Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:32]2[O:36][C:35]([Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])=[N:34][CH:33]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[O:36][C:35]([Si:37]([CH:41]([CH3:43])[CH3:42])([CH:44]([CH3:46])[CH3:45])[CH:38]([CH3:39])[CH3:40])=[N:34][CH:33]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[Si](c1ncc(-c2cc3cc(C4CCN(C(=O)OC(C)(C)C)CC4)oc3cn2)o1)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.20 g), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-triisopropylsilanyl-oxazole (0.35 g), 2 M aqueous Na2CO3 solution (0.8 mL), and N,N-dimethylformamide (3 mL) is sparged with argon for 10 min. PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (0.15 g) is added and the mixture is stirred at 80° C. overnight. The mixture is concentrated, diluted with water and methanol, and purified by HPLC on reversed phase (methanol/water) to give the title compound. LC (method 4): tR=2.07 min; Mass spectrum (ESI+): m/z=526 [m+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>C1(C)C(C)=CC=CC=1>[OH:15][CH2:14][CH2:13][N:12]([CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[CH3:11]
Reactant: CNCCO
Reactant: N#Cc1ccc(CBr)cc1
Solvent: Cc1ccccc1C
Product: CN(CCO)Cc1ccc(C#N)cc1
Reaction time: 7 h

Procedure:
A mixture of 4-bromomethylbenzonitrile (49.7 g), N-methylethanolamine (19.0 g) and xylene (100 ml) was boiled under reflux with stirring for 7 hours and then worked up as described in the previous example to give an oil which was distilled at 142°-146° C. at 0.5 mbar to give 4-[N-(2-hydroxyethyl)-N-methylaminomethyl]benzonitrile as an oil.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].[CH3:9][O:10][CH:11]([O:20][CH3:21])[CH:12]([CH:15](OC)OC)[C:13]#[N:14]>CO>[CH3:6][C:5]1[N:8]=[C:13]([NH2:14])[C:12]([CH:11]([O:20][CH3:21])[O:10][CH3:9])=[CH:15][N:7]=1
Reactant: CC(=N)N
Reactant: COC(OC)C(C#N)C(OC)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1cnc(C)nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
In the same reaction apparatus as in Example 9, there was placed 11.6 g (60 mmoles) of a 28 wt. % solution of sodium methylate in methanol. Thereto was added with stirring 5.67 g (60 mmoles) of acetamidine hydrochloride, and the mixture was stirred at room temperature for one hour. Subsequently, 9.45 g (50 mmoles) of 2-dimethoxymethyl-3,3-dimethoxypropanenitrile was added thereto and the mixture was heated and refluxed for 5 hours. After completion of the reaction, the reaction mixture was cooled and the insoluble sodium chloride was removed by filtration. The filtrate was analyzed by gas chromatography according to the internal standard method. As the result, it was confirmed that 8.51 g (yield: 93%) of 2-methyl-4-amino-5-dimethoxymethylpyrimidine had been formed.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:46][C:47]1[S:48][C:49]2[CH:55]=[C:54]([S:56]([CH3:59])(=[O:58])=[O:57])[CH:53]=[CH:52][C:50]=2[N:51]=1>C(Cl)Cl.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:46][C:47]2[S:48][C:49]3[CH:55]=[C:54]([S:56]([CH3:59])(=[O:58])=[O:57])[CH:53]=[CH:52][C:50]=3[N:51]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)c1ccc2nc(N)sc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc2nc(NC(=O)C(CC3CCCC3)c3ccc(Cl)c(Cl)c3)sc2c1
Yield: 80.4 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 1, 0.213 g, 0.74 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.434 g, 0.98 mmol), and 2-amino-6-methanesulfonylbenzothiazole (0.219 g, 0.96 mmol) in methylene chloride (15 mL) at 25° C. was treated with N,N-diisopropylethylene diluted with water (10 mL) and extracted with methylene chloride (3×10 mL). The combined organic layers were sequentially washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL) The combined organic layers were sequentially washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(6-methanesulfonyl-benzothiazol-2-yl)-propionamide (0.296 g, 80%) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([CH2:20][OH:21])=[CH:5][N:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([CH:20]=[O:21])=[CH:5][N:4]=1
Reactant: COc1ccc(CNc2nc(SC)ncc2CO)cc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(SC)ncc2C=O)cc1Cl
Temperature: 25 °C

Procedure:
To a suspension of 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-hydroxymethylpyrimidine (prepared in the above (1)) 25.10 g in chloroform 150 ml is a manganese dioxide powder 37.6 g (one and a half of the starting material) and the mixture is vigorously stirred at room temperature for a day. Further the mixture is treated with a manganese dioxide powder 12.6 g (a half of the starting material) and the mixture is stirred for three nights. The insoluble materials are filtered off with Celite and the filtrate is concentrated in vacuo. The residue is suspended in ethyl acetate-isopropyl ether. The precipitate is filtered and washed with isopropyl ether and hexane in order, to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine as colorless crystals, 22.43 g. mp 124-125° C.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.[Li].[C-]1C2C(=CC=CC=2)C=CC=1.[Li+].[CH3:23][N:24]1[C:33]2[C:28](=[CH:29][C:30]([O:34][C:35]3(SC4C=CC=CC=4)[CH2:37][CH2:36]3)=[CH:31][CH:32]=2)[CH2:27][CH2:26][C:25]1=[O:45]>C1COCC1.C(OCC)(=O)C.O>[CH:35]1([O:34][C:30]2[CH:29]=[C:28]3[C:33](=[CH:32][CH:31]=2)[N:24]([CH3:23])[C:25](=[O:45])[CH2:26][CH2:27]3)[CH2:36][CH2:37]1
Reactant: CN1C(=O)CCc2cc(OC3(Sc4ccccc4)CC3)ccc21
Agent: [Li+]
Agent: [Li]
Agent: [c-]1cccc2ccccc12
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)CCc2cc(OC3CC3)ccc21
Temperature: -78 °C
Reaction time: 0.28 h
Yield: 36.5 %

Procedure:
Naphthalene (1.0 g, 7.85 mmol) was dissolved in THF (7.5 ml) under nitrogen and freshly cut lithium metal (54 mg, 7.85 mmol) was added. The mixture was stirred at room temperature until a dark green solution of lithium naphthalenide was obtained. This solution was cooled to −78° C., then 1-Methyl-6-(1-phenylsulfanyl-cyclopropoxy)-3,4-dihydro-1H-quinolin-2-one (170 mg, 0.53 mmol) in THF was added over 1 minute. The reaction was stirred for 17 minutes and then water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extract was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using 30% ethylacetate/hexane to give the title compound (42 mg, 36% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=O)[CH2:14][CH2:15]C1SCCS1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:23](C)=[O:24]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH:23]=[O:24])[CH2:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCCOCc1ccccc1)CCC1SCCS1
Reactant: CC(C)=O
Product: CCC(C=O)CCCCOCc1ccccc1

Procedure:
0.135 mole = 44 g of 7-benzyloxy-1-(1,3-dithia-2-cyclopentyl)-heptane-3-one were heated for 1 hour under nitrogen and under reflux in 1 liter of acetone with [0.275 mole] = 47 g of CuCl2. 2 H2O and [0.57 mole] = 44 g of CuO, the copper salts were filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ether, washed twice with 2N- HCl and thrice with water, dried and the solvent was removed by distillation under reduced pressure. The residue was distilled under reduced pressure. B.p.0.5 mm 185°-192° C.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH2:12]1[CH:16]2[CH2:17][C@H:18](O)[CH:14]([CH2:15]2)[CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH:14]12[CH2:15][CH:16]([CH2:17][CH2:18]1)[CH2:12][CH:13]2[O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1]
Reactant: COc1ccc(C=O)cc1O
Reactant: O[C@H]1CC2CCC1C2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1OC1CC2CCC1C2
Temperature: 25 °C
Yield: 40.7 %

Procedure:
To a magnetically-stirred solution of isovanillin (10 mmol, 1.52 g) in dry tetrahydrofuran (15 mL) at -10° C. is added endo-norborneol (10 mmol, 1.12 g) followed by triphenylphosphine (14 mmol, 3.67 g). After a few minutes, a solution of diethylazodicarboxylate (14 mmol, 2.44 g; 2.22 mL) in dry tetrahydrofuran (5 mL) is added dropwise at -10° C. and the resulting solution is allowed to warm to room temperature over 20 hours. The solvent is removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase is dried (Na2SO4) and concentrated in vacuo to afford the crude product. This material is purified by flash chromatography (SiO2 : 20% ethyl acetate/hexane) to give the title compound as a colorless oil (4.07 mmol, 1.00 g; 41%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:9][CH:10]=1)=[O:4].[Li+].[OH-]>CO>[N:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1cnc(-c2ccncc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc(-c2ccncc2)nc1
Yield: 96 %

Procedure:
A solution of 2-pyridin-4-yl-pyrimidine-5-carboxylic acid methyl ester (1.11 g, 5.18 mmol), and aqueous LiOH (1 M, 5.18 mL) in MeOH (7.25 mL) is stirred at room temperature overnight. MeOH is removed in vacuo, and the aqueous solution is treated with 3 N HCl to adjust the pH to between 2 and 3. The solid is filtered off and washed with water and dried in vacuum to yield 2-pyridin-4-yl-pyrimidine-5-carboxylic acid (1 g, 96%) as a solid. MS: 202 (M+H).
Reaction SMILES: [C:1](OC1C=CC(C(C2C=CC(OC(=O)C=C)=CC=2)(C2C=CC(OC(=O)C=C)=CC=2)C)=CC=1)(=[O:4])[CH:2]=C.[C:36]1([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:43]=2[OH:54])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1(=O)OCCO1.[I-].[K+].CN(C)C=O>C(OCC)(=O)C>[C:48]1([C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:43]=2[O:54][CH:1]([OH:4])[CH3:2])[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: C=CC(=O)Oc1ccc(C(C)(c2ccc(OC(=O)C=C)cc2)c2ccc(OC(=O)C=C)cc2)cc1
Reactant: Oc1c(-c2ccccc2)cccc1-c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: O=C1OCCO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(O)Oc1c(-c2ccccc2)cccc1-c1ccccc1

Procedure:
To a 50 ml 1 neck round bottom was added 2,6-diphenylphenol (10 g, 1 eq), ethylene carbonate (3.9 g, 1.1 eq), potassium iodide (0.07 g, 0.01 eq), dimethylformamide (1 g, 0.3 eq) and heated to 150 C. After 4 hours the reaction was cooled to 40 C, added 30 ml ethyl acetate and washed 2 times with 20 ml sodium chloride brine, 3 times with 20 ml DI water and again with 20 ml brine. The ethyl acetate was dried with (1 g) magnesium sulfate, filtered and concentrated invacuo to recover an off-white solid. Mp 77-78
Reaction SMILES: O.[C@@H:2]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.[C:20](NC1C=CN([C@@H]2O[C@H](CO)[C@@H](O)C2)C(=O)N=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:20]([NH:15][C:14]1[C:13]2[N:12]=[CH:11][N:10]([C:19]=2[N:18]=[CH:17][N:16]=1)[C@@H:2]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: O=C(Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1)c1ccccc1
Solvent: O
Product: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1

Procedure:
This compound was prepared from 2'-deoxyadenosine monohydrate by the same procedure used for the preparation of N4 -benzoyl-2'-deoxycytidine.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][CH:5]=1.[Br:26]N1C(=O)CCC1=O.O>O1CCCC1>[Br:26][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Br)(CCCCCc1ccc(Cl)cc1)C(=O)OCC
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
8.1 g (0.186 mol) of 55% sodium hydride in a mineral oil suspension is added in portions to a solution of 63.4 g (0.186 mol) of ethyl 7-(4-chlorophenyl)-2-ethoxycarbonylheptanoate (BM 13.861) in 500 ml of absolute tetrahydrofuran, and stirred for another 15 minutes to complete the salt formation. Then 33.1 g (0.186 mol) of N-bromosuccinimide is added and the mixture is stirred for 8 h at room temperature. Then it is poured into water, acidified, and extracted with ether. The combined extracts are washed, dried and concentrated by evaporation. The concentrate is chromatograhied with toluene on silica gel. 61.3 g (78% of theory) of ethyl 2-bromo-7-(4-chlorophenyl)-2-ethoxycarbonylheptanoate, a colorless oil, is obtained.
Reaction SMILES: [OH-].[Na+].C1(C)C=CC=CC=1.[C:10]([C:14]1[CH:15]=[C:16]([CH:37]=[C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])[C:39]=1[OH:40])[C:17]([O:19][C:20]1[C:28]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][C:23]([C:24]([O-:26])=[O:25])=[CH:22][C:21]=1[C:33]([CH3:36])([CH3:35])[CH3:34])=[O:18])([CH3:13])([CH3:12])[CH3:11].[Na+].Cl>CCOCC>[C:41]([C:38]1[CH:37]=[C:16]([CH:15]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:39]=1[OH:40])[C:17]([O:19][C:20]1[C:21]([C:33]([CH3:34])([CH3:35])[CH3:36])=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][C:28]=1[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:18])([CH3:42])([CH3:43])[CH3:44]
Reactant: CC(C)(C)c1cc(C(=O)Oc2c(C(C)(C)C)cc(C(=O)[O-])cc2C(C)(C)C)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C(=O)Oc2c(C(C)(C)C)cc(C(=O)O)cc2C(C)(C)C)cc(C(C)(C)C)c1O
Temperature: 30 °C

Procedure:
450 ml of 2N sodium hydroxide were added to the toluene filtrate at room temperature and gradually heated to reflux. The reaction was heated at reflux for 41/2 hours. The reaction mixture was cooled to 0° to 5° C. by an ice-water bath whereupon a thick precipitate formed consisting of the intermediate sodium 4-(3,5-di-tert-butyl-4-hydroxybenzoyloxy)-3,5-di-tert-butylbenzoate. 70 ml of concentrated aqueous hydrochloric acid was gradually added dropwise with cooling at 30° C. 150 ml of ether was added with stirring to the reaction mixture at 20° to 25° C. The aqueous phase was separated and the organic phase washed with two 100 ml portions of water. The separated organic phase was then dried over anhydrous sodium sulfate. The residue was isolated from the organic phase by evaporation of the solvent initially at about 20 mm Hg. pressure and finally at 0.5 mm Hg.
Reaction SMILES: BrC[CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1C=CC=CC=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[Br:22]CCCC(C)(C)CO.O1C=CCCC1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:22][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([CH3:15])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CC(C)(CO)CCCBr
Reactant: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(CCCBr)COC1CCCCO1
Yield: 90 %

Procedure:
According to the procedure for the preparation of 207d, 206a (78.0 g, 0.40 mol) was reacted with 3,4-dihydro-2H-pyran (41.5 g, 0.49 mol) and p-toluenesulfonic acid hydrate (0.42 g, 2.2 mmol) in CH2Cl2 (0.5 L) to yield 207a (101.0 g, 90%) as a pale-yellow oil, which was used without further purification. 1H NMR (CDCl3): δ 4.55 (t, 1H, J=2.9), 3.83 (m, 1H), 3.51 (m, 1H), 3.47 (d, 1H, J=9.0), 3.38 (t, 2H, J=6.8), 2.98 (d, 1H, J=9.0), 1.94-1.75 (m, 2H), 1.75-1.44 (m, 6H), 1.40 (t, 2H, J=8.5), 0.91 (s, 3H), 0.90 (s, 3H). 13C NMR (CDCl3): δ 99.01, 76.17, 61.85, 37.89, 34.66, 34.04, 30.62, 27.92, 25.60, 24.64, 24.56, 19.41. HRMS (LSIMS, nba): Calcd for C12H24BrO2 (MH+): 279.0960. found: 279.0955.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:19][CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][NH:21]1>>[CH3:19][CH:20]1[NH:21][CH2:22][CH2:23][N:24]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:25]1
Reactant: Clc1ccc(OCCOc2nccnc2Cl)cc1
Reactant: CC1CNCCN1
Product: CC1CN(c2nccnc2OCCOc2ccc(Cl)cc2)CCN1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine*(150 mg, 0.53 mmol) and 2-methylpiperazine (256 mg, 2.56 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 143 mg (77%) of the title product. HRMS m/z calcd for C17H21CIN4O2(M)+348.1353, found 348.1370. Anal. (C17H21CIN4O2)C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1CCCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccccc1CCCBr
Reaction time: 15 h
Yield: 81.3 %

Procedure:
Compound 17-1 (2.00 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (3.58 g) and N-bromosuccinimide (2.40 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.24 g) as a pale-brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9]C2C=CC(F)=CC=2)=[CH:4][CH:3]=1.BrC1C=CC(F)=CC=1.C([Si](C)(C)C)#C>C(N(CC)CC)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)#[CH:9]
Reactant: Fc1ccc(C#Cc2ccc(F)cc2)cc1
Agent: C#C[Si](C)(C)C
Agent: Fc1ccc(Br)cc1
Solvent: CCN(CC)CC
Product: C#Cc1ccc(F)cc1
Temperature: 80 °C

Procedure:
Referring to FIG. 1, advantageous synthetic routes for the formation of both bis(4-fluorophenyl)ethyne (BFPE) and 4,4'-bis(4-fluorophenylethynyl)benzene (BFPEB) are shown in accordance with embodiments of the present invention. For example, in synthetic route `A1` of FIG. 1, BFPE is prepared by coupling commercially available 4-bromofluorobenzene with ethynyltrimethylsilane in the presence of an appropriate palladium[0] catalyst in triethylamine (TEA). A reaction vessel is charged with the reagents, catalyst and solvent and heated in an inert atmosphere to approximately 80° C. for about 2 h with stirring. The reaction mixture is cooled to about 50° C. and stirred for about an additional 2 h. Heating is stopped and the reaction mixture allowed to cool to ambient, with stirring continued for about an additional 24 h. An intermediate is obtained and desilylated with a weak base to form 1-ethynyl-4-fluorobenzene.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].[OH-].[Na+].Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Si:20]([O:19][CH2:18][CH2:17][CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:12])([F:13])[F:1])[C:10]#[N:11])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: N#CCc1ccccc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCC(C#N)c1ccccc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
(2-Trifluoromethylphenyl)acetonitrile (3 g) and tetrabutylammonium bisulfate (550 mg) were suspended in toluene (30 mL), and a 50% sodium hydroxide aqueous solution (15 mL) was added dropwise under ice-cooling. After stirring for 10 minutes, (2-bromoethoxy)-tert-butyldimethylsilane (5.2 mL) was added at the same temperature. The mixture was brought back to room temperature and stirred overnight. Water was added to the reaction solution, followed by extraction with tert-butyl methyl ether. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (5 g). The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([CH:15]=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:15][C:13]3[O:14][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:17])[F:18])=[CH:9][CH:8]=4)=[CH:11][CH:12]=3)[CH2:32][CH2:31]2)[CH:25]=1)=[O:22]
Reactant: O=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)o1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4ccc(OC(F)(F)F)cc4)o3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-[4-(trifluoromethoxy)phenyl]-2-furaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 487.1 (M+H)+.