Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:19])[C:9]=1[C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])=[CH:2][CH3:3].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24](S(C)(=O)=O)[N:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([O:19][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]=[CH:2][CH3:3])[C:9]=2[C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])=[O:11])[N:23]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CC=Cc1cccc(O)c1C(=O)OCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC=Cc1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OCC[Si](C)(C)C
Yield: 43.6 %

Procedure:
In a 50 ml round bottom-flask, there were charged 2-trimethylsilylethyl 6-(1-propenyl)salicylate (3.1 g, 11.0 mmol), 4,6-dimethoxy-2-methylsulfonylpyrimidine (2.4 g, 11.0 mmol), potassium carbonate (1.8 g, 13.0 mmol) and 10 ml of N,N-dimethylformamide (hereinafter referred to as "DMF"), and the resultant mixture was reacted for 1 hour at 80° C. After cooling the reaction mixture, DMF was distilled off under reduced pressure, and the residue thus obtained was dissolved in ethyl acetate, washed with water and a saturated salt water, dried with anhydrous sodium sulfate and concentrated. The resultant residue was purified by silica gel column chromatography to obtain 2.0 g (yield: 47.6%) of the aimed product (colorless transparent viscous liquid).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:39])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[O:37][N:36]=[C:35]([CH3:38])[CH:34]=2)[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:11]([C:20]#[N:21])=[CH:10][C:9]2[NH:22][C:23](=[O:39])[CH2:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[O:37][N:36]=[C:35]([CH3:38])[CH:34]=4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(C#N)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-cyano-5-(isobutyl-methyl-amino)-2-{3-[3-(3-methyl-isoxazol-5yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M97) (0.39 g, 0.71 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (230 mg, 75%).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[C:19](=[O:20])[CH2:18][CH2:17][C:16]3=[O:21])[CH:10]=2)[C:5]2[N:22]=[CH:23][CH:24]=[CH:25][C:4]=2[N:3]=1.[Br:26]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:26][CH2:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[C:16](=[O:21])[CH2:17][CH2:18][C:19]3=[O:20])[CH:10]=2)[C:5]2[N:22]=[CH:23][CH:24]=[CH:25][C:4]=2[N:3]=1
Reactant: Cc1nc2cccnc2n(-c2cccc(N3C(=O)CCC3=O)c2)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C1CCC(=O)N1c1cccc(-n2c(=O)c(CBr)nc3cccnc32)c1
Yield: 68.6 %

Procedure:
The solution of 2-methyl-4-(3-succinimidophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (18.4 g), N-bromosuccinimide (12.7 g) and benzoylperoxide (1.6 g) were refluxed for 4 hours. The mixture was evaporated and purified by chromatography (chloroform) to obtain 2-bromomethyl-4-(3-succinimidophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (15.6 g) as yellow crystals.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][NH:7][C:8]1[N:13]=[C:12]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[O:20][CH2:21][C:22](=O)[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:11]=[CH:10][CH:9]=1.C(=O)([O-])O.[Na+]>>[CH3:6][NH:7][C:8]1[N:13]=[C:12]([CH2:14][CH2:15][O:16][C:17]2[CH:33]=[CH:32][C:31]3[C:22]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][O:20][C:19]=3[CH:18]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCC(=O)COc1cccc(OCCc2cccc(NC)n2)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)CCc1coc2cc(OCCc3cccc(NC)n3)ccc12
Reaction time: 0.25 h
Yield: 56.5 %

Procedure:
Concentrated sulfuric acid (3ml) was cooled in an ice-water bath to 0° C. and added to a flask containing ethyl 5-(3-{2-[6-(methylamino)(2-pyridyl)]ethoxy}phenoxy)-4-oxopentanoate (190 mg, 0.5 mmol) at 0° C. The reaction was stirred 15 minutes and then poured over ice. The solution was neutralized with solid sodium hydrogencarbonate (pH=7) and the product was extracted with ethyl acetate. The organic layer was dried, filtered and evaporated under vacuum to yield 104 mg (57%) of Ethyl 3-(6-{2-[6-(methylamino)-2-pyridyl]ethoxy}benzo[b]furan-3-yl)propanoate. NMR 1H Cl3CD δ: 7.36 (m, 3H), 7.01 (d, 1H, J=2.1 Hz), 6.87 (dd, 1H, J=8.5, 2.1 Hz), 6.54 (d, 1H, J=7.2 Hz), 6.23 (d, 1H, J=8.2 Hz), 4.68 (br s, 1H), 4.15 (c, 2H, J=7.4 Hz), 3.09 (t, 2H, J=6.9 Hz), 2.97 (t, 2H, J=6.9 Hz), 2.87 (d, 3H, J=5.1 Hz), 2.68 (t, 2H, J=6.9 Hz), 1.26 (t, 1H, J=7.4 Hz).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:19])(=O)[CH2:14][C:15]#[C:16][CH3:17].[NH2:20][C:21]1[CH2:27][N:26]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[C:24]2[CH:35]=[C:36]([CH2:42][CH3:43])[C:37]([S:39][CH2:40][CH3:41])=[CH:38][C:23]=2[N:22]=1>O1CCCC1.CN(C)C=O>[CH2:40]([S:39][C:37]1[C:36]([CH2:42][CH3:43])=[CH:35][C:24]2[C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)=[N:26][CH2:27][C:21]3[N:22]([C:15]([CH2:16][CH3:17])=[CH:14][C:13](=[O:19])[N:20]=3)[C:23]=2[CH:38]=1)[CH3:41]
Reactant: CCSc1cc2c(cc1CC)C(c1ccc(C)cc1)=NCC(N)=N2
Reactant: CC#CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCSc1cc2c(cc1CC)C(c1ccc(C)cc1)=NCc1nc(=O)cc(CC)n1-2

Procedure:
In the manner given in Example 16, carbonyldiimidazole, 3-pentynoic acid and 2-amino-8-ethylthio-7-ethyl-5-(p-methylphenyl)-3H-1,4-benzodiazepine were stirred in tetrahydrofuran-dimethylformamide to give 10-ethylthio 1,9-diethyl-7-(p-methylphenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [CH2:1]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[O:13]C)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].I[C:22]1[CH:31]=[CH:30][CH:29]=C[C:23]=1[C:24]([O:26][CH3:27])=[O:25]>N1C=CC=CC=1.O.[Cu]I>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:22]=[CH:31][CH:30]=[CH:29][C:12]=1[O:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:13])[C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(OC)cccc1OC
Reactant: COC(=O)c1ccccc1I
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: CCCCc1c(O)cccc1Oc1ccccc1C(=O)OC
Temperature: 25 °C
Yield: 13 %

Procedure:
2-Butyl-1,3-dimethoxybenzene (14.98 g, 77.6 mmol) was de-methylated as described above for the preparation of Example 10(B) to provide 19 g crude product as a brown oil. A solution of 15 g of this material and potassium tert-butoxide (9.70 g, 86.5 mmol) in pyridine (150 mL) was added to a second solution of methyl 2-iodobenzoate (11.9 g, 180 mmol) and copper(I) iodide (17.3 g, 91.0 mmol) in pyridine (150 mL). The resulting mixture was refluxed for 36 hours. The mixture was cooled to room temperature, diluted with water, and extracted three times with diethyl ether. The combined ether fractions were filtered through a mat of Celite®, washed once with 5N aqueous hydrochloric acid, once with 2N aqueous sodium hydroxide, and filtered again through a mat of Celite®. The resulting solution was dried over magnesium sulfate, filtered, and evaporated in vacuo. Silica gel chromatography (ethyl acetate/hexane) provided 3.02 g (11%) of the title intermediate product as an orange oil: NMR (CDCl3) 7.91 (d, J=8 Hz, 1H), 7.41 (t, J=8 Hz, 1H), 7.14 (t, J=8 Hz, 1H), 6.97 (t, J=9 Hz, 1H), 6.83 (d, J=8 Hz, 1H), 6.59 (d, J=8 Hz, 1H), 6.39 (d, J=8 Hz, 1H), 5.04 (bs, 1H, —OH), 3.83 (s, 3H), 2.66 (t, J=9 Hz, 2H), 1.54 (quintet, J=5 Hz, 2H), 1.35 (hextet, J=5 Hz, 2H), 0.91 (t, J=8 Hz, 3H); MS-EI m/e 300 (p, 34), 225 (100), 213 (42), 197 (53), 107 (38); IR (mull, cm−1) 3410, 2926, 1709, 1600, 1463, 1234, 1107, 1090, 992.
Reaction SMILES: [CH3:1][Mg]I.[CH:4]1([C:10]2([CH:18]=[O:19])[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12][CH2:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl>CCOCC>[CH:4]1([C:10]2([CH:18]([OH:19])[CH3:1])[CH2:15][O:14][C:13]([CH3:16])([CH3:17])[O:12][CH2:11]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CC1(C)OCC(C=O)(C2CCCCC2)CO1
Reactant: C[Mg]I
Agent: Cl
Solvent: CCOCC
Product: CC(O)C1(C2CCCCC2)COC(C)(C)OC1
Reaction time: 2 h

Procedure:
Methyl magnesium iodide (3.0 ml, 3M solution in ether) was added to a solution of 5-cyclohexyl-2,2-dimethyl-5- formyl-1,3-dioxane (1.8 g.) in dry ether (50 ml.) The mixture was refluxed, with stirring, for two hours, cooled and poured into a mixture of 2N hydrochloric acid solution in ice. The aqueous mixture was extracted with ether. The ether extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. 5-Cyclohexyl-2,2-dimethyl-5-(1-hydroxyethyl)-1,3-dioxane was obtained as a cream solid (1.5 g.)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@:12]([CH3:20])([CH2:18]I)[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[CH3:29])[NH2:25].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[Zn]>[NH2:25][C:24]1[CH:23]=[CH:22][C:28]([CH3:29])=[C:27]([CH2:18][C@@:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])([CH3:20])[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:26]=1
Reactant: Cc1ccc(N)cc1I
Reactant: COC(=O)C[C@](C)(CI)NC(=O)OCc1ccccc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Zn]
Product: COC(=O)C[C@](C)(Cc1cc(N)ccc1C)NC(=O)OCc1ccccc1

Procedure:
Following the General Procedure of Description 15 (Part B), the zinc insertion product of (9c) is used in situ to cross couple with commercial 3-iodo-4-methyl-aniline (466 mg, 2.0 mmol) in the presence of tris(benzylideneacetone)dipalladium (Pd2(dba)3) (46 mg, 0.05 mmol, 2.5 mol-%) and tris(o-tolyl)phosphine (P(o-tol)3) (60 mg, 0.20 mmol, 10 mol-%) in anhydrous degassed DMF (6 mL). Filtration, aqueous work-up, and purification by silica gel column chromatography furnish the title compound (9d).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH:12]([C:17]([CH3:19])=O)[C:13]([O:15][CH3:16])=[O:14]>C(O)C>[CH3:16][O:15][C:13]([C:12]1[O:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[N:8][C:17]=1[CH3:19])=[O:14]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: NC(=O)c1ccc(F)cc1
Solvent: CCO
Product: COC(=O)c1oc(-c2ccc(F)cc2)nc1C
Yield: 10.2 %

Procedure:
A solution of 4-fluorobenzamide (12 g, 86.3 mmol) and methyl 2-chloroacetoacetate (10.5 mL, 86.3 mmol) in ethanol (120 mL) was refluxed overnight. Subsequently the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic solution was washed with saturated sodium bicarbonate solution and brine, dried, and concentrated in vacuo. The residue was purified by flash chromatography eluting from silica gel with a gradient of 0-50% ethyl acetate in hexanes to give 2.08 g of the title compound as a white solid. MS: (+) m/z 236.2 (M+1).
Reaction SMILES: [S:1]([Cl:3])Cl.N1C=CC=CC=1.[CH2:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:11][CH3:12]>ClCCl>[CH2:10]([N:13]([CH2:14][CH2:15][CH3:16])[S:1][Cl:3])[CH2:11][CH3:12]
Reactant: CCCNCCC
Reactant: ClSCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN(CCC)SCl
Reaction time: 0.25 h

Procedure:
22.7 g of sulphur dichloride in 100 ml of dichloromethane was cooled to -5° C. and a solution of 17.4 g of pyridine in 50 ml of dichloromethane was added, over 30 minutes, while the temperature was maintained between -5° and 0° C. The resulting solution was stirred for 15 minutes and a solution of 20.2 g of di(n-propyl)amine dissolved in 50 ml of dichloromethane was added, over 30 minutes, while the temperature was maintained between -5° and 0° C. The resulting solution was stirred for 2 hours, while the temperature was allowed to rise to ambient. The solution was filtered and the solvent was evaporated. 150 ml of diethyl ether was added, the resulting solution was filtered, and the filtrate evaporated. Distillation of the residue gave di(n-propyl)aminosulphenyl chloride (38B), b.p.: 94°-5° C. at 15 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]([O:32]C)=O)=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[CH3:41]COCC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH:30]([OH:32])[CH3:41])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1-c1ccc(COC2C3CCC(CC2c2ccc(Cl)cc2)N3)cc1
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CC(O)c1ccccc1-c1ccc(COC2C3CCC(CC2c2ccc(Cl)cc2)N3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
A solution of 0.330 g (0.71 mmol) of methyl (1RS,2RS,3RS,5SR)-4'-[3-(4-chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-yloxy-methyl]-biphenyl-2-carboxylate in 10 ml of ether was slowly added dropwise to a suspension of 33 mg of lithium aluminium hydride in 5 ml of ether and the mixture was stirred at room temperature for 4 hours. After the addition of aqueous ether and subsequently water the phases were separated, the organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The residue was chromatographed on silica gel using a 140:10:1 mixture of methylene chloride, methanol and ammonia as the eluent. There was obtained 0.210 g (68% of theory) of [4'-[3-(4-chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-yloxymethyl]-biphenyl-2-yl]-ethanol as a colourless foam, Rf : 0.18 (methylene chloride:methanol:ammonia=140:10:1), MS: 434 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]1([CH:25](O)[CH3:26])[CH2:24][CH2:23][CH2:22][CH2:21]1.CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:46]1[C:54]2[C:49](=[CH:50][C:51]([C:55]3[N:59]=[CH:58][N:57](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:56]=3)=[CH:52][CH:53]=2)[C:48]([C:79]2[CH:80]=[C:81]([OH:85])[CH:82]=[CH:83][CH:84]=2)=[N:47]1.Cl>O1CCCC1>[NH:56]1[C:55]([C:51]2[CH:50]=[C:49]3[C:54](=[CH:53][CH:52]=2)[NH:46][N:47]=[C:48]3[C:79]2[CH:84]=[CH:83][CH:82]=[C:81]([O:85][CH2:26][CH2:25][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:80]=2)=[N:59][CH:58]=[N:57]1
Reactant: CC(O)N1CCCC1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCN2CCCC2)cc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 46 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), pyrrolidinylethanol (0.310 mL, 2.65 mmol) and diethylazodicarboxylate (0.418 mL, 2.65 mmol) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 0.662 mmol). The mixture was stirred at ambient temperature for 23 h and poured into aqueous 6 N hydrochloric acid (30 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ether (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (30 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica pretreated with 2% triethylamine/ethyl acetate followed by 0–20% methanol/ethyl acetate. The desired fractions were concentrated, dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated which gave the title compound (0.114 g, 46% yield). 1H NMR (CD3OD) δ 8.72 (s, 1H), 8.34 (s, 1H), 8.09 (dd, 1H), 7.67 (d, 1H), 7.62 (d, 1H), 7.57 (m, 1H), 7.47 (t, 1H), 7.04 (m, 1H), 4.26 (t, 2H), 3.02 (t, 2H), 2.73 (m, 4H), 1.87 (m, 4H). ES-MS (m/z) 375 [M+1]+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:10][C:9]2[CH:11]=[C:12]([CH3:24])[C:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:14][C:8]=2[O:7]1)=O)C.[NH3:25]>O1CCOCC1>[C:18]1([S:15]([C:13]2[C:12]([CH3:24])=[CH:11][C:9]3[O:10][CH:6]([C:4]([NH2:25])=[O:3])[O:7][C:8]=3[CH:14]=2)(=[O:17])=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1Oc2cc(C)c(S(=O)(=O)c3ccccc3)cc2O1
Reactant: N
Solvent: C1COCCO1
Product: Cc1cc2c(cc1S(=O)(=O)c1ccccc1)OC(C(N)=O)O2

Procedure:
34.8 g (0.1 mol) of 5-phenylsulphonyl-6-methyl-1,3-benzodioxole-2-carboxylic acid ethyl ester (from Example 2) are dissolved in 350 ml of dioxan (absolute) and treated in a pressure autoclave with approximately 20 g of ammonia gas. The reaction mixture is heated for 10 hours at 80° in the autoclave, the pressure is released, and the solution is concentrated to dryness by evaporation under reduced pressure. The residue is recrystallised from 120 ml of ethanol, yielding colourless crystals of 5-phenylsulphonyl-6-methyl-1,3-benzodioxole-2-carboxylic acid amide having a melting point of 138°-141°.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].[N+:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)([O-])=O>[Pd]>[NH2:5][C:8]1[C:9]([CH2:2][CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CC[Mg+]
Agent: [Pd]
Agent: [Br-]
Product: CCc1c(N)ccc2[nH]ccc12

Procedure:
Addition of EtMgBr to 5-nitroindole followed by hydrogenation over Pd/C provided 5-amino-4-ethylindole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([SH:9])[CH:3]=1.Br[CH:11]([CH2:17]Br)[C:12]([O:14]CC)=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:11]([C:12]([OH:14])=[O:13])[CH2:17][S:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc(O)c(S)c1
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc2c(c1)SCC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 20.0 g of 4-methyl-2-mercaptophenol in 75 ml of acetone was added slowly to a stirred mixture of 40.2 g of ethyl 2,3-dibromopropionate and 10.2 g of potassium carbonate in 400 ml of acetone, at room temperature. The mixture was stirred at room temperature for 10 minutes, then refluxed for 16 hours. The mixture was filtered and the solid was washed with acetone. The acetone filtrate was stripped of solvent; the residue was dissolved in methylene chloride, the solution was washed with water, then dried (MgSO4) and stripped of solvent. The liquid residue was dry column chromatographed (silica gel) using Solvent No. 2 as eluent. The first band (high Rf) was collected and extracted with ether. The solvent was stripped from the extract. The residue was dried (vacuum, 24 hours) and crystallized from hexane to give the ethyl ester of 2,3-dihydro-6-methyl-1,4-benzoxathiin-2-carboxylic acid (2A), as white needles, mp: 41°-43° C.
Reaction SMILES: [CH2:1]([C:7]1[N:8]=[C:9]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[S:10][C:11]=1[CH:12]=[CH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]([O:26][CH3:27])=[O:25])=[C:18]([CH3:28])[CH:17]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>CO.O1CCCC1.[C].[Pd]>[CH2:1]([C:7]1[N:8]=[C:9]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[S:10][C:11]=1[CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:18]([CH3:28])[CH:17]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [H][H]
Reactant: CCCCCCc1nc(-c2ccc(C)cc2)sc1C=CC(=O)c1ccc(C=CC(=O)OC)c(C)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCc1nc(-c2ccc(C)cc2)sc1CCC(=O)c1ccc(CCC(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.7 %

Procedure:
The obtained methyl 3-[4-[3-[4-hexyl-2-(4-methylphenyl)thiazol-5-yl]propenoyl]-2-methylphenyl]acrylate (112 mg, 0.230 mmol) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL). 10% palladium carbon (22 mg) was added to the solution to cause replacement of hydrogen in the system. The mixture was stirred at room temperature for 3 hours. The reaction mixture was filtrated with Celite. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography with hexane/ethyl acetate (5:1, v/v) to give the desired compound (46 mg) as colorless oil (yield 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A 50 ml flask is charged with 17.06 g p-chlorophenylacetic acid and 11.90 g thionyl chloride. A single boiling chip is added and the flask fitted with air condenser and drying tube. The reaction mixture is heated in a 45° oil bath for 24 hr then cooled to ambient temperature. Five ml of benzene is added to the solution and light materials are pumped off at room temperature and 0.5 mm Hg. The product is then distilled through a short-path vacuum distillation apparatus at 0.10 mm Hg to give p-chlorophenylacetyl chloride as a water-white product; boiling point, 63°-64°. ##STR39##
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:10][C:9]2[CH:11]=[C:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:13]([Cl:15])=[CH:14][C:8]=2[O:7]1)=O)C.[NH3:26].Cl>ClCCl>[Cl:15][C:13]1[C:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:11][C:9]2[O:10][CH:6]([C:4]([NH2:26])=[O:3])[O:7][C:8]=2[CH:14]=1
Reactant: N
Reactant: CCOC(=O)C1Oc2cc(Cl)c(S(=O)(=O)c3ccc(Cl)cc3)cc2O1
Agent: Cl
Solvent: ClCCl
Product: NC(=O)C1Oc2cc(Cl)c(S(=O)(=O)c3ccc(Cl)cc3)cc2O1
Reaction time: 18 h

Procedure:
4.03 mol of 5-chloro-6-(4-chlorophenylsulphonyl)-1,3-benzodioxole-2-carboxylic acid ethyl ester are dissolved in room temperature in 50 ml of dichloromethane. While stirring vigorously, 50 ml of a concentrated aqueous ammonia solution are added, and stirring is continued for 18 hours. A thick crystalline suspension is formed from the initial emulsion. This suspension is then adjusted by 6N HCl to pH 2-3 at room temperature, filtered and subsequently washed with water. After drying, colourless crystals of 5-chloro-6-(4-chlorophenylsulphonyl)-1,3-benzodioxole-2-carboxylic acid amide having a melting point of 240°-242° are obtained.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29].[B:30](OC)([O:33]C)[O:31]C>O1CCCC1>[C:19]([C:17]1[CH:16]=[CH:15][C:14]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[C:13]([B:30]([OH:33])[OH:31])[CH:18]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COB(OC)OC
Reactant: COCCOCOc1ccc(C(C)(C)C)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCCOCOc1ccc(C(C)(C)C)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 97.8 %

Procedure:
n-Butyllithium in hexane (2.5 M, 4.2 mL, 10.5 mmol) was added dropwise to a solution of give 2-bromo-4-(tert-butyl)-1-((2-methoxyethoxy)methoxy)benzene (3.0 g, 9.46 mmol) and trimethyl borate (1.2 mL, 10.76 mmol) in anhydrous tetrahydrofuran (20 mL) at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 20 minutes then at 0° C. for an additional 20 minutes. The reaction was then quenched by the addition of water (20 mL) and the mixture extracted with ether (100 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated under reduced pressure to give (5-(tert-butyl)-2-((2-methoxyethoxy)methoxy)phenyl)boronic acid (2.61 g, 98% yield).