Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[N:16]=[C:10]([C:6]1[N:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=1)[CH3:11]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1cc(C)c(N)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Yield: 31 %

Procedure:
10 g of 2,6-diacetylpyridine (0.0613 mol), 9.54 g of 2-chloro-4,6-dimethylaniline (0.0613 mol) and 0.6 g of p-toluenesulfonic acid were heated under reflux on a water separator in 400 ml of toluene for 90 min. The solvent was distilled off completely and the residue was recrystallized from 50 ml of isopropanol. 5.66 g (0.019 mol) of 1-{6-[1-(2-chloro-4,6-dimethyl-phenylimino)ethyl]pyridin-2-yl}ethanone were obtained in a yield of 31%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.Cl.[CH3:12]O>>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CO
Reactant: Nc1ccc(C(=O)O)cn1
Agent: Cl
Product: COC(=O)c1ccc(N)nc1
Temperature: 25 °C
Yield: 71 %

Procedure:
A mixture of 6-aminonicotinic acid (4.0 g, 28.9 mmol), methanol (75 mL), and concentrated hydrochloric acid (4 mL) was heated under reflux for 16 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The resulting solid was treated with water (20 mL) and enough sodium bicarbonate to adjust the pH=8. The solution was then extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 6-aminonicotinic acid methyl ester (3.12 g, 71%) as white foam: EI-HRMS m/e calcd for C7H8N2O2 (M+) 152.0586, found 152.0586.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[BH3-]C#N.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To 5-Bromo-1H-indole (2.5 g, 12.82 mmol) in acetic acid (10.0 mL), NaCNBH3 (2.38 g, 38.46 mmol) was added portion wise at 10° C. over the period of 20 min. After that the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated NaHCO3, water and brine solution. The combined ether layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound as a pale yellow semi-solid (1.8 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO.CCOCC>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: COc1cc(O)ccc1C(=O)O
Temperature: 40 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a solution of the methyl 2-methoxy-4-hydroxybenzoate (27 g, 147 mmol) from Step 3 above in MeOH (250 mL) was added 2N sodium hydroxide (147 mL, 2 eq) and the reaction was stirred for 5 hours at 40° C. The reaction was brought to pH 4 with the addition of 6N HCl and the solvent was reduced to one-third volume under reduced pressure. The aqueous mixture was extracted with methylene chloride (5×300 mL) and the combined organic phases were washed with water, brine, and dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure to give a solid which was suspended in ether and filtered. 2-Methoxy-4-hydroxybenzoic acid was obtained in 80% yield.
Reaction SMILES: [NH3:1].[Na].[S:3]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4]1.[Cl-].[NH4+].O1[CH2:16][CH2:15]CC1>>[NH2:9][C:8]([C:5]1[CH:6]=[CH:7][S:3][CH:4]=1)=[CH:15][C:16]#[N:1]
Reactant: C1CCOC1
Reactant: N#Cc1ccsc1
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Product: N#CC=C(N)c1ccsc1
Reaction time: 0.75 h

Procedure:
A 500 ml., three-necked flask is equipped with a mechanical stirrer, gas inlet, dry ice condenser, potassium hydroxide drying tube and addition funnel. A 100 ml. portion of ammonia is condensed into the flask and a pellet of sodium is added. When the dark blue color persists, ferric chloride is added discharging the color to brown. A 3.2 g. portion of sodium is added and the mixture is allowed to stand for 45 minutes. A 5.7 ml. portion of acetonitrie in 10 ml. of tetrahydrofuran is added and the reaction is stirred for 20 minutes. The reaction is cooled in a dry ice-acetone bath and 10.9 g. of 3-thiophenecarbonitrile in 25 ml. of tetrahydrofuran is added. The reaction is stirred in the cold bath for 90 minutes and then heated at reflux for 3 hours. A 7.4 g. portion of ammonium chloride is added and the mixture is allowed to evaporate overnight. A 100 ml. portion of water and 100 ml. of chloroform are added and the mixture is filtered. The aqueous phase is extracted with chloroform, the combined organic solution is washed once with water, dried over magnesium sulfate and filtered through Magnesol. The filtrate is evaporation in vacuo to an orange oil. A 30 ml. portion of benzene is added and then petroleum ether until the mixtur is cloudy. Cooling produces a precipitate which is collected and recrystallized from benzene giving the desired product as a solid, mp. 67°-69.5° C.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].N1C=CC=CC=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:5][CH2:1][CH2:2][C:3]#[CH:4])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: C#CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.7 %

Procedure:
To a mixture of 3-butyn-1-ol (0.5 g, 8.3 mmol) in CH2Cl2 (20 mL) and pyridine (1.7 mL, 33.2 mmol) was added p-toluenesulfonyl chloride (1.7 g, 8.7 mmol). This mixture was stirred at ambient temperature for 16 h then diluted with CH2Cl2 (20 mL) and quenched with aqueous 1% HCl (5 mL). The layers were separated and the organic layer was washed with aqueous 1% HCl (5 mL) and brine (5 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via column chromatography (4:1 hexanes:EtOAc) to provide the title compound (0.30 g, 1.3 mmol, 16% yield). MS (DCI/NH3) m/z 242 (M+NH4)+.
Reaction SMILES: O=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[NH2:15][OH:16].Cl>>[OH:16][N:15]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1
Reactant: NC(=O)NC1CCC(=O)c2sccc21
Reactant: NO
Agent: Cl
Product: NC(=O)NC1CCC(=NO)c2sccc21

Procedure:
Similarly, levorotatory 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea is reacted with NH2OH.HCl to afford optically active 4,5,6,7-tetrahydro-7-(hydroxyimino)benzo[b]thien-4-ylurea.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].[Cl:12]C(Cl)(Cl)C(Cl)(Cl)Cl.C([Li])CCC>>[Cl:12][C:8]1[CH:9]=[CH:10][N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CN(C)S(=O)(=O)n1cccn1
Agent: [Li]CCCC
Product: CN(C)S(=O)(=O)n1ccc(Cl)n1

Procedure:
US 20130288893(A1) describes, inter alia, certain (3-halo-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amides and carbamates and their use as pesticides. The route to prepare such compounds involved the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine by the direct coupling of 3-bromopyridine with 3-chloropyrazole. The 3-chloropyrazole was prepared by a) treating 1H-pyrazole with 2 dimethylsulfamoyl chloride and sodium hydride to provide N,N-dimethyl-1H-pyrazole-1-sulfonamide, b) treating the N,N-dimethyl-1H-pyrazole-1-sulfonamide with perchloroethane and n-butyl lithium to provide 3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide, and c) removing the N,N-dimethylsulfonamide from 3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide with trifluoroacetic acid to give the 3-chloropyrazole.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)Cl>[Br:19][CH2:20][C:21]([N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)=[O:22]
Reactant: O=C(Br)CBr
Reactant: CNc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)CBr)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 99 %

Procedure:
A mixture of 2.00 g (13.2 mmol) of N-methyl-4-nitroaniline and 1.46 g (14.5 mmol) of Et3N in 20 mL of CH2Cl2 at O° C. under N2 is treated with a solution of 5.33 g (26.4 mmol) of bromoacetyl bromide in 4 mL of CH2Cl2. After 3.5 h, the reaction is poured into ice water and extracted with CH2Cl2. The extract is treated with Darco, dried (MgSO4) and evaporated. The residue is filtered through Magnesol (CHCl3), evaporated and dried in vacuo to give 3.57 g (100%) of yellow solid. 1H NMR (DMSO-d6) δ 8.27 (d, 2H, J=7.47 Hz), 7.66 (d, 2H, J=7.47 Hz), 4.06 (s, 2H), 3.28 (s, 3H); MS (ESI) m/z 273.0 (M+1).
Reaction SMILES: [Cl-].[CH2:2]([P+:6]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][CH2:8][OH:9])[CH2:3][CH2:4][CH3:5].COC1C=CC(O)=CC=1.[C:27]([Cl:32])(=[O:31])[C:28]([CH3:30])=[CH2:29]>C(#N)C>[Cl-:32].[CH2:10]([P+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:7][CH2:8][O:9][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[CH2:11][CH2:12][CH3:13]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCC[P+](CCO)(CCCC)CCCC
Agent: COc1ccc(O)cc1
Agent: [Cl-]
Solvent: CC#N
Product: C=C(C)C(=O)OCC[P+](CCCC)(CCCC)CCCC
Reaction time: 2 h

Procedure:
Into a 1 L-four-necked flask equipped with a stirrer, a thermometer and a distillation line, was added the obtained tri-n-butyl(2-hydroxyethyl)phosphonium chloride dissolved in 500 ml of acetonitrile. The solution was heated under a normal pressure while stirring and about 200 ml of acetonitrile was distilled. A condenser having a calcium chloride tube was installed, 1.5 g of hydroquinone monomethyl ether was added as a polymerization inhibitor, and 76.3 g (0.730 mol) of methacryloyl chloride was added thereto dropwise at 50° C. over 2 hours through a dropping funnel, then the solution was maturated for 3 hours at the same temperature.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:19](Br)=[CH:18][C:17]([O:21][C:22](=[O:24])[CH3:23])=[CH:16][C:14]=3[N:15]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.CC1C=CC(C)=CC=1>C(OCC)C>[C:22]([O:21][C:17]1[CH:18]=[C:19]([CH:26]=[CH2:27])[C:13]2[O:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([F:25])[CH:7]=3)=[N:15][C:14]=2[CH:16]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Oc1cc(Br)c2oc(-c3ccc(OC(C)=O)c(F)c3)nc2c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccc(C)cc1
Solvent: CCOCC
Product: C=Cc1cc(OC(C)=O)cc2nc(-c3ccc(OC(C)=O)c(F)c3)oc12
Temperature: 130 °C
Reaction time: 5 h
Yield: 56.9 %

Procedure:
Dichlorobis(tri-o-tolyphosphine)palladium (II) (46 mg, 0.06 mmol) was added into a mixture 4-[5-(acetyloxy)-7-bromo-1,3-benzoxazol-2-yl]-2-fluorophenyl acetate (0.8 g, 1.98 mmol), tributyl(vinyl)tin (0.9 g, 2.8 mmol) and p-xylene (9 mL). The reaction mixture was stirred at 130° C. for 5 h, cooled to room temperature, diluted with ethyl ether (10 mL) and treated with activated carbon. The mixture was filtered through MgSO4 and concentrated. Purification by flash chromatography (hexanes/EtOAc 5/1) gave a white solid (0.4 g, 56% yield, m.p. 154–156° C.); MS m/e 356 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[OH-].[Na+].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>>[S:17]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Temperature: 70 °C
Yield: 98.3 %

Procedure:
To a solution of 7 g of L-proline in 120 ml of a 2N aqueous sodium hydroxide solution, there was added 11.8 g of p-toluenesulfonyl chloride and the mixture was heated to 70° C. for one hour with stirring. After the reaction solution was ice-cooled, it was acidified with hydrochloric acid and then extracted with ethyl acetate. The resulting organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated to give 16.1 g (yield 98.3%) of the title compound.
Reaction SMILES: O[C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C1OC1CO.B(F)(F)F.CCOCC.OCC(CO)O>CS(C)=O>[C:8]([OH:10])(=[O:9])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:12][CH:11]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: FB(F)F
Agent: OCC1CO1
Solvent: CS(C)=O
Solvent: OCC(O)CO
Solvent: CCOCC
Product: O=C(O)C=Cc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
8.719 g of p-hydroxy cinnamic acid was dissolved in 10 ml of DMSO, and 19.7 g of glycidol was added. The mixture was stirred and heated to 90° C. Catalystic amount of boron trifluoride ethyl ether was added, heating and agitation was carried out for 2 hours and then the adduct of cinnamic acid and glycerin was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][O:6]2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: OCCO
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(C2OCCO2)cc1Br
Reaction time: 4.5 h
Yield: 78.3 %

Procedure:
A mixture of 3-bromo-4-fluorobenzaldehyde (45.7 g), ethylene glycol (27.39 g), p-toluenesulphonic acid (0.225 g) and dry toluene (110 cm3) was heated at the reflux temperature under a Dean and Stark trap. After 4.5 hours, approximately 12 cm3 of water had collected in the trap, and analysis of the reaction mixture by gas liquid chromatography indicated that no starting aldehyde was present. The mixture was washed with sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave a yellow oil, which was purified by distillation under reduced pressure to give 2-(3-bromo-4-fluorophenyl)-1,3-dioxolane (43.56 g), boiling point 68°-106° C. at 0.04 mmHg.
Reaction SMILES: C([NH:8][C@H:9]([C:14]([NH:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:23](=[O:27])[O:24]2)=[CH:19][CH:18]=1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])(OC(C)(C)C)=O.[BrH:34]>C(O)(=O)C.C(O)C>[NH2:8][C@H:9]([C:14]([NH:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:23](=[O:27])[O:24]2)=[CH:19][CH:18]=1)=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13].[BrH:34]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2cc(-c3ccccc3)c(=O)oc2c1
Agent: Br
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)C[C@H](N)C(=O)Nc1ccc2cc(-c3ccccc3)c(=O)oc2c1
Reaction time: 0.17 h

Procedure:
The product of Example I, above, (175.1 mg, 0.39 mmol) was dissolved at room temperature in 2 mL of 32% hydrobromic acid in acetic acid. After 10 min., 40 mL of 2/1 ether/petroleum ether was added. The precipitated solid was separated and dried overnight at room temperature and 5 Pa to yield a glassy, orange foam which was twice dissolved in 1 mL of absolute ethanol and reprecipitated by addition of 30 mL of ether. After drying overnight at room temperature and 5 Pa, there remained 73 mg (44.5%) of white solid; TLC (SiO2 : 10% methanol in methylene chloride) Rf =0.63; mp=190.1°; NMR (CD3OD) δ(LeuCH3)=1.08 D (6), J=5 Hz, δ(LeuCH2) 1.86 D (2), δ(LeuCH)=4.0 M (1), δ(ArH)=7.7 M (9); IR (KBr) C=O=1700 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:21])[CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][CH:3]=1.O.NN>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:21])[CH2:9][NH2:10])=[CH:6][CH:7]=1
Reactant: C[C@H](CN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1
Agent: NN
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](CN)c1ccc(F)cc1
Temperature: 80 °C
Yield: 100.2 %

Procedure:
To a room-temperature solution of (S)-2-(2-(4-fluorophenyl)propyl)isoindoline-1,3-dione (900 mg, 3.2 mmol, 1.0 equiv) in toluene (14 mL) was added hydrazine hydrate (1.4 mL, 45 mmol, 14 equiv) by syringe. The resulting mixture was heated to 80° C. for 30 minutes and then cooled to room temperature. The resulting solution was decanted from the solid in the reaction mixture, and the solid was washed with additional toluene. The combined organic layers were combined and concentrated in vacuo to provide the title compound (491 mg, 99%), which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][CH:3]=1.[SH:18][CH2:19][CH2:20][OH:21].C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O.CCOCC>[OH:21][CH2:20][CH2:19][S:18][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1C
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: Cc1ccc(C(=O)c2ccc(SCCO)cc2)cc1C
Reaction time: 6 h

Procedure:
12.2 g (0.05 mol) of 4'-chloro-3,4-dimethylbenzophenone and 4.3 g (0.055 mol) of 2-mercaptoethanol in 50 ml of dimethylacetamide are warmed to 95° under nitrogen. 13.8 g (0.1 mol) of calcined K2CO3 are then added. The suspension is kept at 90°-100° C. for 6 hours. 100 ml of water are poured over the resulting reaction mixture and the product is taken up in ether. The ether layer is washed with water, dried over Na2SO4 and concentrated. The resulting crystals are recrystallised from methanol and dried in vacuo at 60° C. Yield: 10.1 g (71%). Melting point 92-93° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[Li+].[Cl-].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH2:15]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1)[CH:14]=[CH2:13]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc(C#N)c(F)c1

Procedure:
To a solution of 4-bromo-2-fluorobenzonitrile (5.0 g, 13 mmol) in 100 ml of toluene was added LiCl (1.7 g, 39 mmol), Pd(PPh3)4 (400 mg), Allyl tributyltin (5.2 g, 16 mmol), and then the mixture was heated to reflux overnight. After the reaction was completed, the reaction solution was diluted with EtOAc and filtered. The filtrate was concentrated and purified with silica gel column chromatograph to give crude 4-allyl-2-fluorobenzonitrile.
Reaction SMILES: O=[O+][O-].[O:4]=O.[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:15]([O:18][C:19](=[O:21])[CH3:20])[CH:16]=C)=[O:12])([CH3:9])([CH3:8])[CH3:7].O=O.S(C)C>C(Cl)CCl>[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@@H:15]([O:18][C:19](=[O:21])[CH3:20])[CH:16]=[O:4])=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: O=O
Reactant: C=C[C@H](OC(C)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=[O+][O-]
Solvent: ClCCCl
Solvent: CSC
Product: CC(=O)O[C@@H](C=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Ozone/oxygen was bubbled at -70° C. into a solution of (3S,4S)-N-[(tert-Butyloxy)carbonyl]-4-amino-3-acetoxy-5-phenylpentene (2.55 g, 8.0 mmol) [prepared by the method of Hanson et al, J. Org. Chem., 50, 5399 (1985)] in 100 mL of ethylene chloride until a deep blue color persisted. Oxygen was introduced until the blue color completely faded, then 3.0 mL of Me2S was added and the solution was allowed to arm to 0°-5° C. and stand overnight. The solvent was removed at 0° C. under vacuum yielding the title compound as a thick yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][F:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH2:35][F:36])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: FCCBr
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CCF)CC4)cn3)nc2n1C1CCCC1
Yield: 46.3 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.229 mmol) and 1-bromo-2-fluoroethane (88 mg, 0.687 mmol) gave 7-cyclopentyl-2-{5-[4-(2-fluoro-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (51 mg, 80%). MS(ESI) m/z 481.3 (M+H)+
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:9]1([OH:16])[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1.N1C=CN=C1>CN(C)C=O.O1CCCC1.[Cl-].[Na+].O>[C:4]([Si:1]([CH3:3])([CH3:2])[O:15][CH:12]1[CH2:13][CH2:14][CH:9]([OH:16])[CH2:10][CH2:11]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: OC1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCC(O)CC1
Yield: 65.6 %

Procedure:
A solution of tert-butyldimethylsilyl chloride (1.5 g, 9.9 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added, dropwise, at 0° C., to a solution of 1,4-cyclohexanediol (1.0 g, 8.6 mmol) and imidazole (1.5 g, 22.0 mmol) in anhydrous tetrahydrofuran (5 mL). After completion of the addition brine was added and the resulting mixture was extracted 3 times with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified on a silica gel plug (hexane/EtOAc, 80/20) to afford 1.3 g (66% yield) of 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanol as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](C#N)=[N:6][CH:7]=1.C[Mg]Br.[CH2:13]1[CH2:17][O:16]CC1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:17](=[O:16])[CH3:13])=[N:6][CH:7]=1
Reactant: C1CCOC1
Reactant: N#Cc1ncc(Br)cn1
Agent: C[Mg]Br
Product: CC(=O)c1ncc(Br)cn1
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
To a solution of 5-bromopyrimidine-2-carbonitrile (221 mg, 1.2 mmol) in THF (10 ml) was added methylmagnesium bromide (3.0 ml, 4.20 mmol, 1.4 molar, THF) at −78 CC under nitrogen. The solution was stirred at −78° C. for 3.5 hours, and then quenched with satd aq NH2Cl, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The reaction was purified by column chromatography on silica gel (petroleum ether: EtOAc=1:0 to 0:1) to afford 1-(5-bromopyrimidin-2-yl)ethanone (1.55 mg, 61.% yield). 1H NMR (CDCl3 500 MHz): δ 9.00 (s, 2H), 2.80 (s, 3H).