Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:31])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.CCN(C(C)C)C(C)C.[C:41]([O:45][C:46]([N:48]([CH2:50][C:51](O)=[O:52])[CH3:49])=[O:47])([CH3:44])([CH3:43])[CH3:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:41]([O:45][C:46](=[O:47])[N:48]([CH2:50][C:51](=[O:52])[NH:1][CH2:2][C@H:3]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2)[CH3:31])[CH3:49])([CH3:44])([CH3:42])[CH3:43]
Reactant: C[C@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CNC(=O)CN(C)C(=O)OC(C)(C)C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reaction time: 18 h

Procedure:
5-[(1R)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 65, preparation of starting materials, 868 mg) was stirred in DCM (40 ml) with DIPEA (1 ml). N-(tert-butoxycarbonyl)sarcosine (400 mg) and HATU (800 mg) were added and mixture was stirred for 18 hours. Volatile material was removed by evaporation and the residue was purified by chromatography, eluting with increasing concentrations of methanol in ethyl acetate (0-10%). Evaporation of the appropriate fractions gave the title compound as a froth (0.50 g); NMR spectrum (DMSO-d6 @ 373k) 1.10 (s, 6H), 1.20 (s, 3H), 1.40-1.42 (d, 3H), 2.72 (s, 3H), 3.40-3.60 (d, 1H, (masked by H2O), 3.60-3.75 (q, 2H), 3.75-3.80 (d, 1H), 4.90-5.00 (bs, 1H), 5.30 (s, 2H), 7.28-7.34 (q, 2H), 7.34-7.40 (m, 1H), 7.42-7.46 (d, 1H), 7.50-7.62 (m, 2H), 7.85-7.91 (dt, 1H), 7.91-7.99 (m, 2H), 8.24-8.34 (bs, 1H), 8.57-8.62 (d, 1H), 8.75 (s, 1H), 10.60-10.70 (bs, 1H); Mass spectrum MH+ 607.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: Clc1cccc(CBr)c1
Product: Nc1nc(N)c2c(N3CCN(Cc4cccc(Cl)c4)CC3)cccc2n1
Yield: 67 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 3-Chlorobenzyl bromide (76 mg; 0.37 mmol) to obtain 49.5 mg. (67% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.4 (s, 1H), 10.0 (s, 1H), 9.0 (s, 1H), 7.72 (m, 2H), 7.34 (m, 4H), 7.22 (d, J=8.0 Hz, 1H), 3.59 (s, 2H), 3.03 (br d, J=10.8 Hz, 2H), 2.90 (m, 4H), 2.31 (m, 2H). ESIMS+369.2 m/z
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18]C(O)=[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])=[O:22])[CH:15]=1.Cl>O1CCCC1.N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:5]2[O:4][C:2](=[O:3])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:31])([F:32])[F:33])[C:21](=[O:22])[C:16]=2[CH:15]=1
Reactant: COC(=O)Cl
Reactant: O=C(Nc1ccccc1C(F)(F)F)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 31 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 5 (1.56 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 17.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C1COCC1.[Br:17][C:18]([CH3:23])([CH3:22])[C:19](Br)=[O:20]>CCN(CC)CC>[Br:17][C:18]([CH3:23])([CH3:22])[C:19]([NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11])=[O:20]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)(Br)C(=O)Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(Br)C(=O)Nc1cc([N+](=O)[O-])ccc1O
Reaction time: 0.75 h

Procedure:
2-Amino-4-nitro-phenol (3.08 g, Aldrich) was stirred with THF (30 ml, Aldrich) in an ice bath. 2-Bromo-2-methyl-propionyl bromide (2.47 ml, Aldrich) and Et3N (2.0 g, Aldrich) was slowly added via syringe. The mixture was stirred for 45 min then poured into ice. The aqueous phase was extracted by EtOAc (50 mL×4). The organic layer was dried and concentrated. The desired product was crystallized from EtOAc. (Chem. Pharm. Bull 1996, 44(1) 103–114).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[F:18][C:19]1[C:20]([OH:29])=[CH:21][C:22]2[CH2:26][O:25][B:24]([OH:27])[C:23]=2[CH:28]=1>>[Cl:1][C:2]1[C:3]([O:29][C:20]2[C:19]([F:18])=[CH:28][C:23]3[B:24]([OH:27])[O:25][CH2:26][C:22]=3[CH:21]=2)=[N:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: OB1OCc2cc(O)c(F)cc21
Reactant: CC(=O)CCCOc1nc(Cl)c(Cl)cc1C#N
Product: CC(=O)CCCOc1nc(Oc2cc3c(cc2F)B(O)OC3)c(Cl)cc1C#N

Procedure:
This compound was prepared from 5,6-dichloro-2-(4-oxopentyloxy)nicotinonitrile and 6-fluorobenzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.63-1.67 (m, 2H), 2.02 (s, 3H), 2.3 (t, J=5.25 Hz, 2H), 3.94 (t, J=4.95 Hz, 2H), 5.0 (s, 2H), 7.51 (d, J=4.8 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 8.62 (s, 1H), 9.4 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[CH2:11]([O:13][C:14]([Sn](CCCC)(CCCC)CCCC)=[CH2:15])[CH3:12].[F-].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:14]([O:13][C:11]([C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1)=[CH2:12])[CH3:15]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCOc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(OCC)c1nccc(OCC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
A solution of 2-chloro-4-ethoxypyrimidine (6.34 g), (1-ethoxyvinyl)-tri-n-butyltin (14.4 g) and bis(triphenylphosphine)palladium(II) chloride (1 g) in DMF (60 ml) was heated at 90° C. for 60 hours. The reaction mixture was cooled to room temperature and potassium fluoride (100 ml of a 10% aqueous solution) was added. The resulting mixture was stirred for 1 hour then filtered through Hyflo supercel filter aid which was rinsed through with ether. The filtrate was extracted with ether (×2) and the combined extracts were washed with brine, then dried, concentrated and chromatographed using ethyl acetate:hexane 1:4 as the eluant to give 1-ethoxy-1-(4-ethoxypyrimidin-2-yl)-ethylene (2.7 g, 35% yield) as an orange oil; IR maximum (film): 1550cm-1 ; 1H NMR (270 MHz): δ1.40(3H,t), 1.50(3H,t), 4.02(2H,q), 4.45(2H,q), 4.58(1H,d), 5.65(1H,d), 6.60(1 H,d), 8.48(1H,d) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11](I)[S:12][C:3]=12.[CH3:14][N:15]([CH3:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.O>COCCOC.C(=O)(O)[O-].[Na+].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>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11]([C:19]3[CH:20]=[CH:21][C:16]([N:15]([CH3:25])[CH3:14])=[CH:17][CH:18]=3)[S:12][C:3]=12
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: N#Cc1cnc2cc(I)sc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN(C)c1ccc(-c2cc3ncc(C#N)c(Cl)c3s2)cc1
Yield: 59.6 %

Procedure:
A mixture of 7-chloro-2-iodothieno[3,2-b]pyridine-6-carbonitrile (321 mg, 1.0 mmol), 4-(dimethylamino)phenylboronic acid (248 mg, 1.5 mmol) and 58 mgs of tetrakis(triphenylphosphine)palladium (0) in 13 mL of ethylene glycol dimethyl ether and 11 mL of aqueous saturated sodium bicarbonate is heated at reflux for 6 hours. 4-(dimethylamino)phenylboronic acid (105 mg) and tetrakis(triphenylphosphine)palladium (0) (29 mg) are added and the reaction mixture is heated at reflux for 6 hours. The mixture is treated with water and extracted into dichloromethane and the organic phase is washed with brine and dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of dichloromethane to 2% ethyl acetate in dichloromethane to provide 187 mg (60%) of 7-chloro-2-[4-(dimethylamino)phenyl]thieno[3,2-b]pyridine-6-carbonitrile as an orange solid, mp 270–272° C.; 1H NMR (CDCl3) δ 3.07 (s, 6H), 6.73 (d, J=5 Hz, 2H), 7.58 (s, 1H), 7.63 (d, J=5 Hz, 2H), 8.74 (s, 1H); HRMS found: 314.05127.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=2)[C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=3[C:12]=2[CH2:13][O:14][CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=3[C:12]=2[CH2:13][O:14][CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1c(C(Nc2ccc(C(=O)OC)cc2)C2CCCCC2)oc2ccc(F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a mixture of methyl 4-({cyclohexyl[5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl]methyl}amino)benzoate (454 mg) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10.0 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (10.0 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (423 mg, 96%) as a white solid.
Reaction SMILES: C(O)C.Cl.[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7][CH:6]1[CH2:15][C:16]1([Cl:47])[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][CH:17]1[O:25][CH:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][C:27]1([Cl:46])[CH2:35][CH:36]1[CH:41]=[CH:40][C:39]2[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=2[O:37]1.[OH-].[Na+]>[Fe].O>[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7][CH:6]1[CH2:15][C:16]1([Cl:47])[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][CH:17]1[O:25][CH:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]1([Cl:46])[CH2:35][CH:36]1[CH:41]=[CH:40][C:39]2[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=2[O:37]1
Reactant: O=[N+]([O-])C1=CC(Cl)(CC2C=Cc3ccccc3O2)C(OC2C=CC([N+](=O)[O-])=CC2(Cl)CC2C=Cc3ccccc3O2)C=C1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC1=CC(Cl)(CC2C=Cc3ccccc3O2)C(OC2C=CC(N)=CC2(Cl)CC2C=Cc3ccccc3O2)C=C1

Procedure:
Under an argon atmosphere, 22.3 g. electrolyte iron, 64 ml. ethanol and 53.4 ml. water were mixed together. To the resultant stirred mixture was added in one portion 1.88 ml. concentrated hydrochloric acid and the resulting mixture heated to reflux. 4.1 g. of the nitro ether prepared in Example I was added to this hot stirred mixture. The addition was made in portions of near reflux temperatures. The mixture was then refluxed for 30 minutes and 1.26 ml. of 50% sodium hydroxide solution was added. This mixture was filtered while hot through dicalite. The filtrate was concentrated in vacuo and then taken up in 200 ml. of methylene chloride, washed with two 500 ml. portions of water and four 100 ml. portions of saturated sodium carbonate solution. The washed mixture was dried over magnesium sulfate and evaporated in vacuo to yield 34 g. of product having a m.p. of 90°-91° C. The product was identified as the title product by IR and NMR analyses.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])=[CH:7][CH:6]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(CCCOS(C)(=O)=O)cc1
Reaction time: 8 h
Yield: 91.9 %

Procedure:
tert-Butyl 4-(3-hydroxypropyl)phenylcarbamate (327 mg, 1.301 mmol) in DCM (15 ml) was cooled in an ice-bath. Triethylamine (0.23 ml, 1.626 mmol) was added, and then methanesulfonyl chloride (164 mg, 1.431 mmol) was added. The mixture was stirred overnight and the temperature was allowed going up to room temperature. It was then washed with water, sodium hydrogencarbonate aqueous solution (1%), water and brine and dried with magnesium sulfate. Evaporation in vacuum to remove the solvent gave the desired product (394 mg), yield 92%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[ClH:13].[N:14]1([C:19](=N)[NH2:20])C=CC=N1>CC#N>[ClH:13].[N:1]1([C:19](=[NH:14])[NH2:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N=C(N)n1cccn1
Reactant: C1CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N=C(N)N1CCCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of pyrrolidine (5.8 mL, 70.30 mmol) in CH3CN (30 mL). Triethylamine (9.8 mL, 70.17 mmol) and 1H-pyrazole-1-carboximidamide hydrochloride (10.2 g, 69.59 mmol) was added to the reaction. The reaction mixture was stirred overnight at 60° C. The product was collected by filtration to yield 7.5 g (71%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[I-].[K+].[OH-].[K+].Cl[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>C(O)C.O>[OH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: OCCCCCCCl
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C=Cc1ccc(OCCCCCCO)cc1
Temperature: 35 °C

Procedure:
To a mixture of 24.62 g (0.15 mole) 4-hydroxycinnamic acid and 0.29 g (1.65 mmole) of potassium iodide in 60 ml of ethanol were added under a nitrogen atmosphere in 10 min a solution of 20.72 g (0.314 mole) of potassium hydroxide in 60 ml of water using a dropping funnel. The resulting solution was heated to 30-40° C. and 6-chlorohexanol (22.54 g, 0.165 mole) was then added in about 10 min. The solution was then refluxed overnight. After cooling, 70 ml of water were added to the solid reaction mixture, and the ethanol was removed using a rotary evaporator. The residue was cooled in an ice/water bath and 70 ml of conc. hydrochloric acid were added under stirring. The solid was collected and washed with water. Then the solid was stirred at 50° C. with 250 ml of acetone. After drying at 100° C. in vacuo 24.5 g (62%) of product 13 were obtained.
Reaction SMILES: O.[C:2]1([C:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(O)[CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34]>>[ClH:34].[C:28]1([C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH2:11]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OC(CC1CCCN(CCc2ccc3c(c2)OCO3)C1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Product: C(=C(c1ccccc1)c1ccccc1)C1CCCN(CCc2ccc3c(c2)OCO3)C1
Yield: 98 %

Procedure:
A solution of 3-(2,2-diphenyl-2-hydroxyethyl)-1-(3,4-methylenedioxyphenethyl)piperidine hydrate (162 mg) (Example 3) in 2M hydrochloric acid (4.5 ml) was heated at 100° C. for 30 minutes and evaporated to give the title compound as a colourless foam (165 mg, 98%), which was characterised as a hydrate.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[S:5]1(=[O:15])(=[O:14])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6]1>S(=O)(=O)(O)O>[N+:1]([C:11]1[CH:12]=[CH:13][C:8]2[CH:7]=[CH:6][S:5](=[O:15])(=[O:14])[C:9]=2[CH:10]=1)([O-:4])=[O:2]
Reactant: O=S1(=O)C=Cc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)C=C2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
Nitric acid (10 mL) was slowly added to sulfuric acid (10 mL) at 0° C., and the mixture was stirred at the same temperature for 10 min. To this solution was slowly added 1-benzothiophene 1,1-dioxide (3.99 g) at 0° C., and the mixture was further stirred at the same temperature for 30 min. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed twice with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound as a pale-yellow solid (yield 4.26 g, 84%).
Reaction SMILES: C(OC(=O)C[C:6]([CH2:8][C:9](=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])=[O:7])C.[CH2:22]([OH:24])[CH3:23]>>[CH2:22]([O:24][C:6](=[O:7])[CH2:8][C:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])=[O:20])[CH3:23]
Reactant: CCO
Reactant: CCOC(=O)CC(=O)CC(=O)Cc1ccccc1[N+](=O)[O-]
Product: CCOC(=O)CC(=O)Cc1ccccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
30 gm (0.103M) ethyl-o-nitrophenylacetylacetoacetate was added over a period of 15-20 minutes to a saturated ammoniacal ethanol solution (prepared by bubbling NH3 gas into 400 cc. absolute alcohol for 15- 20 minutes while cooling the solution to 0- 5° C.). The orangy mixture was stirred for 1 hour at 5°- 10° C. and then left in the refrigerator overnight. The ethyl-γ-2-nitrophenylacetoacetate crystals formed were filtered and dried in vacuum. Additional solid was obtained after evaporation of the filtrate and washing with water to remove any amide formed.
Reaction SMILES: [C:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[CH:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:30])C.O>ClCCl>[CH:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[CH:4]=1)=[O:30]
Reactant: CC(=O)O
Reactant: Cc1cc2c(cc1C#N)C(C)(C)CCC2(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a solution of 18.7 g (82.3 mmol) of 2-cyano-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 280 mL of dichloromethane, cooled at −78°, was added 123 mL (123 mmol) of diisobutyl aluminum hydride (1.0 M in toluene). The reaction mixture was stirred and allowed to gradually warm to room temperature. After 16 hours, the reaction mixture was treated with 30 mL of acetic acid added dropwise, followed by 150 mL of water. The organic layer was separated, diluted with 200 mL of hexane, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution 5-10% ethyl acetate/hexane) on silica gel to afford 11.8 g (63%) of 2-formyl-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][CH2:10][C@@H:9]([CH2:12][O:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)CCl.C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:8]2[C@H:9]([CH2:12][O:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:11][C@@H:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)OC[C@@H]1CC[C@H](c2ccccc2)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[Si](C)(C)OC[C@@H]1CC[C@H](c2ccccc2)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Yield: 47.2 %

Procedure:
To a solution of (2R,5S)-2-phenyl-5-trimethylsilanyloxymethyl-pyrrolidine (0.98 g, 3.9 mmol) in ClCH2CH2Cl (5 mL) was added 1.9 mL (13.7 mmol, 3.5 eq) of Et3N and 1.45 g (6.86 mmol, 1.8 eq) of 4-chlorobenzenesulfonyl chloride. The mixture was heated at 70° C. for 16 hr. After cooling to room temperature, the mixture was diluted with CH2Cl2 (20 mL), washed with water (10 mL), saturated brine (10 mL), dried (Na2SO4) and concentrated under vacuum. The crude product was chromatographed on silica gel (2% EtOAc/hexane) to give 0.78 g (46%) of (2R,5S)-1-(4-chloro-benzenesulfonyl)-2-phenyl-5-trimethylsilanyloxymethyl-pyrrolidine as a yellow gum.
Reaction SMILES: C[O:2][C:3]1[CH:8]=C(CNCCCNCCCCNCCCN)C=[CH:5][C:4]=1O.[OH:25][C:26]1[CH:35]=[C:34]([O:36][CH:37]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH3:38])[CH:33]=[C:32]2[C:27]=1[C:28](=O)[C:29](=CO)[C:30]([CH3:45])([CH3:44])[O:31]2.CC(C=C)=O.[OH-].[K+].Cl>CO.CCOCC.C(O)C.C(N(CC)CC)C>[OH:31][C:32]1[C:27]2[C:28]3=[CH:8][C:3](=[O:2])[CH2:4][CH2:5][CH:29]3[C:30]([CH3:45])([CH3:44])[O:25][C:26]=2[CH:35]=[C:34]([O:36][CH:37]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH3:38])[CH:33]=1
Reactant: CCCCCC(C)Oc1cc(O)c2c(c1)OC(C)(C)C(=CO)C2=O
Reactant: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: C=CC(C)=O
Agent: Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOCC
Product: CCCCCC(C)Oc1cc(O)c2c(c1)OC(C)(C)C1CCC(=O)C=C21
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.3 %

Procedure:
To a solution of dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7-(2-heptyloxy)-4-chromanone (5.17 g., 15.4 mM) and methylvinyl ketone (2.27 ml., 27.9 mM) in methanol (23 ml.) is added triethylamine (0.54 ml.). The reaction is stirred for 16 hours at room temperature and then diluted with ether (250 ml.). The resulting ether solution is extracted with 10% sodium carbonate (6×30 ml.), dried over sodium sulfate, and concentrated under vacuum to yield 6.11 g. of an oil. The residue is refluxed with ethanol (45 ml.) and 2 N potassium hydroxide (45 ml.) for 16 hours. Thereafter, the reaction solution is cooled, acidified with 6 N hydrochloric acid and extracted with dichloromethane (3×100 ml.). The organic phase is dried over sodium sulfate and evaporated to yield 6.3 g. of a dark solid. The solid is triturated in hot ether to yield 1.00 g. of the title compound, m.p. 185°-189° C.; 1.26 g. of further material is obtained via silica gel chromatography of the mother liquor. The total yield is 42.3%.