Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])C.[NH4+:14].[OH-]>>[CH3:12][S:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([NH2:14])=[O:3])(=[O:11])=[O:10]
Reactant: CCOC(=O)CCCNS(C)(=O)=O
Reactant: [NH4+]
Agent: [OH-]
Product: CS(=O)(=O)NCCCC(N)=O

Procedure:
A solution of 4-methanesulfonylamino-butyric acid ethyl ester (7.08 g, 33.8 mmol) in concentrated NH4OH (200 mL) was stirred at room temperature for 66 h. The reaction mixture was concentrated to afford the title compound as a white solid (6.16 g). The product was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.30 (s, 3H), 3.05-3.09 (m, 2H), 2.91 (s, 3H), 2.24-2.30 (m, 2H), 1.80-1.85 (m, 2H); MS 181 (M++1).
Reaction SMILES: [CH2:1]([C:5]1([CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=O)[CH2:2][CH2:3][CH3:4].N1CCCC1.C(O)(=O)C>>[CH2:1]([C:5]12[CH2:17][CH2:18][C:19](=[O:21])[CH:20]=[C:6]1[C:7]1[C:12](=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=1)[CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCC(C)=O)Cc2cc(OC)ccc2C1=O
Solvent: C1CCNC1
Solvent: CC(=O)O
Product: CCCCC12CCC(=O)C=C1c1ccc(OC)cc1C2
Temperature: 60 °C

Procedure:
The solution from step 2 was treated with pyrrolidine (6.9 mL, 82 mmol) and acetic acid (4.7 mL, 82 mmol), placed under a nitrogen atmosphere, and stirred with heating in a 60° C. bath for 22 hours. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (500 mL) and water (500 mL). The EtOAc phase was washed with 0.8N HCl (500 mL), water (500 mL), 5% NaHCO3 (500 mL), and brine (200 mL), dried with MgSO4, filtered, and evaporated under vacuum to a brown oil (22.8 g). This material was purified by column chromatography on EM silica gel 60 (230-400 mesh, 684 g), using 5% EtOAc in CH2Cl2 as eluting solvent, to afford 9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (11.2 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][S:9][CH:8]=2)=[N:4][N:3]=1.CC(N=NC(C#N)(C)C)(C#N)C.C([O-])(=O)C.[Na+].C1C(=O)N([Br:43])C(=O)C1>C(O)(=O)C.C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][Br:43])=[CH:14][CH:13]=3)=[CH:10][S:9][CH:8]=2)=[N:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2cscc2-c2nnc(C)o2)cc1
Agent: CC(=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: Cc1nnc(-c2cscc2-c2ccc(CBr)cc2)o1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
5-Methyl-2-(4-(4-methylphenyl)-3-thienyl)-[1,3,4]oxadiazole (3.4 g, 13.3 mmol) was dissolved into carbontetrachloride (60 ml). AIBN (0.21 g), sodium acetate (0.52 g), NBS (2.6 g, 14.6 mmol) and glacial acetic acid (0.52 ml) were added. The reaction mixture was heated at reflux temperature for 8h and then allowed to cool to ambient temperature. The reaction mixture was filtered through silica gel and the filtrate was evaporated in vacuo. The oily residue was dried in vacuo over sodium hydroxide to give 2.6 g of crude 5-methyl-2-(4-(4-bromomethylphenyl)-3-thienyl)- [1,3,4]oxadiazole.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:9]=[CH:10][N:11](C)C)=[N:5][CH:6]=[N:7][CH:8]=1)#[N:2].N[C:15]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=2)[CH:18]=[CH:17][C:16]=1[S:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1.NC1C=C(C)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(SCC)=NC=1)#N>>[Br:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][O:21][C:19]1[CH:20]=[CH:15][C:16]([S:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[C:17]([NH:2][C:1]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][CH:8]=3)[N:9]=[CH:10][N:11]=2)[CH:18]=1
Reactant: CN(C)C=Nc1ncncc1C#N
Reactant: Nc1cc(OCc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Agent: CCSc1ncc(C#N)c(N=CN(C)C)n1
Agent: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: Oc1ccc(Sc2ccc(OCc3cccc(Br)c3)cc2Nc2ncnc3ncncc23)cc1

Procedure:
The product from Example 194A was reacted with the product from Example 15A according to the procedure from Example 156C substituting the product from Example 15A for the product from Example 6c and substituting the product from Example 194A for the product from Example 156B to provide the crude product which was purified by HPLC with NH4OAc to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 5.12 (s, 2H), 6.64 (d, J=8.82 Hz, 2H), 6.93-7.04 (m, 1H), 7.10 (d, J=8.82 Hz, 2H), 7.14-7.23 (m, 2H), 7.36 (t, J=7.72 Hz, 1H), 7.43-7.49 (m, 1H), 7.54 (dt, J=7.81, 1.61 Hz, 1H), 7.65 (d, J=1.47 Hz, 1H), 9.04 (m, 1H), 9.63 (s, 1H), 10.29 (m, 1H); MS (ESI−) m/z 531 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([CH3:42])[CH:14]([OH:41])[CH:15]([CH3:40])[C:16](=[N:38][OH:39])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:43].[Na].Cl.[N+](=[CH2:48])=[N-]>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([CH3:42])[CH:14]([OH:41])[CH:15]([CH3:40])[C:16](=[N:38][OH:39])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:4]([C:5]([O:7][CH3:48])=[O:6])[C:3]=1[OH:43]
Reactant: CCC(C(=NO)C(C)C(O)C(C)CCc1ccc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Reactant: C=[N+]=[N-]
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Product: CCC(C(=NO)C(C)C(O)C(C)CCc1ccc(C)c(O)c1C(=O)OC)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C

Procedure:
A solution of 3.55 g of (-)-3-methyl-6-{7-ethyl-4-hydroxy-6-hydroxyimino-3,5-dimethyl-7-[5-ethyl-3-methyl-5-(5-ethyl-5hydroxy-6-methyl-2tetrahydropyranyl)-2-tetrahydrofuryl]heptyl}salicylic acid, sodium salt in 100 ml methylene chloride was treated with 1N HCl. The solvent layer was separated, washed with water and concentrated under reduced pressure to a solid. A portion (1.3 g) of the solid, equal to 2.15 millimole, was dissolved in ether and treated with 4.25 millimole of an ethereal solution of diazomethane. At the end of one hour the solvent was removed at reduced pressure leaving an oil which upon standing under a high vacuum solidified to yield 3-methyl-6-{7-ethyl-4-hydroxy-6-hydroxyimino-3,5-dimethyl-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyl} salicylic acid, methyl ester, isomer A; [α]D25 +5.77° (1.03, CH3OH).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].I[CH2:11][CH2:12][CH3:13].OCC(CO)O.[OH-].[K+]>>[C:1]([N:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCI
Reactant: CC(C)CNC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: OCC(O)CO
Product: CCCN(CC(C)C)C(C)(C)C

Procedure:
A mixture of tert-butylisobutylamine (19.39 g, 0.15 mol), 1-iodopropane (20.40 g, 0.12 mol) and glycerol (5.53 g, 60 mmol) was refluxed for 40 h. Aqueous 8 M potassium hydroxide (30 ml, 0.24 mol) was added, the organic layer was separated and the aqueous layer was extracted with n-pentane (50 ml). The organic solutions were combined, dried over anhydrous magnesium sulfate and the product was isolated by distillation to yield 12.52 g, (61%), bp 72-73° C./18 mm Hg; 1H NMR (CDCl3) δ0.80 (t, J=6.2 Hz, 3H, CH3), 0.84 (d, J=6.6 Hz, 6H, CH3), 1.01 (s, 9H, CH3), 1.40 (sextet, J=6.2 Hz, 2H, CH2), 159 (nonet, J=6.6 Hz, 1H, CH), 2.16 (d, J=6.6 Hz, 2H, CH2), 2.34 (m, 2H, CH2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[C@H:35]1[CH2:40][CH2:39][C@H:38]([CH2:41][CH3:42])[CH2:37][CH2:36]1)(=O)=O>C(O)(C)(C)C.CC(=O)CC>[CH2:41]([C@@H:38]1[CH2:39][CH2:40][C@H:35]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:6]=[CH:5]3)[CH2:36][CH2:37]1)[CH3:42]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Reactant: CC[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: CC(C)(C)O
Product: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@@H](CC)CC4)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 1-((6-hydroxynaphthalen-2-yl)methyl)piperidine-4-carboxylate (2.43 g, 8 mmol, 1.0 eq) in the co-solvent t-butanol/2-butanone (40 mL/20 mL) was added cesium carbonate (5.0 g, 16 mmol, 2.0 eq). The mixture was stirred at 80° C. for 10 min and then trans-4-ethylcyclohexyl methanesulfonate (3.2 g, 16 mmol, 2.0 eq) was introduced. The suspension was stirred at 80° C. under N2 for 15 h. Then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (EtOAc/PE=1:5) to give ethyl 1-((6-(cis-4-ethylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylate as a slight yellow solid (1.6 g, yield: 46%). ESI-MS (M+H)+: 424.3. 1H NMR (400 MHz, CD3OD) δ: 7.63-7.56 (m, 3H), 7.30 (dd, J=8.4, 1.6 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 7.03 (dd, J=8.8, 2.4 Hz, 1H), 4.68-4.66 (m, 1H), 4.01 (q, J=7.2 Hz, 2H), 3.66 (s, 2H), 2.85-2.80 (m, 2H), 2.25-2.22 (m, 1H), 2.11-2.08 (m, 2H), 1.96-1.92 (m, 2H), 1.81-1.77 (m, 2H), 1.65-1.45 (m, 6H), 1.33-1.30 (m, 2H), 1.22-1.12 (m, 3H), 1.13 (t, J=7.2 Hz, 3H), 0.82 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]=[C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[C:4]1=O.B.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][CH:3]([CH2:2][OH:1])[CH2:12][CH2:11]2
Reactant: COc1ccc2c(c1)CCC(=CO)C2=O
Agent: B
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc2c(c1)CCC(CO)C2
Reaction time: 1 h
Yield: 75 %

Procedure:
2-Hydroxymethylene-6-methoxy-1-tetralone (2) (4.81 g, 0.024 mole) and borane:t-butylamine complex (10.25 g, 0.12 mole) were dissolved in about 250 mL of methylene chloride and the solution was cooled to about -78°. Boron trifluoride etherate (14.5 mL, 0.12 mole) was added dropwise and the mixture was stirred for about 1 hour then warmed to about 23° and stirred for an additional 2 hours. The reaction mixture was quenched with about 1N HCl and extracted with methylene chloride. The methylene chloride extracts were dried (MgSO4) and concentrated in vacuo. The crude oil was purified by flash chromatography [gradient 3:1 to 1:2 Hexanes:Ether] to yield the title compound as a light yellow oil (3.41 g, 0.018 mole, 75% yield): IR (Film) 3362, 2996, 2918, 1610, 1504, 1464, 1264, 1234, 1040 cm-1 ; 1H NMR (CDCl3) δ1.40 (m, 1H), 1.47 (s, 1H), 1.95 (m, 2H), 1.39,1.45 (d of d, J=10.6,16.1 Hz, 1H), 2.81 (m, 2H), 3.62 (d, J=6.3 HZ, 2H), 3.77 (s, 3H), 6.62 (d, J=2.6 Hz, 1H), 6.68 (d of d, J=8.4,2.6 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H); MS m/e 193 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1F)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.Cl.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][SH:24].C([Li])CCC.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[S:24][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CN(C)CCS
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCSc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
A 25 ml round-bottom flask with magnetic stirrer was charged with 6-chloro-7-fluoro-8-nitro-9H-β-carboline (98 mg, 0.37 mmol) in 2 ml of anhydrous DMF. A second 10 ml round-bottom flask with magnetic stirrer was charged with 2-dimethylamino-ethanethiol hydrochloride (100 mg, 0.70 mmol) in 2 ml anhydrous DMF. To the resulting suspension was added n-butyllithium (0.43 ml of 1.6 M solution in hexanes, 0.69 mmol) via syringe and the mixture was stirred for 5 min at RT. Next, the thioanion solution was added via syringe to 6-chloro-7-fluoro-8-nitro-9H-β-carboline, and the resulting red solution was stirred at RT for 30 min. The reaction mixture was slowly added to a 5:1 mixture of H2O/saturated aqueous sodium bicarbonate (30 ml) and allowed to sit at RT for several hours. The resulting precipitated solid was collected via suction filtration and air-dried to afford 109 mg of [2-(6-chloro-8-nitro-9H-β-carbolin-7-ylsulfanyl)-ethyl]-dimethyl-amine as an orange solid (83%). LCMS (ammonium acetate standard method) retention time=1.35 min. (M+=351; M−=349). 1H-NMR (300 MHz, CD3OD, ppm) δ 8.92 (1H, d, J=1.0 Hz) 8.66 (1H, s) 8.43 (1H, d) 8.19 (1H, dd) 3.18-3.13 (2H, m) 2.57-2.52 (2H, m) 2.21 (6H, s).
Reaction SMILES: O=[CH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[O:12])[CH2:6][CH2:5]1.[Cl:23][C:24]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:25]=1[O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:23][C:24]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:25]=1[O:26][CH:27]1[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][C@H:4]2[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[O:12])[CH2:6][CH2:5]2)[CH2:31][CH2:32]1
Reactant: Clc1cccc(OC2CCNCC2)c1Cl
Reactant: O=CC[C@H]1CC[C@H](NC(=O)c2ccnc3ccccc23)CC1
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(Oc3cccc(Cl)c3Cl)CC2)CC1)c1ccnc2ccccc12

Procedure:
The title compound was prepared analogously to example 71 using quinoline-4-carboxylic acid trans-[4-(2-oxo-ethyl)-cyclohexyl]-amide and 4-(2,3-dichloro-phenoxy)-piperidine as starting materials.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[F:5][C:6]1[CH:7]=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([OH:12])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:12][C:10]1[CH:11]=[C:6]([F:5])[CH:7]=[CH:8][C:9]=1[N+:13]([O-:15])=[O:14])[CH:2]=[CH2:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(F)ccc1[N+](=O)[O-]
Yield: 74.7 %

Procedure:
Allyl bromide (3.4 g, 28 mmol, 1.5 eq) was added to a mixture of 5-fluoro-2-nitro-phenol (3.0 g, 19 mmol, 1 eq) and potassium carbonate (5.2 g, 38 mmol, 2 eq) in anhydrous acetonitrile (25 ml) and the mixture was heated to reflux for 6 hr. The reaction mixture was filtered and washed with acetonitrile and the filtrate concentrated to dryness to give 2-allyloxy-4-fluoro-1-nitro-benzene (2.8 g, 75%). The crude compound was used in the next stage without purification.
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P(=O)(O)(O)O.O>C1(C)C(C)=CC=CC=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[CH3:1][CH:2]1[C:4]([CH3:6])([CH3:5])[C:11]2[C:10](=[CH:9][CH:8]=[C:7]([OH:13])[CH:12]=2)[CH2:3]1
Reactant: C=C(C)C(=C)C
Reactant: Oc1ccccc1
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1Cc2ccc(O)cc2C1(C)C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
90 g of 2,3-dimethyl-1,3-butadiene, stabilized with 0.2 g of phenothiazine, were added dropwise over the course of 7 hours to a solution of 94 g of phenol, 13 g of 85% strength phosphoric acid and 1 ml of water in 240 ml of xylene at 110° C. To complete the reaction, stirring was continued overnight at 110° C. The acid phase was separated off and extracted by shaking with toluene. The combined organic phases were washed until neutral. Fractional distillation gave 72 g of 2,3,3-trimethyl-5-hydroxy-indane; boiling point: 148° C/12 mm Hg; melting point 66° - 67° C. ##STR36##
Reaction SMILES: NC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC#N)C=CC=1OC.[CH2:24]([O:26][C:27]1[CH:28]=[C:29](Br)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH3:25].[Mg].[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[O:44])=[CH:41][C:40]=1[N+:47]([O-:49])=[O:48]>>[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]([C:29]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([O:26][CH2:24][CH3:25])[CH:28]=2)[OH:44])=[CH:41][C:40]=1[N+:47]([O-:49])=[O:48]
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CCOc1cc(Br)ccc1OC
Agent: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1N
Agent: [Mg]
Product: CCOc1cc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)ccc1OC
Yield: 42.4 %

Procedure:
(4-Methoxy-3-nitro-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol was prepared analogously to 3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile using 3-ethoxy-4-methoxy-bromobenzene (7.6 g, 33 mmol), magnesium turning (0.8 g, 33 mmol) and 4-methoxy-3-nitro-benzaldehyde (5.0 g, 27.6 mmol). The crude product was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 9:1) to afford (4-methoxy-3-nitro-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol (3.9 g, 42%): 1H NMR (CDCl3) δ 7.88 (d, J=2 Hz, 1H), 7.53-7.49 (dd, J=3, 9 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 6.84 (s, 3H), 5.75 (d, J=3 Hz, 1H), 4.01 (m, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 2.30 (d, J=3 Hz, 1H), 1.44 (t, 3H).
Reaction SMILES: Cl[C:2](=[N:7][OH:8])[C:3](Cl)=[N:4][OH:5].[CH2:9]([NH2:12])[CH2:10][NH2:11]>CO>[N:4](=[C:3]1[C:2](=[N:7][OH:8])[NH:12][CH2:9][CH2:10][NH:11]1)[OH:5]
Reactant: ON=C(Cl)C(Cl)=NO
Reactant: NCCN
Solvent: CO
Product: ON=C1NCCNC1=NO
Temperature: 5 °C

Procedure:
Dichloroglyoxime (15.7 g, 0.10 mole) and methanol (400 ml) were placed in a one-liter, round-bottom flask. This solution was cooled to 5° C. by means of a salt-ice bath. While the solution was vigorously stirred, a solution of 12.0 g (0.20 mole) of ethylene diamine in 30 ml of methanol was added in one portion. The mixture was stirred for 10 minutes; then the solvent was removed at reduced pressure. The remaining solid was slurried with 20 ml of water and the crude 2,3-dioximinopiperazine was collected and washed with methanol. The crude product weighed 10.2 g (70%). It can be recrystallized from water (70% recovery) to give the pure compound, 2,3-dioximinopiperazine, with a melting point of 195°-196° C. (dec).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:15][C@H:16]1[CH2:18][O:17]1>C(O)C>[O:17]1[CH2:18][C@H:16]1[CH2:15][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClC[C@H]1CO1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H]2CO2)CC1
Reaction time: 5 h
Yield: 73.3 %

Procedure:
Tert-butyl piperazine-1-carboxylate 7a (3.72 g, 20 mmol) was dissolved in 40 mL of ethanol followed by the addition of (R)-2-chloromethyl-oxirane (1.85 g, 20 mmol). The reaction solution was stirred for 5 hours and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[[(2R)-oxiran-2-yl]methyl]piperazine-1-carboxylate 7b (3.55 g, yield: 74.0%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1.C1COCC1>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:6][C:5]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.9 %

Procedure:
A solution of 3,4,5-trimethoxyaniline (500 mg, 2.8 mmol) in pyridine (5 mL) was treated with 4-methoxybenzenesulfonyl chloride (564 mg, 2.8 mmol) in THF (5 mL), stirred at room temperature for 18 hours, concentrated, redissolved in THF (1 mL), treated with water with stirring, and filtered to provide 820 mg of the desired product.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCNCC3)C2=O)c1
Reactant: O=C(CCCI)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)c1
Yield: 83.4 %

Procedure:
tert-Butyl 3-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.30 g, 0.585 mmol), 4-iodobutyrophenone (0.17 g, 0.585 mmol), and potassium carbonate (0.12 g, 0.878 mmol) in N,N-dimethylformamide (8 mL) were stirred at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.28 g, 82%); MS for C35H47N3O4 m/z 574 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>C(=O)(O)[O-].[Na+]>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])=[CH:22][CH:21]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (14 g), p-methoxyphenol (9.3 g), and 1N sodium bicarbonate (200 ml) was stirred at 90°C for 5 hours. After cooling, the resulting 4-(p-methoxyphenoxy)-3-nitro-5-sulphamyl-benzoic acid was precipitated by the addition of 4N hydrochloric acid until the pH was 1, and collected by suction. The crude acid was dissolved in hot methanol (100 ml) and precipitated by the addition of water (100 ml) and cooling. After collection and drying in vacuo, the melting point was 229°-230°C.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[S:10][CH:11]=[C:12]([Br:14])[CH:13]=1.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16]>C1COCC1.[Cu]I>[Br:14][C:12]1[CH:13]=[C:9]([C:16]#[C:15][Si:17]([CH3:20])([CH3:19])[CH3:18])[S:10][CH:11]=1
Reactant: Brc1csc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(Br)cs1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere 0.37 g (1.94 mmol) CuI, 2.24 g (1.94 mmol) tetrakis-triphenylphosphane-palladium and 16.2 mL triethylamine are added to a solution of 10.0 g (38.85 mmol) 2,4-dibromothiophene in 300 mL THF, the reaction mixture is cooled to −78° C. and then at this temperature a solution of 5.6 mL (38.85 mmol)) ethynyl-trimethyl-silane in 250 mL THF is slowly added dropwise. After the addition has ended the mixture is allowed to heat up slowly to RT and stirred overnight. The mixture is evaporated down i. vac., the residue is combined with water, extracted exhaustively with DCM and the combined organic phases are dried over MgSO4. After the desiccant and solvent have been eliminated the residue is triturated with PE, filtered to remove insoluble ingredients and the solvent is evaporated down. The residue is purified by chromatography (silica gel, PE).