Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].C1C[O:16][CH2:15][CH2:14]1.C(OC(=O)C)(=O)C>CC(O)=O.CO.CCOC(C)=O.O=[Pt]=O>[OH:12][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([NH:8][C:15](=[O:16])[CH3:14])=[CH:5][C:4]=1[CH3:11]
Reactant: C1CCOC1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)Nc1cc(C)c(O)c(C)c1
Reaction time: 24 h

Procedure:
A suspension of 2,6-dimethyl-4-nitrophenol (4a, 1.58 g, 9.45 mmol) in AcOH (20 ml), MeOH (15 ml), and THF (10 ml) in a hydrogenator vessel was treated with acetic anhydride (6 ml, 63.6 mmol) and PtO2 (200 mg, 0.881 mmol), pressurized to 50 p.s.i. with H2 and shaken for 24 h. The reaction mixture was returned to atmospheric pressure, diluted with EtOAc, washed with H2O, dried (MgSO4), filtered and concentrated under reduced pressure. N-(4-hydroxy-3,5-dimethylphenyl)acetamide (4b) was isolated as a white solid that was pure based upon LCMS analysis and used without further purification. Potassium carbonate (810 mg, 5.34 mmol) was added to a solution of tetrabutylammonium iodide (78.9 mg, 0.534 mmol), 3-(chloromethyl)-4-methoxybenzaldehyde (5a, 197 mg, 1.07 mmol), and N-(4-hydroxy-3,5-dimethylphenyl)acetamide (4b, 211 mg, 1.18 mmol) in 20 ml of acetonitrile. The reaction mixture was heated to 150° C. in the microwave for 1 h, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with 5-50% EtOAc/DCM gradient to afford the desired product 6a (196 mg, 56%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.15 (s, 3 H), 2.28 (s, 6 H), 3.93 (s, 3 H), 4.83 (s, 2 H), 7.02 (d, J=8.4 Hz, 1H), 7.13 (s, 1 H), 7.17 (s, 2 H), 7.89 (dd, J=8.4, 2.0 Hz, 1 H), 8.12 (d, J=1.8 Hz, 1H), 9.94 (s, 1 H); LCMS: (electrospray+ve), m/z 328.2 (MH)+, tR=3.16 min, UV254=>95%. N-(4-(5-formyl-2-methoxybenzyloxy)-3,5-dimethylphenyl)acetamide (6a, 145 mg, 0.441 mmol), 2-amino-N-(furan-2-ylmethyl)benzamide (3b, 105 mg, 0.486 mmol), and 0.2 equiv of Yb(OTf)3 in 5 ml of EtOH were heated at 80° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was chromatographed on silica-gel using 7-60% ethyl acetate in hexanes to give the desired product 7a (40.9 mg, 0.078 mmol, 17.6% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.15 (s, 3 H), 2.21 (s, 6 H), 3.77 (d, J=15.7 Hz, 1 H), 3.84 (s, 3 H), 4.41 (s, 1 H), 4.70-4.87 (m, 2 H), 5.35 (d, J=15.7 Hz, 1 H), 5.78 (s, 1 H), 6.20 (d, J=2.9 Hz, 1 H), 6.24-6.32 (m, 1 H), 6.53 (d, J=8.0 Hz, 1 H), 6.76-6.91 (m, 2 H), 7.03 (br. s., 1 H), 7.13 (s, 2 H), 7.30-7.37 (m, 2 H), 7.49 (d, J=2.0 Hz, 1 H), 7.92-8.03 (m, 1 H); LC/MS (electrospray+ve), m/z 526.2 (MH)+, Retention time t=5.71 min; Purity: UV220>98%, UV254>98%; HRMS (ESI): m/z calcd for C31H31N3O5 [M+H]+526.2351, found 526.2350.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH:21]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OC(c1ccc(NCc2ccc(Cl)cc2Cl)cc1)(C(F)(F)F)C(F)(F)F
Reaction time: 18 h

Procedure:
A solution of 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (Oakwoood, 1 g, 3.9 mmol) and 2,4-dichlorobenzaldehyde in methanol (21 mL) was stirred at ambient temperature. After 18 hours, glacial acetic acid (0.24 mL, 4.25 mmol) and sodium cyanoborohydride (388 mg, 4.25 mmol) were added. After stirring an additional 18 hours, the mixture was concentrated in vacuo and the residue dissolved in EtOAc. The organic layer was washed several times with brine, dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded the title compound as a white waxy solid (1.6 g, 99%). MS (ES+) m/z 418 (M+), 420 (M+2).
Reaction SMILES: [CH3:1][C@H:2]1[C@:14]23[CH:17]=[C:18]([CH3:21])[C@H:19]([OH:20])[C@@:13]2([OH:22])[C@H:12]([OH:23])[C:11]([CH2:24][OH:25])=[CH:10][C@H:9]([C:15]3=[O:16])[C@@H:5]2[C:6]([CH3:8])([CH3:7])[C@@H:4]2[CH2:3]1>CS(C)=O>[CH3:12]/[CH:13]=[C:14](\[C:15]([O:20][C@@H:19]1[C@@:13]2([OH:22])[C@H:12]([OH:23])[C:11]([CH2:24][OH:25])=[CH:10][C@H:9]3[C@@H:5]4[C:6]([CH3:8])([CH3:7])[C@@H:4]4[CH2:3][C@@H:2]([CH3:1])[C@:14]2([C:15]3=[O:16])[CH:17]=[C:18]1[CH3:21])=[O:16])/[CH3:2]
Reactant: CC1=C[C@]23C(=O)[C@@H](C=C(CO)[C@@H](O)[C@]2(O)[C@H]1O)[C@H]1[C@@H](C[C@H]3C)C1(C)C
Solvent: CS(C)=O
Product: C/C=C(/C)C(=O)O[C@H]1C(C)=C[C@]23C(=O)[C@@H](C=C(CO)[C@@H](O)[C@]12O)[C@H]1[C@@H](C[C@H]3C)C1(C)C

Procedure:
(NOTE: Ingenol purity was calculated as 84.18% by quantitative 1H NMR. As ingenol-3-angelate, PEP015, PEP025 and ingenol-3,20-diangelate were provided as solutions in DMSO, purity was not calculated but assumed to be 100%).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6]1.[NH3:18]>ClCCl>[CH:5]1([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:18])=[O:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1ccc(SC2CC2)cc1
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: NC(=O)c1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionylchloride (342 μL, 4.7 mmol) is added to a solution of 4-cyclopropylsulfanyl-benzoic acid (prepared as described in WO07003960, 190 mg, 0.98 mmol) in dichloro-methane (1.9 mL). The mixture is heated at reflux for 30 min and concentrated under reduced pressure. The residue is treated with toluene, and all volatiles are evaporated. The residue is dissolved in chloroform (1.9 mL) and treated with concentrated aqueous ammonia (770 μL, 9.8 mmol). The mixture is stirred at room temperature for 1 h and then extracted with water. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. Yield: 137 mg (72% of theory); ESI mass spectrum: [M+H]+=194; Retention time HPLC: 0.45 min (X011_S03).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH2:31][CH3:32])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[CH3:49][N:50]1[CH:54]=[CH:53][N:52]=[C:51]1[CH3:55].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:49][N:50]1[C:54]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([NH:13][C:14]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:15]=4[C:16]([CH2:31][CH3:32])=[N:17][N:18]5[CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=4)=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:53][N:52]=[C:51]1[CH3:55]
Reactant: Cc1nccn1C
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(Br)ccn34)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(-c5cnc(C)n5C)ccn34)c12
Temperature: 140 °C
Yield: 15 %

Procedure:
To 7-bromo-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl) imidazo[1,2-a]pyridine-3-carboxamide (prepared as in Example 127, Step A; 129 mg, 0.264 mmol) in DMF (4 mL) was added trifuran-2-ylphosphine (12.2 mg, 0.0527 mmol), 1,2-dimethyl-1H-imidazole (50.7 mg, 0.527 mmol), palladium diacetate (5.92 mg, 0.0264 mmol) and K2CO3 (72.9 mg, 0.527 mmol). The reaction mixture was purged with argon, sealed and heated to 140° C. for 3 hours. The mixture was cooled to ambient temperature, diluted with DCM (20 mL) and washed with H2O. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH, 10:1:0.1) to provide the final product (20 mg). MS (ES+APCI) m/z=505 (M+H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15](=[O:38])[CH2:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)(=[O:28])=[O:27])[C:18]=1[CH3:37].CI>C1COCC1>[CH3:13][O:14][C:15](=[O:38])[CH:16]([C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)(=[O:27])=[O:28])[C:18]=1[CH3:37])[CH3:1]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ncccc12
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1c(C)n(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of diisopropylamine (34 μL, 0.24 mmol) in THF (1 mL), at −78° C., is added a 2.5M solution of n-BuLi in hexanes (105 μL, 0.26 mmol). After 20 minutes, a solution of [1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (Method B; 100 mg, 0.24 mmol) and MeI (15.2 μL, 0.24 mmol) in THF (1 mL) is added. The reaction is continued for 30 minutes, then allowed to warm to room temperature. The reaction mixture is evaporated to dryness and purified by flash chromatography (4:1 iso-hexane/EtOAc elution), to afford 2-[1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-propionic acid methyl ester; MH+=427.
Reaction SMILES: [I:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.Cl[C:23](=[O:30])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>ClCCl.N1C=CC=CC=1>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH2:24][C:23]([NH:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([O:7][C:6]2[CH:16]=[C:2]([I:1])[C:3]([O:20][CH3:21])=[CH:4][C:5]=2[CH:17]([CH3:19])[CH3:18])=[CH:13][N:12]=1)=[O:30]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reactant: COC(=O)CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCC(=O)Nc1ncc(Oc2cc(I)c(OC)cc2C(C)C)c(N)n1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.56 g, 1.4 mmoles) in dichloromethane (40 ml) and pyridine (4 ml) was slowly added methyl 4-chloro-4-oxobutyrate (1.3 ml, 7.5 mmoles). The mixture was stirred at room temperature for 60 hours, and then solvent was removed under reduced pressure. The residue was washed twice with water, dissolved in a mixture of concentrated aqueous ammonium hydroxide and methanol (10 ml/40 ml), and stirred at room temperature for one hour. Solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (1% methanol in dichloromethane) to give crude N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-succinamic acid methyl ester (0.54 g, not shown) as a foam, MS (M+H)=515.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[CH2:14])[CH:8]=2)=[N:4][C:3]=1[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C@H:23]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:22][CH2:21]2.[Li+].[OH-].O>C(O)C.C1COCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[CH2:14])[CH:8]=2)=[N:4][C:3]=1[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C@H:23]([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][CH2:21]2
Reactant: C=Cc1cccc(-c2nc(CCOc3ccc4c(c3)CC[C@H]4CC(=O)OCC)c(C)o2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cccc(-c2nc(CCOc3ccc4c(c3)CC[C@H]4CC(=O)O)c(C)o2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
To a solution of ethyl ((1S)-5-{2-[5-methyl-2-(3-vinylphenyl)-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-inden-1-yl)acetate (40 mg, 0.09 mmol) in ethanol (1.0 mL) and THF (1.0 mL) was added LiOH (39 mg) followed by water (1 mL). The reaction mixture was then stirred at rt for 4 h. The reaction mixture was then acidified to pH 5-6 and concentrated under reduced pressure. The residue redissolved in methanol, and filtered through a C8-Silica plug. The filtrate was then purified by preparative HPLC using with 10 to 70% acetonitrile in water to afford 27.2 mg (72%) of desired product. 1H NMR (CD2Cl2) δ 7.97 (s, 1H), 7.79 (d, 1H), 7.42 (d, 1H), 7.35 (t, 1H), 7.02 (d, 1H), 6.62-6.76 (m, 3H), 5.80 (d, 1H), 5.27 (d, 1H), 4.14 (t, 2H), 3.43 (qr, 1H), 2.90 (t, 2H), 2.66-2.83 (m, 3H), 2.29-2.43 (m, 5H), 1.67-1.72 (m, 1H). EI-LCMS(rel abundance), RT=3.95, m/z 404.4 (MH+, 72%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9](Cl)[CH:8]=1)[CH3:2].CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[S:32][CH:33]=[CH:34][C:35]=3[NH:36][S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:25]2[CH:26]=[CH:27][C:28]([C:31]3[S:32][CH:33]=[CH:34][C:35]=3[NH:36][S:37]([CH:40]([CH3:42])[CH3:41])(=[O:38])=[O:39])=[CH:29][CH:30]=2)[C:10]([C:13]#[N:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(C#N)c(Cl)c1
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccc(C#N)c(-c2ccc(-c3sccc3NS(=O)(=O)C(C)C)cc2)c1
Yield: 84 %

Procedure:
Heat (3-chloro-4-cyano-phenoxy)-acetic acid ethyl ester (120 mg, 0.50 mmol), propane-2-sulfonic acid {2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiophen-3-yl}-amide (204 mg, 0.50 mmol), 2 M aqueous Na2CO3 solution (0.75 mL) and Pd(PCy3)2Cl2(55.4 mg, 0.075 mmol) in 1,4-dioxane (3.0 mL) to 80° C. under nitrogen atmosphere for 20 h. Pour into 0.1 M HCl solution and adjust pH to 7, then extract with diethyl ether (3×50 mL) and dry the combined organic phases (MgSO4) and concentrate to furnish a crude mixture as a yellowish solid. Purification by flash chromatography (Silica gel-Hexane /diethyl ether 1:1) yields 201 mg, 0.42 mmol (83%) of {6-Cyano-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-3-yloxy}-acetic acid ethyl ester as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:13]2[C:5](=[CH:6][C:7]3[NH:8][C:9]([S:14][CH2:15][C:16]4[C:21]([CH3:22])=[C:20]([N+]([O-])=O)[CH:19]=[CH:18][N:17]=4)=[N:10][C:11]=3[CH:12]=2)[C:4]([CH3:27])([CH3:26])[C:3]1=[O:28].[CH3:30][O-:31].[Na+]>CO>[CH3:30][O:31][C:20]1[CH:19]=[CH:18][N:17]=[C:16]([CH2:15][S:14][C:9]2[NH:8][C:7]3[CH:6]=[C:5]4[C:13](=[CH:12][C:11]=3[N:10]=2)[C:2]([CH3:29])([CH3:1])[C:3](=[O:28])[C:4]4([CH3:27])[CH3:26])[C:21]=1[CH3:22]
Reactant: Cc1c([N+](=O)[O-])ccnc1CSc1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)C3(C)C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C

Procedure:
A solution of 4.4 g of 5,7-dihydro-5,5,7,7-tetramethyl-2-[[(3-methyl-4-nitro-2-pyridyl)met hyl]thio]indeno[5,6-d]imidazol-6(lH)-one in 100 ml of absolute methanol was treated with 3 g of sodium methylate, whereupon the mixture was boiled at reflux for 18 hours under argon. After concentrating the reaction mixture in vacuo the residue was treated with methylene chloride whereupon the mixture was buffered by means of glacial acetic acid; the methylene chloride phase was extracted several times with a sodium bicarbonate solution, dried and evaporated. By recrystallisation from ethyl acetate there was obtained 5,7-dihydro-2-[[(4-methoxy-3-methyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d ]imidazol-6(lH)-one of melting point 222-226°.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.O[C:13]1C=CC([N+]([O-])=O)=CN=1.[Na].C(C(CC)(C([O-])=O)C([O-])=O)C>>[Br:1][C:2]1[C:3]([CH3:13])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Agent: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [Na]
Product: Cc1ncc([N+](=O)[O-])cc1Br
Yield: 75 %

Procedure:
3-Bromo-2-chloro-5-nitropyridine (25 g, 105 mmol; prepared from 2-hydroxy-5-nitropyridine according to the procedure of V. Koch and S. Schnatterer, Synthesis 1990, 499-501) was treated with the sodium salt of diethylmalonate (17.6 mL, 116 mmol) according to the procedure of Odashima et al Bull Chem Soc Jpn 1993, 66, 797-803) to provide 17.1 g (78.8 mmol, 75%) of dark red oil: TLC Rf 0.5 (4:1 hexanes/EtOAc); 1H NMR (CDCl3, 300 MHz) δ 2.81 (s, 3H), 8.61 (d, 1H, J=2.0 Hz), 9.26 (d, 1H, J=2.0 Hz).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[CH3:17][N:15]([CH3:16])[CH2:14][C@H:2]([NH:1][S:29]([C:27]1[S:28][C:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)=[CH:25][CH:26]=1)(=[O:30])=[O:31])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(-c2ccccn2)s1
Yield: 40 %

Procedure:
According to the method described in example S20a, (R)-benzyl 3-amino-4-(dimethylamino)butanoate (27 mg, 0.086 mmol) was reacted with 5-(pyridin-2-yl)thiophene-2-sulfonyl chloride to yield the title compound as a white solid (16 mg, 40%). MS ESI 460.2 [M+H]+, calcd for [C22H25N3O4S2+H]+ 460.13
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:14]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: Brc1cccnc1
Reactant: CCOC(=O)c1ccc(C)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)c1ccc(C)c(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-4-methyl-benzoic acid ethyl ester and 3-bromopyridine.
Reaction SMILES: [CH:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([NH:16][CH2:17][C:18]2[C:19]([OH:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])=[C:6]1[CH3:27])([CH2:3][CH3:4])[CH3:2].[CH3:28][CH2:29]CCCC>C(O)C>[CH:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([NH:16][CH2:17][C:18]2[C:19]([OH:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])=[C:6]1[CH3:27])([CH2:3][CH3:4])[CH3:2].[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([NH:16][CH2:17][C:18]2[C:19]([OH:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])=[C:6]1[CH3:27])[CH2:2][CH2:28][CH3:29]
Reactant: CCCCCC
Agent: CCC(C)n1c(C)c(C(=O)NCc2c(C)cc(C)nc2O)c2ccccc21
Solvent: CCO
Product: CCCCn1c(C)c(C(=O)NCc2c(C)cc(C)nc2O)c2ccccc21
Yield: 16 %

Procedure:
1-sec-butyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide (35 mg, 0.1 mmol) was separated by chiral prep-HPLC (Daicel IA (200 mm×20 mm×5 um), hexane: ethanol (0.2% DEA)=70:30, flow rate: 19 mL/min), then (R or S) 1-sec-butyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide (11 mg, 30%) and (S or R)-1-sec-butyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide (6 mg, 16%) was obtained. The retention times were 8.030 minutes (“Peak 1”; Compound 147) and 14.126 minutes (“Peak 2”; Compound 148) respectively in chiral HPLC chromatography. LRMS (M+H+) m/z: calcd 365.2. found 365. HPLC purity (214 nm): 99%. 1H. NMR (300 MHz, CD3OD): δ 7.73-7.70 (m, 1H), 7.56-7.53 (m, 1H), 7.12-7.09 (m, 2H), 6.11 (s, 1H), 4.54 (s, 3H), 2.64 (s, 3H), 2.43 (s, 3H), 2.25 (s, 3H), 1.97-1.90 (m, 2H), 1.61 (d, J=6.9 Hz, 3H), 0.73 (t, J=7.5 Hz, 3H).
Reaction SMILES: C([C:3]1[CH:10]=[CH:9][CH:8]=[C:5]2[CH2:6][CH2:7][C:4]=12)=C.C1[CH:15]2[CH:16]3[CH:20]=[CH:19][CH:18]([CH:14]2C=C1)[CH2:17]3.C(C1C=C(O)C(=CC=1)O)(C)(C)C>>[CH:6]1[C:5]2[CH:8]=[CH:9][C:10]([CH:20]3[CH2:19][CH:18]4[CH2:17][CH:16]3[CH:15]=[CH:14]4)=[CH:3][C:4]=2[CH:7]=1
Reactant: C=Cc1cccc2c1CC2
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: CC(C)(C)c1ccc(O)c(O)c1
Product: C1=Cc2cc(C3CC4C=CC3C4)ccc21
Yield: 42.9 %

Procedure:
A 100-ml autoclave with an agitator was charge with 10 g (77 mmol) of 4-vinylbenzocyclobutene, 4.6 g (35 mmol) of dicyclopentadiene, and 438 mg (2.6 mmol) of 4-tert-butylcatechol and was then tightly closed. The reactants were allowed to react at 170° C. for two hours while stirring at 300 rpm. The product was then cooled and removed from the autoclave. The product was diluted with toluene, and the resulting polyvinylbenzocyclobutene was precipitated in methanol. Polyvinylbenzocyclobutene was filtered out, and the solvent was removed. The residue was transferred to a distillation apparatus. The residue was distilled under reduced pressure (127° C., 5 mmHg) to yield 3.0 g (15 mmol, yield 20%) of 5-(4-benzocyclobutenyl)-2-norbornene as a colorless and transparent liquid. 1H NMR structural identification showed that the present example produced a compound having the formula (2).
Reaction SMILES: [OH:1][CH2:2][CH:3]([S:6][C:7]([CH3:27])([CH3:26])[C:8]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)([OH:15])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[CH2:4][OH:5].[F:28][C:29]([F:41])([F:40])[C:30]1[CH:39]=[CH:38][C:33](/[CH:34]=[CH:35]/[CH:36]=O)=[CH:32][CH:31]=1>>[CH3:26][C:7]([S:6][C@@H:3]1[CH2:4][O:5][C@@H:36](/[CH:35]=[CH:34]/[C:33]2[CH:38]=[CH:39][C:30]([C:29]([F:28])([F:40])[F:41])=[CH:31][CH:32]=2)[O:1][CH2:2]1)([CH3:27])[C:8]([C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=1)([OH:15])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: CC(C)(SC(CO)CO)C(O)(Cn1cncn1)c1ccc(C(F)(F)F)cc1
Reactant: O=C/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(C)(S[C@H]1CO[C@H](/C=C/c2ccc(C(F)(F)F)cc2)OC1)C(O)(Cn1cncn1)c1ccc(C(F)(F)F)cc1

Procedure:
Reaction was carried out in the same manner as in Example 4 using (RS)-3-[(1,3-dihydroxy-2-propyl)thio]-3-methyl-2-[4-(trifluoromethyl)phenyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Reference example 55 and trans-4-(trifluoromethyl)cinnamaldehyde as described in Reference example 22 to obtain the title compound as a colorless foam.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1Cl)([O-:3])=[O:2].[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[NH4+].[OH-]>C(O)C>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: N#Cc1ccc(N)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution under N2 of 3-nitro-4-chloropyridine (4.63 g, 29.2 mmol), prepared as described by Wright, G. C., J. Heterocyclic Chem. 1976, 13, 601, and Kruger, S. and Mann, F. G., J. Chem. Soc. 2 1955, 758, in absolute ethanol (100 mL) was added 4-aminobenzonitrile (3.45 g, 29.2 mmol) and the resulting purple-brown solution was stirred for 17 hours at ambient temperature, during which time it became a green-brown suspension. The reaction mixture was poured into cold 10% aqueous NH4OH and filtered. The solid was suspended in ethanol (75 mL) and heated for 10 min on the steam bath. The suspension was cooled to ambient temperature and filtered to give 4-(N-3-nitropyrid-4-ylamino)benzonitrile as a bright-yellow solid.