Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C:21](=[O:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Cl)([C@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1>C1COCC1>[C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C@@H:21]([OH:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)COc1cccc(Cl)c1
Agent: C[C@@H]1[C@H](B(Cl)[C@@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Solvent: C1CCOC1
Product: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)COc3cccc(Cl)c3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
To a solution of 9.70 g (22.0 mmol) of enone 26 in 60 mL of THF at -23° C. was added dropwise a solution of 11.1 g (34.6 mmol) of (-)-DIPCl in 30 mL of THF. After 4h, the reaction was quenched at -23° C. by the dropwise addition of 5 mL of methanol, and was warmed to room temperature. The mixture was then poured into 200 mL of a 2:1 mixture of ethyl acetate: saturated NH4Cl, the layers were separated, and the aqueous phase was extracted with 2 X 100 mL portions of ethyl acetate. The combined organic layers were dried over MgSO4, concentrated, and the residue was flash chromatographed on a 33 cm tall×76 mm diameter silica gel column eluting with 3:2 v/v ethyl acetate:hexanes to afford 4.7 g (48%) of 27 as a white solid, m.p. 101.0°-102.5° C. 1H NMR δ 8.05-7.95 (m, 2H), 7.62-7.40 (m, 3H), 7.18 (t, J=8.0 Hz, 1H), 7.0-6.92 (m, 1H), 6.85 (t, J=2.1 Hz, 1H), 6.77-6.70 (m, 1H, 5.85 (d of d, J=6.2, 15.5 Hz, 1H), 5.72 (d of d, J=4.5, 15.5 Hz, 1H), 5.30 (q, J=5.8 Hz, 1H), 5.12-5.04 (m, 1H), 4.58-4.48 (m, 1H), 3.92 (d of d, J=3.5, 9.3 Hz, 1H), 3.80 (d of d, J=7.3, 9.4 Hz, 1H), 2.9-2.2 (m, 8H).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(N(CC)CC)C.[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)C>CN(C=O)C>[I:1][C:2]1[N:3]=[CH:4][N:5]([C:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Ic1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
To a solution of 4-iodoimidazole (50 g, 258 mmoles) in DMF (500 ml) was added triethyl amine (37.7 ml, 270.6 mmoles) and than triphenylmethyl chloride (69.7 g, 250 mmoles). After stirring at room temperature for 48 hours, the solution was poured into ice water (2.5 L). The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether (200 ml) was added to the crude compound and the solution was filtered to yield 4-iodo-1-trityl-1H-imidazole (104.1, 93%) as a white solid. MH+(437).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][CH:10]=[C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]2[CH:7]=[C:6]([C:19]([O:21]C)=[O:20])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:23])[CH2:11][CH:10]=[C:9]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2[CH:7]=[C:6]([C:19]([OH:21])=[O:20])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(Sc1ccccc1)=CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC=C(Sc2ccccc2)c2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylate (Compound E18, 300.0 mg, 0.926 mmol) in 4.0 mL of EtOH and 2.0 mL THF was added NaOH (200.0 mg, 5.00 mmol; 5.0 mL of a 1N aqueous solution). After stirring overnight at room temperature the reaction was quenched by the addition of 10% aqueous HCl. The mixture was extracted with EtOAc and the combined organic layers washed with H2O and saturated aqueous NaCl before being dried over Na2SO4. Removal of the solvents under pressure afforded the title compound as a yellow solid.
Reaction SMILES: O.[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9](=O)(=[O:12])([OH:11])[OH:10]>>[CH:7]1[C:2]([OH:8])=[CH:3][CH:4]=[C:5]([S:9]([OH:12])(=[O:11])=[O:10])[CH:6]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=S(=O)(O)c1ccc(O)cc1

Procedure:
Phenolsulfonic acid solution was prepared in sulfuric acid. The method included setting up a recirculating water bath so that the water was at a temperature of 95 degrees Centigrade. Next, the weight of available stock of Liquified Phenol USP containing 3.23 moles of Phenol was calculated. Phenol has a molecular weight of 94.11. The weight of 3.23 moles of Phenol is 3.23×94.11+303.97 grams. The purity of Liquified Phenol USP typically ranges from 89.0% to 91.5%. Using the purity value either from the manufacturer's Certificate of Analysis or the purity value from an internal quality control analysis, the weight of the available stock of Liquified Phenol USP required to deliver 3.23 moles of Phenol was calculated.
Reaction SMILES: C([NH:3][C@H:4]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:5][C:6](=[O:8])[OH:7])=O>Cl.O>[NH2:3][C@H:4]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:5][C:6](=[O:7])[OH:8]
Reactant: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: O
Product: N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 15 °C

Procedure:
45.5 g of formyl-α-L-aspartyl-L-phenylalanine is dissolved in concentrated hydrogen chloride (18.2 ml) and water (141 ml). The mixture is treated at 60° C. for 4 hours to remove the formyl group. 11.7 g of 50% caustic solution is added into the resulting solution and cooled to 15° C. to obtain a precipitate of α-L-aspartyl-L-phenylalanine. After filtration, the precipitate is washed with 10 ml of water at 5° C. and dried to obtain 25.2 g (0.090 mole) of the desired product. The remaining filtrate is mixed with 50% caustic solution (6.5 g) and cooled to obtain the precipitate by filtration. The precipitate is washed with water (10 ml) at 5° C. and dried to obtain additional α-L-aspartyl-L-phenylalanine (12.2 g, 0.043 mole).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](OC=C)(=O)[CH3:11]>[Pd]>[C:1]([O:9][CH:10]=[CH2:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=COC(C)=O
Reactant: O=C(O)c1ccccc1
Agent: [Pd]
Product: C=COC(=O)c1ccccc1

Procedure:
Analogously to the procedure described in Example I, 0.28 g of the polymer prepared according to Example 15 and having a palladium content of 19.7% by weight are warmed with 12.2 g of benzoic acid and 55.4 ml of vinyl acetate. In the first reaction run, 76% of theory of vinyl benzoate are isolated after 22 hours. In a further reaction batch with the same polymer, 76% of theory of vinyl benzoate are obtained after 20 hours.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>N1C=CC=CC=1>[N:11]1([C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][N:3]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCN1
Reactant: Clc1noc2ccccc12
Solvent: c1ccncc1
Product: c1ccc2c(N3CCNCC3)noc2c1
Yield: 76 %

Procedure:
3-Chloro-1,2-benzisoxazole reacted with excess piperazine in the presence of pyridine to provide 3-(piperazin-1-yl)benzo[d]isoxazole (3A) in 76% yield. Reductive amination of compound (3A) with 2-carbomethoxy 2-methyl propionaldehyde gave alkylated piperazine (4A), which was purified over silica gel. Basic hydrolysis of the methyl ester of (4A) in aqueous ethanol followed by acidification gave the carboxylic acid (1) as the mono-HCl salt.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][S-:12].[Na+]>CO>[CH3:11][S:12][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSc1ccc([N+](=O)[O-])nc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a mixture of 5-chloro-2-nitropyridine (3 g, 18 mmol) in MeOH (20 mL), sodium methanethiolate (1.4 g, 20 mmol) was added at 0° C. and the mixture stirred at 20° C. for 2 hours. The resulting suspension was filtered and washed with water, and dried in vacuum to afford crude 117a as a yellow solid (2 g, 66%) without purification for next step. MS: [M+H]+ 171.
Reaction SMILES: [N:1]([N:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)S(C1C=CC(C)=CC=1)(=O)=O)=O.C[O-].[Na+]>COC(C)(C)C.CO>[C:15]1([CH:14]=[N+:3]=[N-:1])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)N(Cc2ccccc2)N=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CO
Product: [N-]=[N+]=Cc1ccccc1
Yield: 30 %

Procedure:
N-Nitroso-N-benzyl-p-toluene sulphonamide (966 mg, 3.33 mmol) was added in small portions to a solution of sodium methoxide (2.0 ml of 2M solution in methanol) in t-butyl methyl ether (12 ml) and methanol (2 ml) at room temperature. After the addition was finished the reaction mixture was refluxed for 15-30 min. The reaction mixture was cooled and washed with water (3×6 ml). The ethereal solution of phenyl diazomethane was dried over sodium sulphate for 30 minutes. The solvent was removed in vacuo and the residue distilled under reduce pressure to give phenyl diazomethane as a dark red oil (30% yield, b.p. 20° C. at 1 mmHg) which was immediately dissolved in t-butyl methyl ether (6 ml).
Reaction SMILES: [CH3:1][CH:2]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[NH:4][CH2:3]1.CC1N([C:26]([CH2:28][C:29]#[N:30])=[O:27])N=C(C)C=1.C(N(CC)C(C)C)(C)C.[Cl-].[Na+]>O.O1CCOCC1>[CH3:1][CH:2]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[N:4]([C:26](=[O:27])[CH2:28][C:29]#[N:30])[CH2:3]1
Reactant: CC1CNC12CCCN(c1ncnc3[nH]ccc13)C2
Reactant: Cc1cc(C)n(C(=O)CC#N)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1CN(C(=O)CC#N)C12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 100 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
An optically-active compound of 4-(3-methyl-1,6-diazaspiro[3.5]non-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (1.8 g) was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (2.3 g), N,N-diisopropylethylamine (2.4 ml) and 1,4-dioxane (18 ml), and the mixture was stirred at 100° C. for 3 hours. The mixture was cooled to room temperature. Then, thereto were added water and saturated aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted with chloroform, and the combined organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=1/1, followed by chloroform/methanol=20/1 to 10/1). The resulting residue was purified by silica gel column chromatography (eluent: chloroform/acetone=10/1 to 1/1) again. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 10/1) again to give the titled compound (1.8 g).
Reaction SMILES: [NH:1]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C@H:2]([C:11]([O:13]C(C)(C)C)=[O:12])[CH2:3][O:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].C(O)(C(F)(F)F)=O>>[NH:1]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][O:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6]
Reactant: C=CCOC(=O)OC[C@H](NN1CCOCC1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)OC[C@H](NN1CCOCC1)C(=O)O

Procedure:
Morpholino-Ser(OAloc) was prepared from SER(OtBu)-OtBu. Reaction of Ser(OtBu)-OtBu with 4-morpholineacarbonyl chloride in pyridine yielded morpholino-Ser(OtBu)-OtBu. Morpholino-Ser(OtBu)-OtBu was hydrolyzed with TFA to yield morpholino-Ser. Esterification of morpholino-Ser with isobutylene in the presence of a catalytic amount of H2SO4 afforded morpholino-Ser-OtBu. Reaction of morpholino-Ser-OtBu with allyl 1-benzotriazolyl carbonate yielded morpholino-Ser(OAloc)-OtBu. Morpholino-Ser(OAloc)-OtBu was hydrolyzed with TFA in CHC 13 (1:1) to yield morpholino-Ser(OAloc).
Reaction SMILES: N1(CC(O)=O)C2C(=CC=CC=2)C=C1.COC(=O)[C@@H](NC(OC(C)(C)C)=O)CSCC1C=CC(N)=CC=1.C(Cl)CCl.C(N(CC)CC)C.C[O:49][C:50](=[O:82])[C@@H:51]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:52][S:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([NH:61][C:62](=[O:73])[CH2:63][N:64]2[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[CH:66]=[CH:65]2)=[CH:57][CH:56]=1.[OH-].[Na+].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C.CCCCCCC.CO.C1COCC1>[C:78]([O:77][C:75]([NH:74][C@@H:51]([CH2:52][S:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([NH:61][C:62](=[O:73])[CH2:63][N:64]2[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[CH:66]=[CH:65]2)=[CH:57][CH:56]=1)[C:50]([OH:82])=[O:49])=[O:76])([CH3:81])([CH3:79])[CH3:80]
Reactant: COC(=O)[C@H](CSCc1ccc(NC(=O)Cn2ccc3ccccc32)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: COC(=O)[C@H](CSCc1ccc(N)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N[C@@H](CSCc1ccc(NC(=O)Cn2ccc3ccccc32)cc1)C(=O)O

Procedure:
A solution of indol-1-yl-acetic acid (1.25 g, 7.14 mmol), (2R)-3-(4-amino-benzylsulfanyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (2.67 g, 7.85 mmol), EDC (1.71 g, 8.93 mmol), triethylamine (2.48 mL, 17.85 mmol) and DMAP (87 mg, 0.714 mmol) in DCM (50 mL) was stirred at ambient temperature. Upon completion (TLC: 2% methanol in dichloromethane), the reaction was quenched with water (75 mL) and extracted with ethyl acetate (3×50 mL). The combined extract was washed sequentially with water and brine, dried over anhydrous MgSO4 , filtered, concentrated in vacuo and purified by flash chromatography (SiO2; 30-40% ethyl acetate/heptane as eluent) To a stirred solution of (2R)-2-tert-butoxycarbonylamino-3-[4-(2-indol-1-yl-acetylamino)-benzylsulfanyl]-propionic acid methyl ester (0.470 g, 0.945 mmol) in methanol (3 mL) and THF (12 mL) was added 2N NaOH solution (2.5 mL, 5.3 mmol). Upon completion (TLC 10% methanol in dichloromethane), the mixture was acidified to pH 2 with 2N HCl solution and extracted with ethyl acetate (3×20 mL). The combined extract was washed sequentially with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield the titled compound as a light yellow solid. Rf 0.40 (20% methanol in dichloromethane); 1H NMR (CDCl3, 300 MHz) δ 7.71 (1H, d, J=7 Hz, Ar—H), 7.37-7.20 (6H, m, Ar—H), 7.16 (1H, d, J=3 Hz, Ar—H), 7.00 (1H, m, Ar—H), 6.69 (1H, d, J=3 Hz, Ar—H), 4.95 (2H, s, NCH2CO), 4.38 (1H, m, CHN), 3.66 (2H, s, PhCH2S), 2.85 (2H, m, CH2CHN), 1.45 (9H, s, CMe3); ESI-LCMS e/z calculated for C25H29N3O5S 483.183, found 484 (M+H)+, 506 (M+Na)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][C:8]=1[F:40].Cl>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[C:8]([F:40])[CH:9]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:33])([CH3:34])[CH3:32])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)O)c(F)c2)c(C)c1
Temperature: 100 °C
Yield: 101.4 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.20 mL) was added to a solution of optically active (4′-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-fluoro-2′-methyl-biphenyl-4-yl)-acetic acid methyl ester (Example 142-(1); 32.8 mg, 38%, >99.7% e.e.) in methanol (1.0 mL), and the mixture was stirred with microwave heating at 100° C. for five minutes. A 2 N hydrochloric acid aqueous solution (0.30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate and washing with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane:methanol=99:1 to 90:10) to give the target compound as a colorless oil (32.4 mg, 100%).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].O.[OH-].[K+]>C(O)(C)C>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=C(O)c1ccccc1S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1ccccc1Sc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-mercapto-benzoic acid (30 g, 0.195 mol) in isopropanol (500 mL) at room temperature were added 1-fluoro-2-nitro-benzene (30.2 g, 0.214 mol), water (100 mL) and potassium hydroxide (31.1 g, 0.555 mol). The reaction mixture was stirred at room temperature overnight, quenched with water and diluted with ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×400 mL) and the combined organic extracts were washed with saturated aqueous sodium chloride (500 mL), dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography on silica gel to give the title compound. ESI-MS (M+1): 276 calc. for C13H9NO4S 275. 1H NMR: (CDCl3, 400 MHz): δ (ppm) 8.12-8.07 (m, 2H), 7.54-7.43 (m, 2H), 7.42-7.39 (m, 2H), 7.35-7.31 (m, 1H), 7.12-7.09 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:20])[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH2:13].S(=O)(=O)(O)O>ClCCl>[C:14]1([CH:12]2[CH2:13][C:4]3[C:3](=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=3)[C:11]2=[O:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Reaction time: 0.5 h
Yield: 75 %

Procedure:
2',3' -Dichloro-4'-methoxy-2-phenylacrylophenone (160 g.) dissolved in dichloromethane (4 liters) is added dropwise to a mixture of 12N sulfuric acid (2 liters) and dichloromethane (2 liters) at <5°C. over a 3-hour period. The reaction mixture is stirred for an additional 30 minutes then poured slowly onto crushed ice. The dichloromethane layer is separated, washed with saturated sodium chloride solution, then dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure leaving a light tan solid residue. On drying in a steam oven at 70°C., 120.5 g. of product (75%) is obtained, mp 187°-192°C. A sample recrystallized from benzene-cyclohexane (2:1) melts at 193°-195°C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.Br[CH2:18][C:19](=O)[CH2:20][CH3:21]>C(O)C>[Br:1][C:2]1[C:3]([C:14]2[S:16][CH:18]=[C:19]([CH2:20][CH3:21])[N:15]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Reactant: CCC(=O)CBr
Solvent: CCO
Product: CCNC(=O)Nc1cc(-c2nc(CC)cs2)c(Br)cn1
Temperature: 25 °C
Yield: 36.8 %

Procedure:
To a mixture of 5-bromo-2-(3-ethylureido)pyridine-4-carbothioamide (Intermediate 42, 1 g, 3.30 mmol) in ethanol (25 mL), 1-bromobutan-2-one (0.337 mL, 3.30 mmol) was added, and the reaction mixture was heated to 80° for 4 h, then cooled to room temperature, concentrated under reduced pressure, and the resulting solid was washed with acetonitrile to give the title compound as an off-white solid (431 mg). MS (ESP): 356 (M+1) for C13H15BrN4OS; NMR: 1.09 (t, 3H); 1.29 (t, 3H); 2.84 (q, 2H); 3.15-3.20 (m, 2H); 7.34 (br s, 1H); 7.66 (s, 1H); 8.38 (s, 1H); 8.50 (s, 1H); 9.36 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([O:16][CH3:17])=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19].C[O-].[Na+].[CH:24](OCC)=O.S(=O)(=O)(O)O>O1CCCC1.O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:18](=[O:20])[CH:19]=[CH:24][NH:1]2)=[CH:4][C:5]=1[O:16][CH3:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC=O
Reactant: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
1-[2-Amino-4-(benzyloxy)-5-methoxyphenyl]-1-ethanone (24.95 g) was dissolved in tetrahydrofuran (450 ml), and sodium methoxide (24.87 g) was added to the solution. The mixture was stirred at room temperature for one hr. Ethyl formate (37.07 ml) was then added thereto, and the mixture was stirred at room temperature for 2 hr. Water (150 ml) was then added thereto, and the mixture was stirred overnight. The reaction solution was adjusted to pH 4 by the addition of concentrated sulfuric acid at 0° C. Water was added thereto, and the mixture was extracted with chloroform. The chloroform layer was dried over sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol (10/1) to give 17.16 g (yield 66%) of the title compound.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1>>[C:1]1([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(-c2ccccc2)nc1
Yield: 86 %

Procedure:
To explain the synthesis in more detail, the Suzuki reaction between phenylboronic acid and 2,5-dibromopyridine gave 2-phenyl-5-bromopyridine in an 86% yield (see scheme 1 above). The reaction occurred preferentially on the 2 position on the pyridine ring, which is activated by the adjacent nitrogen. Reaction of 2-phenyl-5-bromopyridine with trimethylsilylacetylene under Sonogashira conditions gave the 2-phenyl-5-(trimethylsilylethynyl)pyridine (2) in an 88% yield, which could be deprotected to 2-phenyl-5-ethynylpyridine (3) in a yield of 93% using tetra-n-butylammonium hydroxide. The Diels-Alder reaction between (3) and the difluorenylcyclopentadienone (10) gave the dendronised ligand in a 48% yield, after purification by precipitation of the ligand from a dichloromethane solution by pouring the solution into ethanol. The complex was formed by the two-step procedure via the bis(chloro)-bis(iridium) dimer in a yield of 50%. This yield is no lower than those obtained from the complexation of ligands dendronised only on the phenyl ring, showing that the presence of the bulky dendron on the pyridine ring does not inhibit complexation.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2ccccc2)nc1
Temperature: 25 °C

Procedure:
To a solution of 2,5-dibromopyridine (1.00 g) in toluene (10 mL) and ethanol (5 mL) was added phenylboronic acid (515 mg), sodium carbonate (1.34 g) and tetrakis (triphenylphosphine)palladium(0) (24 mg) and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted into ethylacetate (2×30 mL). The organic layers were washed with brine (40 mL), dried (MgSO4), reduced in vacuo and purified on silica to give 5-bromo-2-phenyl-pyridine as a white solid.