Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[N+]=[N-].[Cl:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][C:37]=1[C:38]([O:40][CH3:41])=[O:39])[C:25](ON1C(=O)CCC1=O)=[O:26]>[Pd].CO.C1C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]([NH:1][CH2:4][C:5]2[C:13]3[N:12]=[CH:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]=3[CH:8]=[CH:7][CH:6]=2)=[O:26])[CH:35]=[CH:36][C:37]=1[C:38]([O:40][CH3:41])=[O:39]
Reactant: CC(C)(C)OC(=O)n1cnc2c(CN=[N+]=[N-])cccc21
Reactant: COC(=O)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1Cl
Agent: [Pd]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(C(=O)NCc2cccc3c2ncn3C(=O)OC(C)(C)C)cc1Cl
Reaction time: 1.75 h
Yield: 66.3 %

Procedure:
A mixture of 4-(azidomethyl)benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (Example 13; 1.40, 5.1 mmol), 1-[[3-chloro-4-(methoxycarbonyl)benzoyl]oxy]-2,5-pyrrolidinedione (Example 5; 1.62 g, 5.2 mmol), and 10% palladium on charcoal (210 mg) in methanol (40 mL) and benzene (2 mL) was hydrogenated at atmospheric pressure for 105 min and then filtered through Celite. Tlc indicated that the reaction was not complete so more 10% palladium on charcoal (210 mg) was added and the mixture was hydrogenated at atmospheric pressure for 3 h and then shaken at 50 psi of hydrogen for 3 h. The reaction mixture was allowed to stand under hydrogen for 12 h, then filtered through Celite, evaporated, and chromatographed (20-100% ethyl acetate/hexanes) to give 2-chloro-4-[[[[1-[(1,1-dimethylethoxy)carbonyl]benzimidazol-4-yl]methyl]amino]carbonyl]benzoic acid, methyl ester (1.50 g, 66%). A solution of the ester (1.45 g, 3.3 mmol) in methanol (15 mL) and 3 M lithium hydroxide solution (5.5 mL) was stirred at room temperature overnight. A white solid was filtered off and discarded. The filtrate was evaporated to dryness. Water and 1 M HCl (16.6 mL) were added, and the mixture was filtered and washed with water to give 2-chloro-4-[[[(benzimidazol-4-yl)methyl]amino]carbonyl]-benzoic acid (925 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:24]([N:23]([CH3:28])[CH3:22])(=[O:26])=[O:25])=[CH:6][CH:7]=1
Reactant: Clc1ccc(NCc2cccnc2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N(Cc1cccnc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 2.8 g. portion of 3-(4-chlorophenylaminomethyl)pyridine was dissolved in dichloromethane, and to it was added 2.1 g. of potassium carbonate and 1.6 ml. of dimethylsulfamoyl chloride. The mixture was stirred at ambient temperature for 1 day, and was then stirred under gentle heating for 3 days. The solvent was then evaporated under vacuum, and the oily residue was purified by chromatography on silica gel in chloroform to obtain 3.9 g. of the desired product. Its elemental analysis was as follows.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH:17](OC)(OC)OC>CO.O>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=1[OH:1]
Reactant: COC(OC)OC
Reactant: O=C(O)c1ccc(O)cc1O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(O)cc1O
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution in methanol (50 mL) of 2,4-dihydroxybenzoic acid (1.54 g, 10 mmol) was added sulfuric acid (0.5 mL) and trimethyl orthoformate (1.6 mL, 15 mmol) and the reaction mixture was stirred at reflux for 36 hours. The reaction mixture was cooled to ambient temperature and diluted with water. The methanol was evaporated in vacuo. The residue was diluted with water and extracted with ether (3×). The combined ether extracts were washed with saturated aqueous sodium bicarbonate (2×) and brine, dried, filtered and concentrated in vacuo to give 2,4-dihydroxybenzoic acid methyl ester (1.34 g) as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:19])([CH3:18])[CH2:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH2:13][CH2:12][CH2:11]2)=[O:6].Cl[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=O>C(O)C>[CH:17]1[C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([CH3:19])([CH3:18])[CH3:2])=[CH:9][C:10]2[CH2:11][CH2:12][CH2:13][N:14]3[C:15]=2[C:16]=1[C:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=13
Reactant: O=C1CCCCC1Cl
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)CCCN2
Agent: Cl
Solvent: CCO
Product: CC(C)(C)CC(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCC1
Temperature: 150 °C
Yield: 32.5 %

Procedure:
A mixture of 3,3-dimethyl-N-1,2,3,4-tetrahydroquinolin-6-ylbutanamide hydrochloride (50 mg, 0.18 mmol) and 2-chlorocyclohexanone (28 mg, 0.21 mmol) in ethanol (2.5 mL) was heated in a microwave to 150° C. for 50 min. The reaction mixture was concentrated and the crude material was purified by flash column chromatography (elution with 20% ethyl acetate-hexane) to provide N-5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-2-yl-3,3-dimethylbutanamide (19 mg). MS (ESI) m/z 325; HPLC purity major: no impurities are detected at 210-370 nm window; and no impurities are detected at 252 nm (max. abs), RT=10.8 (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min).
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:39]([N:41]=[C:42]=[O:43])[CH3:40]>N1C=CC=CC=1>[C:18]([C:8]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[N:4]2[N:3]=[C:2]([NH:1][C:42]([NH:41][CH2:39][CH3:40])=[O:43])[N:31]=[C:5]2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[C:7]=1[CH3:20])#[N:19]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CCN=C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCNC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (15 mg, 33 μmol) was dissolved in abs. pyridine (2 ml), and solid sodium sulfate (spatula tip) and ethyl isocyanate (46.6 mg, 655 μmol, 20 eq.) were added. The reaction mixture was then heated in a microwave reactor (2.5 h at 100° C., then 2 h at 110° C. and finally 2 h at 125° C.). After cooling, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (7.8 mg, 48% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-])=O)=[C:18]([NH:23][CH2:24][CH2:25][C:26]#[N:27])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:28]1CCC[CH2:29]1>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][N:17]=[C:18]3[C:19]=2[NH:20][C:29](=[O:28])[N:23]3[CH2:24][CH2:25][C:26]#[N:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(NCCC#N)c2[N+](=O)[O-])CC1
Reactant: C1CCOC1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2[nH]c(=O)n3CCC#N)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-[6-(2-Cyano-ethylamino)-5-nitro-pyrimidin-4-yl]piperazine-1-carboxylic acid t-butyl ester (1.0 g) was dissolved in tetrahydrofuran (12 mL), and then 10% palladium on carbon powder (wet type) (200 mg) was added to this solution. The reaction solution was stirred under a hydrogen atmosphere at room temperature for 20 hours. Insoluble substances were then removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The obtained residue was dissolved in acetonitrile (30 mL), and then N,N′-disuccinimidyl carbonate (1.13 g) was added to this solution. The reaction solution was stirred at room temperature for five hours, then 40 mL of water was added. This reaction solution was then concentrated under reduced pressure to 40 mL. The precipitate was collected by filtration. The obtained solid was washed with water and hexane to give the title compound (623 mg). A portion of the obtained compound was purified by silica gel column chromatography for use in NMR analysis.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[C:17]1([CH:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[C:25]2=[O:34])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>ClCCl.O1CCCC1>[C:35]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([OH:33])([C:8]3[CH:9]=[C:10]4[C:5]([CH2:4][CH2:3][CH2:2][O:1]4)=[CH:6][C:7]=3[OH:11])[C:25]2=[O:34])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Oc1ccc2c(c1)CCCO2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)CCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 500 mL round-bottom flask was charged with chroman-6-ol (9.2 g, 61 mmol) and tetrahydrofuran (120 mL). A 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (32.5 mL, 65.0 mmol) was added at 5° C. and the reaction mixture was stirred for 15 min and concentrated in vacuo. To the residue was added dichloromethane (180 mL), followed by a solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (18.8 g, 60.0 mmol) in dichloromethane (180 mL) at 5° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 24 h. Saturated aqueous ammonium chloride (7 mL) was added and the reaction mixture was concentrated in vacuo. Trituration of the residue in methanol/water (1/100, 200 mL) afforded 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one. A mixture of the 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one, triethylsilane (23.2 g, 200 mmol), trifluoroacetic acid (50.0 g, 438 mmol) and dichloromethane (200 mL) was stirred at ambient temperature for 20 h and concentrated in vacuo. Trituration of the residue in diethyl ether (150 mL) afforded 1-(diphenylmethyl)-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one (24.3 g, 90%) as an off-white solid: MS (ES+) m/z 448.0 (M+1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([C:9]2[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24].O>CCO>[CH3:22][N:23]([CH3:24])[C:2]1[S:6][C:5]([C:7]([C:9]2[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(c1ccc(Br)s1)c1nc(C(F)(F)F)nc2ccsc12
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(C(=O)c2nc(C(F)(F)F)nc3ccsc23)s1
Yield: 42 %

Procedure:
A suspension of 5-bromo-2-thienyl 2-trifluoromethylthieno[3,2-d]pyrimidin-4-ylmethanone (0.3 g, 0.76 mmol) in EtOH (20 mL) was treated with 40% aqueous dimethylamine (5 mL), refluxed for 1 h, cooled, treated with water (25 mL), concentrated in vacuo and the aqueous mixture extracted with EtOAc (2×25 mL), the combined extracts washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo. The resulting red oil was purified by chromatography [SiO2; heptane-EtOAc (1:1)] to give the title compound (0.115 g, 42%) as a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl.CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10]/[CH:11]=[N:19]/[S@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=CCCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[S@@](N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/CCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
To a solution of Intermediate 16A (1.0 g, 4.9 mmol) in CH2Cl2 (5 mL) was added (S)-2-methylpropane-2-sulfinamide (0.72 g, 5.9 mmol) followed by the addition of pyridine 4-methylbenzenesulfonate (0.062 g, 0.25 mmol) and MgSO4 (2.96 g, 24.6 mmol). The reaction mixture was stirred at rt for 18 h, and then filtered through a celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by ISCO chromatography (EtOAc/Hexanes 0-30% over 15 min, column 80 g, flow rate 85 mL/min) to give Intermediate 16B (1.20 g, 3.93 mmol, 80.0% yield) as a white solid. HPLC/MS (Method D) RT=1.13 min, [M+1]+ 306.0.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH:33]([CH3:35])[CH3:34])[CH3:15])=[CH:8][C:7]=1[CH3:36].[OH-].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[CH:33]([C:17]1[N:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[S:20][C:16]=1[CH:14]([CH3:15])[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[C:7]([CH3:36])[CH:8]=1)([CH3:34])[CH3:35]
Reactant: COC(=O)CCc1ccc(OCC(C)c2sc(-c3ccc(-c4cccnc4)cc3)nc2C(C)C)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(OCC(C)c2sc(-c3ccc(-c4cccnc4)cc3)nc2C(C)C)ccc1CCC(=O)O
Yield: 27 %

Procedure:
3-(4-{2-[4-Isopropyl-2-(4-pyridin-3-yl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionic acid methyl ester from step A is dissolved in tetrahydrofuran (1 mL) and 5N sodium hydroxide (1 mL) solution is added at room temperature. The reaction is heated to reflux and monitored by HPLC. Upon complete conversion, the reaction is allowed to cool to room temperature and neutralized with 5N hydrochloric acid (1 mL), diluted with ethyl acetate, and extracted. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 3-(4-{2-[4-Isopropyl-2-(4-pyridin-3-yl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionic acid (86 mg, 0.172 mmol, 27% yield) may also be obtained by recrystalization from ethyl acetate. MS (ES): 501.1 (M++1-HCl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[C:4]([O:10][CH2:11][CH3:12])[N:3]=1.C(#N)C.[C:16](=S)=[S:17].OO>O>[Cl:1][C:2]1[N:3]=[C:4]([O:10][CH2:11][CH3:12])[N:5]2[C:16](=[S:17])[NH:9][N:8]=[C:6]2[CH:7]=1
Reactant: CCOc1nc(Cl)cc(NN)n1
Reactant: S=C=S
Agent: OO
Solvent: CC#N
Solvent: O
Product: CCOc1nc(Cl)cc2n[nH]c(=S)n12
Temperature: 0 °C

Procedure:
A mixture containing 20 g of 93 percent purity (99 mmol) 4-chloro-2-ethoxy-6-hydrazinopyrimidine in a solvent composed of 90 mL of acetonitrile and 26 mL of water was prepared under nitrogen in a 500 mL flask equipped with a condensor and an opening covered by a septum through which the syringe of a syringe pump was inserted. To this was added 11.3 g (148 mmol) of carbon disulfide and, after a 15-min reaction period, 16.7 g of 30 percent aqueous hydrogen peroxide (147 mmol) was added over a 15-min period by means of the syringe with stirring and cooling to hold the temperature at about 25° C. The mixture was allowed to react for another 4 hours and then was cooled to about 0° C. The precipitated product and sulfur by-product were recovered by vacuum filtration and washed with water, a 1:1 mixture of water and acetonitrile, and finally acetonitrile. The wet cake was slurried in 1 L of water at 70° C. and about 600 mL of acetonitrile was added to dissolve the solid. The resulting mixture was gravity filtered and the filtrate was allowed to cool over the weekend. The mixture was further cooled in a refrigerator and the crystals that formed were recovered by vacuum filtration, washed with acetonitrile, and dried to constant weight to obtain 14.1 g (62 percent of theory) of the title compound as an amber solid which decomposed on heating above 187° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[Br:14]Br>C(Cl)Cl>[Br:14][C:11]1[CH:12]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([OH:13])=[C:7]([CH:10]=1)[CH:8]=[O:9]
Reactant: BrBr
Reactant: CC(C)(C)c1cccc(C=O)c1O
Solvent: ClCCl
Product: CC(C)(C)c1cc(Br)cc(C=O)c1O
Reaction time: 1 h

Procedure:
step 1—To a solution of 3-tert-butyl-2-hydroxybenzaldehyde (CASRN 24623-65-2, 5.00 g) DCM (20 mL) at 0° C. was added dropwise a solution of Br2 (1.45 mL) in DCM (15 mL) over a period of 30 min. After the addition was complete the reaction was stirred for 1 h before the organic volatiles were removed under reduced pressure to afford 7.23 g of 5-bromo-3-tert-butyl-2-hydroxybenzaldehyde (B-1b, R4=tert-Bu) as a light yellowish solid.
Reaction SMILES: [CH:1]1([C:4]2[C:8]([C:9]([OH:11])=O)=[C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[S:25]([NH:28][C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:30])(=[O:27])=[O:26])=[CH:15][CH:14]=3)[N:6]([CH2:37][CH2:38][CH3:39])[N:5]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)([N:42]1C=CN=C1)=O.N.CCO>C1COCC1>[CH:1]1([C:4]2[C:8]([C:9]([NH2:42])=[O:11])=[C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[S:25]([NH:28][C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:30])(=[O:27])=[O:26])=[CH:15][CH:14]=3)[N:6]([CH2:37][CH2:38][CH3:39])[N:5]=2)[CH2:3][CH2:2]1
Reactant: CCCn1nc(C2CC2)c(C(=O)O)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CCO
Solvent: C1CCOC1
Product: CCCn1nc(C2CC2)c(C(N)=O)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a solution of the compound obtained in example 60 (0.15 g, 0.28 mmol) in THF (10 mL) was added 1,1'-carbonyldiimidazole (0.057 g, 0.35 mmol) and the mixture was stirred at room temperature under an argon atmosphere for 3 h. Next, ammonia (32% aqueous solution, 0.33 mL) and EtOH (0.7 mL) were added and the reaction mixture was stirred at room temperature overnight and then at reflux for 1 h. The solvent was removed, the residue was taken up in CH2Cl2 and H2O was added. The aqueous phase was acidified to pH=6 and extracted with EtOAc. The combined organic extracts were dried and concentrated to a crude product. This was chromatographed on silica gel (hexane-EtOAc mixtures of increasing polarity) to afford the title compound as a white solid (40%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:34][C:35]1[CH:36]=[CH:37][C:38]([O:42][CH3:43])=[C:39]([OH:41])[CH:40]=1.[CH3:44][N:45]1[CH2:50][CH2:49][CH:48](O)[CH2:47][CH2:46]1>C1(C)C=CC=CC=1>[Br:34][C:35]1[CH:36]=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:40]=1)[O:41][CH:48]1[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]1
Reactant: CN1CCC(O)CC1
Reactant: COc1ccc(Br)cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Br)cc1OC1CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Into a 40 mL screw-cap vial were added triphenylphosphine (1.55 g, 5.91 mmol) and toluene. The solution was stirred a 0° C. for 5 min then a diisopropylazodicarboxylate (1.18 mL, 5.99 mmol) was added drop-wise over 2 min. The solution was allowed to warm to room temperature over 1 h, then a solution of 5-bromo-2-methoxy-phenol (1.01 g, 4.98 mmol) and 1-methyl-piperidin-4-ol (701 mg, 6.08 mmol) in 4 mL of toluene was added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was adsorbed onto silica gel and purified by silica gel flash chromatography with a 0-20% MeOH/CH2Cl2 gradient to afford titled compound as a light yellow oil that solidified upon standing (906 mg, 61%). 1H NMR (MeOH-d4) 7.10 (d. J=8.8, 1H), 7.08 (dd. J=8.8, 2.4, 1H), 6.89 (d, J=8.8, 1H), 4.34 (m, 1H), 3.80 (s, 3H), 2.73 (m, 2H), 2.34 (m, 2H), 2.29 (s, 3H), 1.95 (m, 2H), 1.81 (m, 2H). LC/MS (Method B) 1.85 min, [M+1]+ 300/302.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]1[CH:19]=[C:15]([C:16]([OH:18])=[O:17])[C:14]([OH:20])=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:20][C:14]1[CH:13]=[CH:12][C:11]([CH:9]=[O:10])=[CH:19][C:15]=1[C:16]([O:18][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Reaction time: 72 h

Procedure:
Benzyl bromide (25.6 mL, 0.22 mol, 2.5 eq) was added dropwise to a stirred solution of 5-formylsalicylic acid (10 g, 0.06 mol, 1 eq) and cesium carbonate (84.2 g, 0.26 mol, 3 eq) in N,N-dimethylformamide (150 mL). The reaction mixture was stirred for 3 days and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and the organic solution washed with water (200 mL) and brine (4×200 mL), then dried over sodium sulfate and evaporated in vacuo. This gave a gummy solid which was recrystallized from ethyl acetate and petroleum ether to give a cream coloured powder (16.1 g, 77%). RF (petroleum ether:ethyl acetate 1:1) 0.73. 1H NMR (CDCl3) δ9.91 (s, 1H, O═C—H), 5.38 (s, 2H, CH2Ph), 5.28 (s, 2H, CH2Ph).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.CCCCCC.C([Li])CCC.[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=O)=[CH:20][CH:19]=1>O1CCCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:2]2[CH:1]=[CH:5][CH:4]=[CH:3]2)=[CH:31][CH:32]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: C1=CCC=C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Clc1ccc(C(=C2C=CC=C2)c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Yield: 57 %

Procedure:
A reaction vessel equipped with a dropping funnel was charged with 40 ml of dehydrated tetrahydrofuran and 2.15 ml (25.9 mmol) of cyclopentadiene under nitrogen atmosphere, and 18.0 ml (28.5 mmol) of a hexane solution of n-butyllithium of 1.58 mol/L was added dropwise and stirred while cooling the above solution at 0° C. Then, a solution prepared by dissolving 5.00 g (19.9 mmol) of 4,4′-dichlorobenzophenone in 30 ml of dehydrated tetrahydrofuran was placed in the dropping funnel and added dropwise while cooling at 0° C., and the solution was allowed to return to room temperature and stirred for one day. This reaction solution was extracted with diethyl ether, and the separated organic layer was washed with 1N hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution and a saturated salt solution and dried over anhydrous magnesium sulfate. Then, magnesium sulfate was removed by filtration, and the solvent contained in the filtrate was removed by distillation under reduced pressure by means of a rotary evaporator. The residue was purified through a silica gel column to obtain a targeted product (amount obtained: 3.37 g, yield: 57%). The targeted product was identified by means of 1H-NMR.