Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([NH:16][C:17]([NH2:19])=[N:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:5][CH:4]=[C:3]([C:20]([NH:22][C@@H:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:21])[CH:2]=1.[OH-].[Na+:33]>CCO>[CH:5]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([NH:16][C:17]([NH2:19])=[N:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:1][CH:2]=[C:3]([C:20]([NH:22][C@@H:23]([C:29]([O-:31])=[O:30])[CH2:24][CH2:25][C:26]([O-:28])=[O:27])=[O:21])[CH:4]=1.[Na+:33].[Na+:33]
Reactant: Nc1nc2[nH]cc(CCc3ccc(C(=O)N[C@H](CCC(=O)O)C(=O)O)cc3)c2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc2[nH]cc(CCc3ccc(C(=O)N[C@H](CCC(=O)[O-])C(=O)[O-])cc3)c2c(=O)[nH]1

Procedure:
A suspension of Pemetrexed in EtOH containing 0% to 2% water (v/v) was heated to reflux and 2.0 eq of aq. NaOH (30% w/w) were added within 1 min. The mixture was stirred at reflux for 16 h before the suspension was cooled to 20° C. to 30° C. The solid was isolated by filtration, washed with EtOH and dried in vacuo to constant weight to give Pemetrexed Disodium Form A.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].S([CH2:22][N+:23]#[C-:24])(C1C=CC(C)=CC=1)(=O)=O.CO>COCCOC>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[O:8][CH:24]=[N:23][CH:22]=2)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Solvent: COCCOC
Solvent: CO
Product: O=[N+]([O-])c1cccc(-c2cnco2)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
2.04 g (13.5 mmol, 1 eq.) of 3-nitrobenzaldehyde, 2.90 g (14.85 mmol, 1.1 eq.) of tosylmethyl isocyanide, 200 mL of MeOH and 200 mL of DME are introduced into a 1 L flask. 25 g of Amberlyst A26 OH— resin are added and the mixture is heated under reflux for 1 hour. The reaction medium is cooled to room temperature, then the resin is filtered over a frit and rinsed with methanol. After concentration to dryness, 2.56 g (yield=100%) of 5-(3-nitrophenyl)oxazole are obtained. The product is used without subsequent purification.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:11][CH:12]=1.Br[CH2:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]>CN(C=O)C>[Cl:26][C:24]1[CH:23]=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[C:20]([CH:25]=1)[CH2:19][N:11]1[CH:12]=[C:8]([CH3:7])[CH:9]=[C:10]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cc(C)c[nH]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)cn1Cc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 73.3 %

Procedure:
Under a nitrogen atmosphere with stirring add cesium carbonate (96 g, 295 mmoles) to a solution of ethyl 4-methyl-1H-pyrrole-2-carboxylate (30 g, 196 mmoles) in DMF (240 mL) and heat the reaction mixture to 40° C. to 45° C. for 1 hour. Cool the reaction mixture to room temperature and add a solution of 2-(bromomethyl)-4-chloro-1-nitro-benzene (54 g, 216 mmoles) in DMF (120 mL) drop-wise. Stir the resulting suspension for 1.5 h to 2.0 h, filter the solids and rinse the filtercake with DMF (45 mL). Transfer the solids to a clean reaction vessel, add water (200 mL) and cool the suspension to 10° C. to 15° C. with stirring for 1 h to 2 h. Filter the suspension, rinse with water (75 mL) and transfer the solids to another reaction vessel. Add ethanol (125 mL) and stir the suspension at 5° C. to 10° C. for 1 h to 2 h. Filter the solids, rinse the filtercake with ethanol (20 mL), and dry the solids in an oven at less than 50° C. under reduced pressure to give ethyl 1-(5-chloro-2-nitrobenzyl)-4-methyl-1H-pyrrole-2-carboxylate as a yellow solid (54 g, 94.1% purity, 73.3% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.C[Si]([C:18]#[N:19])(C)C>[Zn+2].[I-].[I-].CC#N>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:18]#[N:19])=[CH:8][CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc2c(c1)OCCC2=O
Agent: [I-]
Agent: [Zn+2]
Solvent: CC#N
Product: COc1ccc2c(c1)OCC=C2C#N

Procedure:
7-Methoxy-4-chromanone (7 g) was added to trimethylsilyl cyanide (TMSCN) (7 ml), CH3CN (10 ml) and a catalytic amount of ZnI2 and refluxed for 2 hrs. The reaction was cooled, evaporated to dryness, then isopropyl alcohol saturated with HCl(g) (100 ml) was added and this solution refluxed 2 hrs. The reaction was cooled, evaporated to dryness, and saturated aqueous NaCl added. This was then extracted with CH2Cl2, the organic layer separated, dried (Na2SO4), filtered and evaporated affording 7.1 g of product. IR(CHCl3): 2218 cm-1.
Reaction SMILES: [CH3:1][O-:2].[K+].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7](F)[CH:6]=1>O1CCCC1>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:2][CH3:1])[CH:6]=1
Reactant: C[O-]
Reactant: N#Cc1ccc(Br)cc1F
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
A suspension of potassium methoxide (4.24 g, 60.0 mmol) in tetrahydrofuran (40 mL) was added in portions to a solution of 4-Bromo-2-fluorobenzonitrile (8.0 g, 40.0 mmol) in tetrahydrofuran (50 mL) at −50° C. After one hour, the dry ice bath was removed and the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 6 hours. The reaction mixture was poured onto water (250 mL) and the solid was collected by filtration to give 4-bromo-2-methoxybenzonitrile (7.85 g, 92%). 1H NMR (DMSO-d6) δ 3.94 (s, 3H), 7.32 (d, J=8.23 Hz, 1H), 7.15 (s, 1H), 7.69 (d, J=8.23 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1occc(=O)c1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1occc(=O)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
3-Hydroxy-2-methyl-4-pyrone (25 g, 0.198 mol) was dissolved in 70 ml of DMF. To the solution was added 8.7 g (0.218 mol) of sodium hydride (60% in mineral oil). The mixture was stirred under ice cooling for 30 min. Benzyl bromide (37.3 g, 0.218 mol) was added dropwise to the reaction solution under ice cooling, and a reaction was allowed to proceed at room temperature overnight. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The organic layer was washed with water, and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The reddish brown oil thus obtained (64 g) was applied to column chromatography on silica gel (Wako Gel C-200, n-hexane-ethyl acetate) to give 41.6 g (yield 97%) of 3-benzyloxy-2-methyl-4-pyrone.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].O.Cl[CH2:12][C:13]([OH:15])=[O:14]>C(OCC)(=O)C>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(O)CCl
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(NCC(=O)O)cc1
Temperature: 100 °C

Procedure:
In a 500-ml three-necked flask, 4-cyanoaniline (100 g, 847.4 mmoles) was placed, followed by addition of 300 ml of water and attachment of a water cooling pipe, a mechanical stirrer and a dropping funnel. The flask was heated on an oil bath heated at 100° C. To the flask, an aqueous solution (water 150 ml) of monochloroacetic acid (104 g, 1116 mmoles) was added dropwise for about 30 minutes, followed by reflux with heating for 2.5 hours. After cooling naturally, about 100 ml of ethyl acetate was added to the flask to dissolve an insoluble matter. An organic layer was separated by a separatory funnel. The residual water layer and an aqueous layer obtained by extracting the organic layer with 100 ml of 5% (by weight) NaOH solution were combined, followed by acidolysis with 1/10N HCl. A precipitate produced was filtered and washed with water several times. After drying in an oven heated at 60° C. for 3 hours, the dried precipitate was dried in a vacuum desiccator overnight. The resulting product was a beige powder which showed no melting point but decomposed at 233.1° C. The yield was 38.8 g (26%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:27])=[O:26])[CH2:23][CH2:22]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Reactant: O=S(=O)(CCCCCCCl)NC1CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1)NC1CC1
Yield: 9 %

Procedure:
1-[(3-Chlorophenyl)phenylmethyl]piperazine (543.7 mg, 1.90 mmol) and N-cyclopropyl-6-chlorohexanesulfonamide (500 mg, 2.09 mmol) were refluxed in toluene (15 ml) for 4 hours in the presence of triethylamine (211 mg, 2.09 mmol). The reaction mixture was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (84.1 mg) as an oil (yield based on 1-[(3-chlorophenyl)phenylmethyl]piperazine: 9.0%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[C:16]1(=[O:20])[CH2:19][CH2:18][CH2:17]1>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:16]1([OH:20])[CH2:19][CH2:18][CH2:17]1
Reactant: Brc1cccnc1
Reactant: O=C1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1(c2ccncc2Br)CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.7 %

Procedure:
3-Bromopyridine (1 g, 6.3 mmol) was added in a dropwise fashion to a stirred, −78° C. solution of lithium diisopropylamide (1.8 M commercial solution; 3.7 mL, 6.7 mmol) in THF (16 mL). After 10 minutes, cyclobutanone (0.52 mL, 7.0 mmol) was added dropwise and stirring was continued for 1 hour at −78° C., prior to warming to ambient temperature. After stirring for a further 30 minutes, the reaction was quenched by addition of saturated aqueous NH4Cl (10 mL) and the mixture partitioned between EtOAc (100 mL) and water (100 mL). The organic fraction was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting crude product was purified by flash column chromatography on silica (eluent 50% EOAc/isohexane) to afford 1-(3-bromopyridin-4-yl)cyclobutanol as an off-white solid (412 mg). m/z (ES+) 228/230 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=O)=[CH:5][CH:4]=1.[Na].Cl.[C:15](#[N:17])[CH3:16]>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH2:16][C:15]#[N:17])=[O:9])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(OC)cc1
Reactant: CC#N
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C(=O)CC#N)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-methoxybenzoate (7.2 kg) in dimethyl sulfoxide (21.6 L) were added sodium methoide (3.046 kg) and acetonitrile (2.135 kg) and the mixture was stirred at 110° C. for 2 hours. Then, water (10.83 L) was added dropwise thereto at 15° C. or lower and further acetonitrile (14.4L) was added to the mixture. Then, 6 N HCl was added thereto to adjust to pH 7.9 and the mixture was extracted with ethyl acetate (72L). The aqueous layer was further extracted with ethyl acetate (36.32 L). The organic layers were combined and concentrated until the content became 17.39 kg. Methanol (17.84 L) was added thereto and water (17.84 L) was added dropwise. Then, the mixture was stirred at 5° C. for 1 hours and crystals deposited were filtered off and washed with methanol-water (1:1) to obtain the titled compound '6.40 kg, 82.7 g). 1H-NMR (CDCl3) δ:3.90 (3H, s), 4.03 (2H, s), 6.98 (2H, d, J=11.25 Hz), 7.50 (2H, d, J=11.25 Hz).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[O:10](C(C)=O)[C:11]([CH3:13])=O>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11](=[O:10])[CH3:13])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(F)ccc1N
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A mixture of 4-fluoro-2-methylaniline (20 g) and (CH3CO)2O (400 mL) was stirred at RT for 3 hours. The reaction mixture was subsequently poured into ice water (1000 mL), stirred for 10 minutes, filtered, and dried under vacuum to give the title compound (20 g, 74%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>C1COCC1>[O:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH2:13][CH2:12]1
Reactant: OC1CCOCC1
Reactant: N#Cc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(COC2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
Add sodium bis(trimethylsilyl)amide (2.8 mL, 5.61 mmol, 2M solution in THF) to a solution of tetrahydro-pyran-4-ol (572 mg, 5.61 mmol) in anhydrous THF (20 mL) and stir for 30 min. Add a solution of 4-bromomethyl-benzonitrile (1 g, 5.1 mmol) in anhydrous THF (5 mL) and stir the resulting mixture overnight at room temperature. Concentrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with cyclohexane/EtOAc (98:2 to 1:1 gradient) to obtain the desired intermediate as a white solid (845 mg, 76%). GC-MS m/z: 217 (M+);
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[C:13](O)(=[O:17])[C:14]([CH3:16])=[CH2:15]>O>[C:1]([C:5]1[CH:10]=[C:9]2[C:8]([CH2:15][CH:14]([CH3:16])[C:13]2=[O:17])=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(C)C(=O)O
Reactant: COc1ccccc1C(C)(C)C
Solvent: O
Product: COc1cc2c(cc1C(C)(C)C)C(=O)C(C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To Eaton's reagent obtained from 118 g of P4O10 and 600 ml of methanesulfonic acid a mixture of 70.3 g (0.428 mol) of 1-tert-butyl-2-methoxybenzene and 295.0 g (3.43 mol, 8 eqv.) of methacrylic acid was added for ca. 1 h at 50-55° C. The resulting mixture was stirred for 0.5 h at this temperature, then cooled to room temperature, and poured on a mixture of 1.5 liter of cold water and 2 kg of ice. After the ice melts, the precipitated crude 6-tert-butyl-5-methoxy-2-methylindan-1-one was filtered off and then washed with 2×100 ml of cold water. The crude product was dissolved in 500 ml of dichloromethane, and this solution was washed by aqueous K2CO3, dried over anhydrous K2CO3, and then evaporated on Rotavap. The residue was distilled in vacuum to give 70.6 g of crude 6-tert-butyl-5-methoxy-2-methylindan-1-one, b.p. 155-165° C./5 mm Hg. This product was dissolved in 200 ml of hot hexanes. Crystals precipitated from this solution at 5° C. were collected, washed by 50 ml of cold hexanes, and dried in vacuum. This procedure gave 64.1 g (65%) of the analytically pure substituted indanone.
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.[Br:12]Br.O>C(Cl)(Cl)Cl>[Br:12][C:4]1[C:5]([OH:6])=[C:7]([O:8][CH3:9])[CH:10]=[CH:11][C:3]=1[CH:2]=[O:1]
Reactant: COc1ccc(C=O)cc1O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(C=O)c(Br)c1O

Procedure:
Isovanillin (76.1 g, 0.5 m) was suspended in 750 ml of chloroform. Bromine (27.3 ml, 0.5 m) in 200 ml of chloroform was added at 0° slowly. Water was added to give the desired 2-bromo-3-hydroxy-4-methoxybenzaldehyde, m.p. 197°-203°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(Cl)Cl.[Cl:11][CH2:12][C:13](Cl)=[O:14]>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:13](=[O:14])[CH2:12][Cl:11]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccn1
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)Nc1ccccn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 9.42 g. (0.1 mole) of 2-aminopyridine in 50 ml. of methylene chloride was added dropwise 4.0 ml. (0.05 mole) of chloroacetyl chloride in 20 ml. of the same solvent, keeping the reaction temperature at -20° to -10° C. for one hour. After stirring at room temperature for 10 hours, 50 ml. of water was added and the organic layer separated. The organic solution was washed with water and a brine solution and was dried over magnesium sulfate. Removal of the solvent in vacuo gave 6.64 g. (78%), m.p. 114°-117° C., of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1(Br)[CH2:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: BrC1CCC1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CCC2)cc1
Temperature: 120 °C

Procedure:
The mixture of 2.50 g (14.5 mmol) of 4-bromophenol, 2.04 ml (21.7 mmol) of cyclobutyl bromide and 7.99 g (57.8 mmol) of K2CO3 in 25 ml DMF is stirred at 120° C. over night. The reaction mixture is extracted with water and EtOAc. The organic layer is dried, filtered and the solvent is removed in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[O:10]=[P:11](Cl)([Cl:13])[Cl:12]>CCOCC>[P:11]([Cl:13])([Cl:12])([O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(O)cc1
Solvent: CCOCC
Product: COc1ccc(OP(=O)(Cl)Cl)cc1

Procedure:
p-methoxyphenyl dichlorophosphate (11d) was prepared as described in Example 2 from p-methoxyphenol (4.00 g, 0.032 mol), POCl3 (3.00 mL, 0.032 mol) and TEA (4.49 mL, 0.032 mol) and dry Et2O (25 mL). The dichlorophosphate 11d was obtained as a yellow clear oil (5.1 g, 0.021 mol, 67%) and used without further purification.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6]O)[CH3:2].P(Br)(Br)[Br:16].O>ClCCl>[O:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Br:16])[CH3:2]
Reactant: COc1cc(CO)cc(OC)c1OC
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: COc1cc(CBr)cc(OC)c1OC
Yield: 86.7 %

Procedure:
Dissolving 3,4,5-trimethoxyl benzyl alcohol (14.05 g, 70.89 mmol) in dichlormethane (100 ml) in a 250 ml three-necked flask; phosphorus tribromide (6.73 ml, 70.89 mmol) in dichlormethane (25 ml) was added dropwise and allowed to react at room temperature for 50 minutes, cooling in ice bath, slowly adding deionized water (18 ml, 1.0 mol) dropwise to quench the reaction, washing with deionized water (100 ml) twice, drying with anhydrous magnesium sulfate, filtering, washing the filter residue with dichlormethane (20 ml), the combined organic layer was concentrated in rotatory evaporater to dry, and was further dried under vacuum to afford 3,4,5-trimethoxyl benzyl bromide (16.05 g of faint yellow solid), yield 84.44%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([O:14][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1 equiv.) in DMF is added TMSCl (1.5 equiv.) and triethylamine (1.5 equiv.) and the reaction solution is heated at 80° C. After 3 hrs the reaction is allowed to cool to RT and the DMF is removed in vacuo. The remaining residue is dissolved in CH2Cl2 and the solution is washed with 10% NaHCO3, dried over Na2SO4, and concentrated to afford the crude title compound. This is used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([OH:14])[C:10]([CH3:23])([CH3:22])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][C:10]2([CH3:22])[CH3:23])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNCCC1(O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.) solution of 4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (10.42 g, 30.7 mmol) in methylene chloride (300 mL) was slowly added trifluoroacetic acid (60 mL) over 1.25 hours. The resulting yellow solution was stirred at 0° C. for an additional 1.5 hours. The mixture was concentrated under reduced pressure and the residue dissolved in ethyl acetate (1.2 L), and washed with aqueous sodium hydroxide (1 N, 150 mL). The aqueous layer was extracted with additional ethyl acetate (200 mL) and the combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting solid residue was triturated with ether to afford 4-(4-Chloro-phenyl)-3,3-dimethyl-piperidin-4-ol as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]([CH3:15])[CH3:14].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:13]([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)c1nc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 94.5 %

Procedure:
A solution of 2,4-dichloro-quinazoline (102 g, 530 mmol) in THF (1.2 L) was cooled to 4° C. and 50% aqueous Me2NH (139 mL, 1.33 mol) was added. The mixture was stirred at ambient temperature for 80 min. The solution was alkalized with saturated aqueous NaHCO3 (pH=9), and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was suspended in 50% Et2O in hexane (250 mL) and stirred at ambient temperature for 30 min. The solid was collected by filtration, washed with 50% Et2O in hexane, and dried at 80° C. to give (2-chloro-quinazolin-4-yl)-dimethyl-amine (104 g, 94%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CN=C1.[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc(Br)cc1)(C(C)C)C(C)C
Yield: 97.9 %

Procedure:
To a solution of 4-bromophenol (17.3 g, 100 mmole) in dry DMF (100 mL) at RT was added imidazole (13.62 g, 200 mmole), followed by triisopropylsilyl chloride (22.5 mL, 105 mmole). After 4 hr the mixture was diluted with H2O (50 mL) and extracted with hexanes (3×75 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound (32.23 g, 100%) as a clear oil which was used without purification: 1H NMR (300 MHz, CDCl3) δ 7.29 (d, J=6 Hz, 2 H), 6.71 (d, J=6 Hz, 2 H), 1.22 (m, 3 H), 1.09 (m, 18 H).