Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])=[CH:27][CH:26]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].Cl.O1CCOCC1>O>[Cl:1][C:2]1[C:3]([C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:26]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]1=[O:14]
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)(=O)C4)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)(=O)C4)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A mixture of the compound obtained in Example 114 (200 mg), 10% aqueous hydrochloric acid (3 ml) and dioxane (5 ml) was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4) and the solvent was distilled off under reduced pressure to obtain (4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-dioxido-5,8-dihydro-6H-thiopyrano-[4′,3′:4,5]-thieno[2,3-b]pyridin-4-yl}phenoxy)acetic acid (130 mg, 72%). It was recrystallized from acetone-hexane. Colorless prisms. Melting point 260-261° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]1[CH:23]=[C:24]([CH3:41])[CH:25]=[C:26]2[C:31]=1[O:30][CH:29]([C:32]([F:35])([F:34])[F:33])[C:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:27]2.[C:42]1([SH:48])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:41][C:24]1[CH:25]=[C:26]2[C:31](=[C:22]([CH2:21][S:48][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:23]=1)[O:30][CH:29]([C:32]([F:34])([F:35])[F:33])[C:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:27]2
Reactant: CCOC(=O)C1=Cc2cc(C)cc(CO)c2OC1C(F)(F)F
Reactant: Sc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cc(C)cc(CSc3ccccc3)c2OC1C(F)(F)F
Reaction time: 0.25 h
Yield: 98 %

Procedure:
The polymer bound triphenylphosphine (1.2 g, 3.6 mmole) was suspended in anhydrous THF (10 mL) and the mixture was allowed to stir for 15 minutes. The ethyl 8-(hydroxymethyl)-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 605b, Step 1 (0.38 g, 1.20 mmole), benzenethiol (0.20 g, 1.80 mmole) and DEAD (0.31 g, 1.80 mmole) were added to above mixture, which was allowed to stir for 18 hours. The resulting mixture was filtered through a plug of celite and condensed in vacuo to give a yellow oil (0.49 g, 98%). No further purification was performed. GCMS m/z 408.0 (M+).
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:20][C@H:21]([C:26]([N:28]1[CH2:36][CH2:35][CH2:34][C@H:29]1[C:30]([O:32][CH3:33])=[O:31])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24].N(C(OCC1C=CC=CC=1)=O)[C@H](C(O)=O)C(C)C>C(Cl)Cl>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([NH:20][C@H:21]([C:26]([N:28]1[CH2:36][CH2:35][CH2:34][C@H:29]1[C:30]([O:32][CH3:33])=[O:31])=[O:27])[CH2:22][CH:23]([CH3:24])[CH3:25])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(C)C
Agent: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Z-Leu-OH (1 equivalent), H-Leu-Pro-OMe (1 equivalent) synthesized in (a) and TEA (1 equivalent) were dissolved in dry methylene chloride, and WSCD (1 equivalent) was added under cooling with ice. Thereafter, the mixture was stirred at room temperature for 20 hours, and the reaction mixture was washed successively with IN HCl, water, saturated aqueous sodium bicarbonate, water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under vacuum. The resulting crude product was purified by medium-pressure liquid column chromatography to obtain the end compound. Z-Leu-Leu-Pro-OMe (1 equivalent) thus obtained was dissolved in ethanol, and boron trifluoride-ether complex (1 equivalent) and palladium on carbon (a small amount) were added. The mixture was subjected to catalytic reduction in a hydrogen atmosphere to remove the Z group, and the solvent was distilled off under vacuum to obtain the end compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](N(OC)C)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:21]1.O1CCCC1.C[Mg]Cl>CCOCC>[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)(=[O:15])[CH3:21]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C1CCOC1
Agent: C[Mg]Cl
Solvent: CCOCC
Product: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 500 ml round bottom flask was added tert-butyl-4-{[methoxy(methyl)amino]carbonyl}piperidine-1-carboxylate (29 g, 106 mmol) and 150 ml tetrahydrofuran. The resulting solution was cooled with ice bath and methylmagnesium chloride tetrahydrofuran solution (42.6 ml, 3M, 128 mmol) was added by a syringe. The mixture was stirred at 0° C. for 30 minutes. It was diluted with 200 ml of ether and the resulting mixture was washed twice with 150 ml saturated ammonium chloride solution. The organics were dried over sodium sulfate, filtered and concentrated. The crude product was used for next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.O1CCCC1.Cl.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=1>O>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:17][CH:16]=2)[C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=2)=[CH:9][CH:10]=1)#[N:13]
Reactant: N#Cc1ccc(NCc2ccc(O)cc2)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(N(Cc2ccc(O)cc2)C(=O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
224 mg of 4-[N-(4-hydroxybenzyl)amino]benzonitrile, 0.28 ml of triethylamine, and 7 ml of tetrahydrofuran were mixed, and 178 mg of nicotinoyl chloride hydrochloride was slowly added thereto, followed by stirring at room temperature overnight. After water was added to the reaction mixture, the product was extracted with tetrahydrofuran-diethyl ether (1:1). After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by TLC (using a 9:1 mixture of chloroform and acetone as the developing solvent) to obtain 292 mg of N-(4-cyanophenyl)-N-(4-hydroxybenzyl)-nicotinamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10](C3CCN(C(OC(C)(C)C)=O)CC3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[ClH:26].C(O[CH2:31][CH3:32])(=O)C>>[ClH:26].[ClH:26].[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:9]3[CH2:32][CH2:31][CH2:3][CH2:4][CH2:8]3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(F)c3)cs2)CC1
Agent: Cl
Product: Fc1cccc(-c2csc(N3CCCCC3)n2)c1
Temperature: 25 °C
Reaction time: 30 h
Yield: 70 %

Procedure:
To a solution of tert-butyl 4-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (2.89 g, 7.95 mmol) in ethyl acetate (200 ml) was added a 4N solution (50 ml) of hydrogen chloride in ethyl acetate, and the mixture was stirred at room temperature for 30 hours. The solvent was distilled off under reduced pressure to give 1.86 g (70.0%) of the desired product as a solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[C:14]([NH:21][C@H:22]([C:38]([OH:40])=O)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:14]([NH:21][C@H:22]([C:38]([N:2]([CH3:1])[CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:40])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:26][CH:25]=1)([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CNCc1cccc2ccccc12
Product: CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C

Procedure:
In substantially the same manner as Working Example 2, N-methyl-1-naphthalenemethylamine (877 μl) was condensed with Boc-(O-benzyl)-L-tyrosine (2.00 g) to give N-[Boc-(O-benzyl)-L-tyrosyl]-N-methyl-1-naphthalenemethylamine (2.60 g) as a white powdery product (yield 92%). The Boc group of the product was deprotected by using TFA, and 2.02 g of thus-obtained compound was condensed, in substantially the same manner as Working Example 2, with Compound 1 (1.40 g) to give N-[N-[(2S,3S)-N-Z-3-ethoxycarbonylaziridine-2-carbonyl]-(O-benzyl)-L-tyrosyl]-N-methyl-1-naphthalenemethylamine (1.73 g) as a white powdery product (yield 52%). This compound was subjected to catalytic reduciton to thereby deprotect the Z group and benzyl group in substantially the same manner as Working Example 3 to give the above-titled compound (compound 133; 580 mg) as white crystals (yield 53%).
Reaction SMILES: [CH2:1](OC(Cl)=O)C(C)C.[CH2:9]([O:13][C:14](=[O:21])[C:15]([CH2:17][C:18]([OH:20])=O)=C)[CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[BH4-].[Na+].Cl>C1COCC1.O>[CH2:9]([O:13][C:14](=[O:21])[CH2:15][C:17]([CH2:18][OH:20])=[CH2:1])[CH2:10][CH2:11][CH3:12]
Reactant: CC(C)COC(=O)Cl
Reactant: C=C(CC(=O)O)C(=O)OCCCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C=C(CO)CC(=O)OCCCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
iso-Butylchloroformate (6.83 g, 50.0 mmol) was added to a solution of itaconic acid mono-n-butyl ester (9.31 g, 50.0 mmol) and triethylamine (5.06 g, 50.0 mmol) in THF (40 mL) under a nitrogen atmosphere and cooled to 0° C. The reaction was stirred for 0.5 h, filtered to remove the solids, added to a solution of sodium borohydride (3.78 g, 100.0 mmol) in water (20 mL), and cooled to 10° C. The reaction was stirred for 2 h, made acidic with 3 N HCl and extracted with ethyl ether (3×). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to give an oil. The product was purified by FCC on silica gel, eluting ethyl acetate:hexanes (1:2) to give 3-hydroxymethyl-but-3-enoic acid butyl ester (2.56 g, 30%) as an oil. MS found: (M+H)+=173.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[F:21])[N:17]=[C:16]([C:22]([OH:24])=O)[C:15]([OH:25])=[N:14]2.[Cl:26][C:27]1[CH:28]=[C:29]([CH:36]=[CH:37][CH:38]=1)[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][NH:32]1>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:36]=[CH:37][CH:38]=1)[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:22]([C:16]1[C:15]([OH:25])=[N:14][C:13]2[C:18](=[CH:19][C:20]([F:21])=[C:11]([F:10])[CH:12]=2)[N:17]=1)=[O:24]
Reactant: O=C(O)c1nc2cc(F)c(F)cc2nc1O
Reactant: Clc1cccc(CC2CCCN2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1nc2cc(F)c(F)cc2nc1O)N1CCCC1Cc1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
Diisopropylethylamine (0.32 mL, 1.8 mmol) was added dropwise to a mixture of 6,7-difluoro-3-hydroxyquinoxaline-2-carboxylic acid (100 mg, 0.44 mmol), racemic 2-(3-chlorobenzyl)pyrrolidine (72 mg, 0.37 mmol) and O-HATU (210 mg, 0.55 mmol) in anhydrous DMF (2.0 mL) at room temperature under nitrogen, after which the mixture was heated to 85° C. and stirred for 4 h. The cooled mixture was directly purified by flash column chromatography on silica gel, eluting with 10% concentrated ammonium hydroxide in methanol/methylene chloride (gradient from 2:98 to 10:90), to provide a yellow solid. The residue was further purified by preparative reverse phase HPLC to provide (+/−)-[2-(3-chlorobenzyl)pyrrolidin-1-yl](6,7-difluoro-3-hydroxyquinoxalin-2-yl)methanone as a light yellow solid: 1H NMR (400 MHz, CDCl3, ˜2:1 mixture of rotamers) δ 7.72-7.63 (m, 2H, rotamers A and B), 7.38-7.21 (m, 2H, rotamers A and B), 7.10-7.03 (m, 1H, rotamers A and B), 6.90-6.79 (m, 1H, rotamers A and B), 4.63-4.56 (m, 1H, rotamers A and B), 3.89-3.82 (m, 1H, rotamer B), 3.76-3.69 (m, 1H, rotamer A), 3.56-3.47 (m, 1H, rotamers A and B), 3.33 (dd, 1H, rotamer A), 3.17 (q, 1H, rotamer B), 2.94-2.89 (m, 1H, rotamer A), 2.86-2.63 (m, 1H, rotamer B), 2.12-1.92 (m, 2H, rotamers A and B), 1.91-1.73 (m, 2H, rotamers A and B) ppm; ESI MS m/z 404 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1>C1C=CC=CC=1.C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH3:12])=[O:6]
Reactant: COc1ccccc1N
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccccc1NC(=O)c1c(N)cccc1Cl
Temperature: 25 °C

Procedure:
SO2Cl2 (5.4 mL, 74 mmol, 2.5 eq) was added to a rapidly stirring solution of 2-amino-6-chlorobenzoic acid (5 g, 29.14 mmol) in benzene (146 mL) and the mixture was stirred at reflux for 24 h. The mixture was concentrated under reduced pressure, and stripped down twice with benzene to give brown oil. The resulting oil was dissolved in CHCl3 (146 mL) and to that solution was added o-anisidine and the mixture was stirred at 65° C. for 2 h. The mixture was cooled to rt and the resulting precipitate was removed by filtration. The filtrate was concentrated under reduced pressure and purified by column chromatography on a 120 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 20 min as eluent to provide 2-amino-6-chloro-N-(2-methoxyphenyl)benzamide as yellow solid. 1H NMR (DMSO-d6) δ ppm 9.44 (1 H, s), 7.86 (1 H, dd, J=7.9, 1.3 Hz), 7.13-7.21 (1 H, m), 7.04-7.11 (2 H, m), 6.97 (1 H, t, J=7.6 Hz), 6.66 (2 H, dd, J=28.0, 7.9 Hz), 5.37 (2 H, s), 3.81 (3 H, s). Mass Spectrum (ESI) m/e=277.0 (M+1).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[C:11]([O:20][C:21]([F:24])([F:23])[F:22])[CH:10]=1.C([C@H]1COC(=O)N1C(=O)[CH2:39][C@@H:40]([C:46]1[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=1)[C:41]1[CH:45]=[CH:44][O:43][N:42]=1)C1C=CC=CC=1.[Li+].[OH-]>CN(C=O)C.O.C1COCC1>[F:22][C:21]([F:24])([F:23])[O:20][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][C:16]([F:19])([F:18])[F:17])[CH2:8][O:52][C:49]1[CH:48]=[CH:47][C:46]([C@@H:40]([C:41]2[CH:45]=[CH:44][O:43][N:42]=2)[CH2:39][C:1]([OH:2])=[O:4])=[CH:51][CH:50]=1
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1OC(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C[C@@H](c1ccc(OCc2ccc(OC(F)(F)F)c(OC(F)(F)F)c2)cc1)c1ccon1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.4 %

Procedure:
Cesium carbonate (137 mg, 0.4 mmol) was added to a mixture of 4-(bromomethyl)-1,2-bis(trifluoromethoxy)benzene 22.1 (71 mg, 0.21 mmol) and 7.5 (82 mg, 0.21 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 16 hours. To the reaction mixture was added LiOH in water (0.5 mL, 1N solution) and THF (1 mL). The mixture was stirred at 23° C. for 3 hours. The mixture was filtered and purified by reverse phase HPLC to give 22 (19 mg) after lyophilization. MS ESI (pos.) m/e 492.1 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.31 (1H, s), 7.45 (1H, s), 7.39 (2H, s), 7.21 (2H, d, J=8.3 Hz), 6.93 (2H, d, J=8.8 Hz), 6.08 (1H, s), 5.05 (2H, s), 4.57 (1H, t, J=7.6 Hz), 3.37 (1H, dd, J=16.6, 7.8 Hz), 3.00 (1H, dd, J=16.6, 7.8 Hz).
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=1.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16].O>CCOCC>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:15]([CH3:17])([CH3:16])[CH3:14])[CH:8]=1
Reactant: Brc1cccc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(C)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
26.49 ml (42.39 mmol) of a solution of BuLi (1.5M/hexane) are added dropwise, with stirring, over 30 min, to a solution of 10 g (42.39 mmol) of 1,3-dibromobenzene in 80 ml of anhydrous Et2O, cooled to −78° C. and maintained under a nitrogen atmosphere. After stirring for a further 30 min at −78° C., 5.96 ml (46.63 mmol) of TMSCl are introduced dropwise into the reaction mixture. The stirring is maintained at this temperature for 90 min and the reaction mixture is subsequently hydrolysed by adding 15 ml of water. The product is extracted with ethyl acetate (3×50 ml). The combined organic phases are washed with a saturated aqueous solution of NaCl (2×25 ml), dried over Na2SO4, filtered and evaporated under reduced pressure. The reaction crude is purified by silica gel column chromatography, elution being carried out with heptane, so as to isolate 9.3 g of the expected 1-bromo-3-trimethylsilylbenzene, in the form of a colourless oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.N1C=CC=CC=1.[CH:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][C:40]=1[S:49](Cl)(=[O:51])=[O:50]>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:49]([C:40]3[CH:41]=[CH:42][C:43]4[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:39]=3)(=[O:51])=[O:50])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccc5ccccc5c4)ccc3N2)=C(O)c2ccccc21
Yield: 39.1 %

Procedure:
A mixture of Example 39H (23.8 mg, 0.050 mmol), pyridine (31.6 mg, 0.40 mmol), and 2-naphthalenesulfonyl chloride (45.3 mg, 0.20 mmol) in acetone (1.5 mL) was stirred at rt for 18 h. The reaction mixture was evaporated in vacuo and partitioned between ethyl acetate and 1 N HCl. The organic phase was separated, dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with 4:1 hexane/ethyl acetate to provide the title compound (12.3 mg, 39% yield). 1H NMR (300 MHz, DMSO-d6) 8 ppm 0.37 m, 1 H) 0.66 (d, J=6.62 Hz, 3 H) 0.68 (d, J=6.62 Hz, 3 H) 0.77 m, 1 H) 1.29 m, 1 H) 1.52 (s, 3 H) 2.02 m, 1 H) 2.18 m, 1 H) 7.52 (m, 4 H) 7.68 m, 2 H) 7.73 (d, J=4.04 Hz, 2 H) 7.79 (dd, J=8.46, 1.84 Hz, 1 H) 8.01 (d, J=7.72 Hz, 1 H) 8.13 (m, 3H) 8.50 (s, 1 H) 10.93 (s, 1 H) 13.71 (s, 1 H). MS (ESI+) m/z 630.0 (M+H)+, 647.1 (M+NH4)+, (ESI−) m/z 628.1 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1.Cl.O>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]3[NH:23][C:20]4[C:21]([C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1)=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4
Reactant: COc1ccc(NN)cc1
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CCc1c-2[nH]c2ccc(OC)cc12
Yield: 74 %

Procedure:
10.0 g (57 mmol) of 6-methoxy-1-tetralone in 125 ml of ethanol is added in drops within 35 minutes to a boiling solution of 10.0 g (57 mmol) of p-methoxyphenylhydrazine-hydrochloride and 5.0 ml of concentrated hydrochloric acid in 180 ml of ethanol. Then, it is refluxed for 5 hours. After 370 ml of hot water is added, it is allowed to cool. The almost colorless reaction product is suctioned off and recrystallized from ethanol. Yield 74%, melting point 189-191° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([C:33]1[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=1)[CH3:32]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([CH2:31][CH3:32])[CH:34]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: CCc1cccc(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCc1cccc(NC(=O)c2cc(Br)ccc2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method B; 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) in THF (6 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min and 3-ethylbenzenamine (79 mg, 0.65 mmol) was added dropwise. After refluxing for 14 h, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography eluting with hexane:ethyl acetate (10:1) to yield the title compound. 80 mg.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[CH:14]12[CH2:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][CH:15]2[NH2:21].C(N(CC)CC)C>C(O)(C)C>[CH:14]12[CH2:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][C@@H:15]2[NH:21][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: NC1CC2CCC1C2
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC2CCC1C2
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.064 g, 0.30 mmol) (Example 1, Step 2), bicyclo[2.2.1]heptan-2-amine (from Aldrich, 0.050 g, 0.45 mmol) and triethylamine (0.083 mL, 0.60 mmol) in isopropyl alcohol (1.4 mL) was heated at 90° C. for 2 h. The mixture was concentrated to give the desired product, which was used in the next step without further purification. LCMS calculated for C14H16N3O2S (M+H)+: m/z=290.1. Found: 290.0.