Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]([OH:16])[CH:15]=1)[C:12](=[O:17])[C:11]1[C:6](=[CH:7][CH:8]=[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]3=1)[O:5]2.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>CC(C)=O>[OH:16][C:14]1[CH:15]=[C:2]([O:1][CH2:22][CH:24]2[CH2:25][O:26]2)[CH:3]=[C:4]2[C:13]=1[C:12](=[O:17])[C:11]1[C:6](=[CH:7][CH:8]=[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]3=1)[O:5]2
Reactant: ClCC1CO1
Reactant: O=c1c2c(O)cc(O)cc2oc2ccc3ccccc3c12
Solvent: CC(C)=O
Product: O=c1c2c(O)cc(OCC3CO3)cc2oc2ccc3ccccc3c12
Temperature: 57.5 °C
Yield: 40.4 %

Procedure:
The compound 9,11-dihydroxy-12H-benzo[a]xanthen-12-one (0.1 g, 0.18 mmol) synthesized in Step 1 of Examples 14 and 15, CS2CO3 (0.36 g, 0.54 mmol), and anhydrous acetone (20 mL) were charged to a dry round-bottom flask. Under stirring, epichlorohydrin (0.2 g, 1.08 mmol) was added thereto using a syringe. The reaction liquid was stirred with reflux at a temperature of 55 to 60° C. under a nitrogen atmosphere (48 h). Solid of the reaction mixture was filtered and removed. The filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:3 (v/v)) to give a yellow solid compound 11-hydroxy-9-(oxiran-2-ylmethoxy)-12H-benzo[a]xanthen-12-one (24.3 mg, 20.3%) and a yellow solid compound 9,11-bis(oxiran-2-ylmethoxy)-12H-benzo[a]xanthen-12-one (32 mg, 22.1%).
Reaction SMILES: C1COC2C=CC([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=4)[N:13]=3)=CC=2O1.ClC1N=C(N[C:35]2[CH:40]=[CH:39][C:38]([CH2:41][OH:42])=[CH:37][CH:36]=2)C(F)=CN=1.[CH2:44]1[CH2:54]OC2C=CC(N)=CC=2[O:45]1>>[CH2:54]1[CH2:44][O:45][C:23]2[CH:24]=[CH:25][C:20]([N:19]([C:35]3[CH:36]=[CH:37][C:38]([CH2:41][OH:42])=[CH:39][CH:40]=3)[C:14]3[N:13]=[C:12]([NH2:11])[C:17]([F:18])=[CH:16][N:15]=3)=[CH:21][C:22]=2[O:26]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: OCc1ccc(Nc2nc(Cl)ncc2F)cc1
Product: Nc1nc(N(c2ccc(CO)cc2)c2ccc3c(c2)OCCO3)ncc1F

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-[4-(hydroxymethyl)phenyl]-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-(hydroxymethyl)phenyl]-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.92 (bs, 1H), 7.62 (d, 2H, J=8.7 Hz), 7.36 (d, 2H, J=8.7 Hz), 7.19 (d, 1H, J=2.1), 6.87 (dd, 1H, J=2.7 and 8.7 Hz), 6.79 (d, 1H, J=8.7 Hz), 4.68 (s, 2H), 4.284.23 (m, 4H); 19F NMR (CDCl3): −4.7466; LCMS: ret. time: 17.86 min.; purity: 93%; MS (m/e): 369 (MH+).
Reaction SMILES: C([C:3]1[C:4](=[O:28])[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)O[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)C.CO.[CH3:31][NH2:32]>O.C(O)(=O)C>[CH3:31][N:32]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:3][C:4](=[O:28])[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:6]1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1
Reactant: CN
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc(-c2ccc(Cl)cc2)c(CC)c1=O
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)n(C)c(-c2ccc(Cl)cc2)cc1=O
Reaction time: 3 h

Procedure:
5.0 gms of ethyl 2,6-di(4'-chlorophenyl) 3-ethoxycarbonyl-pyr-4-one, 100 mls of methanol, 19 mls of 40% aqueous methylamine, 19 mls of water and 2.9 mls of glacial acetic acid were mixed and allowed to stand at room temperature for 3 hours. The mixture was poured into water and extracted with methylene chloride to provide 5 gms of crude ethyl 1-methyl-2,6-di(4-chlorophenyl)-4-oxonicotinate as a yellowish semi-solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([NH:27]C(=O)C(F)(F)F)[CH2:23]2)=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]1[CH:12]([CH3:14])[S:13][C:9]1=[C:8]([C:15]([O:17]CC)=[O:16])[C:7]2=[O:20].[OH-].[K+].C(O)(C)(C)C.O>C(O)(=O)C>[NH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:20])[C:8]([C:15]([OH:17])=[O:16])=[C:9]4[S:13][CH:12]([CH3:14])[N:10]43)=[CH:5][C:4]=2[F:21])[CH2:23]1
Reactant: CCOC(=O)c1c2n(c3c(Cl)c(N4CC[C@H](NC(=O)C(F)(F)F)C4)c(F)cc3c1=O)C(C)S2
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Solvent: O
Product: CC1Sc2c(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](N)C4)c(Cl)c3n21
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.5 %

Procedure:
A mixture of 1.90 g of ethyl 8-chloro-6-fluoro-1-methyl-4-oxo-7-((S)-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]-thiazeto[3,2-a]quinoline-3-carboxylate, 1.23 g of 85% potassium hydroxide, 6.0 ml of tert-butanol and 12 ml of water was stirred at room temperature for 5 hours. The reaction mixture was neutralized with aqueous acetic acid. The precipitate was collected by filtration and recrystallized from water to give 0.51 g of yellow crystals, which were consistent with that of Example 29.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.O>CC(C)=O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:13][S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])=[O:25])=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2c(c1)OCO2
Yield: 75 %

Procedure:
To a solution of 26.9 g of 1,3-benzodioxole-5-sulfonamide in 100 ml of acetone was added 150 ml of a 1N sodium hydroxide solution. A solution of 26.4 g of 4-chlorophenylisocyanate in 85 ml of acetone was added to the reaction mixture with stirring. After stirring at room temperature for 18 hours, the reaction mixture was filtered and 150 ml of 1N hydrochloric acid were added to the filtrate, thereby providing a precipitate. One liter of water was added, and the solid was recovered by filtration to provide the desired title product in 75% yield.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](F)=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][O:7]1.[CH3:23][S-:24].[Na+].[OH-].[Li+]>CN(C)C=O>[CH3:23][S:24][C:14]1[CH:15]=[CH:16][C:11]([CH:4]([CH2:5][C@H:6]2[CH2:10][CH2:9][CH2:8][O:7]2)[C:3]([OH:2])=[O:22])=[CH:12][C:13]=1[C:18]([F:21])([F:20])[F:19]
Reactant: COC(=O)C(C[C@H]1CCCO1)c1ccc(F)c(C(F)(F)F)c1
Reactant: C[S-]
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1ccc(C(C[C@H]2CCCO2)C(=O)O)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
A solution of 2-(4-fluoro-3-trifluoromethyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid methyl ester (1.97 g, 6.15 mmol) in dry N,N-dimethylformamide (20 mL) at 25° C. under argon was carefully treated with sodium thiomethoxide (0.680 g, 9.27 mmol) and was then heated at 100° C, for 3 h. The reaction mixture was then concentrated in vacuo to remove N,N-dimethylformamide. The remaining residue was suspended in a saturated aqueous ammonium chloride solution (100 mL) and was extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was then dissolved in methanol (40 mL) and was treated with a 0.8M aqueous lithium hydroxide solution (20.60 mL, 16.7 mmol). The reaction mixture was stirred at 25° C. for 16 h and then was concentrated in vacuo to remove methanol. The remaining aqueous layer was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid (1.71 g, 83%) as a light yellow oil: [αC]23589=−23.26° (c=0.49, chloroform); EI-HRMS m/e calcd for C15H17F3O3S (M−H2O)+ 316.0744. found 316.0749.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[CH2:6][C:7]1[CH:8]=[CH:9][N:10]2[C:15]=1[C:14](=[O:16])[N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([C@@H:23]([NH:25]C(=O)OC(C)(C)C)[CH3:24])=[N:11]2.Cl.O1CCOCC1>>[NH2:25][C@H:23]([C:12]1[N:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14](=[O:16])[C:15]2=[C:7]([CH2:6][C:5]3[CH:33]=[CH:34][CH:35]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:8]=[CH:9][N:10]2[N:11]=1)[CH3:24]
Reactant: COc1cccc(Cc2ccn3nc([C@H](C)NC(=O)OC(C)(C)C)n(-c4ccccc4)c(=O)c23)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(Cc2ccn3nc([C@H](C)N)n(-c4ccccc4)c(=O)c23)c1
Yield: 139.3 %

Procedure:
(S)-tert-Butyl (1-(5-(3-methoxybenzyl)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (129 mg, 0.23 mmol) was treated with a solution of hydrochloric acid in dioxane (4M, 2 mL, 8 mmol) according to the method described in Preparation 1 to obtain 120 mg (99% yield) of the title compound as a hydrochloride salt that was used in the following step without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[NH:3]1.[C:9](Cl)([Cl:11])=[O:10]>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[C:9]([Cl:11])=[O:10]
Reactant: O=C(Cl)Cl
Reactant: CC1CCCC(C)N1
Solvent: c1ccccc1
Product: CC1CCCC(C)N1C(=O)Cl

Procedure:
To a solution of 50 g. of 2,6-dimethylpiperidine in 300 ml. of benzene is added 60 g. of phosgene and the mixture is refluxed for 3 hours. The solid which had separated was filtered and the filtrate was concentrated and distilled under vacuum to obtain 2,6-dimethylpiperidinoyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([C:16]([F:15])([F:24])[F:25])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and 4-(trifluoromethyl)aniline (3.85 g) was treated in the same manner as described in Preparation Example 37 to give white powder of the title compound.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[CH:16]=[C:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[O:18][CH:19]=1>[Cu]I>[N:23]1[CH:22]=[CH:21][C:20]([C:17]2[O:18][CH:19]=[C:15]([N:3]3[CH2:4][C@:5]4([CH:10]5[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]5)[CH2:6]4)[O:1][C:2]3=[O:13])[CH:16]=2)=[CH:25][CH:24]=1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Reactant: Brc1coc(-c2ccncc2)c1
Agent: [Cu]I
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1coc(-c2ccncc2)c1

Procedure:
The title compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 4-bromo-2-(4-pyridyl)furan using 4 equivalents of copper (I) iodide. The title compound (124 mg) was obtained as a pale yellow solid, m/z 342 (MH+).
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[BH3-][C:20]#N.[Na+]>CC(O)=O.CO>[Cl:3][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][CH3:20])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
Formaldehyde (108 mg, 1.33 mmol, 37% wt solution in H2O) was added to a solution of 1-(4-chlorobenzyl)-4-(aminomethyl)piperidine (318 mg, 1.33 mmol) and NaBH3CN (668 mg) in 10% CH3COOH/CH3OH (3 mL). The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was loaded on DOWEX™ 50W×2 column (10 mL) and washed with CH3OH (100 mL). Product was eluted off using 2 N NH3 in CH3OH (100 mL) and concentrated to afford 173 mg of crude 1-(4-chlorobenzyl)-4-{(methylamino)methyl}piperidine as a colorless oil used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:23][CH:24]=[CH2:25]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:25][CH:24]=[CH2:23])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: C=CCBr
Reactant: Clc1ccc(NC2CCNCC2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCN1CCC(Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred mixture of 15 parts of N-(4-chlorophenyl)-4-piperidinamine, 12 parts of N,N-diethylethanamine in 130 parts of benzene is added dropwise a solution of 10.3 parts of 3-bromo-1-propene in 70 parts of benzene. Upon completion, the whole is stirred first for 20h.30 at room temperature and further for 40 minutes at reflux. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is taken up in 1,1'-oxybisethane and treated with activated charcoal. The latter is filtered off and the 1,1'-oxybisethane is evaporated again, yielding 2.9 parts of N-(4-chlorophenyl)-1-(2-propenyl)-4-piperidinamine; mp. 90° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])[CH:8]=1)#[N:2].Cl.N#[C:15][NH2:16].[CH2:17]([OH:20])[CH2:18][CH3:19]>>[C:15]([N:2]=[C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])[CH:8]=1)[O:20][CH2:17][CH2:18][CH3:19])#[N:16]
Reactant: N#CN
Reactant: CCCO
Reactant: CC(C)Nc1cncc(C#N)c1
Agent: Cl
Product: CCCOC(=NC#N)c1cncc(NC(C)C)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 44 %

Procedure:
Into a solution of 3-cyano-5-isopropylaminopyridine (118 mg, 0.73 mmol) in 1-propanol (20 ml) was passed hydrogen chloride gas under ice-cooling for 30 minutes. The reactor was tight sealed, and the mixture was stirred at room temperature for 17 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was neutralized with a saturated sodium carbonate solution and extracted with chloroform (50 ml×3). The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow syrup. To the syrup was then added an aqueous solution (6 ml) of cyanamide (61 mg, 1.45 mmol), Na2HPO4 (104 mg, 0.73 mmol) and NaH2PO4 ·2H2O (456 mg, 2.92 mmol), and the mixture was stirred at room temperature for 22 hours. After the reaction was completed, the reaction mixture was extracted with chloroform (30 ml×3), and the chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give propyl N-cyano-5-isopropylamino-3-pyridinecarboximidate (80 mg, 0.33 mmol) as a yellow syrup (Yield 44%).
Reaction SMILES: CO.[CH3:3][O:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:15])[CH3:14])=[CH:8][C:7]=1[OH:16].[CH:18]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[CH3:3][O:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:15])[CH3:14])=[CH:8][C:7]=1[O:16][CH3:18]
Reactant: COC(=O)c1ccc(OC(C)=O)cc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(OC(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 96 h
Yield: 106.7 %

Procedure:
MeOH (0.3 mL, 7.4 mmol) was added to the product from step 1 (0.962 g, 4.6 mmol), Ph3P (1.79 g, 6.8 mmol), and dichloromethane (10 mL). Then DEAD (1.32 mL, 8.4 mmol) was added to the reaction. Reaction was stirred at room temperature for 4 days. Reaction solution was concentrated by rotary evaporation and the resulting residue was purified with silica gel prep plates and 1:3 EtOAc/Hexane as eluent. Obtained 1.10 g of 4-Acetoxy-2-methoxy-benzoic acid methyl ester in quantitative yield.
Reaction SMILES: Br.C[O:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][N:5]=1.C(O)(=O)C>O>[CH3:10][C:9]1[C:4]([OH:3])=[N:5][CH:6]=[C:7]([C:11]([F:14])([F:12])[F:13])[CH:8]=1
Reactant: COc1ncc(C(F)(F)F)cc1C
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C(F)(F)F)cnc1O

Procedure:
Two ml of 48 percent hydrobromic acid were added with stirring to mixture of 1.38 g (5.5 mol) of 2-methoxy-3-methyl-5-(trifluoromethyl)pyridine and 6 ml of glacial acetic acid at 100° C. and the mixture was allowed to react at about 95° C. for 20 min. The mixture was then cooled and poured onto ice and the solid that formed was collected by filtration. A second crop of solid was obtained by adding more water to the filtrate. The combined solids were dried to obtain 0.40 g (40 percent of theory) of the title compound as a white powder melting at 141°-143° C. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20]Cl)[C:9]2=[O:22])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1.C(N(CC)CC)C>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][S:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[C:9]2=[O:22])=[CH:4][CH:3]=1
Reactant: O=C1C(CCCl)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reactant: Fc1ccc(S)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1C(CCSc2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reaction time: 20 h

Procedure:
To a stirring solution of 1-(4-fluorophenyl)-3-(2-chloroethyl)-4-(4-hydroxyphenyl)azetidin-2-one (Method 12; 0.750 g, 2.35 mmol) in MeCN (10 ml) was added 4-fluorothiophenol (0.500 ml, 4.60 mmol) and triethylamine (0.500 ml, 3.59 mmol) at room temperature. After 20 hours there were still start materiel left (approximately 20%, LC/MS) and more 4-fluorothiophenol (0.250 ml, 2.30 mmol) and triethylamine (0.170 ml, 1.22 mmol) were added. After 24 hours, the solvent was removed under reduced pressure and the residue was partitioned between water (20 ml) and EtOAc (20 ml). The organic layer was washed with brine (5 ml), dried over magnesium sulphate and concentrated. The residue was refluxed in heptane for 30 minutes before the title compound was filtered off as a grey solid (0.946 g; 98%). NMR (CD3OD, 400 MHz) 2.00-2.20 (m, 2H), 3.05 (t, 2H), 3.25 (dt, 1H), 4.75 (d, 1H), 6.75-6.80 (m, 2H), 6.90-7.05 (m, 4H), 7.15-7.40 (m, 6H); m/z: 412.0.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C=CC(O)=CC=1)[OH:10].[N:17]1[CH:22]=[CH:21]C=C[CH:18]=1>C1(C)C=CC=CC=1>[C:2]1([CH2:1][O:8][C:18]([NH:17][CH:22]=[CH2:21])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: OCc1ccccc1
Reactant: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CNC(=O)OCc1ccccc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 878.1 %

Procedure:
Into a 500 mL single neck flask were placed benzyl alcohol (76.5 mL, 792 mmol), hydroquinone (3.05 g, 27.7 mmol), pyridine (3 mL, 27.7 mmol) and the mixture was stirred at 100° C. while treated with the toluene solution of 1-aza-1-diazobuta-1,3-dien-2-one (200 mL) dropwise. The mixture was stirred at 110° C. for 30 minutes and at RT for 12 hours. The reaction mixture was concentrated and the resulting crude oil was distilled under reduced pressure (0.4 mm Hg) to provide the intermediate title compound, (phenylmethoxy)-N-vinylcarboxamide, (43.1 g, 45%) as a pure oil (came out at 110-115° C.) which solidified upon sitting at RT. Electron spray M.S. 178 (M*+H) Analysis for C10H11NO2:
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[CH:14]=[CH:13]2>O1CCCC1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16]([C:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:14][CH2:13]2)=[CH:17][CH:18]=1
Reactant: CCCCC[Mg]Br
Reactant: COc1ccc2c(c1)C=CC2=O
Solvent: C1CCOC1
Product: CCCCCC1=CCc2cc(OC)ccc21

Procedure:
A solution of pentyl magnesium bromide (2M; 83 mL) was added with stirring to a chilled (-5° C.) solution of 5-methoxy-1-indenone (24.33 g) in dry tetrahydrofuran (100 mL) and the mixture was stirred at room temperature for 1.5 hours. A few chips of ice were added to destroy excess reagent and after the solvents had been removed under reduced pressure, the residue was taken up in a mixture of dichloromethane (250 mL) and 2N hydrochloric acid and stirred at room temperature for 3 hours. The separated aqueous phase was extracted with dichloromethane (150 mL) then the combined organic layers were dried (MgSO4) and evaporated to provide 30 g of crude product as an oil. Purification of the material by HPLC (dichoromethane-hexane; 2:5) gave 21.62 g of 6-methoxy-3-pentyl-1H-indene as an oil
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]([C@@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C@H:15]1[NH:23][C:24](OCC)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)C>O1CCCC1>[NH:7]([C@@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C@H:15]1[NH:23][CH3:24])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN[C@@H]1Cc2ccccc2[C@H]1Nc1ccccc1

Procedure:
To a stirred suspension of LiAlH4 (1.35 g, 0.035 mol) in dry tetrahydrofuran (25 ml) under nitrogen was added dropwise a solution of (±) trans-1-anilino-2-ethoxycarbonylaminoindane (3.50 g, 0.012 mol) in dry tetrahydrofuran (25 ml). The mixture was heated under reflux for 3.25 h. After cooling in ice, wet diethyl ether was added to quench excess LiAlH4, followed by a minimum amount of water. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo to give a cream coloured solid (2.64 g) which was purified by recrystallisation to give the title compound as a colourless solid, m.p.121°-122° C. (from diethyl ether).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=1[F:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]Br.CN1CCCC1=O>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:21][C:20]=1[F:26])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1cc(Br)ccc1OCc1ccccc1
Reactant: Cc1cc2ccccc2[nH]1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc2ccccc2n1-c1ccc(OCc2ccccc2)c(F)c1
Temperature: 180 °C

Procedure:
To a mixture of 2-methylindole (6.23 g, 47.5 mmol), 4-benzyloxy-3-fluoro bromobenzene (14.066 g, 50 mmol), potassium carbonate (5.83 g, 55 mmol), and N-methylpyrrolidinone (500 mL) was added copper (I) bromide (1.0 g, 7 mmol). The stirred solution was heated to 180° C. and maintained for 18 hr. The reaction mixture was cooled, poured onto ice and extracted with ethyl acetate. After washing the organic layer with water and brine, and drying over anhydrous MgSO4 the solvent was removed to yield a dark liquid, which was purified by silica gel chromatography (2% ethyl acetate-hexanes) to provide the title compound alley as a white solid (3.45 gr. 22% yd): mp 70-71° C.; 1H NMR (DMSO-d6): δ 2.26 (3H, s), 5.28 (2H, s), 6.39 (1H, s), 6.99-7.05 (3H, m), 7.21-7.24 (2H, m), 7.36-7.54 (7H, m)); MS m/z (M+H)+332: Anal. for C22H18NOF 0.1H2O: Calc'd: C, 79.31; H, 5.51; N, 4.20. Found: C, 79.29; H, 5.39; N, 4.16