Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:22]#[N:23])=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:12][C:13]=1[CH:14]=O.C(O)(C)(C)C.[NH2:29][CH2:30][CH:31]([NH2:33])[CH3:32].II.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:22]#[N:23])=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:12][C:13]=1[C:14]1[NH:29][CH2:30][CH:31]([CH3:32])[N:33]=1
Reactant: N#Cc1c(N2CCOCC2)sc(C=O)c1-c1ccc(Cl)cc1Cl
Reactant: CC(N)CN
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1CNC(c2sc(N3CCOCC3)c(C#N)c2-c2ccc(Cl)cc2Cl)=N1
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
To 4-(2,4-dichlorophenyl)-5-formyl-2-morpholin-4-ylthiophene-3-carbonitrile (52.0 mg, 0.000142 mol) in tert-butyl alcohol (0.75 g, 0.010 mol) was added 1,2-diaminopropane (12.9 mg, 0.000174 mol) and the mixture was stirred for 30 min. Iodine (51 mg, 0.00020 mol) and potassium carbonate (65.7 mg, 0.000475 mol) was added the mixture was stirred at 70° C. for 3 hr. The reaction mixture was quenched by saturated sodium bicarbonate solution and brine. The organic layer was collected and purified by column chromatography to afford 4-(2,4-dichlorophenyl)-5-(4-methyl-4,5-dihydro-1H-imidazol-2-yl)-2-morpholinothiophene-3-carbonitrile (19 mg, 32%). LCMS: (FA) ES+ 421. 1H NMR (400 MHz, d1-chloroform) δ: 7.60 (s, 1H), 7.50-7.40 (m, 1H), 7.40-7.30 (m, 1H), 4.20-4.05 (m, 1H), 3.90-3.75 (m, 5H), 3.60-3.70 (m, 4H), 3.38-3.20 (m, 1H), 1.25 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[N+:9]([O-])([OH:11])=[O:10].[OH-].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1
Reactant: Cc1cccc(N)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc([N+](=O)[O-])c(N)n1
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 23.6 %

Procedure:
2-Amino-6-picoline (5.1 g, 47.1 mmol) was weighed into a 500 mL round bottom flask, and the flask was cooled to -30° C. Concentrated H2SO4 (20 mL) was added, which caused some fuiming to occur. Concentrated HNO3 (10 mL, 160 mmol) was then added dropwise slowly. The reaction was allowed to warm to RT over 30 min, then was heated in an oil bath set at 80° C. After 90 min, the reaction was removed from the heating bath, and ice was added. 6.25 N NaOH (150 mL, 937.5 mmol) was added slowly, and the resulting yellow precipitate was collected on a sintered glass funnel. Drying in a vacuum desiccator gave the title compound (1.7 g, 24%): TLC Rf (5% MeOH/CHCl3) 0.77; 1H NMR (250 MHz, CDCl3) δ 8.31 (d, 1H), 6.32 (d, 1H), 2.46 (s, 3H); MS (ES) m/e 154.0 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[ClH:15].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]([Cl:1])=[O:10])[CH2:5][CH2:4]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCC(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 111.1 %

Procedure:
To a suspension of 1-methyl-piperidine-4-carboxylic acid hydrochloride (11.36 mmol, 2.04 g) and N,N-dimethylformamide (0.129 mmol, 0.01 ml, 9.40 mg) in dichloromethane (10 ml) at 0° C. was added oxalyl chloride (14.76 mmol, 1.40 ml) drop wise. The cooling bath was removed and the reaction mixture stirred at room temperature for 20 hours. Then the reaction mixture was concentrated in vacuo to give 1-methylpiperidine-4-carbonyl chloride hydrochloride (2.5 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[NH:10]1[CH:14]=[CH:13]N=[CH:11]1>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O>[CH3:1][Si:2]([CH3:9])([CH3:8])[N:3]1[CH:13]=[CH:14][N:10]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C1NS(=O)(=O)c2ccccc21
Product: C[Si](C)(C)n1ccnc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 105.8 %

Procedure:
31.5 ml (0.15 mole) of hexamethyldisilazane were added dropwise over the course of 45 minutes to 13.62 g (0.2 mole) of imidazole and 28 mg (0.15 mmoles) of saccharin heated to 100° C. and during this addition, the bath temperature was raised from 100° to 140° C. After addition of the hexamethyldisilazane, the mixture was stirred for 30 minutes at a bath temperature of 140° C. Excess hexamethyldisilazane was evaporated under reduced pressure and the residue was vacuum distilled to obtain 22,25 g (79.5%) of N-trimethylsilylimidazole boiling at 103°-105° C. at 22 mm Hg and nD 23.5°=1.4740.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([N:13]([CH2:15][CH:16]=C)[CH3:14])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClCCl.[O:21]=[O+][O-]>CO>[C:1]([C:5]1[O:9][N:8]=[C:7]([N:10]2[CH:16]([OH:21])[CH2:15][N:13]([CH3:14])[C:11]2=[O:12])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=[O+][O-]
Reactant: C=CCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Solvent: CO
Solvent: ClCCl
Product: CN1CC(O)N(c2cc(C(C)(C)C)on2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2.96 g. portion of 1-(5-t-butylisoxazol-3-yl)-3-allyl-3-methylurea was dissolved in 25 ml. of 1:1 by volume dichloromethane:methanol, and the solution was cooled to -78°. Ozone diluted in dry air was bubbled into the solution with good stirring for 30 minutes, after which tlc analysis indicated that the starting material was gone. Nitrogen was bubbled through the mixture for 10 minutes to remove residual dissolved ozone, and then 1 ml. of dimethyl sulfide was added and the mixture was allowed to warm to ambient temperature with continual stirring. The reaction mixture was then diluted with water, the layers were separated, and the product was isolated from the organic layer substantially as shown in Example 2 above to obtain 2.6 g. of the desired product, m.p. 168°-174°. The nuclear magnetic resonance analysis of the product indicated that it was substantially identical to that of Example 1 above.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[K+]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a cooled (0° C.) solution of methyl 3-cyano-4-[(1-methylethyl)oxy]benzoate (100 g, 463 mmol) in tetrahydrofuran (500 mL) was added 10% potassium hydroxide (500 mL). The resulting solution was allowed to warm to room temperature and maintained for 16 h, at which time it was concentrated to remove the tetrahydrofuran. The residue was diluted with water (500 mL) and washed with ether (2×500 mL). The aqueous layer was then acidified with 3 N HCl and stood for 2 h. The solids were collected by filtration and washed several times with water, then dissolved in methylene chloride (1 L). The mostly homogeneous mixture was filtered through Celite and concentrated to a minimal volume of methylene chloride. Collection of the solids by filtration gave 82 g (87%) of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid as a white solid.
Reaction SMILES: N12CCCCC1C=NCCC2.Br[CH2:13][CH:14]1[CH2:29][N:17]2[CH2:18][CH2:19][CH2:20][CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:16]2[C:15]1=[O:30].[C:31]([O-:34])(=[S:33])[CH3:32].[K+].C(O)(=S)C>O1CCOCC1.CC(C)=O.ClCCl>[C:31]([S:33][CH2:13][CH:14]1[CH2:29][N:17]2[CH2:18][CH2:19][CH2:20][CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:16]2[C:15]1=[O:30])(=[O:34])[CH3:32]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)C1CCCN2CC(CBr)C(=O)N12
Agent: C1=NCCCN2CCCCC12
Agent: CC(O)=S
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)SCC1CN2CCCC(C(=O)OC(C)(C)C)N2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
2.3 ml of 1,5-diazabicyclo[5.4.0]undec-5-ene in 10 ml of dioxan were added at 5° C. to a solution of 4.4 g of tert.butyl 2-bromomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]-pyridazine-5-carboxylate (diastereomer B) in 25 ml of dioxan. The mixture was left to stand at room temperature for 2 hours and then filtered. The filtrate was evaporated and the residue was dissolved in ethyl acetate. The solution was filtered through 6 g of silica gel and evaporated. The residue obtained was dissolved in 10 ml of acetone. The solution was treated with 1.6 g of potassium thioacetate and subsequently with 10 ml of thioacetic acid, whereupon the mixture was stirred overnight at room temperature. The mixture was diluted with 100 ml of dichloromethane and washed with 50 ml of saturated aqueous sodium bicarbonate. The separated organic phase was dried over magnesium sulfate and evaporated to give an oil which was chromatographed over 200 g of silica gel using diethyl ether/hexane for the elution. After recrystallization from ethyl acetate/hexane, there were obtained 1.69 g of tert.butyl 2-acetylthiomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (diastereomer A) and 0.9 g of the corresponding diastereomer B.
Reaction SMILES: C[NH2:2].[C:3]([O:13]C)(=O)[C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].Cl.[Cl-].[Na+]>>[C:3]([NH2:2])(=[O:13])[C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: COC(=O)[C@@H](O)c1ccccc1
Reactant: CN
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: NC(=O)[C@@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of methylamine (40% in water, 3.8 equivalents) is added, at ambient temperature, methyl (S)-mandelate (1.0 equivalent; commercially available), while keeping the temperature below 30° C. and stirred at ambient temperature until full conversion is achieved. After neutralisation with aqueous hydrochloric acid the aqueous solution is saturated with sodium chloride and extracted several times with dichloromethane. The organic layers are combined and the water is removed by azeotropic distillation.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[Sn](CCCC)(CCCC)CCCC.Br[C:28]1[N:33]=[C:32]2[C:34]([C:56]([NH:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[CH:35][N:36]([C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:31]2=[N:30][CH:29]=1>CN(C=O)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.[Cu](I)I>[C:59]([NH:58][C:56]([C:34]1[C:32]2=[N:33][C:28]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([O:3][CH:2]([F:1])[F:26])[CH:5]=4)[NH:9][N:8]=3)=[CH:29][N:30]=[C:31]2[N:36]([C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=1)=[O:57])([CH3:62])([CH3:60])[CH3:61]
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2ccc(OC(F)F)cc12
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Temperature: 90 °C
Yield: 56.8 %

Procedure:
A mixture of 5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazole (250 mg, 0.57 mmol), 2-bromo-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (280 mg, 0.58 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), copper iodide (26 mg, 1.36 mmol) in 10 mL of dry DMF was heated to 90° C. for 3 hours under N2. The reaction mixture was cooled to room temperature, diluted with 50 mL of water, product extracted with ethyl acetate (3×20 mL), organics combined dried with sodium sulfate, filtered and concentrated to give N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (208 mg, crude). LCMS: (M+H)+=643.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](\[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)/[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)#[CH:33]>O1CCCC1.C(N(CC)CC)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.[Cu]I>[CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](/[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)\[C:25]2[CH:26]=[CH:27][C:28]([C:33]#[C:32][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:29][CH:30]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: C#Cc1ccccn1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(C#Cc3ccccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl (Z)-[2-methyl-4-[3(4-iodophenyl)-3-(4-methylphenyl)allyloxy]-phenoxy]acetate (310 mg, 0.587 mmol; example 3) in a mixture of tetrahydrofuran (9 mL) and triethylamine (9 mL) was degassed and 2-ethynylpyridine (121 mg, 1.17 mmol) was added in argon atmosphere. The solution was cooled down; tetrakis(triphenylphosphine)palladium (55 mg, 0.047 mmol) and copper(I) iodide (17.8 mg, 0.094 mmol) were added. The reaction mixture was stirred at ambient temperature for 48 h, then evaporated in vacuo and the residue was dissolved in ethyl acetate (20 mL). The solution was washed with water (3×15 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (Z)-[2-methyl-4-[3(4-methylphenyl)-3-[4-(pyridin-2-ylethynyl)phenyl]allyloxy]-phenoxy]acetate.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH3:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1CCCC1.C(OCC)(=O)C>CO.[Pd]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH3:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
To a solution of 4-[9-(t-butyldimethylsilyloxy)-1-nonynyl]-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (2.64 g, 4.77 mmol) in methanol (150 ml) and tetrahydrofuran (15 mg) was added 10% Pd-C (850 mg), which was then stirred at room temperature under hydrogen (atmospheric pressure) for 1 day. Ethyl acetate was added to the reaction solution. The resulting solution was filtered, extracted several times with ethyl acetate, and concentrated under reduced pressure to remove the organic solvent. Hydrogenation reaction was repeated three times under the same condition. After the organic solvent was removed, the residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=9:1) to give the title compound (2.20 g, yield 83%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[K+].F[C:10]1[CH:11]=[CH:12][C:13]2[S:14](=[O:25])(=[O:24])[C:15]3[C:20]([O:21][C:22]=2[CH:23]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3>CN(C)C=O>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:10]1[CH:11]=[CH:12][C:13]2[S:14](=[O:24])(=[O:25])[C:15]3[C:20]([O:21][C:22]=2[CH:23]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: OCC(F)(F)F
Reactant: O=S1(=O)c2ccccc2Oc2cc(F)ccc21
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccccc2Oc2cc(OCC(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
1,1,1-Trifluoro-2-ethanol (Aldrich) (0.44 g, 0.004 mole) was added to a stirred, ice-bath cooled mixture of potassium hydride (approximate 50% dispersion in mineral oil) (Aldrich) (0.32 g, 0.004 mole) and N,N-dimethylformamide (75 mL). The ice-bath was removed, and the reaction was stirred at ambient temperature for 1 hour. 3-Fluorophenoxathiin 10,10-dioxide (Example 47) (1.00 g, 0.004 mole) was added, and the mixture was heated at reflux under nitrogen for 2 hours. The reaction was cooled, and the volatiles were removed by spin evaporation in vacuo. The residue was purified by column chromatography on Silica Gel 60 using ethyl acetate-hexanes:2-8. The appropriate column fractions were combined, and the volatiles were removed by spin evaporation in vacuo to give 0.43 g (32% yield) of 3-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide. Recrystallization from ethanol gave 0.23 g (17% yield) of 3-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide, m.p. 165-166° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[N:15]([O-])=O.[Na+]>Cl>[NH:1]([C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)=[CH:4][CH:3]=1)[NH2:15]
Reactant: O=N[O-]
Reactant: Nc1ccc(C[C@H]2COC(=O)N2)cc1
Agent: Cl
Agent: [Na+]
Product: NNc1ccc(C[C@H]2COC(=O)N2)cc1

Procedure:
In an embodiment, (S)-4-(4-aminobenzyl)-1,3-oxazolidin-2-one of formula (II), which was prepared using prior art methods was treated with an aqueous solution of sodium nitrite in concentrated hydrochloric acid at −5 to 10° C. After completion of reaction based on HPLC, the resulting diazonium salt was treated with stannous chloride in hydrochloric acid at −15 to 10° C. to give (S)-4-(4-hydrazinobenzyl)-1,3-oxazolidin-2-one of formula (III).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[OH-].[Na+].[CH2:19](O)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:19][CH3:20])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Cc1cccc(Br)c1
Reaction time: 8 h
Yield: 93 %

Procedure:
3-Bromophenylacetic acid, 35i-a, (50 g, 0.23 mol) was dissolved in ethanol (250 mL) and sulfuric acid was added drop-wise. The mixture was heated to reflux and stirred overnight. The solution was adjusted to about a pH of 7-8 with sodium hydroxide solution and concentrated in vacuo. The water phase was extracted with ethyl acetate (3×150 mL) and the combined organics was washed with brine (50 mL) and dried, concentrated to give the compound, 35i-b, (52.6 g, 93%) as colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.24-1.29 (m, 3H), 3.58 (s, 2H), 4.11-4.19 (m, 2H), 7.18-7.25 (m, 2H), 7.38-7.44 (m, 2H). LC-MS (M+H)+ 243, 245.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>>[N:7]1([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: C1COCCN1
Reactant: Brc1nccs1
Product: c1csc(N2CCOCC2)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
2-Bromothiazole (4.592 g) was added to morpholine (24 ml), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system) to give the title compound as a pale yellow oil (4.531 g, yield; 95%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]Br.CCOC(C)=O.CCCCCCC>COCCOC>[Br:26][C:10]1[C:11]([CH3:25])=[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Cc1cc(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1c(C)c(OCc2ccccc2)c(Br)c(C)c1OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 2,5-bis(benzyloxy)-3,4,6-trimethylbenzene in 100 mL DME (5 g, 15.0 mmol) was treated with a solution of Br2 (0.85 mL, 16.5 mmol, 1.1 equiv.) in 10 mL DME (1.6 M) over ten minutes. The reaction was judged incomplete by HPLC. Additional Br2 in DME (0.42 mL, 1.31 g, 8.19 mmol, 0.55 equiv.) was added and stirred overnight. The reaction was treated with 200 mL EtOAc, which dissolved the crystals, and washed with H2O until the aqueous washings were colorless (3×100 mL). The combined aqueous layers were back extracted with EtOAc (3×50 mL) and the combined organics washed 2×100 mL saturated NaCl, dried over Na2SO4 and concentrated to a brown solid. The solid was adsorbed onto silica and purified by flash chromatography (gradient elution 2-20% EtOAc/heptane) to give a yellow solid. The solid was suspended into heptane, stirred overnight, filtered and the filter cake rinsed with heptane. The resulting white powder was dried in vacuo and yielded 3.31 g of 2-bromo-1,4-bis(benzyloxy)-3,5,6-trimethylbenzene as a white powder. 1H NMR (400 MHz, CDCl3) δ=7.57 (d, 2H), 7.48 (d, 2H), 7.44-7.36 (m, 6H), 4.87 (s, 2H), 4.74 (s, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H) ppm.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:16][OH:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.I[CH3:19].[H-].[Na+]>O1CCCC1>[CH3:19][O:1][CH2:2][C:3]1([CH2:16][OH:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CI
Reactant: OCC1(CO)c2ccccc2-c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1(CO)c2ccccc2-c2ccccc21
Yield: 62 %

Procedure:
Under nitrogen atmosphere and anhydrous condition, to a reactor were added in succession 80 ml of tetrahydrofuran, 22.6 g (0.1 mol) of 9,9-bis(hydroxymethyl)fluorene and 57 g (0.4 mol) of iodomethane. After the reaction mixture was admixed homogeneously by stirring, 4.6 g of 52% NaH in mineral oil (0.1 mol) was added batch-wise over 2 hours at room temperature, Upon completing the addition, the reaction mixture was stirred for further 2 hours. The unreacted iodomethane was recovered by distillation. The remainder was diluted with 100 ml of water, and extracted twice using 100 ml of diethyl ether for each time. The combined diethyl ether extract was dried over anhydrous sodium sulfate. After drying, thee ether solution was evaporated to dry to give 22.8 g of crude. The crude was purified through column chromatography to give 14.9 g of 9-methoxymethyl-9-hydroxymethyl-fluorene (yield 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]1([S:35]([OH:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)(=O)C.CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]1([S:35]([O-:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(O)c1ccccc1
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=S(=O)([O-])c1ccccc1

Procedure:
3.790 g of Donepezil is dissolved in 70 ml of ethyl acetate. A solution (35 ml) of benzenesulfonic acid (1.852 g) in acetone is added slowly and drop-wisely. The solid precipitated is filtered under suction to give the title compound.