Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]Cl.[Cl:3][C:4]1[C:5]([C:12]([Cl:15])([Cl:14])[Cl:13])=[N:6][CH:7]=[C:8]([Cl:11])[C:9]=1[Cl:10]>>[Cl:3][C:4]1[C:5]([C:12]([Cl:15])([Cl:13])[Cl:14])=[N:6][C:7]([Cl:1])=[C:8]([Cl:11])[C:9]=1[Cl:10]
Reactant: Clc1cnc(C(Cl)(Cl)Cl)c(Cl)c1Cl
Reactant: ClCl
Product: Clc1nc(C(Cl)(Cl)Cl)c(Cl)c(Cl)c1Cl
Yield: 65 %

Procedure:
Summarizing Example 1, starting with fifty grams of a mixture rich in 3,4,5-trichloro-2-trichloromethyl pyridine, the analysis of which is set forth in Table One, and which contained 3% by weight ferric chloride, its chlorination with 70 grams per hour of chlorine, sparged into a 250 ml glass reactor at 200° C. for 5 hours, resulted in a product the analysis of which is set forth in Table One. As will be noted, a molar yield in excess of 65% of 3,4,5,6-tetrachloro-2-trichloromethyl pyridine based on 3,4,5-trichloro-2-trichloromethyl pyridine conversion was obtained.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11]C[C@H:9]2[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:27]1COCC1>>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:9]2[CH2:14][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:27]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([C@@H]1CCCCN1Cc1ccccc1)N1CCCC1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: c1ccc(CN2CCC[C@H]2CN2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
(2S)-1-(Phenylmethyl)-2-(1-pyrrolidinylcarbonyl)piperidine (901 mg, 3.307 mmol) was dissolved in 20 mL of THF, cooled to 0° C., and then LiAlH4 (251 mg, 6.615 mmol) was added portion wise. The mixture was heated to 80° C. for 2 h, then allowed to cool to RT. The reaction was quenched in succession with H2O (0.300 mL), 15% aq. NaOH (0.300 mL) and H2O (0.900 mL) and was stirred at room temperature overnight. The contents were filtered, and the filtrate was concentrated in vacuo to provide 1-{[(2S)-1-(phenylmethyl)-2-pyrrolidinyl]methyl}piperidine (710 mg, 83%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]Br)(=[O:3])[CH3:2].[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P:11]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCCCCOC(C)=O)OCC

Procedure:
100.34 g (0.48 mol) of 5-bromopentyl acetate were heated at 150° C. for 8 hours with 79.8 g (0.048 mol) of triethyl phosphite while stirring and passing in nitrogen. The mixture was then fractionally distilled under reduced pressure.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:36]=[CH:35][C:7]2[O:8][C:9]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH:20]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:10][O:11][C:6]=2[CH:5]=1.[CH3:37]I>CN(C)C=O>[CH3:37][O:3][C:4]1[CH:36]=[CH:35][C:7]2[O:8][C:9]([C:12]([N:14]3[CH2:15][CH2:16][N:17]([CH:20]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[CH2:18][CH2:19]3)=[O:13])=[CH:10][O:11][C:6]=2[CH:5]=1
Reactant: CI
Reactant: O=C(C1=COc2cc(O)ccc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC=C(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)O2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
Add 0.98 mmol of 60% sodium hydride suspended in oil to a solution of 0.82 mmol of 6-hydroxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin in 10 cm3 of N,N-dimethylformamide under a nitrogen atmosphere. Stir for 15 minutes at room temperature, then add dropwise 0.98 mmol of methyl iodide. Stir for 2 hours at room temperature and then concentrate to dryness under reduced pressure and purify the resulting crude product by chromatography on a silica column (eluant:petroleum ether/ethyl acetate, 50:50). 6-Methoxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin is thereby obtained in a yield of 83%.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13](=[O:16])([O-])[O-].[K+].[K+].[CH3:19]N(C=O)C>>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([I:1])[C:3]=1[O:12][CH2:19][CH2:13][OH:16])[CH:7]=[O:8]
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(C=O)cc(I)c1OCCO
Temperature: 40 °C
Yield: 57 %

Procedure:
5-Iodovanillin (25 g, 90 mmol) in DMF (100 mL) was added to potassium carbonate (18.6 g, 135 mmol). The mixture was heated at 40° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and quenched with water (500 mL) and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl solution, and dried over MgSO4, filtered and evaporated in vacuo to an oil, and then purified by column chromatography (silica, 2:1 hexane/ethyl acetate), to provide the product (16.6 g, 57%). 1H NMR (CDCl3) δ2.70 (t, 1H); 3.92 (t, 2H); 3.92 (s, 3H); 3.94 (s, 3H); 4.29 (t, 2H); 7.44 (s, 1H); 7.87 (s, 1H); 9.85 (s, 1H).
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+].C(OC([N:28]1[C:36]2[C:31](=[CH:32][C:33]([P:37]([O:41]C)([O:39][CH3:40])=[O:38])=[CH:34][CH:35]=2)[C:30](I)=[N:29]1)=O)(C)(C)C>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.CN(C)C=O>[CH3:40][O:39][P:37]([C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][CH:34]=1)[NH:28][N:29]=[C:30]2[C:9]1[NH:8][CH:12]=[CH:11][CH:10]=1)(=[O:38])[OH:41]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: COP(=O)(OC)c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C
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: CN(C)C=O
Product: COP(=O)(O)c1ccc2[nH]nc(-c3ccc[nH]3)c2c1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
44.8 mg (0.25 eq; 0.039 mmol) of tetrakis(triphenylphosphine)palladium(0), 65.3 mg (2 eq; 0.310 mmol) of 1-boc-pyrrole-2-boronic acid, 3 ml of dimethylformamide and 150 μl of saturated sodium bicarbonate solution are added to 70 mg (1 eq; 0.155 mmol) of 5-(dimethoxyphosphoryl)-3-iodo-indazole-1-carboxylic acid tert-butyl ester. The medium is stirred at 130° C. for 5 hours. The reaction medium is filtered through paper and the solvent is evaporated off under reduced pressure in a rotary evaporator. The reaction crude is purified by LC/MS to obtain 4.10 mg of ([3-(1H-pyrrol-2-yl)-1H-indazol-5-yl]-phosphonic acid monomethyl ester.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[CH:19]=[C:20]([O:26][CH3:27])[CH:21]=[C:22]([F:25])[C:23]=1[F:24]>>[NH2:15][C:7]1[C:6]([C:4]([C:19]2[C:20]([O:26][CH3:27])=[CH:21][C:22]([F:25])=[C:23]([F:24])[C:18]=2[F:17])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: COc1cc(F)c(F)c(F)c1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2c(OC)cc(F)c(F)c2F)c(N)n1

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 3,4,5-trifluoroanisole (Aldrich) in an analogous manner as described in Example 169.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH:4]([OH:13])[C:5]1[CH:10]=[CH:9][C:8](OC)=[CH:7][CH:6]=1.Br[C:19]1C=C(C)C=CC=1C=O.C1([Mg]Br)C=CC=CC=1>>[Br:1][C:2]1[CH:17]=[C:16]([CH3:19])[CH:15]=[CH:14][C:3]=1[CH:4]([OH:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccc(C=O)c(Br)c1
Reactant: COc1ccc(C(O)c2ccccc2Br)cc1
Agent: Br[Mg]c1ccccc1
Product: Cc1ccc(C(O)c2ccccc2)c(Br)c1

Procedure:
Friedel-Crafts acylation of m-bromoanisole with benzoyl chloride and p-fluorobenzoyl chloride provides 2-bromo-4-methoxybenzophenone, m.p. 83°-84°, and 2-bromo-4'-fluoro-4-methoxybenzophenone, m.p. 79°-81°, respectively, which are reduced with sodium borohydride to 2-bromo-4-methoxybenzhydrol, b.p. 160° (0.05 mm.), and 2-bromo-4'-fluoro-4-methoxybenzhydrol, a liquid. Acylation of benzene with 2-bromo-5-chlorobenzoyl chloride, 2-bromo-4,5-methylene dioxybenzoyl chloride, and 2-bromo-4,5-dimethoxybenzoyl chloride provides 2-bromo-5-chlorobenzophenone, 2-bromo-4,5-methylene-dioxybenzophenone, and 2-bromo-4,5-dimethoxybenzophenone, m.p. 76°-77°, which are reduced with sodium borohydride to 2-bromo-5-chlorobenzhydrol, 2-bromo-4,5-methylenedioxybenzhydrol, and 2-bromo-4,5dimethoxybenzhydrol, m.p. 83°-85°. Acylation of anisole with 2-bromobenzoyl chloride provides 2-bromo-4'-methoxybenzophenone, m.p. 93°-95°, which is reduced to 2-bromo-4'-methoxybenzhydrol, m.p. 64°-65°. Reaction of 2-bromo-4-methylbenzaldehyde and phenylmagnesium bromide provides 2-bromo-4-methylbenzhydrol.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:17]([C:19]1[C:24]([CH3:25])=[N:23][CH:22]=[C:21]([CH3:26])[N:20]=1)[NH2:18]>C(O)(=O)C>[CH3:25][C:24]1[C:19]([N:17]=[N:18][C:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[OH:16])=[N:20][C:21]([CH3:26])=[CH:22][N:23]=1
Reactant: Cc1cnc(C)c(NN)n1
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Solvent: CC(=O)O
Product: Cc1cnc(C)c(N=Nc2c(O)c3ccccc3c3ccccc23)n1
Temperature: 90 °C

Procedure:
Next, a reaction flask was loaded with acetic acid (80 ml) and 9,10-phenanthrenequinone (4.0 g), and heated up to 90° C. with stirring to dissolve 9,10-phenanthrenequinone. To the resultant, the crystals of 2-hydrazino-3,6-dimethylpyrazine (2.7 g) was added in 20 minutes. After stirring at 90 to 100° C. for two hours, the reaction mixture was cooled and filtrated. An aqueous solution of sodium hydroxide was added to the filtrate with stirring so that crystals precipitated. The crystals were filtrated and washed with methanol, followed by being recrystallized with dioxane-water. The crystals were then filtrated and dried to give intended crystals (3.3 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([Br:14])[C:12]=1[OH:13])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].S(Cl)(Cl)=O.[CH3:19]O>>[C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([Br:14])[C:12]=1[OH:13])[C:7]([O:9][CH3:19])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)cc(Br)c1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)c(O)c(C(C)=O)c1
Temperature: 80 °C
Yield: 42.7 %

Procedure:
To a stirred suspension of 3-acetyl-5-bromo-4-hydroxybenzoic acid (240 g, 926 mmol) in MeOH (2 L) was added dropwise sulfurous dichloride (68 mL, 926.5 mmol) under nitrogen and the mixture was heated at 80° C. for 3 h. The reaction mixture was cooled to room temperature concentrated, diluted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to afford a crude compound, which was purified on silica, eluting with 70% of DCM in petroleum ether. The solvents were evaporated to dryness to afford methyl 3-acetyl-5-bromo-4-hydroxybenzoate (108 g, 42.7%) as a white powder. Mass Spectrum: m/z [M−H]−=229.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13](=O)[C:14](=O)[CH3:15]>>[CH3:12][C:13]1[C:14]([CH3:15])=[N:11][C:6]2[C:7](=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: CC(=O)C(C)=O
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Product: Cc1nc2ccc([N+](=O)[O-])cc2nc1C

Procedure:
A stirred mixture of 4-nitro-o-phenylenediamine (Fairmont) (105 g, 0.69 mole) and 2,3-butanedione (Aldrich) (59 g, 0.69 mole) in 1.5 L of SDA-32 was heated at reflux for 4 hours. The reaction mixture was let stand at room temperature overnight. The crystallized intermediate was chilled and collected to give after ether wash 62.9 g (44.9%) of known solid. The intermediate was used without further purification in step B.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:14]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].Cl>CC1C=C(C)C=C(C)N=1>[CH2:34]([O:33][C:31]([O:12][CH2:11][C@H:9]1[O:10][C@@H:2]([O:1][C:13]2[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:14]=2[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=2)[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])=[O:32])[CH3:35]
Reactant: CCc1ccc(Cc2ccc(CO)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2cc(CO)ccc2Cc2ccc(CC)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 22.6 %

Procedure:
To a solution of 2-(4-ethylbenzyl)-5-hydroxymethylphenyl β-D-glucopyranoside (0.075 g) in 2,4,6-trimethypyridine (2 mL) was added ethyl chloroformate (0.037 mL, 2 mol equivalent), and the mixture was stirred at room temperature for 17 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid and water, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/-methanol=10/1) and recrystallized (recrystallization solvent: acetone/hexane=1/1) to give 2-(4-ethylbenzyl)-5-hydroxymethylphenyl 6-O-ethoxycarbonyl-β-D-glucopyranoside (0.020 g).
Reaction SMILES: C(C1C=CC(S[CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[CH:21]=3)[NH:16][C:15]([CH3:32])([CH3:31])[CH:14]=2)=CC=1)(C)(C)C.BrCC1[C:44]2[C:39](=[CH:40][CH:41]=[C:42](C3C=CC=CC=3OC)[CH:43]=2)[NH:38]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+].C(C1C=CC(C2C=CC=CC=2S)=CC=1)(C)(C)C>>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:32])([CH3:31])[CH:14]=[C:13]2[CH2:12][NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSc1ccc(C(C)(C)C)cc1)=CC(C)(C)N2
Agent: CC(C)(C)c1ccc(-c2ccccc2S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-(4-tert-Butylphenylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 60 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 25 μL of 4-tert-butylphenylthiophenol reacted to give 9 mg of the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[CH:5]=[CH:6][C:7]2=[O:12].[Br:14]Br.C(O)(=O)C.C(O)C>C(Cl)(Cl)Cl>[CH:10]1[CH:11]=[C:2]([OH:1])[C:3]2[C:4]([C:5]([Br:14])=[CH:6][C:7](=[O:12])[C:8]=2[CH:9]=1)=[O:13]
Reactant: BrBr
Reactant: O=C1C=CC(=O)c2c(O)cccc21
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C1C=C(Br)C(=O)c2c(O)cccc21
Yield: 80 %

Procedure:
To a solution of 5-hydroxynaphthalene-1,4-dione (171 mg, 1 mmol) in chloroform was added bromine, and the mixture was stirred. Then, to the resulting mixture were added acetic acid and ethanol, and the mixture was stirred under reflux to give 3-bromojuglone (80%). To the resulting 3-bromojuglone was added dimethylamine, and the mixture was stirred in toluene at room temperature to give 2-dimethylaminojuglone and 3-dimethylaminojuglone (85%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=1)[CH2:10][C:9]([CH3:20])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[C:26]([C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[C:35]([CH3:43])[CH:36]2[Si:39](Cl)([CH3:41])[CH3:40])=[C:32]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:31]=1[O:50][CH3:51])([CH3:29])([CH3:28])[CH3:27].O>CCOCC.C([Cu])#N>[C:26]([C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[C:35]([CH3:43])[CH:36]2[Si:39]([CH:8]2[C:7]3[C:11](=[C:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:13]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=3)[CH:10]=[C:9]2[CH3:20])([CH3:41])[CH3:40])=[C:32]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:31]=1[O:50][CH3:51])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC1=Cc2cc(C(C)(C)C)cc(-c3ccccc3)c2C1
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)C=C(C)C2[Si](C)(C)Cl
Agent: N#C[Cu]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)C=C(C)C2[Si](C)(C)C1C(C)=Cc2c(-c3ccccc3)cc(C(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a solution of 14.5 g (55.4 mmol) of 5-tert-butyl-2-methyl-7-phenyl-1H-indene in 400 ml of ether cooled to −78° C., 22.2 ml (55.5 mmol) of 2.5 M nBuLi in hexanes was added. This mixture was stirred overnight at room temperature, then cooled to −78° C., and 200 mg (2.23 mmol) of CuCN was added. The resulting mixture was stirred for 30 min at −20° C., then cooled to −78° C., and a solution of 21.2 g (55.4 mmol) of (6-tert-butyl-5-methoxy-2-methyl-4-phenyl-1H-inden-1-yl)(chloro)dimethylsilane in 200 ml of ether was added. This mixture was stirred overnight at room temperature, then 1 ml of water was added. The obtained mixture was passed through a short layer of silica gel 60 (40-63 um), the elute was evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-63 um; eluent: hexanes-dichloromethane=10:1, vol., then 3:1, vol.). This procedure gave 24.5 g (72%) of yellowish glassy solid.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:21]([Cl:22])=[CH:20][C:17]([CH2:18]O)=[CH:16][C:15]=3[Cl:23])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:24]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1>C(#N)C>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:21]([Cl:22])=[CH:20][C:17]([CH2:18][Br:24])=[CH:16][C:15]=3[Cl:23])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(CO)cc3Cl)cc12
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(CBr)cc3Cl)cc12

Procedure:
Analogously to the procedure of Example VII, 4.8 g (12.66 mmol) of benzyl alcohol derivative from Example XVII are reacted with 6.95 g (16.46 mmol) of dibromotriphenylphosphorane and 1.6 g (20.26 mmol) of pyridine in 80 ml of acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[C:4]([NH:10][CH3:11])[CH:3]=1.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:17]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]([NH:10][CH3:11])[CH:3]=1
Reactant: CNc1cc(Cl)ncc1C=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cnc(Cl)cc1NC

Procedure:
To a solution of 6-chloro-4-(methylamino)pyridine-3-carboxaldehyde (3.41 g, 20 mmol) in THF (120 mL) was added (carbethoxymethylene)triphenylphosphorane (8.35 g, 24 mmol). The mixture was heated at reflux for 16 h, and was then cooled and concentrated. The residue was chromatographed on silica gel (12% ethyl acetate in hexanes eluant) to provide the title compound. MS (m/z) 241.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([NH:19][CH2:20][C:21]#[CH:22])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>C(NC(C)C)(C)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]#[C:21][CH2:20][NH:19][C:9](=[O:10])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3][CH:4]=1
Reactant: C#CCNC(=O)OCc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: O=C(NCC#Cc1ccc(Br)cn1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A mixture of 2,5-dibromopyridine (1.19 g), N-Cbz-propargylamine (1.04 g), Pd(PPh3)2Cl2 (73 mg), and CuI (10 mg) in diisopropylamine (20 mL) was stirred at ambient temperature for 3 hours under nitrogen. The mixture was diluted with ethyl acetate (50 mL). The mixture was filtered and washed with ethyl acetate (20 mL). The filtrate and wash were combined, concentrated under reduced pressure and triturated in MTBE to give crystalline 7-1 (1.28 g). The mother liquor was further purified by silica gel column chromatography using a mixture of MTBE: hexanes (1:1) to give an additional 280 mg of 7-1.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:10]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:15][C:11]=2[N:12]=[CH:13][N:14]=1)C.Cl.O>CC(C)=O>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]2[C:10]3[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH:4]=[O:3])=[N:14][CH:13]=[N:12][C:11]=3[O:15][C:16]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:23][CH:22]=1
Reactant: CCOC(CCCNc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12)OCC
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCC=O)c23)cc1
Reaction time: 1 h

Procedure:
Dissolve 640 mg (1.39 mmol) N-(4,4-diethoxybutyl)-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine-4-amine in 5 ml acetone and, at RT, add 1 ml 1 N hydrochloric acid. After 1 h, add the reaction mixture to water and extract three times with dichloromethane. Combine the organic phases and wash with buffer solution (pH 7) and saturated sodium chloride solution, dry over magnesium sulphate and concentrate under vacuum. Purify the raw product by chromatography on silica gel (solvent: dichloromethane/ethyl acetate 2:1). 191 mg (35.6% of theor.) of the target compound is obtained.
Reaction SMILES: O1CCCC1.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C([Li])CCC.[F:17][C:18]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=1[CH:20]=[O:21]>CCCCCC>[F:17][C:18]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=1[CH:20]([OH:21])[C:7]1[S:8][CH:9]=[CH:10][N:11]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1nccs1)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a tetrahydrofuran (10 ml) solution of 2-bromothiazole (180 μg, 2 mmol) was added dropwise a hexane solution of n-butyl lithium (1.57M, 1.40 ml, 2.2 mmol) at −78° C. After stirring for 10 minutes, 2,5-difluorobenzaldehyde (238 μl, 2.2 mmol) was added and while stirring, the temperature of the mixture was gradually raised to 0° C. The reaction was then quenched by the addition of an aqueous solution of ammonium chloride, followed by the addition of ether. The ether layer was washed with water and brine, and then, dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1), whereby the title compound (358 mg, 79%) was obtained as an oil.