Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:22])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:22][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([F:23])[CH:25]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCCC1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.036 g, 0.1 mmol), 3-fluoro-benzoyl chloride (14.6 μL, 0.12 mmol) and triethylamine (18.1 μL, 0.13 mmol)) in methylene chloride (2 mL) was stirred at room temperature overnight and concentrated to give a crude product that was subjected to a purification by prep HPLC. The corresponding fractions were collected and lyophilized to give a TFA-salt of Compound 455 as a tan solid in 85.4% yield. LCMS m/z (%)=487 (M+H 79Br, 97), 489 (M+H 81Br, 100). 1H NMR (400 MHz, DMSO-d6) δ: 10.42 (s, 1H), 9.71 (bs, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.83-7.73 (m, 3H), 7.66 (s, 1H), 7.63-7.57 (m, 1H), 7.46 (t, J=8.7 Hz, 1H), 7.30 (d, J=9.1 Hz, 1H), 4.45-4.21 (m, 2H), 3.68 (s, 3H), 3.51-3.42 (m, 2H and water), 3.43-3.20 (m, 2H), 2.93-2.60 (m, 2H), 1.97-1.68 (m, 4H).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:14][C:13]1[C:12]([O:15][CH3:16])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[Cl:5]
Reactant: BrCCBr
Reactant: COc1cc(C=O)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)cc(Cl)c1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
1,2-Dibromoethane (46 mL, 0.54 moles) was added to a mixture of 3-chloro-4-hydroxy-5-methoxybenzaldehyde (10 g, 54 mmoles) and potassium carbonate (37 g, 0.27 moles) in DMF (180 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with saturated sodium chloride (150 mL), dried over MgSO4 and evaporated in vacuo to afford 9.33 g (59%) of 4-(2-bromoethoxy)-3-chloro-5-methoxybenzaldehyde. M.p. 52-54° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=1.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][NH:28][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=3)[CH2:11][N:12]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=2)=[CH:32][CH:33]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CS(=O)(=O)N(CCc1ccccn1)Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CS(=O)(=O)N(CCc1ccccn1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 17 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 504. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.5 (d, 1H) 8.3 (d, 1H) 7.9 (m, 2H) 7.6 (m, 1H) 7.4 (m, 2H) 7.2 (m, 2H) 7.0 (d, 2H) 6.9 (d, 1H) 6.7 (d, 2H) 5.4 (s, br, 1H) 4.4 (s, 2H) 3.7 (m, 2H) 3.6 (m, 2H) 3.0 (m, 2H) 2.8 (m, 2H) 2.8 (s, 3H).
Reaction SMILES: C(S[CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:37])[CH:6]1[CH2:38][CH3:39])C=C.[Cl:40]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:40][CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:37])[CH:6]1[CH2:38][CH3:39]
Reactant: C=CCSC1C(CC)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccccc1)C(=O)C(C)(C)C
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC1C(=O)N(C(C(=S)OCc2ccc([N+](=O)[O-])cc2)=C(Oc2ccccc2)C(=O)C(C)(C)C)C1Cl
Temperature: 25 °C
Yield: 77.3 %

Procedure:
To a solution of 2.47 g 4-nitrobenzyl 2-(4-allylthio-3-ethylazetidin-2-on-1-yl)-3-phenoxy-3-trimethylacetylthiopropenate in dichloromethane at -20° was added a solution of 8.4 mmol of chlorine in carbon tetrachloride. After 30 minutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Elution with hexane-ethane acetate mixtures afforded 1.782 g of the title compound as a pale yellow foam (78% of the theoretical yield).
Reaction SMILES: [C:1]([N:4]=[C:5]([N:10]1[CH2:14][CH2:13][S:12][CH:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[CH2:26][CH2:25]1)[O:6]C(=O)C)(=[O:3])[CH3:2].Cl>C(O)C.O1CCCC1.[OH-].[Na+]>[C:1]([NH:4][C:5]([N:10]1[CH2:14][CH2:13][S:12][CH:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[CH2:28][CH2:29]1)=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N=C(OC(C)=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)NC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
0.59 g of N,O-diacetyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboximidic acid is dissolved in a mixture of 15 ml of ethanol and 5 ml of tetrahydrofuran, and 1.34 ml of 10% aqueous sodium hydroxide solution is added thereto under ice-cooling. The mixture is stirred for 15 minutes, and the mixture is neutralized with 10% hydrochloric acid. The mixture is concentrated under reduced pressure to remove solvent. The residue is extracted with ethyl acetate, and the extract is washed with an aqueous sodium chloride solution, dried and then concentrated under reduced pressure to remove solvent. The residue is recrystallized from a mixture of ethyl acetate and ether. 0.49 g of N-acetyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:12].[CH2:13]([OH:15])[CH3:14]>>[ClH:12].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8](=[NH:9])[O:15][CH2:13][CH3:14])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCOC(=N)c1ccc([N+](=O)[O-])cc1

Procedure:
Ethyl 4-nitrobenzimidate hydrochloride was synthesized in the same manner as in Reference Example 2. That is, 4-nitrobenzonitrile (26.5 g, 0.179 mol) was reacted with hydrogen chloride in ethanol (250 mL) to give 35.7 g (86%) of the target compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][C@H:8]2[NH2:14])=[O:4].[CH:15]([C:17]1[N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](C)=[CH:20][CH:21]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11]([CH2:10][CH2:9][C@H:8]2[NH:14][CH2:15][C:17]2[N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: Cc1ccc(C=O)n1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](NCc1cccn1C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A solution of (3R)-3-amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester (A-03) (361 mg, 1.88 mmol, 1 eq.) in methylene chloride (3 ml) was added to a solution of tert-butyl 2-formyl-5-methyl-1H-pyrrole-1-carboxylate (434 mg, 2.08 mmol, 1.1 eq.) in dry methylene chloride (17 ml) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was cooled to 0° C. and then Na(OAc)3BH (1.2 g, 5.66 mmol, 3 eq.) was added portionwise and it was stirred at 25° C. for 14 h. The reaction mixture was diluted with methylene chloride (200 ml) and washed with saturated sodium bicarbonate (50 ml), water (2×50 ml) and brine (50 ml), and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (silica gel; 5% EtOAc/hexanes) to give the desired product as a light yellow oil. Yield: 82% (600 mg, 1.56 mmol).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:11][N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[S:8]1)=[N+:2]=[N-:3].[C:26]([N:34]=[C:35]=[S:36])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]([C:35]([NH:34][C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[S:36])[N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[S:8]1)=[N+:2]=[N-:3]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (1.00 g, 2.79 mmol) in 20 mL of anhydrous THF was added benzoyl isothiocyanate (0.45 mL, 3.34 mmol). The reaction was allowed to stir overnight at reflux, then cooled and concentrated in vacuo. The residue was purified by flash column chromatography (5-35% ethyl acetate/hexanes) to afford the desired product as a yellow gum, 1.45 g, 54%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[NH2:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[C:4]=2[N:5]=[C:6]([NH:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29])[N:7]=1
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3ccc(C(F)(F)F)cc3)c2n1
Reactant: NC(CO)CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1ccc(C(F)(F)F)cc1
Yield: 45 %

Procedure:
A solution of 4-Chloro-2-methylsulfinyl-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (0.29 g, 0.75 mmol) in dichloromethane (30 mL) was mixed with a solution of serinol (0.075 g, 0.82 mmol) in DMF (0.75 mL). The resultant mixture was stirred at room temperature for 1 hour before concentrated under vacuum. Flash chromatography (EtOAc:Hexane, 3:1) then provided the title compound (0.14 g, 45%): MS (ES) m/z 415 (M+H)+; 1H-NMR(CDCl3) δ 2.25 (s, br, 2H), 3.66 (m, br, 5H), 6.15 (m, br, 1H), 6.55 (d, J=9.2 Hz, 1H), 7.36 (m, 2H), 7.81 (d, J=8.1 Hz, 2H), 7.92 (d, J=9.2 Hz, 1H).
Reaction SMILES: C1C=CC(O[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]#[N:11])=CC=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl>[O:12]([C:8](=[N:9][C:10]#[N:11])[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: N#CN=C(Oc1ccccc1)N1CCCCC1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
a)To a stirred solution of 6 g of diphenyl cyanocarbonimidate in 50 ml of dichloromethane at room temperature were added portionwise 2.1 g of piperidine. Stirring was continued for 30 minutes at room temperature. The reaction mixture was evaporated and the residue was crystallized from 2,2'- oxybispropane. The crystals were filtered off and dried, yielding 4.6 g (80.7%)of [phenoxy(1-piperidinyl)methylene]cyanamide; mp. 85.7° C. (interm. 32).
Reaction SMILES: C(C1C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC(CC)=CN=1)C.[CH2:22]([C@@H:24]1[C@H:32]([NH2:33])[C:28]2[CH:29]=[CH:30][S:31][C:27]=2[CH2:26][CH2:25]1)[CH3:23].Br[C:35]1[C:40]([CH2:41][CH3:42])=[N:39][C:38]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=2[Cl:50])=[C:37]([CH2:51][CH3:52])[N:36]=1>>[Cl:50][C:44]1[CH:45]=[C:46]([Cl:49])[CH:47]=[CH:48][C:43]=1[C:38]1[N:39]=[C:40]([CH2:41][CH3:42])[C:35]([NH:33][C@@H:32]2[C:28]3[CH:29]=[CH:30][S:31][C:27]=3[CH2:26][CH2:25][C@@H:24]2[CH2:22][CH3:23])=[N:36][C:37]=1[CH2:51][CH3:52]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1Br
Reactant: CC[C@H]1CCc2sccc2[C@H]1N
Agent: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccsc2CC[C@@H]1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting cis-5-ethyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine and 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ; 7.50, 7.32, 7.08, 6.98, 5.77, 4.42, 2.99, 2.95, 2.62, 2.50, 1.98, 1.73, 1.39-1.18, 1.00; HRMS (FAB) calcd for C24H27Cl2N3S+H 460.1381, found 460.1376.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18]S(C)(=O)=O.[O:24]=[C:25]1[CH2:34][CH2:33][CH2:32][C:31]2[C:30](O)=[C:29]([CH2:36][CH:37]=[CH2:38])[CH:28]=[CH:27][C:26]1=2.C(=O)([O-])[O-].[K+].[K+].COCCOCCN(CCOCCOC)CCOCCOC>CCOCC.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:30]1[C:31]2[CH2:32][CH2:33][CH2:34][C:25](=[O:24])[C:26]=2[CH:27]=[CH:28][C:29]=1[CH2:36][CH:37]=[CH2:38]
Reactant: COC(=O)/C=C/c1ccccc1OCCCCCOS(C)(=O)=O
Reactant: C=CCc1ccc2c(c1O)CCCC2=O
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=CCc1ccc2c(c1OCCCCCOc1ccccc1/C=C/C(=O)OC)CCCC2=O
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A mixture of 1.37 g (4 mmol) of (E)-3-[2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]phenyl]-2-propenoic acid methyl ester from example 76, 0.81 g (4 mmol) of 5-oxo-2-(2-propenyl)-5,6,7,8-tetrahydro-1-naphthalenol, 0.8 g (5.8 mmol) of anhydrous, granular potassium carbonate, 0.08 mL of TDA-1, and 25 mL of toluene was stirred under reflux for 5.5 hr and at room temperature for 12 hr. After being treated with 0.3 g of additional potassium carbonate, the mixture was stirred and refluxed for a further 24 hr. The mixture was cooled and diluted with ether. The organic phase was washed with water and saturated brine and work-up was completed in the usual manner giving a brown oil. This material was chomatographed on 50 g of silica gel. Elution with 1:1 hexane-ether afforded 1.72 g (96%) of (E)-3-[2-[5-[(5-oxo-2-(2-propenyl)- 5,6,7,8-tetrahydro-1-naphthalenyl)oxy]pentyloxy]phenyl]-2-propenoic acid methyl ester as a yellow-orange oil.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][NH:6][CH2:5]2)[CH2:3][N:2]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=1.CS(C)=O>O>[C:11]([O:10][C:8]([N:2]1[CH2:3][C:4]2([CH2:7][N:6]([C:16]3[CH:21]=[N:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:5]2)[CH2:1]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(C1)CN(c1ccc([N+](=O)[O-])nc1)C2
Temperature: 90 °C
Reaction time: 40 h

Procedure:
In a 25 mL pear-shaped flask, tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (2.81 g, 14.2 mmol), 5-bromo-2-nitropyridine (2.88 g, 14.2 mmol), and TEA (1.58 g, 2.17 ml, 15.6 mmol) were combined with DMSO (12 ml) to give a light yellow solution. The reaction mixture was heated to 90° C. and stirred for 40 h. Cooled to 25° C. and the reaction mixture was diluted with 50 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were combined, washed with sat NaCl (1×50 mL), dried over Na2SO4 and concentrated in vacuo. The purple oil was used crude in the subsequent reduction. (M+H)+=321 m/e.
Reaction SMILES: C(O)(=O)C.C[O:6][C:7]([CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([S:23]([N:26](C(OCC(C)C)=O)[C:27]3[C:32]([O:33][CH3:34])=[N:31][C:30]([CH3:35])=[CH:29][N:28]=3)(=[O:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=[O:8].N(C([O-])=O)=NC([O-])=O.[K+].[K+]>C(COC)OC>[C:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([S:23]([NH:26][C:27]3[C:32]([O:33][CH3:34])=[N:31][C:30]([CH3:35])=[CH:29][N:28]=3)(=[O:24])=[O:25])=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)([OH:8])=[O:6]
Reactant: COC(=O)C=Cc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(=O)O
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CCC(=O)O)cc1
Temperature: 45 °C
Reaction time: 18 h
Yield: 21.2 %

Procedure:
A 1M solution of acetic acid in dimethoxyethane (5.6 ml) was added dropwise over 3 hours to a mixture of 2-[4-(2-[methoxycarbonyl]vinyl)phenyl]-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (250 mg) and potassium azodicarboxylate (1.4 g) in dry dimethoxyethane (20 ml) at 45° C. The mixture was heated at 45° C. for 18 hours. Insoluble material was removed by filtration and the filtrate was concentrated. The residue was eluted through a pad of silica gel with ethyl acetate/hexane (1:3 v/v) and the resulting solid (230 mg) was dissolved in a mixture of tetrahydrofuran (16 ml) and methanol (4 ml). A solution of lithium hydroxide (118 mg) in water (4 ml) was added and the solution was stirred for 18 hours. Volatile material was removed by evaporation and the residue was dissolved in water (15 ml). The solution was washed with ethyl acetate (2×15 ml) and acidified with 20% aqueous citric acid. The mixture was extracted with ethyl acetate (2×15 ml) and the extracts were washed with water (10 ml) and saturated sodium chloride solution (50 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was triturated with ether to give 2-[4-(2-carboxyethyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (42 mg), m.p. 166°-168° C.; 1H NMR (CDCl3): 2.25 (s, 3 H), 2.6 (t, 2 H), 3.0 (t, 2 H), 3.8 (s, 3 H), 7.2-7.3 (m, 5 H), 7.45-7.55 (m, 1 H), 8.65 (d, 1 H), 8.8 (d, 1 H), 10.25-10.5 (br, 1 H).
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Cl[C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.CN(C=O)C>O>[CH2:1]([S:3][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:18]=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC[S-]
Reactant: O=C(Nc1cc(C(F)(F)F)ccn1)c1ncccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cccnc1C(=O)Nc1cc(C(F)(F)F)ccn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
0.86 g of sodium ethanethiolate was added to a mixture of 1.23 g of 3-chloro-N-(4-trifluoromethylpyridin-2-yl)picolinamide and 3 mL of DMF, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture cooled to room temperature was poured to water, and the precipitated solid was taken by filtration. The resulting solid was dissolved in ethyl acetate, and the mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.23 g of 3-ethylsulfanyl-N-(4-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 8).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:24])C=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[OH:24][CH2:3][CH:2]1[CH2:1][C:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:12]=[CH:13][C:14]=2[O:15]1
Reactant: C=CCc1cc(C(=O)OCC)ccc1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2c(c1)CC(CO)O2
Reaction time: 4 h
Yield: 81.9 %

Procedure:
A solution of ethyl 3-allyl-4-hydroxybenzoate (6.74 g, 32.7 mmol) in chloroform (105 ml) was added with meta-chloroperbenzoic acid (11.40 g, 66.1 mmol) and the mixture was refluxed under stirring for 4 h. Afterwards, the solvent was evaporated, the crude was redissolved in ethyl acetate and washed with a 1M NaOH solution. After drying and removing the solvent, a crude was obtained which was purified by chromatography through a silica gel column, eluting with n-hexane:ethyl acetate, 90:10, to recover 5.95 g of the title compound (82% yield).
Reaction SMILES: [C:1]([C:8]([NH2:32])([CH2:12][CH2:13][CH2:14][C:15]1([CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+](=[CH2:35])=[N-]>C(Cl)Cl>[C:1]([C:8]([NH2:32])([CH2:12][CH2:13][CH2:14][C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:9]([O:11][CH3:35])=[O:10])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)C(N)(CCCC1(CC(=O)OCc2ccccc2)CCCCC1)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)C(N)(CCCC1(CC(=O)O)CCCCC1)C(=O)OC(C)(C)C

Procedure:
The Boc-benzyl ester (J) (4 mmol) is dissolved in methylene chloride and treated with excess ethereal diazomethane at room temperature. The residual diazomethane is quenched with acetic acid and the solution is evaporated at reduced pressure. The crude diester is dissolved in methanol and hydrogenated over 10% palladium-on- carbon to give, after flash chromatography (silica gel), the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][O:14][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][O:15]2)=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)c2ccccc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Brc1ccc(CCOC2CCCCO2)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.1 %

Procedure:
To a solution of 1-bromo-4-(2-hydroxyethyl)naphthalene (1.71 g, 6.8 mmol) in dichloromethane (20 mL) was added 3,4-dihydro-2H-pyrane (1 mL, 0.92 g, 11.0 mmol) and p-toluene sulfonic acid (80 mg). The mixture was stirred at room temperature for 90 min, diluted with dichloromethane (20 mL), washed with satd. NaHCO3 sol. (20 mL), dried (MgSO4), and concentrated. Flash chromatography using hexane/ethyl acetate 9:1 as eluent provided 1.69 g (75%) of a colorless oil.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.N1CCCCC1>C1C=CC=CC=1>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[CH:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:7]1=[O:15]
Reactant: O=C1Cc2ccccc2N1C1=NCCS1
Reactant: COc1ccc(C=O)cc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(C=C2C(=O)N(C3=NCCS3)c3ccccc32)cc1
Yield: 53.7 %

Procedure:
To a warmed benzene solution of 1-(2-thiazolin-2-yl)-indolin-2-one (2.0 g, 7.2 mmol) and p-methoxybenzaldehyde (1.5 g, 11 mmole) is added piperidine (0.6 ml). The mixture is heated at reflux temperature for 2 hours. The reaction mixture is then washed with NaHSO3 solution, diluted HCl and water. The organic phase is dried over anhydrous MgSO4 and concentrated in vacuo. The residue is recrystallized once each from acetone/hexane, acetonitrile and CHCl3 /methanol and gives 1.3 g (43%) of the product (m.p. 164.5°-167° C, softens at 149° C).