfate. Removal of the solvent in vacuum left the title compound as a light brown oil (1.224 g, 91%), which was used without further purification. MS (ISP): m/z=242.2 [(M−NH2)+] and 244.2 [(M+2−NH2)+].
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][CH2:8][C:9]1[O:10][C:11]([SH:14])=[N:12][N:13]=1)=[O:5])C.Cl>>[C:4]([CH2:6][O:7][CH2:8][C:9]1[O:10][C:11]([SH:14])=[N:12][N:13]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)COCc1nnc(S)o1
Agent: Cl
Product: O=C(O)COCc1nnc(S)o1

Procedure:
A sample of the product of Example V was converted to the free acid by treatment with dilute hydrochloric acid in the usual manner. In this way, there was obtained pure 2-(carboxymethoxymethyl)-1,3,4-oxadiazole-5-thiol, m.p. 126°-129° C.
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].[CH:6]1([C:12](OC)=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C1C=CC=CC=1>[CH:6]1([C:12]([CH2:4][C:3]#[N:5])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C1CCCCC1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: N#CCC(=O)C1CCCCC1
Temperature: 25 °C

Procedure:
60% Sodium hydride (oil suspension) is added to benzene (90 ml) and the mixture is refluxed under heating. Acetonitrile (23 ml) dissolved in benzene (23 ml) is added and the mixture is refluxed for 1 hour. A solution of methyl cyclohexanecarboxylate (63 g) dissolved in benzene (70 ml) is dropwise added and the mixture is refluxed under heating for 5 hours. After the completion of the reaction, the mixture is cooled to room temperature and poured into ice water (200 ml). The organic layer is removed and the aqueous layer is washed with isopropyl ether. The aqueous layer is adjusted to pH 2 with conc. hydrochloric acid and extracted 3 times with isopropyl ether. The extract is dried over anhydrous magnesium sulfate and the solvent is distilled away under reduced pressure to give 34 g of cyanomethyl cyclohexyl ketone. The obtained cyanomethyl cyclohexyl ketone (34 g), morpholine (17.6 ml) and ethyl methyl ketone (18 ml) are dissolved in ethanol (150 ml) and sulfur (6.47 g) is suspended. The suspension is refluxed under heating for 10 hours. After the completion of the reaction, the solvent is distilled away under reduced pressure.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:24])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=3)[S:7][C:6]=2[C:22]=1[F:23].CCOCC.[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:1][C:2]1[C:3]([O:24][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:15]=3)[S:7][C:6]=2[C:22]=1[F:23]
Reactant: CCCCCCCBr
Reactant: CCCCCCc1ccc(-c2cc3cc(O)c(F)c(F)c3s2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: CCCCCCCOc1cc2cc(-c3ccc(CCCCCC)cc3)sc2c(F)c1F

Procedure:
is obtained by reacting 2,3-difluoro-4-ethoxythiophenol (obtainable analogously to Reference 7 from 2,3-difluoro-4-ethoxyaniline [189751-13-1]) and 4-hexylphenacyl bromide analogously to Reference 5 to give 6,7-difluoro-2-(4-hexylphenyl)-5-ethoxybenzo[b]thiophene, ether cleavage by means of hydrobromic acid/acetic acid to give 6,7-difluoro-2-(4-hexylphenyl)-5-hydroxybenzo[b]thiophene and Williamson ether synthesis using heptyl bromide in 2-butanone in the presence of potassium carbonate.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:5]=2[N:4]=[CH:3]1.C([Li])(C)(C)C.C1C(=O)N([I:25])C(=O)C1>O1CCCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:5]=2[N:4]=[C:3]1[I:25]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc2ncn(C)c2cc1C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc2nc(I)n(C)c2cc1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
In an oven dried nitrogen purged 3 neck 50 mL round bottom flask, 1.00 g (0.624 mmol) of 1,5,6-trimethylbenzimidazole in 2 mL of dry tetrahydrofuran is cooled to −78° C. 0.881 mL (1.498 mmol) of 1.7 M t-butyllithium in hexanes is added and the reaction mixture is stirred at −78° C. for 1 h. 0.154 g (0.686 mmol) of NIS in 2 mL of dry tetrahydrofuran is added. Reaction is removed from bath and stirred at room temperature for 1 hour, quenched with saturated aqueous solution of ammonium chloride, and diluted with dichloromethane. The layers are separated, the aqueous is extracted 3×25 mL dichloromethane, dried (MgSO4), and concentrated. The crude mixture is purified by chromatography using hexanes:ethyl acetate as a solvent system. The product containing fractions are combined to obtain 0.055 g of the title compound, 31% yield. MS, ES+=287.0 (M+1); 1H NMR (DMSO-d6) δ 7.337-7.324 (d, 2H); 3.684 (s, 3H); 2.309 (s, 3H); 2.275 (s, 3H) ppm.
Reaction SMILES: C(O)(C(F)(F)F)C(F)(F)F.[CH3:11][C@H:12]1[P:16]([C:17]2[C:22]([P:23]3[C@H:27]([CH3:28])[CH2:26][CH2:25][C@H:24]3[CH3:29])=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:15]([CH3:30])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[CH3:28][C@@H:27]1[P:23]([C:22]2[C:17]([P:16]3[C@@H:12]([CH3:11])[CH2:13][CH2:14][C@@H:15]3[CH3:30])=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@@H:24]([CH3:29])[CH2:25][CH2:26]1
Reactant: C[C@@H]1CC[C@@H](C)P1c1ccccc1P1[C@H](C)CC[C@H]1C
Solvent: ClC(Cl)Cl
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: C[C@H]1CC[C@H](C)P1c1ccccc1P1[C@@H](C)CC[C@@H]1C

Procedure:
Molar optical rotation: [Φ]D25 =-64.0° (c=3.26 mg/ml, CHCl3), [Φ]D25 =+7° (c=7.27 mg/ml (CF3)2CHOH). (R,R)-Me-DUPHOS Ligand: Molar optical rotation: [Φ]D25 =+65.0° (c= 3.26 mg/ml, CHCl3), [Φ]D25 =-7° (c=7.27 mg/ml, (CF3)2CHOH).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=3)[C:12](=[O:26])[CH:11]=2)=[N:6][CH:7]=1.[C:27]([O-])([O-])=O.[Na+].[Na+].CB(O)O>O1CCOCC1>[OH:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][N:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:27])=[CH:7][N:6]=3)=[CH:11][C:12]2=[O:26])=[CH:19][CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(OCc2ccc(Br)cn2)ccn1CCc1ccc(CO)cc1
Agent: CB(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(COc2ccn(CCc3ccc(CO)cc3)c(=O)c2)nc1

Procedure:
To 300 mg (0.72 mmol) 4-(5-bromo-pyridin-2-ylmethoxy)-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (example 12.1a) is added 25 mg (0.04 mmol) bis(triphenylphosphan)palladium(II)-chloride, 1.08 mL (2.17 mmol) 2 M aqueous Na2CO3-solution and a solution of 65 mg (1.08 mmol) methyl-boronic acid in 10 mL 1,4-dioxane/5 mL MeOH. The reaction mixture is refluxed for 48 h. The solvent is evaporated and the residue is dissolved in water/DCM. The layers are separated and the aqueous phase is extracted with DCM. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [Na].C[O-].[Na+].[ClH:5].[NH2:6][OH:7].[Cl-].[Na+].[NH2:10][C:11]1[CH:25]=[CH:24][C:14]([C:15]([NH:17][CH2:18][C:19](OCC)=[O:20])=[O:16])=[CH:13][CH:12]=1>CO>[ClH:5].[NH2:10][C:11]1[CH:25]=[CH:24][C:14]([C:15]([NH:17][CH2:18][C:19]([NH:6][OH:7])=[O:20])=[O:16])=[CH:13][CH:12]=1
Reactant: NO
Reactant: CCOC(=O)CNC(=O)c1ccc(N)cc1
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: Nc1ccc(C(=O)NCC(=O)NO)cc1
Yield: 72 %

Procedure:
5.75 g (0.25 gram atom) of sodium are added in small pieces to 150 ml of anhydrous methanol, and this cold solution of sodium methylate is then poured into a solution of 10.5 g (0.15 mol) of hydroxylamine hydrochloride in 100 ml of anhydrous methanol. The mixture is stirred for half an hour in the cold, the sodium chloride precipitate is filtered off and 22.2 g (0.1 mol) of ethyl 4-aminobenzamidoacetate are added to the filtrate; after leaving the reactants in contact overnight, the mixture is evaporated to dryness in vacuo, the residue is taken up in 100 ml of water and the hydrochloride is precipitated by adding 6 N HCl up to pH=1, and is filtered off and washed with 10 ml of cold water. CRL 40,473 is thus obtained by recrystallisation from a 4:1 (volume/volume) mixture of methanol and water. Melting point 182°-185° C. (with decomposition). Yield: 72%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([NH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)[CH2:7][CH2:8][CH3:9].C(Cl)(Cl)Cl.CN(C)[CH:27]=[O:28]>>[CH2:6]([N:10]([CH2:6][CH2:7][CH2:8][CH3:9])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([CH:27]=[O:28])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCNc1cc(OC)cc(OC)c1
Reactant: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCN(CCCC)c1cc(OC)c(C=O)c(OC)c1
Temperature: 7.5 °C
Yield: 80 %

Procedure:
In a stream of argon, to 30 ml of N,N-dimethylformamide was added 16.0 g (104 mmol) of phosphorus oxychloride under cooling at 5 to 10° C. and stirring. After the mixture was well-stirred, 23.5 g (80.1 mmol) of 4-butylamino-2,6-dimethoxybenzene dissolved in 10 ml of N,N-dimethylformamide was added dropwise. The mixture was reacted with stirring for 1.5 hours. After the mixture was poured into 70 ml of ice water, extraction with 200 ml of chloroform, washing with a saturated saline solution, drying over anhydrous magnesium sulfate, and concentration were performed. The residue was purified by silica gel chromatography to give 18.8 g (yield: 80%) of 4-dibutylamino-2,6-dimethoxybenzaldehyde as a dark purple crystal (mp: 55-56° C.)
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][O:11]C(Cl)Cl.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1ccc(CCBr)cc1
Reaction time: 0.17 h
Yield: 40.8 %

Procedure:
To a solution of (2-bromoethyl)benzene (100 mmol, 18.5 g) in methylene chloride (185 ml) at 0° C. was added dropwise titanium tetrachloride (200 mmol, 22 ml). The mixture was stirred for 10 minutes and alpha,alpha-dichloromethyl methyl ether (100 mmol, 9 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and poured into saturated NaHCO3 (1 liter). Ethyl acetate (750 ml) was added and the solution was filtered through diatomaceous earth, the organic layer separated, dried (Na2SO4) and solvent removed in vacuo. The residue was triturated with hexane to afford 8.7 g of title product; m.p. 49°-52° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:24]2[CH2:29][CH2:28][CH:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26][CH2:25]2)[CH:9]=1.[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].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.O>[CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:24]2[CH2:29][CH2:28][CH:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26][CH2:25]2)[CH:9]=1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(Cl)nc4)c3n2)CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To 10-20 mL microwave flask was added ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (Int-5m, 500 mg, 741 μmol), phenylboronic acid (181 mg, 1.48 mmol), K3PO4 (314 mg, 1.48 mmol), Pd(PPh3)4 (86 mg, 74 mol) and 3:1 1,4-dioxane:H2O (8 mL). The flask was flushed with argon and sealed. The reaction was stirred in a microwave at 150° C. for 30 minutes. After 30 minutes, the reaction was diluted with DCM and washed with H2O. The aqueous was extracted with DCM (x2) and the combined organic layers were dried over Na2SO4. The solvent was reduced in vacuo and the title compound was purified via silica gel chromatography.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([OH:5])=O.C([Li])[CH2:11][CH2:12][CH3:13].CCCCCC.C1(C(Cl)=O)CC1.Cl>C1COCC1.CCOCC.O>[CH:11]1([C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:12][CH2:13]1
Reactant: CCOC(=O)CC(=O)O
Reactant: [Li]CCCC
Agent: Cl
Agent: O=C(Cl)C1CC1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 23.8 g ethyl hydrogen malonate (180 mmoles) in 350 mL of dry THF, and cooled to -75° C. under nitrogen atmosphere, was added dropwise 145 mL of 2.5M n-butyllithium in hexane (363 mmoles), keeping the temperature below -55° C. The resultant suspension was warmed to ca. 0° C. and held at 0° to 10° C. for 20 minutes; it was then recooled to ←70° C. and cyclopropanecarbonyl chloride (10.0 mL, 11.5 g, 109 mmoles) was added dropwise. with stirring, maintaining the temperature below -60° C. It was then warmed to room temperature, diluted with 300 mL of ether, and carefully treated, with stirring, with 25 mL of concentrated hydrochloric acid in 200 mL of water. The phases were separated, the organic phase was washed once with water, and the aqueous phases were combined. The aqueous phases were extracted three times with ether, the ether phases combined, washed once with water, and combined with the original organic phase. Finally, the entire organic phase was washed once with saturated aqueous NaHCO3, dried over MgSO4, and the ether evaporated to give 14.9 g crude product. Distillation under reduced pressure gave 9.8 g final product, bp 88°-92° C./5 mm Hg. (Lit. 90°-95° C./4 mm Hg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:13][CH:12]([OH:14])[CH:11]([CH:15]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:16][CH:17]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:10]1)=[O:8].C(N(CC)CC)C.[CH3:47][C@@H:48]([C@@H:55]1[C@@:59]2([CH3:77])[CH2:60][CH2:61][CH:62]3[C@@:67]4([CH3:76])[CH2:68][CH2:69][CH:70]([O:72][C:73](Cl)=[O:74])[CH2:71][C:66]4=[CH:65][CH2:64][CH:63]3[CH:58]2[CH2:57][CH2:56]1)[CH2:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53].CO.C(Cl)(Cl)Cl>ClCCl>[CH3:47][CH:48]([CH:55]1[C:59]2([CH3:77])[CH:58]([CH:63]3[CH:62]([CH2:61][CH2:60]2)[C:67]2([CH3:76])[C:66]([CH2:71][CH:70]([O:72][C:73](=[O:74])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]4[CH2:13][CH:12]([OH:14])[CH:11]([CH:15]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[O:16][CH:17]([C:26]5[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=5)[C:18]5[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=5)[CH2:10]4)=[O:8])[CH2:69][CH2:68]2)=[CH:65][CH2:64]3)[CH2:57][CH2:56]1)[CH2:49][CH2:50][CH2:51][CH:52]([CH3:53])[CH3:54]
Reactant: COc1ccc(C(OC(c2ccccc2)C2CN(C(=O)CCCCCN)CC2O)c2ccc(OC)cc2)cc1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(OC(c2ccccc2)C2CN(C(=O)CCCCCNC(=O)OC3CCC4(C)C(=CCC5C4CCC4(C)C(C(C)CCCC(C)C)CCC54)C3)CC2O)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Referring to scheme 16, compound 65 (7.75 g, 14.5 mmol) was dissolved in anhydrous dichloromethane (50 mL) and cooled to 0° C. To the solution were added triethylamine (3 g, 4.2 mL, 30 mmol) and cholesteryl chloroformate (6.5 g, 29 mmol) successively. The reaction temperature was brought to ambient temperature and stirred further for 2 h. The completion of the reaction was ascertained by TLC (10% MeOH/CHCl3). The reaction mixture was evaporated under the vaccum to afford the crude product. Compound 66 (12.4 g, 88%) was obtained as a white foamy solid after column chromatography over silica gel using 3% MeOH/DCM.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1.[CH3:28][C:29]1([CH3:41])[CH2:33][C:32]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=2[O:30]1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:28][C:29]1([CH3:41])[CH2:33][C:32]2[CH:34]=[C:35]([N:4]3[C:5](=[O:27])[C:6]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:15][CH:14]=4)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]3[O:2][CH3:1])[CH:36]=[CH:37][C:31]=2[O:30]1
Reactant: CC1(C)Cc2cc(B(O)O)ccc2O1
Reactant: CCCc1nc(OC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1nc(OC)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 50.6 %

Procedure:
To a suspension of 4′-[(2-methoxy-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.6 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (2.78 g), triethylamine (5.0 mL), pyridine (2.9 mL) and molecular sieves 4 A (5.2 g) in dichloromethane (50 mL) was added copper(II) acetate (2.6 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.85 g, 51%).