Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([F:14])[C:3]=1[NH2:15].[CH:16]1([CH2:21][C:22](Cl)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[CH:16]1([CH2:21][C:22]([NH:15][C:3]2[C:2]([F:1])=[CH:7][C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)=[CH:5][C:4]=2[F:14])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1c(F)cc(N2CCOCC2)cc1F
Reactant: O=C(Cl)CC1CCCC1
Solvent: CC#N
Product: O=C(CC1CCCC1)Nc1c(F)cc(N2CCOCC2)cc1F
Temperature: 150 °C
Yield: 75 %

Procedure:
2,6-Difluoro-4-morpholin-4-yl-phenylamine (0.20 g) and cyclopentylacetyl chloride (149 μL) were dissolved in acetonitrile (4 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction mixture was concentrated in vacuo and purified by flash chromatography to furnish 228 mg (75%) of the title compound as a white solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH3:22])([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12](=[O:14])[N:13]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(N(C(C)C)CC)(C)C>C(Cl)Cl.[Cl-].[Na+].O>[C:23]([N:19]1[CH2:20][CH2:21][CH:16]([CH2:15][C:11]2([CH3:22])[S:10][C:9]([NH:8][C@H:2]3[CH2:3][CH:4]4[CH2:7][CH:1]3[CH2:6][CH2:5]4)=[N:13][C:12]2=[O:14])[CH2:17][CH2:18]1)(=[O:25])[CH3:24]
Reactant: CC1(CC2CCNCC2)SC(N[C@H]2CC3CCC2C3)=NC1=O
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(CC2(C)SC(N[C@H]3CC4CCC3C4)=NC2=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methyl-5-(piperidin-4-ylmethyl)thiazol-4(5H)-one (130 mg, 0.41 mmol), acetic anhydride (Aldrich, 83 mg, 0.81 mmol) and diisopropylethylamine (157 mg, 1.22 mmol) in CH2Cl2 (3 mL) was stirred at room temperature for ca. 18 h. Brine was then added, and the mixture was extracted with CH2Cl2 (4×60 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Flash column chromatography (silica gel, 0-3.5% MeOH in CH2Cl2) afforded the title compound as a colorless thin film (116 mg). MS (ESI, pos. ion) m/z: 364 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC([O-])(C)C.[K+].F[C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20].CN(C)C=O>CC1CCCO1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:17]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:4][C:3]=1[F:9]
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: Oc1cnc(Cl)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)cc1Oc1cnc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-chloro-5-fluoropyridin-3-ol (0.977 g) in 2-methyltetrahydrofuran (12 mL) was added potassium 2-methylpropan-2-olate (1.0M in tetrahydrofuran, 7.28 mL). After stirring for 15 minutes at room temperature, methyl 2,4-difluorobenzoate (1.710 g) was added as a solution in 2-methyltetrahydrofuran (2 mL) followed by N,N-dimethylformamide (2 mL) then the reaction was heated to 75° C. under a nitrogen atmosphere. After stirring overnight the reaction was cooled, diluted with ethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (GraceResolv 40 g) eluting with a gradient of 2% to 15% ethyl acetate/hexanes gave the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.[NH:23]1[CH2:26][CH:25]([C:27]2[O:28][CH:29]=[C:30]([CH3:32])[N:31]=2)[CH2:24]1>>[CH3:32][C:30]1[N:31]=[C:27]([CH:25]2[CH2:26][N:23]([C:13]3[N:14]4[C:18]([N:19]=[C:11]5[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]=35)=[CH:17][CH:16]=[N:15]4)[CH2:24]2)[O:28][CH:29]=1
Reactant: Cc1coc(C2CNC2)n1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Product: Cc1coc(C2CN(c3c4c(nc5ccnn35)CCNCC4)C2)n1

Procedure:
The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 2-azetidin-3-yl-4-methyl-oxazole was used as the amine.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](F)(F)F)=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1.[OH:26]S(O)(=O)=O.[OH2:31]>>[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Cl:1])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1)([OH:26])=[O:31].[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: O
Reactant: O=S(=O)(O)O
Agent: c1ccc2nnccc2c1
Product: O=C(O)c1ccc2c(Cl)ccnc2c1

Procedure:
As shown in Scheme 7, halogenated azaarenes 23, exemplified by 4-chloro-7-trifluoromethylquinoline or cinnoline, are treated with H2SO4 (70-95%) at 180-220° C. for about 16 to 48 hours in a sealed reaction vessel. The solution is cooled, poured into water and neutralized with base to pH ˜3-4. The product is dissolved in aqueous base and precipitated by acidification to yield 7-carboxy-4-chloroquinoline or cinnoline. This material is converted to the alkyl ester, such as methyl (24) or ethyl, by standard methods. 7-Alkyloxycarbonyl-4-chloroquinoline or cinnoline is dissolved in an anhydrous, aprotic solvent (THF or ether). The solution is cooled (−60 to −95° C.) and treated with a reducing agent such as lithium aluminum hydride. The solution is warmed (to approximately −40 to −50° C.) for about 15 to 30 minutes and quenched with a solvent such as ethyl acetate. Standard workup gives the product 7-hydroxymethyl-4-chloroquinoline, or cinnoline (25). Material 25 is treated with 45-50% HBr and heated to about 100-140° C. for about 45 to 90 minutes. After cooling and standard workup, 7-bromomethyl-4-chloroquinoline (or cinnoline) 26 is obtained. Alkylation as described before provides 4-chloroquinoline (or cinnoline) 27 followed by deprotection under the usual acidic conditions gives 4-chloroquinoline (or cinnoline) 28.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.[CH2:13]([C:20]1[C:21](=[O:38])[N:22]([CH2:33][CH2:34][CH2:35][CH2:36]Cl)[C:23](=[O:32])[N:24]2[CH2:29][CH2:28][CH2:27][S:26](=[O:31])(=[O:30])[C:25]=12)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:36][CH2:35][CH2:34][CH2:33][N:22]3[C:21](=[O:38])[C:20]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:25]4[S:26](=[O:31])(=[O:30])[CH2:27][CH2:28][CH2:29][N:24]4[C:23]3=[O:32])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: O=c1c(Cc2ccccc2)c2n(c(=O)n1CCCCCl)CCCS2(=O)=O
Reactant: Sc1cccc2nccn12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Cc2ccccc2)c2n(c(=O)n1CCCCSc1cccc3nccn13)CCCS2(=O)=O
Reaction time: 0.5 h

Procedure:
To a suspension of 0.22 g (5.5 mmol) of 60% oily sodium hydride in 30 ml of N,N-dimethylformamide, 0.83 g (5.5 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 30 minutes. To this mixture, 1.98 g (5 mmol) of 9-benzyl-7-(4-chlorobutyl)-1,1-dioxo-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 0.82 g (5.5 mmol) of sodium iodide were added, followed by stirring at 100° C. for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate→ethyl acetate/ethanol=10/1) to yield 1.95 g (78.2%, white powder) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:32]([O:39][C:40](Cl)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CS(C)=O.C1COCC1.O>[CH2:32]([O:39][C:40]([NH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])=[CH:6][CH:7]=2)[CH2:22][CH2:21]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCC(NC(=O)OCc3ccccc3)CC2)cc1
Temperature: 130 °C
Reaction time: 20 h
Yield: 57.3 %

Procedure:
4-Fluorobenzoic acid ethyl ester (25.0 g, 149 mmol) was dissolved in dimethyl sulfoxide (hereinafter referred to as DMSO) (100 mL), and potassium carbonate (31.0 g, 224 mmol) and 4-aminopiperidine (18.8 mL, 177 mmol) were added thereto, followed by stirring at 130° C. for 20 hours. After the reaction mixture was cooled to room temperature, water was added to the mixture and the precipitate was collected by filtration, thereby giving ethyl 4-(4-aminopiperidin-1-yl)benzoate (36.0 g, 98%) as a yellow solid. This amino compound (15.7 g, 63.2 mmol) was dissolved in THF (200 mL), and a 2N sodium carbonate aqueous solution (63 mL) was added thereto. Subsequently, benzyloxycarbonyl chloride (11.7 mL, 82.2 mmol) was added to the mixture, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to precipitate a solid, which was collected by filtration and dried under reduced pressure, thereby giving the title compound (18.0 g, 74%) as a white solid.
Reaction SMILES: [BH4-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.C(Cl)Cl>CO.O1CCCC1>[O:6]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[O:3][CH2:4][CH2:5]1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCc1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (3.78 g, 100 mmol) was added in four portions to a stirred solution of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde (4.94 g, 20 mmol) (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) in methanol/tetrahydrofuran (1:1, 100 mL) at 0° C. and the resulting solution was stirred at 0° C. for 30 minutes and then at room temperature for 1 hour. Methylene chloride was added and the solution was washed with water and dried over sodium sulfate. The solvents were removed and the residue was solidified upon standing (5.0 g, 100%); 1H NMR (300 MHz, CDCl3) δ 1.84 (t, J=5.7 Hz, 4 H), 3.33 (t, J=5.7 Hz, 3.99(s, 4 H), 4.59 (d, J=5.8 Hz, 2 H), 6.93 (d, J=8.7 Hz, 2 H), 7.24 (d, J=8.7 Hz, 2 H); MS (ES) m/z: 249.9 (MH+); HRMS Calcd. for C14H20NO3(MH+): 250.1443. Found: 250.1434.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([CH3:15])([OH:14])[CH3:13])=[CH:7][CH:6]=1.[CH3:33]I>C1COCC1>[CH3:33][O:14][C:12]([CH3:15])([CH3:13])[C@H:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:10]([CH2:9][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:32][CH:31]=1)[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)[C@@H](c2ccccc2)C(C)(C)O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)[C@@H](c2ccccc2)C(C)(C)OC)cc1
Reaction time: 0.25 h

Procedure:
At 0° C., to a suspension of NaH (0.13 g, 2.96 mmol) in anhydrous THF (5 mL), was added a solution of (S)-1-(bis(4-methoxybenzyl)amino)-2-methyl-1-phenylpropan-2-ol 4 (1.0 g, 2.47 mmol) in anhydrous THF (10 mL). After 15 min, MeI (0.55 g, 3.71 mmol) was added and the contents were heated to reflux. After 8 h, the reaction was brought back to ambient temperature, quenched carefully with ice cold H2O (10 mL), and the organic contents were extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (1×20 mL), dried over Na2SO4, concentrated to afford (S)-2-methoxy-N,N-bis(4-methoxybenzyl)-2-methyl-1-phenylpropan-1-amine. H1NMR (CD3OD, 400 MHz) δ 7.45-7.44 (m, 2H), 7.37-7.34 (m, 2H), 7.33-7.28 (m, 5H), 6.88-6.86 (m, 4H), 4.20 (s, 1H), 3.78 (s, 6H), 3.25 (s, 4H), 2.81 (s, 3H), 1.4 (s, 3H), 0.81 (s, 3H). MS: [M+H]+ m/z 420.
Reaction SMILES: O[CH:2]1[C:6]2[CH:7]=[C:8]([CH3:19])[CH:9]=[C:10]([C:11]([CH3:18])([CH3:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=2[O:4][C:3]1=[O:20].S(Cl)(Cl)=O.Cl>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:19][C:8]1[CH:9]=[C:10]([C:11]([CH3:18])([CH3:17])[CH2:12][C:13]([CH3:15])([CH3:14])[CH3:16])[C:5]2[O:4][C:3](=[O:20])[C:2](=[C:2]3[C:6]4[CH:7]=[C:8]([CH3:19])[CH:9]=[C:10]([C:11]([CH3:18])([CH3:17])[CH2:12][C:13]([CH3:15])([CH3:14])[CH3:16])[C:5]=4[O:4][C:3]3=[O:20])[C:6]=2[CH:7]=1
Reactant: Cc1cc2c(c(C(C)(C)CC(C)(C)C)c1)OC(=O)C2O
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1cc2c(c(C(C)(C)CC(C)(C)C)c1)OC(=O)C2=C1C(=O)Oc2c1cc(C)cc2C(C)(C)CC(C)(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
7.1 g of 3-hydroxy-5-methyl-7-(1,1,3,3-tetramethylbutyl)-3H-benzofuran-2-one (U.S. Pat. No. 5,614,572, Column 35, Compound No. 111) are introduced into 12.5 ml of toluene as initial charge and admixed with 3 drops of DMF and 2.7 ml of thionyl chloride. The solution is then gradually heated to 100° C. so that the evolution of HCl and SO2 remains lively but still controllable. Thereafter the reaction mixture is stirred at 100° C. for a further 1 h. About 12 ml of liquid are subsequently distilled off to remove excess thionyl chloride. The residue is diluted with 37.5 ml of toluene and admixed at room temperature with 3.5 ml of triethylamine added dropwise. The thick red reaction mixture is then refluxed for 30 min. The precipitated triethylamine hydrochloride is filtered off after cooling to room temperature and the filtrate is concentrated in a rotary evaporator to an oily consistency. The isoxindigo is crystallized out by addition of 25 ml of acetonitrile, filtered off, washed with acetonitrile and dried to leave 3.45 g (53% of theory) of 5,5′-dimethyl-7,7′-bis(1,1,3,3-tetramethylbutyl)[3,3′]bibenzofuranylidene-2,2′-dione of the formula
Reaction SMILES: [Ti:1](Cl)(Cl)(Cl)[Cl:2].[CH3:6][C:7]1([Si](C)(C)C)[C:15]2[C:10](=[C:11]([CH3:19])[C:12]([CH3:18])=[C:13]([CH3:17])[C:14]=2[CH3:16])[C:9]([CH3:20])=[C:8]1[CH3:21]>C1(C)C=CC=CC=1>[Cl-:2].[Cl-:2].[Cl-:2].[CH3:6][C:7]1([Ti+3:1])[C:15]2[C:10](=[C:11]([CH3:19])[C:12]([CH3:18])=[C:13]([CH3:17])[C:14]=2[CH3:16])[C:9]([CH3:20])=[C:8]1[CH3:21]
Reactant: Cl[Ti](Cl)(Cl)Cl
Reactant: CC1=C(C)C(C)([Si](C)(C)C)c2c(C)c(C)c(C)c(C)c21
Solvent: Cc1ccccc1
Product: CC1=C(C)C(C)([Ti+3])c2c(C)c(C)c(C)c(C)c21
Product: [Cl-]

Procedure:
Titanium tetrachloride in an amount of 15.2 g (80 mmol, 8.8 mL) was dissolved in 100 mL of dehydrated toluene, and to the resultant solution was added dropwise, at room temperature, a solution of 19.52 g of 1,2,3,4,5,6,7-heptamethylindenyltrimethylsilane in 150 mL of toluene over a period of 3 hours. After one hour of heating refluxing of the mixed solution thus obtained, there was produced a toluene-soluble portion at 80° C., which then was extracted twice with 100 mL each of toluene. By filtering off the toluene-insoluble portion, there was obtained a green toluene solution, and the volatile components of which were distilled away at 40° C. under reduced pressure to afford dark green solid. Thereafter, the solid was incorporated with 20 mL of toluene and then with 200 mL of hexane, and the insoluble portion was collected by filtration as the objective product in a yield of 9.43 g (26 mmol) and in a yield rate of 39%. The product was slightly soluble in boiling hexane, readily soluble in toluene, and was analyzed by NMR with the results as follows:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[C:5]([CH3:20])[CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[C:5]([CH3:20])[CH:4]=1
Reactant: COc1ccc(-c2ccc3cc(O)ccc3c2)c(C)c1
Agent: BrB(Br)Br
Product: Cc1cc(O)ccc1-c1ccc2cc(O)ccc2c1

Procedure:
The title compound was prepared by reacting 6-(4-methoxy-2-methylphenyl)-2-naphthol (420 mg, 1.59 mmol) with boron tribromide (4.53 mL of 1.0 M solution in CH2Cl2, 4.53 mmol) according to method D to yield 400 mg (quantitative yield) of a yellowish solid: mp 191-193° C.; 1H NMR (DMDO-d6): δ 6.68 (1H, dd, J=8.41 Hz, J=2.21 Hz), 6.72 (1H, d, J=2.21 Hz), 7.07-7.11 (2H, m), 7.14 (1H, d, J=2.21 Hz), 7.33 (1H, dd, J=8.41 Hz, J=2.21 Hz), 7.64 (1H, d, J=0.885 Hz), 7.68 (1H, d, J=8.41 Hz), 7.77 (1H, d, J=9.29 Hz), 9.33 (1H, s), 9.69 (1H, s); 13C NMR (DMDO-d6): δ 108.34, 112.82, 116.84, 118.68, 125.47, 127.13, 127.56, 128.02, 129.26, 130.71, 132.26, 133.02, 135.63, 135.90, 155.11, 156.31; MS (ESI) m/z 249 (M−H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][N:31]=1>C(O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:29]=[C:30]4[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][N:31]4[C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccnc(N)c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(C#N)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
A mixture of {1-[4-(2-bromo-2-phenyl-acetyl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester [Int-1-A] (2.65 g, 5.69 mmol), 2-amino-4-cyanopyridine (1.42 g, 11.9 mmol, 2 equiv) and powdered activated 3 Å molecular sieves (10 g) in ethanol (22 mL) was heated for 4 h at the reflux temperature. The reaction mixture was cooled to room temperature, additional 2-amino-4-cyanopyridine (0.71 g, 6.0 mmol, 1 equiv) was added, and the resulting mixture was heated at the reflux temperature for 5 h. The resulting solution was separated between EtOAc (75 mL) and an saturated aqueous NaHCO3 solution (75 mL). The organic phase was washed with a saturated aqueous NaCl solution (25 mL), dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 25 g SNAP cartridge: 80% hexane/20% EtOAc for 3.0 min., gradient to 70% hexane/30% EtOAc over 13.7 min.) to give {1-[4-(7-cyano-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (0.57 g, 21%).
Reaction SMILES: [Na].[SH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]>C(O)C=C>[CH2:7]([O:6][C:4]([CH2:3][S:2][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[O:5])[CH3:8]
Reactant: C=CCOC(=O)CCCCl
Reactant: CCOC(=O)CS
Agent: [Na]
Solvent: C=CCO
Product: C=CCOC(=O)CCCSCC(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
Sodium (9.06 g; 0.39 mole) was decomposed in allyl alcohol (380 ml). The obtained solution was treated by dropwise adding of first ethyl mercaptoacetate (42.7 ml; 0.39 mole) at the temperature of 0° C. and then of allyl 4-chlorobutyrate (58.3 g; 0.36 mole) prepared according to the process disclosed in Example 2a. The obtained mixture was stirred for three hours at room temperature and then for 1 hour at reflux temperature. The mixture was concentrated by evaporation and poured into a mixture of diethylether (200 ml) and of an ice/water mixture (100 g). The obtained solution was acidified with 1M hydrochloric acid solution to achieve a pH value of the medium between 3 and 6. The ether phase was separated and the obtained aqueous phase was extracted with diethyl ether (200 ml). The combined ether fractions were washed with water (200 ml) and 4% aqueous sodium hydrogencarbonate solution (200 ml) and dried with magnesium sulfate. After the removal of the drying agent and evaporation of ether, the title compound (78.1 g; 84%) was obtained, which was used in the crude form in the next reaction.
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.[NH2:8][C@H:9]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]([C:38]([OH:40])=[O:39])[CH2:36][OH:37])=[O:33])[CH2:28][C:29](=[O:31])[NH2:30])=[O:25])[C@@H:21]([CH3:23])[OH:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:41]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:42]([C:47](ON1C(=O)CCC1=O)=[O:48])[C@H:43]([CH2:45][CH3:46])[CH3:44].C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C>CN(C=O)C>[NH:41]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:42]([C:47]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]([C:38]([O:40][CH3:1])=[O:39])[CH2:36][OH:37])=[O:33])[CH2:28][C:29](=[O:31])[NH2:30])=[O:25])[C@@H:21]([CH3:23])[OH:22])=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:48])[C@H:43]([CH2:45][CH3:46])[CH3:44]
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@H](O)[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)OC)[C@@H](C)O
Yield: 85.9 %

Procedure:
A solution cooled on an ice bath of 5.14 g of TFA, H-Phe-Thr-Asn-Ser-Ome (8.78 mM) in 100 ml of DMF has 3.17 g of Boc-Ile-OSu (9.66 mM), 1.30 g of HOBt (9.62 mM) and N-ethyl morpholine added thereto until a pH of 7 is obtained. After 20 hours of reaction at ambient temperature, the solution is concentrated under reduced pressure and the residue taken up in ether gives a precipitate which is filtered and dried in vacuo. 5.24 g of product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:9]1/[C:10]2[CH:17]=[C:16]([C:18]([O:20]C(C)(C)C)=[O:19])[S:15][C:11]=2[NH:12][C:13]/1=[O:14].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:9]1/[C:10]2[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[S:15][C:11]=2[NH:12][C:13]/1=[O:14]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2sc(C(=O)OC(C)(C)C)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2sc(C(=O)O)cc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
tert-Butyl (Z)-5,6-dihydro-4-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxylate (0.5 g, 1.45 mmol) was dissolved in dichloromethane (8 ml), cooled to 0° C., treated with trifluoroacetic acid (2 ml) and stirred for 3 hours warming to room temperature. The reaction mixture was evaporated to dryness and triturated with diethyl ether to give 300 mg of (Z)-5,6-dihydro-4-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxylic acid as a red solid. MS(ES): m/e 291 [M+H].