Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:8]1[NH:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][C:12]([Cl:19])=[CH:13][CH:14]=2)[N:9]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[C:20]([NH:27][CH2:28][CH2:29][CH2:30][NH2:31])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].O.C(OCC)(=O)C>CN(C)C=O>[Cl:19][C:12]1[CH:11]=[C:10]2[C:15]([C:16](=[O:18])[NH:17][C:8]([CH:2]([NH:31][CH2:30][CH2:29][CH2:28][NH:27][C:20](=[O:21])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])=[N:9]2)=[CH:14][CH:13]=1
Reactant: CN(C)C(=O)C(Br)c1nc2cc(Cl)ccc2c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(NCCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)[nH]1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a solution of 2-bromo-2-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide (950 mg, 1 eq.) in N,N-dimethylformamide (10 ml), was added N-Boc-1,3-diaminopropane (2.4 g, 5 eq.). The reaction was stirred at 60° C. for 30 minutes. Water and ethyl acetate was added. Ethyl acetate layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated to give tert-butyl 3-{[1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]amino}propylcarbamate (1.2 g) as a pale orange solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[Br:8][C:9]1[CH:10]=[N:11][C:12](Cl)=[N:13][CH:14]=1>C1COCC1.O>[Br:8][C:9]1[CH:10]=[N:11][C:12]([O:7][CH2:6][CH:3]2[CH2:5][CH2:4]2)=[N:13][CH:14]=1
Reactant: OCC1CC1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cnc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 94.7 %

Procedure:
A suspension of 607.92 mg (15.20 mmol) of sodium hydride in 50 mL of THF is prepared under argon. A solution of 1.10 g (15.20 mmol) of cyclopropanemethanol in 5 mL of THF is added dropwise. The mixture is stirred for 50 minutes at room temperature. 1 g (5.07 mmol) of 5-bromo-2-chloropyrimidine in 5 mL of THF is then added. The mixture is stirred at room temperature overnight. The reaction mixture is taken up in water and extracted with ethyl acetate. The organic phase is washed with aqueous NaHCO3 solution and with saturated aqueous NaCl solution, dried and evaporated to dryness to give 1.10 g of 5-bromo-2-cyclopropylmethoxypyrimidine, corresponding to the following characteristics:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[S:14][C:13]=1[C:23]([O:25]CC)=[O:24].CO.O1CCCC1.O.[OH-].[Li+]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)[S:14][C:13]=1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1sc(-c2ccncc2)cc1Cc1ccc2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc(-c2ccncc2)cc1Cc1ccc2ccccc2c1

Procedure:
Ethyl 3-(2-naphthylmethyl)-5-pyridin-4-ylthiophene-2-carboxylate (80.0 mg, 0.214 mmol) was placed in a round bottomed flask equipped with a stirbar. Methanol (3 mL, 70 mmol) and tetrahydrofuran (3 mL, 40 mmol) were added followed by water (2 mL, 100 mmol). The resulting solution was stirred and lithium hydroxide in water (1.0 M, 0.643 mL, 0.643 mmol) was added. The flask was sealed and stirred overnight at RT. LCMS of an aliquot indicated that all starting material had been consumed to give a single product with the correct mass for the desired product. To the stirring reaction was added ˜30 mL water and a few mL saline. The mixture was stirred and acidified to ˜pH 1 with 1N HCl—a gelatinous precipitate formed. The mixture was stirred rapidly and diethyl ether (10 mL) was added—the precipitate became more granular and became suspended mostly in the organic layer. The quench mixture was stirred at room temperature for ˜30 minutes then the solid was collected on a fritted funnel, washed well with water then diethyl ether, then dried in vacuo to yield product 60 mg (81% yield) as a white powder. LC/MS (FA) ES+ 346. 1H NMR (400 MHz, DMSO) δ 13.62-13.20 (s, 1H), 8.63-8.52 (dd, J=4.7, 1.5 Hz, 2H), 7.91-7.80 (m, 3H), 7.80-7.72 (d, J=3.0 Hz, 2H), 7.70-7.63 (dd, J=4.6, 1.5 Hz, 2H), 7.53-7.40 (m, 3H), 4.57-4.48 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-])=O.C(O)(C)C.[Cl-].[NH4+]>[Fe].O>[NH2:10][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1cc(CO)ccc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: Nc1cc(CO)ccc1F

Procedure:
A flask equipped with overhead stirrer was charged with 4-fluoro-3-nitrobenzyl alcohol (20 g, 0.117 mol) and 200 mL of 5:1 isopropanol:water. Ammonium chloride (62 g, 1.17 mol) was added followed by iron filings (65 g, 1.17 mol). The mixture was stirred at 70 C for 1.5H when it was shown to be complete by LC-MS. The liquid was decanted and the solids were washed with additional isopropanol: water. The isopropanol was removed and the residue was diluted with 0.5 N HCl and was extracted with ethyl acetate. The aqueous layer was brought to pH 12-14 with 2.5 N NaOH and was extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4 and concentrated in vacuo. 3-Amino-4-fluorophenyl methanol was isolated as a brown solid (4.5 g, 27%) and was used without further purification. LC/MS, tr=2.40 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 142 (M+H). ES-HRMS m/z 142.0692 (M+H calcd for C7H8FNO requires 142.0663).
Reaction SMILES: C(N(CC)C(S[CH:7]([CH3:17])[C:8]([NH:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])=[O:9])=S)C.[CH3:20][C:21]1([CH3:30])[N:26]([O])[C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23][CH2:22]1.C(OCC)(=[O:33])C>>[CH3:16][C:11]([NH:10][C:8](=[O:9])[CH:7]([O:33][N:26]1[C:21]([CH3:30])([CH3:20])[CH2:22][CH2:23][CH2:24][C:25]1([CH3:29])[CH3:28])[CH3:17])([CH3:15])[C:12]([OH:14])=[O:13]
Reactant: CC1(C)CCCC(C)(C)N1[O]
Reactant: CCOC(C)=O
Reactant: CCN(CC)C(=S)SC(C)C(=O)NC(C)(C)C(=O)O
Product: CC(ON1C(C)(C)CCCC1(C)C)C(=O)NC(C)(C)C(=O)O
Yield: 42 %

Procedure:
A mixture of 2-(2-diethylthiocarbamoylsulfanylpropionylamino)-2-methylpropionic acid (4.00 g; 0.0132 mol), TEMPO (2.04 g; 0.0132 mol) and ethyl acetate (35 ml) in a glass jar was purged with nitrogen gas for 20 minutes. The jar was then sealed and the mixture was irradiated with a 350 mn ultraviolet lamp (Sylvania 350 Blacklight F15T8/350BL available from Osram Sylvania, Danvers, Mass.) for 65 hours. The mixture was then concentrated under vacuum and diluted with diethyl ether (50 ml). The solid was isolated by filtration and was dried under vacuum to afford 1.75 g (42% yield) of 2-methyl-2-[2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-propionylamino]-propionic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.S(=O)(=O)(O)O.[N+:18]([O-])([O-:20])=[O:19].[K+].N>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[C:8]=2[N+:18]([O-:20])=[O:19])[N:3]=1
Reactant: Cc1ccc2nc(C)ccc2c1
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1ccc2c([N+](=O)[O-])c(C)ccc2n1

Procedure:
3 g (19.08 mmol) of 2,6-dimethylquinoline is introduced into 15 ml of concentrated sulfuric acid at 10° C. After one-half hour, a solution of 2.03 g of potassium nitrate in 11.4 concentrated sulfuric acid is added in drops, specifically so that the temperature remains between 5° and 15° C. The batch is stirred for one more hour and then poured onto ice water. It is made ammonia-alkaline, and the deposited precipitate is suctioned off. After washing with water, the crude product is dissolved in ethyl acetate and shaken from water. The organic phase is treated as usual. After the solvent is spun off, 3.69 g (95.6%) of the desired compound remains, which is used in the reduction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19](C)[CH2:18][CH2:17]3)[C:6]=2[CH:23]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:18][CH2:17]3)[C:6]=2[CH:23]=1
Reactant: CN1CCN(C2=Nc3ccccc3Sc3ccc(Cl)cc32)CC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(C2=Nc3ccccc3Sc3ccc(Cl)cc32)CC1
Temperature: 0 °C
Yield: 69.6 %

Procedure:
A mixture of 0.86 g of 2-chloro-11-(4-methyl-1-piperazinyl)dibenzo[b,f][1,4]thiazepine and 0.81 g of ethyl chloroformate in 5 ml of toluene was refluxed for 5 hrs. Ice water was added to the reaction mixture and made alkaline with sodium bicarbonate. The mixture was extracted with methylene chloride and the methylene chloride layer was washed with water, dried and concentrated. The residue was chromatographed on silica gel using methylene chloride as an eluent to give 0.70 g of colorless crystals, which were recrystallized from a mixture of isopropyl ether and n-pentane to give colorless prisms, mp 96.5°-97.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N+:13]([O-])=[C:12]([CH3:17])[C:11]=2[CH3:18])[O:4][CH2:3]1.C(OC(=O)C)(=[O:22])C.[OH-].[Na+]>>[CH3:1][C:2]1([CH3:19])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:17][OH:22])[C:11]=2[CH3:18])[O:4][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OCC2OCC(C)(C)CO2)cc[n+]([O-])c1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CO
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 39.7 %

Procedure:
The 4-((5,5-dimethyl-1,3-dioxan-2-yl)methoxy)-2,3-dimethylpyridine1-oxide (3.1 g, 11.6 mmol) obtained by the step (1c) was mixed with acetic anhydride (9.87 ml, 104 mmol). After the mixture was stirred at 85° C. for 45 minutes, acetic anhydride was removed. The residue was dissolved in methanol (40 ml) and a 5N aqueous sodium hydroxide solution (5.1 ml, 25.5 mmol) was added to the mixture while cooling on ice. The mixture was stirred at room temperature for one hour. Methanol was distilled off and ice water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resultant mixture was purified by silica gel column chromatography (silica gel: 120 g, elution solvent: ethyl acetate/heptane=1/4 to 4/1) to obtain the title compound (1.23 g, yield: 39.7%) as a light yellow oil.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].C(O[C:8](=[O:16])[C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:10])C.C(O)(=O)C.O>C(OCC)C>[CH2:14]([N:11]([CH2:12][CH3:13])[C:9](=[O:10])[C:8](=[O:16])[CH2:1][CH3:2])[CH3:15]
Reactant: CCOC(=O)C(=O)N(CC)CC
Reactant: CC[Mg]Br
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCC(=O)C(=O)N(CC)CC
Temperature: -15 °C
Reaction time: 1.25 h
Yield: 68.1 %

Procedure:
mL ethyl magnesium bromide solution (191.8 mmol, 1.10 eq) were diluted with 182.6 mL diethylether. The solution was cooled to −15° C. and a solution of 30.20 g of compound (8) as obtained from example 1 (174.4 mmol) in 60.4 mL diethylether was added dropwise. The resulting viscous suspension was stirred for additional 75 min at −15° C. Subsequently, the reaction was quenched by addition of 14.96 mL acetic acid (261.6 mmol, 1.5 eq). Then, 35 mL water were added to dissolve all salts and the cooling bath was removed. After 15 min, the mixture was washed twice with 200 mL, pH-7-buffer and the organic phase was dried over 20 g sodium sulfate and was filtered. The filter cake was washed with 40 mL diethylether. After evaporation of solvent in a rotary evaporator (40° C./10 mbar), the crude product (26.33 g, 96% by weight) was obtained as a yellow liquid. Purification was achieved using a high vacuum distillation (bp 86° C. at 2.5 mbar) furnishing the title compound (18.66 g, 118.7 mmol, 68% by weight) as colorless liquid.
Reaction SMILES: II.[Br-:3].COC(=O)[C@@H]1CCCN1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1.CCOCC>[Br:3][C:13]1[CH:18]=[CH:17][C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@H]1CCCN1Cc1ccccc1
Reactant: [Br-]
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Brc1ccc(-c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromobiphenyl (7.42 g, 31.87 mmol) in 40 mL THF was prepared, and 10 mL was added to Mg (0.85 g, 35.05 mmol) and one crystal of I2 in THF (10 mL). The Grignard reaction was initiated with the aid of gentle warming by a heat gun. After the iodine color had dissipated, the remaining 30 mL of bromide solution was added dropwise to the reaction mixture. After the reflux subsided, the solution was warmed over an oil bath (70° C.), for 30 minutes, then cooled to 0° C. N-benzyl-(S)-proline methyl ester (5, 2.18 g, 9.96 mmol) in THF (10 mL) was added. After the addition, the solution was allowed to warm to room temperature and stirred for another 8 hours. Saturated NH4Cl (150 mL) was added and the resulting mixture was diluted with Et2O (200 mL). The phases were separated and the organic phase was washed with H2O and brine, dried (MgSO4), and concentrated. The residue was purified over a short silica gel column using 5 to 20% EtOAc/pet ether to a give a white solid, which was recrystalized with CH2Cl2/pet ether to obtain white needles (4.106 g, 83%): mp 85-86° C., 1H NMR (300 MHz, CDCl3) δ 1.60-1.74 (m, 2H), 1.76-1.88 (m, 1H), 1.94-2.08 (m, 1H), 2.40 (dd, J=16.6, 9.0 Hz, 1H), 2.92-3.00 (m, 1H), 3.10 (d, J=12.7 Hz, 1H), 3.38 (d, J=12.5 Hz, 1H), 4.06 (dd, J=9.3, 4.6 Hz, 1H), 5.04 (s, 1H), 7.04-7.60 (m, 14H), 7.68 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([CH3:45])[CH2:4][CH2:5][N:6]([CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[C:7]([C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)[N:14]([CH2:28][CH2:29][CH2:30][NH:31]C(OC(C)(C)C)=O)[C:13]=2[CH:39]=1)=[O:8]>O1CCOCC1.C(OCC)(=O)C>[ClH:1].[ClH:1].[NH2:31][CH2:30][CH2:29][CH2:28][N:14]1[C:13]2[CH:39]=[C:9]([C:7]([N:6]([CH2:5][CH2:4][CH:3]([CH3:2])[CH3:45])[CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[O:8])[CH:10]=[CH:11][C:12]=2[N:16]=[C:15]1[NH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCCN)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of hydrochloric acid in dioxane (4N, 2 ml) is added to a solution of methyl 4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[(tert-butoxycarbonyl)amino]propyl}-1H-benzimidazol-2-yl)amino]benzoate (180 mg) in ethyl acetate (2 ml). After stirring for 1 hour at a temperature of approximately 20° C., the mixture is concentrated under reduced pressure at 40° C. The solid obtained is washed with ethyl ether and dried (165 mg; 96% yield).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.[Cl-].[Na+].O>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[N:19]/[S@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)F)cc1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[S@](=O)/N=C/c1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a stirred solution of 4-(difluoromethoxy)benzaldehyde (10 g, 58 mmol) and (S)-2-methylpropane-2-sulfinamide (13 g, 105 mmol) in THF (50 mL) was added Ti(OEt)4 (43 mL, 209 mmol) and the reaction was stirred at RT overnight. The mixture was poured into brine (400 mL) and stirred for 10 min, filtered, and the filtered solids rinsed with additional THF/EtOAc. The organic layer was separated, and the aqueous layer extracted with additional EtOAc. The combined extracts were washed with brine, dried (MgSO4), and concentrated. The residue was dry loaded and passed through a SiO2 plug eluting with a EtOAc/hexane gradient (10 to 15% EtOAc) to afford 16 g (100%) of (S,E)-N-(4-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (378) as pale yellow liquid.
Reaction SMILES: O[C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12](=[O:17])[N:13]([CH2:15][CH3:16])[CH3:14])[CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:25]([NH2:28])[C:26]#[CH:27]>ClCCl>[CH2:25]([NH:28][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12](=[O:17])[N:13]([CH2:15][CH3:16])[CH3:14])[CH:9]=2)[CH2:4][CH2:3]1)[C:26]#[CH:27]
Reactant: C#CCN
Reactant: CCN(C)C(=O)Oc1ccc2c(c1)[C@H](O)CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN[C@H]1CCc2ccc(OC(=O)N(C)CC)cc21
Temperature: 25 °C
Yield: 70.3 %

Procedure:
Methanesulfonyl anhydride (1.544 g, 8.9 mmol) as a solution in dichloromethane (7.5 mL+2.5 mL) was added to a stirred solution of (R)-ethyl-methyl-carbamic acid 3-hydroxy-indan-5-yl ester (1.04 g, 4.4 mmol) and triethylamine (2.5 mL, 17.7 mmol) in dichloromethane (10 mL) at −35° C. (external) over 10 minutes. The reaction was maintained at this temperature for 45 minutes before propargylamine (3.0 mL, 44.3 mmol) was added. The reaction was allowed to warm slowly to room temperature overnight before being partitioned between ethyl acetate (100 mL) and ice-water (100 mL). The organic material was concentrated under reduced pressure to afford a brown oil which was partitioned between methyl tert-butyl ether (50 mL) and aqueous hydrochloric acid (1M, 50 mL). The aqueous layer was basified by addition of aqueous sodium hydroxide solution (2M, 40 mL) before being extracted with ethyl acetate (50 mL). This final organic extract was dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound (842 mg, 70%). 1H NMR (400 MHz, CDCl3) δ ppm 7.19 (1H, d, J8, Ar), 7.09 (1H, s, Ar), 6.94 (1H, brd, J, 8, Ar), 4.39 (1H, dd, J6 and 6, NHCH), 3.55 (1H, Dd, J 17 and 2, NCHH), 3.49 (1H, Dd, J 17 and 2, NCHH), 3.46 (rotamer A, 1H, q, J 8, MeCHHN), 3.40 (rotamer B, 1H, q, J 7, MeCHHN), 3.06 (rotamer A, 1.5H, s, MeN), 3.03-2.95 [2.5H, m, NCHCH2CHH and rotamer B, Me, incl. at 2.98 (rotamer B, 1.5H, s, MeN)], 2.83-2.75 (1H, m, NCHCH2CHH), 2.48-2.39 (1H, m, NCHCHH), 2.25 (1H, t, J2, ≡H), 1.92-1.83 (1H, m, NCHCHH), 1.23 (rotamer A, 1.5H, t, J7, MeN) and 1.18 (rotamer B, 1.5H, t, J7, MeN). Analysis of this material by chiral LC indicated it to be 62% e.e.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][C:17]=1[F:24]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][C:2]2[CH:3]=[C:4]3[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]3[C:6](=[O:8])[N:7]=2)=[CH:18][C:17]=1[F:24]
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(Cl)c(F)c1
Product: CN1c2cc(OCc3ccc(Cl)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (4-chloro-3-fluorophenyl)methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[OH:9])[CH:7]=1.N1C(C)=CC=CC=1C.[Si:38](OS(C(F)(F)F)(=O)=O)([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:18][O:19][Si:20]([CH:21]([CH3:22])[CH3:23])([CH:27]([CH3:28])[CH3:29])[CH:24]([CH3:26])[CH3:25])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[O:9][Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])[CH:7]=1
Reactant: CCc1ccc(C(O)c2cc(Br)ccc2CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCc1ccc(C(O[Si](C(C)C)(C(C)C)C(C)C)c2cc(Br)ccc2CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
Step 4) To a solution of (5-bromo-2-((triisopropylsilyloxy)methyl)phenyl)(4-ethylphenyl)methanol (4.76 mmol) and 2,6-lutidine (1.6 mL, 13.51 mmol) in dichloromethane (30.0 mL) was slowly added TIPSOTf (1.8 mL, 6.75 mmol) at 0° C., and the reaction mixture was stirred for 12 h at room temperature. The resulting mixture was quenched with CH3OH, diluted with EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography to provide the title compound (2.94 g, 97% 2-step) as yellow oil.
Reaction SMILES: CCN(C1C=CC=CC=1)CC.Cl[C:13]([O:15][CH3:16])=[O:14].[CH3:17][C:18]([CH3:25])=[CH:19][CH:20]=[N:21][CH:22]([CH3:24])[CH3:23].Cl>C1(C)C=CC=CC=1.O>[CH3:16][O:15][C:13](=[O:14])[N:21]([CH:22]([CH3:24])[CH3:23])[CH:20]=[CH:19][C:18]([CH3:25])=[CH2:17]
Reactant: COC(=O)Cl
Reactant: CC(C)=CC=NC(C)C
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: C=C(C)C=CN(C(=O)OC)C(C)C

Procedure:
To a stirred solution of 657 g diethylaniline in 2 liter toluene is added dropwise over ca. 5 minutes 416 g methyl chloroformate. Then to the stirred mixture 500 g N-(3-methyl-2-butenyliden)-isopropylamine in 500 ml toluene is added dropwise over 2 hours, maintaining the temperature between 25° and 30° C. Stirring is continued for 1 hour upon completion of the addition and the reaction mixture is treated with 400 ml of water and 90 ml conc. hydrochloric acid. The organic phase is washed with 600 ml of saturated aqueous sodium bicarbonate solution and with 600 ml water, dried and evaporated in vacuo to give the heading compound.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15]>C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15].[S:2]([O-:5])(=[O:4])(=[O:3])[CH3:1]
Reactant: CS(=O)(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
Methanesulfonic acid (0.65 ml, dissolved in 35 ml of acetone) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 181.1° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([O:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(O)c1)c1ccccc1N1CCCCC1
Product: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCc2ccccc2)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from ethyl 2-hydroxy-4[N-{1-(2-piperidinophenyl)-1-butyl}-aminocarbonylmethyl]-benzoate, using benzyl bromide.