Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][C:9]2([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:25][CH:24]=2)[CH3:22])[CH:5]=[CH:6][CH:7]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][Cl:38].[OH-].[Na+].O>CC(C)=O>[Cl:38][CH2:37][CH2:36][CH2:35][CH2:34][O:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][C:9]2([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:27][CH:28]=2)[CH3:22])[CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2cccc(O)c2)cc1
Reactant: ClCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2cccc(OCCCCCl)c2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
(3RS,4RS)-4-(3-Hydroxyphenyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-2,3-dihydro-4H-benzopyran (260 mg, 0.59 mmol), 1-bromo-4-chlorobutane (0.8 ml, 2.98 mmol) and aqueous 2N-NaOH solution (0.8 ml) were dissolved in acetone (10 ml) and then stirred for 4 hours at 50° C. The reaction mixture was cooled to room temperature and then water was added thereto. The reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=4:1) to obtain 300 mg (yield: 96%) of the title compound as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22].O>CC(C)=O>[C:23]1([CH:21]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]2)[CH3:22])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(Br)c1ccccc1
Reactant: COC(=O)c1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1nn(C(C)c2ccccc2)c2ccccc12

Procedure:
To a solution of methyl 1H-indazole-3-carboxylate (2.0 g, 11.4 mmol) in acetone (50 mL), were added potassium carbonate (1.6 g, 11.4 mmol) and (1-bromoethyl)benzene (2.2 g, 11.9 mmol). Then the mixture was refluxed for 12 hours. The reaction mixture was concentrated to give a residue. To the residue was added water (50 mL), extracted with dichloromethane (50 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to afford two isomers.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[N:18][CH:19]=1>C(Cl)(Cl)Cl>[Cl:8][CH2:9][C:10]([NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)=[O:11]
Reactant: N#Cc1ccc(N)cn1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(NC(=O)CCl)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Triethylamine (0.50 g, 4.9 mmol) and chloroacetyl chloride (0.56 g, 4.9 mmol) were added dropwise at 0° C. to a stirred suspension of 5-Amino-2-cyanopyridine (0.27 g, 2.25 mmol) in chloroform (10 mL). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with chloroform (50 mL) and washed with water (2×50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and the crude product obtained was crystallized from chloroform:petroleum ether (1:2) to obtain the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[F:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(F)c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1cccc(F)c1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A solution of 2-bromo-1-(3-fluorophenyl)ethanone (1.00 g, 4.61 mmol) and potassium thiocyanate (448 mg, 4.61 mmol) in ethanol (10 ml) was stirred at 80° C. for 3 hours. After cooling to room temperature, water (12 ml) was poured into the reaction solution, and a crystal was separated by filtration, which was washed with 50% aqueous ethanol solution to give the desired product (668 mg, 74.3%) as a solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]#[N:14])(=[O:3])[CH3:2].C(N(CC)CC)C.[SH2:22]>N1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13](=[S:22])[NH2:14])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2CC1C#N
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccccc2CC1C(N)=S
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 1-acetyl-2,3-dihydro-1H-indole-2-carbonitrile (0.00988 mol) and Triethylamine (0.0197 mol) in pyridine (50 ml) was treated with hydrogen sulfide (gas) at room temperature via a bubbler for 2 hours and the resultant saturated reaction mixture was closed and allowed to set for 16 hours. The reaction mixture was poured into 200 ml of an ice water slurry. A voluminous precipitate formed. The mixture was recooled in an ice bath and the precipitate was collected by suction filtration, washed with cold water, and air dried, yielding 1.62 g of 1-acetyl-2,3-dihydro-1H-indole-2carbothioamide (intermediate 13, mp. 194–195° C.).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5](=[O:12])[CH2:6][C:7](OCC)=O)[CH3:2].[CH3:16][C:17]([CH3:21])=[CH:18]CCl.[O-]CC.[Na+].[OH-].[Na+]>>[CH2:14]([O:13][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:12])[CH2:6][CH2:7][CH:16]=[C:17]([CH3:21])[CH3:18])[CH3:15]
Reactant: CC(C)=CCCl
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCOC(OCC)C(=O)CCC=C(C)C
Yield: 57.2 %

Procedure:
Following the procedure stated in Referential example 1, reaction of 7.3 g of ethyl 4,4-diethoxyacetoacetate with 4.0 g of 3-methyl-2-butenyl chloride was carried out in the presence of sodium ethoxide and the resultant was decarboxylated with the alcoholic sodium hydroxide to yield 4.1 g of the desired product, b.p. 102°-103° C./1 mmHg.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][NH:19]2)=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1.N1C=CC=CC=1>[F:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][N:19]2[S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc2c(c1)NCC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
4-Toluenesulfonyl chloride (460 mg, 2.4 mmol) was slowly added to a solution of 6-fluoro-2,3-dihydro-1H-indole (220 mg, 1.6 mmol) in THF (6 mL) and pyridine (260 μL). The reaction mixture was stirred at room temperature overnight. Upon the completion of the reaction, the mixture was cooled to 0° C., neutralized with aq. sat. NH4Cl (10 mL) and extracted with EtOAc (3×10 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3×10 mL), brine (10 mL) and dried (MgSO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc/hexanes=1/3) gave 283 mg (0.98 mmol) of the title product. Yield: 61%, colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.67 (d, J=8.2 Hz, 2H), 7.35 (dd, J=10.0, 2.3 Hz, 1H), 7.23 (d, J=8.2 Hz, 2H), 6.97 (m, 1H), 6.62 (m, 1H), 3.90 (t, J=8.4 Hz, 2H), 2.84 (t, J=8.4 Hz, 2H), 2.35 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 162.5 (d, J=241.4 Hz), 144.5, 143.3 (d, J=11.7 Hz), 133.6, 129.8, 127.2, 127.0 (d, J=2.6 Hz), 125.7 (d, J=9.8 Hz), 110.0 (d, J=22.6 Hz), 102.8 (d, J=28.4 Hz), 50.7, 27.1, 21.5 ppm.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][CH:12]([CH3:15])[NH:13][CH3:14].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][C:27](Cl)=[O:28])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][CH:12]([N:13]([CH3:14])[C:27](=[O:28])[CH2:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=1)[CH3:15]
Reactant: CNC(C)CCc1cc(OC)ccc1I
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(I)c(CCC(C)N(C)C(=O)Cc2ccc(OC)c(OC)c2)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 17.87 g (0.056 mole) of 2-iodo-5-methoxy-N,alphadimethylbenzenepropanamine in 58 ml of dry methylene chloride was added dropwise to a cooled (5° C.) solution of 3,4-dimethoxyphenylacetyl chloride in 68 ml of dry methylene chloride over a period of five minutes while stirring under an atmosphere of nitrogen. After about two minutes of stirring, 5.67 g (0.056 mole) of triethylamine was added followed by an additional 20 ml of dry methylene chloride. The reaction mixture was allowed to warm to room temperature while stirring overnight. An additional 80 ml of methylene chloride was added and the mixture washed successively with 200 ml of water, 300 ml of 5% hydrochloric acid, and 200 ml of sodium hydroxide solution. The organic phase was dried over anhydrous magnesium sulfate and evaporated in vacuo to yield 27.5 g (99%) of N-[3-(2-iodo-5-methoxyphenyl)-1-methylpropyl]-3,4-dimethoxy-N-methylbenzeneacetamide as an orange gum, MS (high resolution):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[N:15][OH:16]
Reactant: NO
Reactant: COc1cccc2c1CCCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cccc2c1CCCC2=NO
Temperature: 25 °C
Yield: 97.7 %

Procedure:
In a mixture of 240 ml of ethanol and 80 ml of water were dispersed 50 g of 5-methoxytetralone, 20 g of hydroxylamine hydrochloride, and 56 g of sodium acetate, and the dispersion was heat-refluxed for 4 hours. After cooling to room temperature, the reaction mixture was poured into 400 ml of water. The precipitated crystals were collected by filtration and dried to obtain 53 g of 5-methoxytetralone oxime.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].C(=O)([O-])[O-].[K+].[K+].[I:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>CC(C)=O>[Cl:5][CH2:4][CH2:3][CH2:2][O:19][C:16]1[CH:17]=[CH:18][C:13]([I:12])=[CH:14][CH:15]=1
Reactant: Oc1ccc(I)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCOc1ccc(I)cc1
Temperature: 25 °C
Yield: 111.3 %

Procedure:
1-Bromo-3-chloropropane (21.4 g, 136 mmol) and potassium carbonate (30 g, 217 mmol) were added to an acetone (300 mL) solution of 4-iodophenol (20 g, 90.9 mmol), and stirred under reflux for 20 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the entitled compound (30 g, 100%).
Reaction SMILES: C(OC(C[N:7]1[C:16](=[O:17])[CH:15]2[CH:10]([CH:11]3[C:18](=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]2[C:13]([C:32]([OH:45])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:12]3)[C:8]1=[O:9])=O)C.[C:46]([O:52][CH2:53]Cl)(=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:45][C:32]([C:13]1[CH:14]2[C:18](=[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:11]([CH:12]=1)[CH:10]1[C:8]([N:7]([CH2:53][O:52][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C:16](=[O:17])[CH:15]21)=[O:9])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)CN1C(=O)C2C3C=C(C(O)(c4ccccc4)c4ccccn4)C(C3=C(c3ccccc3)c3ccccn3)C2C1=O
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCN1C(=O)C2C3C=C(C(O)(c4ccccc4)c4ccccn4)C(C3=C(c3ccccc3)c3ccccn3)C2C1=O
Yield: 48 %

Procedure:
A similar procedure (Hursthouse, M. B.; Khan, A.; Marson, C. M.; Porter, R. A. Tetrahedron Lett 1995, 36, 33, 5979-5982) to that described for the preparation of 207 was followed using NRB (200 mg, 0.39 mmol) in dimethylformamide (2 mL), chloromethyl pivalate (41) (59 mg, 0.39 mmol) in dimethylformamide (0.5 mL), and potassium carbonate (54 mg, 0.39 mmol). Purification by flash chromatography (hexane/ethyl acetate 1:1) afforded 8 as a colourless solid (118 mg, 0.19 mmol, 48%). mp 95-98° C.; 1H NMR (400 MHz, CDCl3) δ 1.18-1.19 (8.4H, m, tBu), 1.25-1.26 (0.6H, m, tBu), 3.38 (0.2H, dd, J=7.9 and 4.5 Hz, W/H-3), 3.45 (0.5H, dd, J=7.9 and 4.5 Hz, Y/H-3), 3.51-3.59 (0.4H, m, 0.2H U/H-2 and U/H-3, 0.2H V/H-2), 3.63-3.64 (0.2H, m, W/H-4), 3.67-3.76 (0.9H, m, 0.2H V/H-3, 0.2H W/H-2 and 0.5H Y/H-2), 3.88-3.92 (0.3H, m, 0.1H U/H-1 and 0.2H V/H-1), 4.00-4.01 (0.5H, dt, J=4.5 and 1.3 Hz, Y/H-4), 4.20-4.21 (0.1H, m, U/H-4), 4.35-4.36 (0.2H, dt, J=4.5 and 1.3 Hz, V/H-4), 4.49-4.52 (0.7H, m, 0.2H W/H-1 and 0.5H Y/H-1), 5.26-5.29 (0.7H, m, CH2), 5.31-5.62 (3H, m, 1.3H CH2, 0.2H V/H-6, 0.5H Y/H-6 and 1H OH), 6.04-6.06 (0.3H, m, 0.1H U/H-6 and 0.211 W/H-6), 6.71-7.57 (16H, m, Ar), 8.42-8.50 (0.6H, m, 0.2H 2U/αPyr and 0.4H 2VαPyr), 8.54-8.55 (0.7H, m, 0.2H W/αPyr and 0.5H Y/αPyr), 8.61-8.63 (0.7H, m, 0.2H W/αPyr and 0.5H Y/αPyr); vmax(nujol)/cm−1 1140 and 1212 (C—O ester), 1586 (C═O imide), 1715 (C═O ester); m/z (FAB+) 626 (MH+, 67%), 120 (100); (Found: MH+ 626.2644, C39H36N3O5 requires 626.2655).
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Br:5][C:6]1[CH:7]=[C:8]([C:16]2[N:17]=[C:18]3[N:23]([CH:24]=2)[N:22]=[C:21](Cl)[CH:20]=[CH:19]3)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13]>C1COCC1>[Br:5][C:6]1[CH:7]=[C:8]([C:16]2[N:17]=[C:18]3[CH:19]=[CH:20][C:21]([O:3][CH2:2][CH3:1])=[N:22][N:23]3[CH:24]=2)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13]
Reactant: FC(F)(F)c1ccc(-c2cn3nc(Cl)ccc3n2)cc1Br
Reactant: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc2nc(-c3ccc(C(F)(F)F)c(Br)c3)cn2n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
NaOEt (21% in EtOH, 2.97 mL) is added to a mixture of 2-[3-bromo-4-(trifluoromethyl)phenyl]-6-chloro-imidazo[2,1-f]pyridazine (1.5 g, 3.98 mmol) in THF (50 mL). The mixture is stirred for 4 hours at 50° C., then the THF solution is concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (1.36 g, 88.8% yield). LCMS (m/z)=386.3, 388.3 [M+H]+, tR=3.34 min. (compound same as Example 204)
Reaction SMILES: [CH2:1]1[CH:8]([NH2:9])[C:6](=[O:7])[NH:5][C:3](=[O:4])[CH2:2]1.Cl.Br[CH2:12][C:13]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:14]=1[C:15](OC)=[O:16].C(N(CC)CC)C>CN(C)C=O>[O:16]=[C:15]1[C:14]2[C:13](=[C:22]([CH3:23])[CH:21]=[CH:20][CH:19]=2)[CH2:12][N:9]1[CH:8]1[CH2:1][CH2:2][C:3](=[O:4])[NH:5][C:6]1=[O:7]
Reactant: COC(=O)c1cccc(C)c1CBr
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 16.25 g of 2,6-dioxopiperidin-3-ammonium chloride, and 30.1 g of methyl 2-bromomethyl-3-methylbenzoate, and 12.5 g of triethylamine in 100 mL of dimethylformamide is stirred at room temperature for 15 hours. The mixture is then concentrated in vacuo and the residue mixed with methylene chloride and water. The aqueous layer is separated and back-extracted with methylene chloride. The combined methylene chloride solutions are dried over magnesium sulfate and concentrated in vacuo to give 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].CC(C)([O-])C.[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: COc1ccccc1S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccccc1SCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 25.0 g (178 mmol) of 2-methoxythiophenol in 50 mL of dry tetrahydrofuran was added dropwise to a mixture of 22.0 g (196 mmol) of potassium t-butoxide and 100 mL of tetrahydrofuran at 0° C. with stirring. A solution of 25 mL (214 mmol) of benzyl chloride in 50 mL of tetrahydrofuran was added to this with stirring and cooling and the mixture was then allowed to warm to ambient temperature and was stirred for 18 hours. The resulting mixture was concentrated by evaporation under reduced pressure and the residue was diluted with 300 mL of dichloromethane. The solution obtained was washed with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was the title compound, a white solid melting at 69-70° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C.O>[Br:20][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:12])[C:3]2([CH2:1][CH3:2])[CH2:13][CH3:14]
Reactant: CCC1(CC)C(=O)Nc2ccccc21
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC1(CC)C(=O)Nc2ccc(Br)cc21

Procedure:
A solution of 3,3-diethylindol-2-one (8 g, 40 mmol) and sodium acetate (4 g, 48 mmol) in aceticacid (100 ml) was treated with bromine (6.4 g, 40 mmol). After 30 min. the mixture was diluted with water and extracted with EtOAc (2×); the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, then brine, dried (MgSO4) and evaporated to afford the crude product (7.6 g, 75%). A sample was recrystallized from EtOAc/hexane to obtain the title compound, m.p. 164-165° C.; 1H-NMR (DMSO-d6) δ 10.45 (s, 1H), 7.41-7.40(d, 1H, J=2.2 Hz), 7.34-7.31 (m, 1H), 6.78-6.76 (d, 1H J=8.2 Hz), 1.78-1.65 (t, 4H), 0.50-0.46 (m, 6H); MS (−ESI) m/z 266/268 (M−H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[CH:16]=3)[N:11]([CH3:27])[C:10](=[O:28])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Si:29]([C:33]#[CH:34])([CH3:32])([CH3:31])[CH3:30]>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:15]2[CH:16]=[C:17]3[C:12](=[N:13][CH:14]=2)[N:11]([CH3:27])[C:10](=[O:28])[CH:9]=[C:8]3[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:34]#[C:33][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:3]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: Cn1c(=O)cc(-c2cccc(Br)c2)c2cc(C(=O)c3ccc(Cl)cc3)cnc21
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(=O)cc(-c2cccc(C#C[Si](C)(C)C)c2)c2cc(C(=O)c3ccc(Cl)cc3)cnc21
Temperature: 60 °C
Yield: 79.3 %

Procedure:
To a solution of compound I (1 g, 2.21 mmol) in THF (10.0 mL), TEA (4 mL) was added followed by (PPh3)4Pd (0.25 g, 0.22 mmol) and CuI (42 mg, 0.22 mmol). The mixture was degassed using N2 for 30 min and TMS-acetylene (0.92 g, 6.64 mmol) was added. The mixture was heated in a microwave oven at 60° C. for 30 min. The reaction mixture was diluted with EtOAc (25 mL) and passed through a pad of celite. The filtrate was concentrated. Purification of the crude product provided 825 mg (80%) of compound J.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:15][CH2:14][C:13](=O)[CH2:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:17]([O:21][C:22](=[O:28])[NH:23][CH:24]1[CH2:27][NH:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:17]([O:21][C:22](=[O:28])[NH:23][CH:24]1[CH2:27][N:26]([CH:13]2[CH2:14][CH2:15][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[CH:11][CH2:12]2)[CH2:25]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C1CC=C(c2ccc3c(c2)OCO3)CC1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CN(C2CC=C(c3ccc4c(c3)OCO4)CC2)C1
Reaction time: 4 h

Procedure:
A solution of 4-benzo[1,3]dioxol-5-yl-cyclohex-3-enone (as prepared in the previous step, 680 mg, 3.15 mmol) and azetidin-3-yl-carbamic acid tert-butyl ester (BetaPharma, 542 mg, 3.15 mmol) in DCM (10 mL) was treated with NaBH(OAc)3 (Aldrich, 2.0 g, 9.45 mmol) at room temperature. The reaction was stirred for 4 hours and quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using hexanes and ethyl acetate as eluent (from pure hexanes to pure ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:24][CH3:25])=[CH:12][C:13]2[O:18][C:17](=[O:19])[C:16]3[CH2:20][CH2:21][CH2:22][C:15]=3[C:14]=2[CH:23]=1)(=O)=O.[C:26]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>C(O)C>[CH3:25][O:24][C:11]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:35]2[CH2:36][CH2:37][CH:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:33][CH2:34]2)=[CH:23][C:14]2[C:15]3[CH2:22][CH2:21][CH2:20][C:16]=3[C:17](=[O:19])[O:18][C:13]=2[CH:12]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCOS(C)(=O)=O)CCC3
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)O
Solvent: CCO
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCC(c2ccccc2)CC1)CCC3
Yield: 65 %

Procedure:
Method B (60 h at 25° C.); starting materials: 2,3-dihydro-8-[3-(methanesulfonyloxy)propoxy]-7-methoxy-cyclopenta[c][1]-benzopyran-4(1H)-one (example 82) and 4-phenylpiperidine; yield 65%; fusion point 164°-166° C. (from isopropanol). Fumarate: method E; yield 86%; fusion point 195°-198° C. (from ethanol).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)[CH3:5].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[S:20]([CH2:2][CH2:3][N:4]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)[CH3:5])([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(CCO)c1ccc(C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCN(C)c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 0.5 mol of 4-[N-2-hydroxyethyl-N-methylamino]benzaldehyde in methylene chloride at 0° C. are added 0.51 mol of p-toluenesulfonyl chloride, 0.51 mol of triethylamine, and 0.005 mol of N,N-dimethylaminopyridine, and the reaction medium is warmed slowly to room temperature. After standing at room temperature for one hour, the reaction product medium is washed with cold 1N HCL, saturated sodium bicarbonate solution, and water. The organic solution is separated and dried over molecular sieves, filtered through cotton, and evaporated to yield the 4-[N-2-tosylethyl-N-methylamino]-benzaldehyde as a crystalline product, which then is recrystallized from ethanol.