Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:8]2=[O:23])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CCCCCC.C(Cl)(Cl)Cl>[O:23]=[C:8]1[C:9]([CH2:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: O=C1C(Cc2ccncc2)c2ccccc2N1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CCOC(=O)CC1(Cc2ccncc2)C(=O)N(N2CCOCC2)c2ccccc21

Procedure:
The product obtained from Example 20 could be reacted with sodium hydride and ethyl bromoacetate in a manner similar to Example 8 to render the product as a crystalline white solid, m.p. 168°-2/3° C. (hexane-chloroform). High Res. Mass Spec. Calcd. for C22H25N3O4 : 396.1923 (M+H). Found: 396.1922.
Reaction SMILES: [NH:1]([C:31]([O:33]C(C)(C)C)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1)=[O:20])[CH2:15][C:16](=[O:18])[OH:17])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH3:38]C(ON1C(=O)CCC1=O)=O.C([O-])(O)=O.[Na+].CN(C=O)C>C(O)(C(F)(F)F)=O.Cl>[NH:1]([C:31]([CH3:38])=[O:33])[C@H:2]([C:6]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1)=[O:20])[CH2:15][C:16](=[O:18])[OH:17])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)O)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)O)C(=O)Nc1ccc([N+](=O)[O-])cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-BOCValAlaAsp-p-nitroanilide (174 mg, 0.33 mmole) was dissolved in neat TFA (5 mL) and stirred at room temperature for 1 hour. The TFA was removed in vacuo and the residue was then dissolved in 5 mL of CH2Cl2 which was then evaporated in vacuo. This dissolution with CH2Cl2 and subsequent evaporation repeated two more times. The residue was dissolved in dioxane/water (5 mL, 4:1 ) and treated with acetic acid N-hydroxysuccinimide ester (63 mg, 0.40 mmole) and NaHCO3 (139 mg, 1.65 mmole). After 18 hours, the mixture was diluted with 1N HCl (25 mL) and extracted three times with ethyl acetate. The combined extracts were dried with MgSO4, filtered and concentrated to a yellow solid which was recrystallized from ethyl acetate/ethanol to give 33 mg (21%) of light yellow powder: mp 196°-200° C. (dec.); 1H NMR (DMSO-d6) δ 0.80 (d, J=6.6 Hz, 3H), 0.82 (d, J=5.1 Hz, 3H), 1.20 (d, J=7.2 Hz, 3H), 1.85 (s, 3H), 1.85-2.0 (m, 1H), 2.60 (dd, J=7.5, 16.6 Hz, 1H), 2.75 (dd, J=6.2, 16.6 Hz, 1H), 4.1-4.2 (m, 1H), 4.2-4.3 (m, 1H), 4.6-4.7 (m, 1H), 7.8-7.9 (m, 3H), 8.11 (d, J=6.8 Hz, 1H), 8.21 (d, J=9.3 Hz, 2H), 8.27 (d, J=7.2 Hz, 1H), 10.51 (s, 1H), 12.45 (br s, 1H); MS (LSIMS) m/e 488 (6, M+ +Na), 466 (23, M+ 1), 449 (7) 328 (15), 213 (44), 142 (100); [α]D20 -24.9° (c=1.0, DMF); Analysis calculated for C20H27N5O8 : C, 51.60; H, 5.85; N, 15.05; found: C, 50.16; H, 5.79; N, 14.06.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=3[O:23][CH3:24])=[N:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[SH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:35]([S:34][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=3[O:23][CH3:24])=[N:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1n[nH]c(=O)c2cc(Br)ccc12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1n[nH]c(=O)c2cc(SCc3ccccc3)ccc12
Temperature: 80 °C
Yield: 60.1 %

Procedure:
To a pressure tube containing a solution of 7-bromo-4-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazin-1(2H)-one (1.14 g, 2.86 mmol) and N,N-diisopropylethylamine (0.99 mL, 5.71 mmol) in 1,4-dioxane (20 mL) was added XantPhos (0.083 g, 0.143 mmol) and tris(dibenzylideneacetone) dipalladium (0) (0.065 g, 0.071 mmol) followed by (mercaptomethyl)benzene (0.352 mL, 3.00 mmol). The reaction tube was purged with nitrogen. The tube was sealed and heated at 80° C. for 30 min. After cooling to RT, the reaction was filtered over a pad of diatomaceous earth, rinsing well with EtOAc. The filtrate was concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (120 g), eluting with a gradient of 0% to 50% EtOAc in heptane, to provide 7-(benzylthio)-4-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazin-1(2H)-one (0.76 g, 60% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 3.77 (s, 3H), 4.44 (s, 2H), 7.15 (d, J=8.55 Hz, 1H), 7.21-7.28 (m, 1H), 7.32 (t, J=7.43 Hz, 2H), 7.40-7.50 (m, 4H), 7.57 (d, J=7.69 Hz, 1H), 7.72 (dd, J=8.60, 2.08 Hz, 1H), 8.11 (d, J=1.92 Hz, 1H), 12.85 (s, 1H). m/z (ESI) 443.0 (M+H)+.
Reaction SMILES: [CH3:1][Li].CC1C=CC(S(O[CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])(=O)=O)=CC=1>CCOCC.C(Cl)Cl.[Cu]I>[CH2:14]([C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[CH3:1]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Reactant: [Li]C
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCOCC
Product: CC[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To copper(I) iodide (1.25 g, 6.55 mmol) in Et2O (25 mL) was added methyllithium (8.2 mL, 13.1 mmol) at 0° C. A solution of phenylmethyl(2S)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarboxylate (0.85 g, 2.182 mmol) in CH2Cl2 (4 mL) was added next, and the reaction mixture was stirred for 2 hours at 0° C. The reaction was quenched with saturated aqueous NH4Cl, and extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% hexanes to 20% EtOAc/hexanes) afforded the title compound (230 mg, 45%) as a colorless oil. LC-MS (ES) m/z=234 [M+H]+.
Reaction SMILES: [N:1]1[C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](O)=[N:3][CH:2]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2ncccc12
Solvent: CCN(CC)CC
Product: Clc1ncnc2ncccc12
Yield: 16.7 %

Procedure:
A solution of pyrido[2,3-d]pyrimidin-4-ol (490 mg, 3.33 mMol), triethylamine (4.4 mL, 31.6 mMol), and phosphorous oxychloride (2.8 mL, 30 mMol) was heated at reflux for 2 hours. The mixture was concentrated in-vacuo, and the residue was stripped from methylene chloride (3×50 mL) to remove excess phosphorous oxychloride. The residue was dissolved in ethyl acetate (100 mL), saturated sodium bicarbonate (100 mL) was added carefully, causing vigorous gas evolution, and the mixture was stirred for ten minutes. The layers were separated, the organic phase was washed with saturated sodium bicarbonate (30 mL), water (30 mL), brine (30 mL), dried over sodium sulfate, then concentrated in-vacuo. The residue was purified over silica gel, eluting with 40% ethyl acetate/heptane, to yield 92 mg of a tan solid as product. MS (ES+)=166 (M+H)+. Yield=17%.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17](O)=[O:18].O=S(Cl)Cl.Cl.[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH2:29]>CCN(CC)CC>[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH:29][C:2]([C:3]1[C:17](=[O:18])[C:16]2[C:11]([C:4]=1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:1]
Reactant: COC(=O)CN
Reactant: O=C(O)C1=C(c2ccccc2)c2ccccc2C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COC(=O)CNC(=O)C1=C(c2ccccc2)c2ccccc2C1=O
Reaction time: 0.25 h
Yield: 101.4 %

Procedure:
A mixture of 1-oxo-3-phenyl-1H-indene-2-carboxylic acid (2.13 g, 8.5 mmol; can be obtained according to M. R. Barvian et al. in Bioorg. Med. Chem. Lett. 1997, 7, 2903-2908) and SOCl2 (17 ml) was refluxed with stirring for 15 min. Excess SOCl2 was then evaporated in vacuo. The residue was dissolved in anhydrous CH2Cl2 (20 ml), and subsequently the solution was concentrated in vacuo again to remove last traces of SOCl2. The residue was dissolved in anhydrous CH2Cl2 (20 ml). The solution was cooled with an ice bath before glycine methyl ester hydrochloride (1.27 g, 10 mmol) and subsequently NEt3 (3.52 ml, 25 mmol, dropwise addition) were added with stirring. The ice bath was then removed and stirring was continued at ambient temperature for 45 min before the mixture was concentrated in vacuo. To the residue was added water (10 ml) and aqueous 2N HCl (15 ml) and the mixture was extracted with ethyl acetate (×70 ml). The organic phase was dried over MgSO4 and evaporated in vacuo to give an orange solid (2.77 g). Purification by flash column chromatography on silica gel using hexanes:EtOAc 2:1 as the eluent gave the title compound as an orange solid (2.11 g); MS-(+)-ion: M+1=322.0.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:20]1([NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].P>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:27][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: COc1ccc2c(c1)CCc1cc(Cl)ccc1C2=O
Reactant: Nc1ccccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: P
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)CCc1cc(Nc3ccccc3N)ccc1C2=O
Yield: 35 %

Procedure:
In accordance with general method O, 0.48 g (1.8 mmol) of 2-chloro-8-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 1.05 g (9.7 mmol) of phenylenediamine, 0.04 g of Pd(OAc)2, 0.20 g of phosphine ligand and 1.65 g (17 mmol) of Na—O-tert-butylate are reacted in 10 ml of toluene and 2 ml of tert-BuOH. Purification is carried out by column chromatography (flash; SiO2; hexane 80%/ethyl acetate 20%). Yield: 35%; m.p.: 200° C.
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O>[F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
(+)-[2-Fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (1.00 g, 2.6 mmol, prepared in example 1a), 4-carboxybenzene boronic acid (627 mg, 3.8 mmol), potassium carbonate (520 mg, 3.8 mmol), tetrakis(triphenyl phosphine)palladium(0) (206 mg, 0.2 mmol) and dioxane/water (112 mL, 3:1) were mixed together in a 250 mL single neck flask and stirred at 80° C. for 4 hours. The reaction was cooled to room temperature and poured into 1N HCl and the desired product was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to yield 1.43 g as a dark oil. This material was purified via silica gel chromatography employing the chromatotron and using a 4000 micron rotor while eluting with a solvent of methylene chloride/methanol 9:1 to yield the title compound (355 mg, 36%) as a tan solid. Ion spray M.S. 378.3 (M*−1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][N:11]=1.[Cl:17]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:9][C:10]1[C:15]([F:16])=[C:14]([Cl:17])[CH:13]=[CH:12][N:11]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Fc1cccnc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1c(Cl)ccnc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of lithium diisopropylamide (2 M in heptane/THF/ethylbenzene, stabilised with 0.5% w/w LiBr; 3.8 ml, 7.6 mmol) and THF (3 ml) was cooled to −78° C. and a solution of 2-chloro-3-fluoropyridine (1.0 g, 7.6 mmol) in THF (2 ml) was added dropwise over 1 min. After 2 h, a solution of hexachloroethane (2.0 g, 8.4 mmol) in THF (3 ml) was added dropwise and stirring continued for 2 h before quenching with saturated aqueous NH4Cl solution (20 ml) and extraction of the reaction product with EtOAc (100 ml). The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. The crude material was purified by column chromatography (silica; 15% Et2O/isohexane) to afford 2,4-dichloro-3-fluoropyridine (795 mg, 63%): δH (400 MHz, CDCl3) 7.34 (1H, t, J 5.1), 8.13 (1H, d, J 5.1); m/z (ES+) 166 (100%, [MH]+).
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:10][NH:11][C:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20]I)[N:19]=1)=[O:13].[CH3:26][C:27]1[C:31]([S:32]([O-:34])=[O:33])=[C:30]([CH3:35])[O:29][N:28]=1.[Na+]>O>[Cl:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:10][NH:11][C:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][S:32]([C:31]2[C:27]([CH3:26])=[N:28][O:29][C:30]=2[CH3:35])(=[O:34])=[O:33])[N:19]=1)=[O:13]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CI)cs1
Reactant: Cc1noc(C)c1S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(C)c1S(=O)(=O)Cc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1

Procedure:
A DMF (0.30 mL) solution of Intermediate 6: 1-(3,4-dichlorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea (45 mg, 0.10 mmol) and sodium 3,5-dimethylisoxazole-4-sulfinate (56 mg, 0.2 mmol, ˜60% pure) was stirred for an hour. The mixture was diluted with water and extracted with EtOAc. The organics were washed with brine, dried and evaporated to a residue that was purified by chromatography (silica gel) to afford the title compound. 1H NMR (400 MHz, CDCl3): 9.80 (1H, br), 7.39 (m, 2H), 7.15 (dd, 1H), 6.77 (s, 1H), 4.42 (d, 2H), 4.37 (s, 2H), 2.37 (s, 3H), 2.22 (s, 3H). MS (ES+): M/Z 475 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].Cl[CH2:13][C:14]#[N:15]>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:13][C:14]#[N:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: N#CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCSc1ccc(Cl)c(Cl)c1

Procedure:
17.9 g (0.10 mol) of 3,4-dichlorobenzenethiol are mixed in the cold with a solution of 4.1 g of sodium hydroxide (about 0.1 mol) in 50 ml of water. The mixture is heated to 60°-70° C. and 7.5 ml (0.12 mol; 20% excess relative to the 3,4-dichlorobenzenethiol) of chloroacetonitrile are added dropwise. The whole is then heated under reflux for about 30 minutes and cooled, the oil which has formed is extracted with ether, the ether solution is washed with dilute sodium hydroxide solution and water, until the pH of the wash waters is neutral, and dried over SO4Mg, the SO4Mg is filtered off, the ether is evaporated off and the expected nitrile, which is in the form of a chromatographically pure oil, is collected.
Reaction SMILES: [CH2:1]=[C:2]1[C:7](=[CH2:8])[CH:6]2[O:9][CH:3]1[C:4](=[CH2:11])[C:5]2=[CH2:10].[CH:12]([C:14]([CH3:16])=[O:15])=[CH2:13].C1(C=CC(O)=CC=1)O>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[CH2:11]=[C:4]1[C:5](=[CH2:10])[CH:6]2[O:9][CH:3]1[C:2]1[CH2:1][CH2:13][CH:12]([C:14]([CH3:16])=[O:15])[CH2:8][C:7]=12
Reactant: C=CC(C)=O
Reactant: C=C1C(=C)C2OC1C(=C)C2=C
Agent: Oc1ccc(O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: C=C1C(=C)C2OC1C1=C2CC(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
A mixture of 11.4 g of 2,3,5,6-tetramethylene-7-oxabicyclo[2.2.1]heptane, 2 g of anhydrous zinc chloride, 30 ml of methyl vinyl ketone and 75 ml of chloroform, containing 10 mg of hydroquinone, was stirred at room temperature for 20 hours under nitrogen. The mixture was concentrated under reduced pressure (ca 15 mmHg, room temperature) and rapidly eluted with methylene chloride/ethyl acetate (2:1) on a short column filled with 18 g of SiO2 (70-230 mesh). The first fractions contained methyl (1,2,3,4,5,6,7,8-octahydro-2,3-dimethylene-1,4-epoxynaphthalene-6-yl) ketone and unreacted methyl vinyl ketone. After the addition of 5 mg of hydroquinone, the mixture was concentrated to dryness at room temperature under reduced pressure (1 mmHg) until the methyl vinyl ketone had been completely removed. There were obtained 14.5 g (86%) of methyl (1,2,3,4,5,6,7,8-octahydro-2,3-dimethylene-1,4-epoxynaphthalen-6-yl) ketone in sufficient purity for the next step.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH3:13].[CH2:14]([Mg]Br)[CH3:15]>O1CCCC1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:14]([C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH3:13])[CH3:15]
Reactant: CC[Mg]Br
Reactant: COc1cc(OC)c(C#N)nc1Br
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nc(C#N)c(OC)cc1OC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Impure 6-bromo-3,5-dimethoxy-pyridine-2-carbonitrile (462 mg; <1.9 mmol) was dissolved in tetrahydrofuran (20 mL) under nitrogen, and to the solution was added 1,3-bis(diphenylphosphino)propane nickel (II) chloride (105 mg; 0.19 mmol). The solution was cooled to 0° C., and a solution of ethyl magnesium bromide (1.0 molar in THF; 2.7 mL; 1.4 eq.) was slowly added. The reaction was stirred for five minutes, and quenched with saturated aqueous ammonium chloride (10 mL). To the reaction was added ethyl acetate (40 mL) and water (40 mL). The organic layer was isolated, dried over sodium sulfate, evaporated, and purified by column chromatography to give 6-ethyl-3,5-dimethoxy-pyridine-2-carbonitrile (114 mg; 0.6 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[N:12]=[C:13](Br)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1.C(OCC)(=O)C>CN(C=O)C>[Br:10][C:11]1[N:12]=[C:13]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: N#Cc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Nc2nc(Br)cn3ccnc23)cc1
Temperature: 140 °C

Procedure:
A mixture of 4-aminobenzonitrile (220 mg; 1.89 mmol) and 6,8-dibromo-imidazo[1,2-a]pyrazine (500 mg; 1.81 mmol) is slurried in DMF (1 mL) and heated to 140° C. for 20 minutes. The reaction is allowed to cool, and when the bath reaches 75° C., ethyl acetate (40 mL) is added and the slurry is stirred to break up large solid lumps into fine powder. The powdered 4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzonitrile is filtered, washed with diethyl ether (2×50 mL) and dried under vacuum to a fine orange/tan solid (600 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:6]=[C:5]([CH3:15])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CC(=O)CC.O>[CH3:15][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:10][CH:9]=2)[N:6]=1
Reactant: ClCCCN1CCCC1
Reactant: Cc1cc(CO)n(-c2ccc(O)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1cc(CO)n(-c2ccc(OCCCN3CCCC3)cc2)n1
Temperature: 80 °C
Yield: 62.4 %

Procedure:
To a solution of 4-(5-hydroxymethyl-3-methylpyrazol-1-yl)phenol (326 mg, 1.60 mmol) in 2-butanone (8 mL) was added potassium carbonate (243 mg, 1.76 mmol) and 1-(3-chloropropyl)pyrrolidine (260 mg, 1.76 mmol). The reaction was heated overnight at 80° C. After the reaction was diluted with water and extracted with methylene chloride, the organic layer was dried (MgSO4) and concentrated to give 315 mg of the desired product. LC-MS (C18H25N3O2 calculated 315) m/z 316 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][Si](CC(C)C)(C)C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH3:39][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:37][CH:38]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O)cc2)=CCC3(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-((2,2-dimethylethyl)-dimethylsiloxy)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound I) 50.0 mg (0.095 mmol) in 1.0 ml of THF at room temperature was added 73.2 mg (0.29 ml, 0.29 mmol) of tetrabutylamonium fluoride (1 M solution in THF). After stirring overnight, the solution was diluted with EtOAc and washed with H2O and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure, followed by column chromatography (4:1, Hexanes:EtOAc) afforded the title compound as a colorless solid. 1H NMR (CDCl3): δ 7.98 (2H, d, J=8.2 Hz), 7.52 (2H, d, J=8.3 Hz), 7.41-7.20 (5H, m), 6.88 (2H, d, J=8.4 Hz), 5.96 (1H, t, J=4.5 Hz), 4.37 (2H, q, J=7.1 Hz), 2.34 (2H, d, J=4.5 Hz), 1.39 (3H, t, J=7.1 Hz), 1.34 (6H, s).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[OH:2][CH2:3][C:5]1[C:10]([CH2:11][OH:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)c1cccnc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCc1cccnc1CO
Temperature: 20 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A solution prepared by dissolving 29.5 g, of 2,3-dimethoxycarbonylpyridine in 200 ml of ethylether was added dropwise to a solution prepared by suspending 10 g of lithium aluminum hydride in 300 ml of dried ethylether at 0° C. This mixed solution was stirred at 20° C. for 3 hours and 30 ml of water was slowly added thereto at 0° C. The resulting solution was stirred for 5 hours at the room temperature and solid was filtered through celite. The filtrate was evaporated under reduced pressure and then the residual product was purified by a silica gel column chromatography (chloroform : methanol (10:1)) to give 10.4 g of the above title compound (yield: 75%).