Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:39]=[CH:38][C:24]([O:25][C@H:26]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]5)=[CH:23][CH:22]=4)=[O:20])[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH:15]3[CH2:16][N:17]([C:19]([C:21]4[CH:39]=[CH:38][C:24]([O:25][C@H:26]5[CH2:30][CH2:29][NH:28][CH2:27]5)=[CH:23][CH:22]=4)=[O:20])[CH2:18]3)[CH2:13][CH2:14]2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(=O)N3CC(N4CCN(C(=O)c5ccccc5)CC4)C3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCN(C2CN(C(=O)c3ccc(O[C@H]4CCNC4)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound 434 (87.7 mg, 0.164 mmol) in CH2Cl2 (1 mL) was added TFA (0.5 mL). The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure to give compound 33a, which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[C].[Pd].O1CCCC1>[OH:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:15]2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3ccccc3)cc2)cc1-c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A mixture of ethyl(E)-3-[1-(4-benzyloxybenzyl)-4-phenyl-3-pyrrolyl]propenoate (19.50 g), 5% palladium-carbon (20.00 g), and tetrahydrofuran (200 ml) was stirred overnight at room temperature under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (14.92 g, yield: 96%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH:29][C:9](=[O:10])[C:8]2[CH:12]=[CH:13][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)cc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2ccc(S(C)(=O)=O)cc2)sc1C(=O)NCc1ccccc1
Yield: 9 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 4-methanesulfonylbenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 9% yield; m.p. 262-265° C.; 1H NMR (DMSO-d6, 300 MHz) δ 8.65 (s, 1H), 8.27 (d, J=8.3 Hz, 2H), 8.06 (d, J=8.3 Hz, 2H), 7.31-7.21 (m, 5H), 4.38 (d, J=3.7 Hz, 2H), 3.27 (s, 3H), 2.51 (s, 3H); MS (ES+) m/z 430.1 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.CC#N.[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]CO)=[C:38]([N+:45]([O-:47])=[O:46])[CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCOC(C)=O.CCCCCC>[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:20][Br:24])=[C:38]([N+:45]([O-:47])=[O:46])[CH:37]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1CCBr
Reaction time: 8 h
Yield: 97.3 %

Procedure:
Triphenylphosphine (1.92 g, 7.33 mmol), CBr4 (7.28 g, 21.96 mmol), and dry CH3CN (16.6 mL) were added to a round bottom flask containing 2-(4-benzyloxy-2-nitrophenyl)ethanol (1.00 g, 3.66 mmol). A red solution resulted which was allowed to stir overnight under a positive pressure of nitrogen. The solution was checked by TLC (20% EtOAc/hexane) and concentrated down on a rotoevaporator. The excess CBr4 was removed by vacuum kugelrohr distillation (60° C., 0.25 mmHg). Column chromatography (SiO2, 10% EtOAc/5% CHCl3/85% petroleum ether gradient elution) afforded 2-(4-benzyloxy-2-nitrophenyl)ethyl bromide as a brownish solid (1.33 g, 3.56 mmol, 92%). Mp 30-34° C.; TLC (20% EtOAc/hexane) Rf=0.48; 1H-NMR (CDCl3, 500 MHz) 7.52 (d, 2.5, 1H), 7.34 (m, 5H), 7.24 (d, 8.5, 1H), 7.11 (dd, 2.5, 8.5, 1H), 5.04 (s, 2H), 3.57 (t, 7.0, 2H), 3.30 (t, 7.0, 2H); 13C-NMR (CDCl3, 125 MHz) 158.0, 149.4, 135.6, 133.8, 128.7, 128.4, 127.5, 125.8, 120. 5, 110.8, 70.6, 35.9, 32.0; IR (neat) 3070, 3027, 2919, 2855, 1618, 1570, 1526, 1499, 1451, 1408, 1381, 1343, 1289, 1262, 1240, 1149, 1025, 842, 804, 733, 695; EI-MS m/z (relative intensity) 335 (M+, 9); isotope pattern of M+ and M++2 agrees with the presence of one bromine atom. Accurate mass (EI-MS) for C15H14NO3Br: calcd. 335.0157, obsd. 335.0160.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.Br[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[CH2:25]([O:24][C:22]([CH2:21][CH2:20][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH:7]2[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]2)=[N:11]1)=[O:23])[CH3:26]
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: CCOC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1nc(C2CCN(C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a stirred suspension, under nitrogen, of 1.7 g of a 50% oil dispersion of sodium hydride in 75 ml of dimethylformamide was added, dropwise, 6.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 30 ml of hot dimethylformamide. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for 1 hr and a solution of 6.5 g of ethyl 3-bromopropionate was added dropwise. The reaction mixture was stirred at ambient temperature for 3 hrs and then poured into water. The aqueous mixture was extracted with ethyl acetate and the extracts were washed with water, dried over anhydrous magnesium sulfate and filtered. Evaporation of the filtrate under vacuum gave 6.5 g (70.8%) of product, as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][CH2:21][CH:22]([NH2:24])[CH3:23].CCN(C(C)C)C(C)C>C(#N)C>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:24][CH:22]([CH3:23])[CH2:21][O:20][CH3:19])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1Cl
Reactant: COCC(C)N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCC(C)Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 85.1 %

Procedure:
2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.20 g, 0.66 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of 2-methoxy-1-methyl-ethylamine (0.12 g, 1.32 mmol) and Hunig's base (0.037 g, 0.29 mmol). The reaction was stirred at reflux for 64 h. The solution was cooled to room temperature and extracted with EtOAc/H2O. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to yield 0.20 g (87%) of [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine: MS (AP) m/z 356.2 [(M+H)+, 86].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([CH:16]=1)[CH2:14][CH2:13][O:12]2.C1C(=O)N([I:24])C(=O)C1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[I:24])[CH2:14][CH2:13][O:12]2
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2cn3c(n2)OCC3)c(F)c1
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3n(c2I)CCO3)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
The 6-(2,4-difluorophenyl)-2,3-dihydroimidazo[2,1-b]oxazole (0.500 g, 2.25 mmol) was dissolved in DMF (6 mL) then NIS (0.533 g, 2.25 mmol) was added in one portion. The mixture was stirred at ambient temperature for about 15 min. The solvent was removed under reduced pressure then the residue was dissolved in DCM (6 mL) and purified by flash chromatography on silica gel using DCM/EtOAc (1:1) as an eluent. The desired fractions were combined and concentrated under reduced pressure to give a brown solid that was then triturated with water (10 mL). The solid was collected by filtration then dried under vacuum at about 70° C. for about 12 h to give the title compound (0.635 g, 81%): LC/MS (Table 1, Method h) Rt=1.39 min; MS m/z: 349 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CC(=C)CCO.Cl[C:19]1C=C[CH:22]=[C:21]([C:25]([O:27]O)=O)[CH:20]=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]2[C:10]([O:11][CH2:19][CH2:20][C:21]3([CH3:22])[CH2:25][O:27]3)=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cccc(O)c2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C=C(C)CCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1nc2cccc(OCCC3(C)CO3)c2s1
Temperature: 25 °C
Yield: 63 %

Procedure:
2-Methyl-7-hydroxybenzothiazoie was alkylated with 3-methyl-3-buten-1-ol according to Method VI. The product of this alkylation (0.30 g, 1.28 mmol) was dissolved in CH2Cl2 at about 0° C. to which was then added a solution of m-chloroperbenzoic acid (0.95 g, 5.53 mmol) in CH2Cl2. The reaction was allowed to warm to room temperature and after about 0.5 h the reaction was complete. 1N NaOH was added, the layers separated and the organic layer was washed with additional 1N NaOH and H2O. The organic layer was then dried over MgSO4 and the solvent was removed by rotary evaporation to give the title compound (0.20 g, 63%) as a yellow oil which was used in subsequent reactions without further purification.
Reaction SMILES: [OH-].[Na+].CO.[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([C:23]([O:25]C)=[O:24])=[CH:20][CH:19]=3)=[CH:14][C:13]=2[C:27]#[N:28])[CH:9]=[CH:10][CH:11]=1.Cl>O1CCCC1>[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=3)=[CH:14][C:13]=2[C:27]#[N:28])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(-c2ccc(-c3cccc(N)c3)c(C#N)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(-c2ccc(C(=O)O)s2)ccc1-c1cccc(N)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.2 ml of aqueous 1 M sodium hydroxide solution was added to a methanol (0.25 ml)/tetrahydrofuran (0.25 ml) solution of methyl 5-(3′-amino-2-cyanobiphenyl-4-yl)thiophene-2-carboxylate, followed by stirring overnight at 60° C. 1 M hydrochloric acid was added to the reaction liquid to make it acidic, and the solvent was evaporated under reduced pressure. The residue was purified by HPLC [elution through column: SunFire (registered trademark) C18 5 μm, 19 mm×100 mm, solvent: MeOH/aqueous 0.1% formic acid solution 10/90 for 1 minute, ratio change to 95/5, taking 8 minutes, and further elution with 95/5 for 3 minutes, flow rate: 25 mL/min), thereby obtaining 2.5 mg of 5-(3′-amino-2-cyanobiphenyl-4-yl)thiophene-2-carboxylic acid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:7][C:6]=1[CH3:18])=O.[NH2:19][C:20]([NH2:22])=[S:21]>CCO>[CH3:17][O:16][CH2:15][CH2:14][CH2:13][O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:19]=[C:20]([NH2:22])[S:21][CH:2]=2)=[C:6]([CH3:18])[CH:7]=1
Reactant: NC(N)=S
Reactant: COCCCOc1cc(C)c(C(=O)CBr)c(C)c1
Solvent: CCO
Product: COCCCOc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 68.8 %

Procedure:
A reaction mixture containing 2-bromo-1-(4(3-methoxypropoxy)-2,6-dimethylphenyl)ethanone (500.0 mg, 1.6 mmol, 1.0 equiv) and thiourea (126.8 mg, 1.6 mmol, 1.0 equiv) in EtOH (10.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 4-(4-(3-methoxypropoxy)-2,6-dimethylphenyl)thiazol-2-amine (328.9 mg, 1.1 mmol) as yellow solids in 71% yield: 1H NMR (CDCl3, 500 MHz) δ 9.35 (brs, 1 H), 9.00 (brs, 1 H), 6.64 (s, 2 H), 6.22 (s, 1 H), 4.04-4.05 (m, 2 H), 3.54-3.56 (m, 2 H), 3.37 (s, 3 H), 2.19 (s, 6 H), 2.03-2.06 (m, 2 H); ESI-MS m/z 293.8 (M+H)+.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH3:13][S:14][CH2:15]Cl.C(N(CC)CC)C>>[C:1]([O:12][CH2:13][S:14][CH3:15])(=[O:11])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CSCCl
Reactant: CC(C)=CCC/C(C)=C/C(=O)O
Solvent: CCN(CC)CC
Product: CSCOC(=O)/C=C(\C)CCC=C(C)C

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting geranic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 111°-112° C./2 mm Hg, n20 1.4912.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:17][SiH3])(C(C)(C)C)[C:4](C)(C)[C:5](=[CH2:10])[C:6]=1[CH2:7][CH:8]=[CH2:9].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][C:2]1[CH:3]([OH:17])[CH2:4][C:5](=[CH2:10])[C:6]=1[CH2:7][CH:8]=[CH2:9]
Reactant: C=CCC1=C(C)C(O[SiH3])(C(C)(C)C)C(C)(C)C1=C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCC1=C(C)C(O)CC1=C
Temperature: 25 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
3 To a solution of (RS)-2-methyl-4-methylidene-3-(2-propenyl)-1-tert-butyldimethyl-silyloxycyclopent-2-ene (1.0 g, obtained above) in dry tetrahydrofuran (10 ml) was added a tetrahydrofuran solution (5.7 ml) of 1M tetrabutylammonium fluoride under ice-water cooling. The solution was then stirred at room temperature for 12 hours. The reaction solution was poured into ice-water, and extracted with ether (100 ml×2). The ether layers were combined and washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate=3:1) to afford the desired product (RS)-2-methyl-4-methylidene3-(2-propenyl)cyclopent-2-ene-1-ol (460 mg, yield 82.3%) as a pale yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[C:12]([OH:21])=[C:13]([C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][C:16]=1[OH:17].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:10][C:11]1[C:12]([OH:21])=[C:13]([C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][C:16]=1[O:17][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=1
Reactant: BrCc1ccc(I)cc1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(OCc2ccc(I)cc2)c(Cl)c1O
Reaction time: 18 h
Yield: 29.5 %

Procedure:
Add 1-bromomethyl-4-iodo-benzene (10.00 g, 33.7 mmol) to a solution of 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone (7.92 g, 42.4 mmol) and cesium carbonate (16.6 g, 50.9 mmol) in dimethylformamide (250 mL) and stir. After 18 hours, pour reaction into water and extract with ethyl acetate. Combine organic layers and wash with 2N NaOH. Dry with sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with a gradient of ethyl acetate:hexanes to yield the title product as a tan solid (4.00 g, 23%): 1H NMR (DMSO-d6) δ 2.62 (s, 3H), 5.33 (s, 2H), 6.87 (d, 1H), 7.27 (d, 2H), 7.78 (d, 2H), 7.94 (d, 1H), 13.13 (s, 1H).
Reaction SMILES: O.NN.[OH-].[Na+].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=O)[CH2:14][N:15]1[C:23]2[C:18](=[N:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1>C(O)COCCO>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][N:15]1[C:23]2[C:18](=[N:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: COc1ccc2c(ccn2CC(=O)c2ccccc2Br)n1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: COc1ccc2c(ccn2CCc2ccccc2Br)n1
Temperature: 160 °C
Reaction time: 24 h

Procedure:
140 μl (2.9 mmol) of hydrazine hydrate and 80 mg (2 mmol) of sodium hydroxide are added to a solution of 200 mg (0.6 mmol) of the compound obtained in Step B in 2 ml of diethylene glycol. After 24 hours' stirring at 160° C., the mixture is hydrolysed and then extracted with ethyl acetate. The organic phase is washed several times with water, dried over magnesium sulphate, concentrated and then purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 7:3) to yield the title compound in the form of a yellow oil.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCCl>[C:20]1([S:26]([N:1]2[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])[CH2:4][C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]2=3)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1CCNc2ccccc2C1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccccc2)c2ccccc2C1

Procedure:
To a stirred room temperature solution of tert-butyl 2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-ylcarbamate (39.3 mg, 0.15 mmol) in 1,2-dichloroethane (4 mL) was added benzenesulfonyl chloride (26.4 mg, 0.15 mmol). After 16 hours the mixture was evaporated to dryness to yield tert-butyl 1-(phenylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-ylcarbamate.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1.[CH2:19]([OH:22])[CH2:20][CH3:21]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14]([O:22][CH2:19][CH2:20][CH3:21])=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1
Reactant: O=C(Cl)c1csnc1-c1cccc(C(F)(F)F)c1
Reactant: CCCO
Product: CCCOC(=O)c1csnc1-c1cccc(C(F)(F)F)c1
Yield: 100.5 %

Procedure:
A solution of 2.92 g (0.010 mol) of 3-(α,α,α-trifluoro-m-tolyl)-4-isothiazolecarbonyl chloride and 4 g (0.0667 mol) of 1-propanol was heated on a steam bath for 1 hour and was concentrated under vacuum to 70° (0.5 torr) to give 3.17 g of clear oil, nD20.8 = 1.5261, infrared (film) 5.80 μ.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]([CH3:18])[CH3:17])/[CH:10]=[CH:11]/[C:12]([OH:14])=O)=[O:7])([CH3:4])[CH3:3].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:55]1[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH2:57][CH2:56]1>CN(C=O)C.O>[N:55]1([C:12](=[O:14])/[CH:11]=[CH:10]/[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH2:57][CH2:56]1
Reactant: CC(C)C[C@@H](/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)CCN2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.8 %

Procedure:
To a solution of (2E,4S)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-6-methyl-2-heptenoic acid (4.70 g, 18.26 mmol) in DMF (30.0 mL) were added BOP reagent (8.08 g, 18.26 mmol) and DIPEA (6.38 mL, 36.5 mmol). After stirring at RT for 5 min, 2,3-dihydro-1H-indole (2.053 mL, 18.26 mmol) was added and stirring continued overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by flash column chromatography (0-20% EtOAc/hexanes) to afford the title compound (4.83 g, 74%) as a white solid. LC-MS m/z 359 (M+H)+, 1.18 min (ret time).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:21]1([S:27]([CH2:30][C:31]2[C:36]([C:37](O)=[O:38])=[C:35]([OH:40])[C:34]([Br:41])=[CH:33][CH:32]=2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C1C=CN=CC=1)C.C1COCC1>[C:21]1([S:27]([CH2:30][C:31]2[C:36]([C:37]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:38])=[C:35]([OH:40])[C:34]([Br:41])=[CH:33][CH:32]=2)(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Reaction time: 18 h

Procedure:
tert-Butanol (1 mL) and N,N′-dicyclohexylcarbodiimide (0.4 g) were added to a solution of 6-(benzenesulfonylmethyl)-3-bromo-2-hydroxybenzoic acid (Intermediate 39, 0.48 g) and DMAP (0.016 g) in THF (10 mL) and the mixture was stirred for 18 hours. It was evaporated to dryness and the residue was suspended in DCM and the insoluble material was removed by filtration. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with DCM to give tert-butyl 6-(benzenesulfonylmethyl)-3-bromo-2-hydroxybenzoate (0.34 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]3[N:12]([CH:22]=[C:23]([CH3:25])[N:24]=3)[CH:13]=[CH:14][C:15]=2[NH:16]C(=O)OCC)=[CH:4][CH:3]=1.[K+].[Br-]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]=[C:15]3[C:10](=[C:11]4[N:24]=[C:23]([CH3:25])[CH2:22][N:12]4[CH:13]=[CH:14]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Nc1ccn2cc(C)nc2c1C#Cc1ccc(F)cc1
Agent: [Br-]
Agent: [K+]
Product: CC1=Nc2c3cc(-c4ccc(F)cc4)nc-3ccn2C1

Procedure:
From 25b (yield: 43%); 280° C. (dec.); IR (KBr) 3461, 3119, 2917, 1645, 1521, 1489, 1229 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 2.31 (s, 3H), 6.96 (d, 1H, J=7.2 Hz), 7.12 (d, 1H, J=1.6 Hz), 7.30 (m, 2H), 7.51 (s, 1H), 7.88 (m, 2H), 8.06 (d, 1H, J=7.2 Hz), 11.98 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.2, 98.1, 100.6, 109.4, 114.1, 115.9 (d, 2JCF=22.0 Hz), 120.9, 126.6 (d, 3JCF=7.9 Hz), 128.6, 131.5, 134.8, 139.0, 140.7, 161.3 (d, 1JCF=242.8 Hz). Anal. Calcd for C16H12FN3: C, 72.44; H, 4.56; N, 15.84. Found: C, 72.78; H, 4.12; N, 16.15.