Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC1N2C(SC([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=N2)=NC=1.CN(C1C=C(B(O)O)C=CC=1)C.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([NH2:10])=[CH:12][CH:13]=1
Reactant: COc1ccc(Nc2nn3c(I)cnc3s2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(N)cc1
Temperature: 140 °C
Yield: 32.5 %

Procedure:
(5-Iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-(4-methoxyphenyl)amine (55 mg, 0.10 mmol) was suspended in 1,4-dioxane (1 mL) at room temperature and argon was bubbled into the mixture while tetrakis(triphenylphosphine)palladium(0) (0.011 mmol, 12 mg), 3-(N,N-dimethylamino)phenylboronic acid (0.202 mmol, 33 mg), cesium carbonate (0.268 mmol, 88 mg) and water (1 mL) were added. The mixture was deoxygenated for 10 minutes and heated under microwave irradiation at 140° C. for 1 hour. On cooling, the mixture was diluted with dichloromethane, adsorbed in silica and purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.2:9.8 to 2:8). The obtained residue was further purified by preparative HPLC to give {5-[3-dimethylaminophenyl)-imidazo[2,1-b][1,3,4]thiadiazol-2-yl]}-(4-methoxyphenyl)-amine as a white solid (4 mg, 7% yield).
Reaction SMILES: I.CS[C:4](=[NH:16])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.[OH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([NH:24][NH2:25])=O)=[CH:20][CH:19]=1>N1C=CC=CC=1>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:7]=[C:6]([NH:5][C:4]2[NH:16][C:22]([C:21]3[CH:26]=[CH:27][C:18]([OH:17])=[CH:19][CH:20]=3)=[N:24][N:25]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: CSC(=N)Nc1cccc(C(F)(F)F)c1
Agent: I
Solvent: c1ccncc1
Product: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Temperature: 25 °C
Yield: 47.6 %

Procedure:
S-methyl N-[3-(trifluoromethyl)phenyl]isothiourea hydroiodide (9.09 g, 25.11 mmol) and 4-hydroxybenzoic acid hydrazide (3.82 g, 25.11 mmol) were suspended in ca. 50 mL of anhydrous pyridine under Ar. The mixture was brought to reflux and refluxed under Ar for 12 hrs. Then the dark-yellow solution was cooled down to ambient temperature and pyridine was removed in vacuo. The resulting reddish-yellow solid was re-dissolved in ca. 50 mL of 4:1 mixture of EtOAc/MeOH, ca. 20 g of silica gel was added and solvent was removed in vacuo. The impregnated silica gel was loaded into 25 g ISCO sample cartridge and the product was purified using ISCO system (solid method, 80 g column, 45 min, 0% to 50% EtOAc gradient in hexane). Solvent was removed in vacuo to give the title product as a white solid (3.83 g). Yield 47.6%.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]([CH2:10][O:11][C:12]2[C:20]3[C:19]4[CH:21]=[C:22]([C:25]#[N:26])[N:23]=[CH:24][C:18]=4[N:17](COCC[Si](C)(C)C)[C:16]=3[N:15]=[CH:14][CH:13]=2)([CH3:9])[CH2:5][CH2:4]1)[CH3:2].Br.[OH-].[Na+].Cl>O1CCOCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6]([CH2:10][O:11][C:12]2[C:20]3[C:19]4[CH:21]=[C:22]([C:25]#[N:26])[N:23]=[CH:24][C:18]=4[NH:17][C:16]=3[N:15]=[CH:14][CH:13]=2)([CH3:9])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(C)(COc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)CC1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN1CCC(C)(COc2ccnc3[nH]c4cnc(C#N)cc4c23)CC1
Temperature: 75 °C
Yield: 31 %

Procedure:
4-((1-ethyl-4-methylpiperidin-4-yl)methoxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (58 mg, 0.12 mmol) was dissolved in 1,4-dioxane (0.5 mL) and then treated with 48% HBr(aq) (0.5 mL) and heated at 75° C. for 15 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a white solid (13 mg, 30%). 1H NMR (400 MHz, d6-DMSO) δ 8.98 (d, J=0.8, 1H), 8.54 (d, J=5.7, 1H), 8.35 (d, J=0.8, 1H), 7.06 (d, J=5.8, 1H), 4.12 (s, 2H), 2.56 (m, 2H), 2.42-2.25 (m, 4H), 1.75 (m, 2H), 1.54 (m, 2H), 1.19 (s, 3H), 1.08-0.97 (m, 3H). LCMS (Method D): RT=8.49 min, M+H+=450.1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:11])=[C:8]([SH:10])[CH:9]=1.C(N(CC)CC)C.[Br:19][C:20]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=O.[OH-].[Na+]>CN1CCCC1=O>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:22]([C:21]3[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH3:30])[C:20]=3[Br:19])[S:10][C:8]=2[CH:9]=1
Reactant: COc1cccc(C(=O)Cl)c1Br
Reactant: COc1ccc(N)c(S)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COc1ccc2nc(-c3cccc(OC)c3Br)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
5-Methoxy-2-aminobenzenethiol hydrochloride (83 g, 4.33 mmol) was dissolved in 1-methyl-2-pyrrolidinone (10 mL). After triethylamine (0.60 mL, 4.33 mmol) was added, the mixture was stirred at room temperature for 10 min. 2-Bromo-3-methoxybenzoyl chloride (1.08 g, 4.33 mmol) in 1-methyl-2-pyrrolidinone (10 mL) was then added and the mixture was heated at 100° C. for 40 min. The mixture was cooled to room temperature and 1N NaOH was added to PH 9. The mixture was extracted with ethylacetate and combined ethylacetate were washed with brine, concentrated. After chromatographic purification gave 6-methoxy-2-(2-bromo-3-methoxy-phenyl)-benzothiazole (0.98 g, 65% yield) as a yellow solid. Mass spec: MH+=350.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:17]=O)[C:11]2[O:15][CH:14]=[CH:13][C:12]=2[CH:16]=1.[C-]#N.[Li+].O1CCCC1.[C:27](P(=O)(OCC)OCC)#[N:28].C(O)(C)(C)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH2:17][C:27]#[N:28])[C:11]2[O:15][CH:14]=[CH:13][C:12]=2[CH:16]=1
Reactant: O=Cc1cc(OC2CCCCO2)cc2ccoc12
Reactant: CCOP(=O)(C#N)OCC
Agent: [C-]#N
Agent: [Li+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: N#CCc1cc(OC2CCCCO2)cc2ccoc12
Reaction time: 0.33 h

Procedure:
Combine 5-(tetrahydropyran-2-yloxy)benzofuran-7-carboxaldehyde (3.75 g, 0.015 mol) with lithium cyanide-tetrahydrofuran (1:1.5 complex, 0.215 g, 0.1 equivalent) in tetrahydrofuran (80 mL) under nitrogen. Add diethyl cyanophosphonate (3.0 ml, 1.3 equivalents) and stir at 20° C. for 2 days. Add tert-butanol (1.6 mL, 1.1 equivalents) then SmI2 in tetrahydrofuran (0.1 M solution, approximately 400 mL). Concentrate the solution in vacuo then redissolve in a solution of ethyl acetate:diethyl ether (approximately 3:1, 100 mL). Add saturated aqueous ammonium chloride and stir for 20 min, until the release of hydrogen cyanide is complete. Filter to remove insoluble material, then extract against 1 N hydrochloric acid. Dry over sodium sulfate, then filter and concentrate. Purification by a plug column (4:1 hexanes:ethyl acetate) to provide the title compound as a light yellow oil.
Reaction SMILES: I[C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:4][NH:5][CH:6]=1.C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>O1CCCC1.[Pd+2].[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:13]([C:9]1[CH:8]=[C:7]([C:3]2[C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:6][NH:5][N:4]=2)[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]cc2I)c1
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1c[nH]nc1-c1cccc([N+](=O)[O-])c1
Reaction time: 4 h

Procedure:
415 mg (1.32 mmol) of 4-iodo-3-(3-nitrophenyl)-1H-pyrazole (prepared as described in Example 27) were dissolved in 15 ml of dry tetrahydrofuran and 494 μL (3.42 mmol)of triethylamine, 80 mg (0.106 mmol) of palladium(II)-bis(triphenylphosphine) dichloride, 26 mg (0.166 mmol) of cuprous iodide and 406 μL (2.9 mmol) of trimethylsilylacetylene were added consecutively in a nitrogen atmosphere. The reaction was refluxed under stirring for 4 hours. The solvent was then removed in vacuo and the residue re-dissolved with dichloromethane and washed with water. The organic phase was dried over sodium sulphate and evaporated, affording, after trituration with diisopropylether, 300 mg (80%) of the title compound, that was employed for the next step without any further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:13]=1[NH2:14])([CH3:11])[CH3:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:21][CH:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:12]([CH:9]([CH3:11])[CH3:10])[C:13]=1[NH:14][C:6](=[O:7])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH3:20]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.2 %

Procedure:
To a solution of acetoxyacetyl chloride (13.5 g, 98.7 mmol) in toluene (70 mL) at 0° C. is added dropwise via a dropping funnel a solution of 2,6-diisopropylaniline (17.5 g, 98.7 mmol) and triethylamine (20.6 mL, 148.1 mmol) in toluene (20 mL). After completion of the addition, the mixture is allowed to warm to room temperature and stirred for 24 hours. The mixture is filtered through a small pad of silica gel. The filtrate is concentrated to afford 11 g of a brown solid. The precipitate is suspended in ethyl acetate and stirred overnight. After filtration, the filtrate is concentrated to give another 10 g of a brown solid. Recrystallization (ethyl acetate/hexane) of the combined material provided 12 g of the title compound as an off-white solid; mp 179°-182° C.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[F:21].C(OC([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=O)(C)(C)C.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[C:15]([C:11]1[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[C:3]([F:21])[CH:4]=2)[CH:14]=[CH:13][CH:12]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)c(F)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)c(F)c2)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
The 4-bromo-N-(3-tert-butyl-phenyl)-3-fluoro-benzamide (0.15 mmol) was added piperazine-1-carboxylic acid tert-butyl ester (0.195 mmol), NaOtBu (0.375 mmol), XantPhos (0.03 mmol), Pd2 dba2 (0.009 mmol) and 1,4 dioxane (0.2 mL). The reaction vial was purged with Ar, sealed, and heated at 85° C. overnight. The reaction was worked up by diluting with ethyl acetate (mL) washed with NH4Cl (1.5 M, 4 mL), and brine (4 mL), filtered through a plug of Na2SO4, and dried under a stream of nitrogen. To the intermediate was added DCM (1 ml) and TFA (0.2 mL) and stirred at room temperature for 1 hr. The reaction was diluted ethyl acetate (mL) washed with NaHCO3 (saturated, 4 mL, twice), and brine (4 mL), filtered through a plug of Na2SO4 and dried under a stream of nitrogen yielding the product, N-(3-tert-butyl-phenyl)-3-fluoro-4-piperazin-1-yl-benzamide. LCMS calcd for C21H26FN3O (m/e) 355, obsd 356 (M+H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:33])/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>C1COCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:33])/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28]([CH2:31][NH:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:27][CH:26]=3)=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: NC1CCCCC1
Reactant: O=C(/C=C/c1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(CNC2CCCCC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
0.082 mL (0.72 mmol) of cyclohexylamine is added to a suspension of 150 mg (0.39 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-chloromethylphenyl)acrylamide in 5 mL of THF and the mixture is refluxed for 18 hours. Then the reaction mixture is poured onto water and the precipitate formed is suction filtered. Further purification is carried out by column chromatography on silica gel (eluant: dichloromethane/methanol (95:5 to 50:50)). Yield: 70 mg (40% of theory); C28H29ClN2O (M=444.99); melting point: 247° C.-248° C.; Calc.: molecular ion peak (M+H)+: 445/447 (Cl); found: molecular ion peak (M+H)+: 445/447 (Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([S:28][C:29]2[CH:38]=[C:37]([CH3:39])[C:32]3[NH:33][C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([S:28][C:29]5[CH:38]=[C:37]([CH3:39])[C:32]6[NH:33][C:34](=[O:36])[O:35][C:31]=6[CH:30]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Sc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Sc4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2
Temperature: 130 °C
Reaction time: 2 h

Procedure:
187 mg (0.681 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 180 mg (0.490 mmol) 6-(6-chloro-pyrimidin-4-ylsulphanyl)-4-methyl-3H-benzoxazol-2-one and 200 mg (1.45 mmol) potassium carbonate were combined in 5.0 mL NMP and stirred for 2 h at 130° C. The reaction mixture was cooled overnight, filtered and the filtrate was purified by preparative HPLC. The product-containing fractions were combined, evaporated down and dried i. vac.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:25]([C:28]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:6]2[NH:10][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:8][C:7]=2[CH:24]=1.C(=O)(O)[O-].[Na+:43]>C(COC)OC.O>[Na+:43].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:25]([C:28]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)(=[O:26])=[O:27])[C:6]2[NH:10][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:8][C:7]=2[CH:24]=1
Reactant: COc1cc(S(=O)(=O)c2ccc(OCC(=O)O)cc2)c2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(S(=O)(=O)c2ccc(OCC(=O)[O-])cc2)c2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 88.1 %

Procedure:
To a suspension of the sulfoxide acid (4.47 g, 0.008 mol) in glyme (75 mL) was added a solution of sodium bicarbonate (0.672 g, 0.008 mol) in water (50 mL). The reaction mixture was extracted with ethyl acetate (4×50 mL). The combined organic layers were back extracted with water (2×25 mL). The combined aqueous layers were lyophilized to give 4.1 g (88%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:11]=1[O:12]C)[C:5]([O:7][CH3:8])=[O:6].B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCCCNc1cc(C(=O)OC)cc(Br)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCNc1cc(C(=O)OC)cc(Br)c1O
Temperature: 0 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
To a −78° C. solution of the Methyl 3-bromo-5-(butylamino)-4-methoxybenzoate (520 mg) in methylene chloride (10 mL) was added BBr3 (8 ml of 1.0 M solution in methylene chloride) dropwise and the reaction mixture was stirred for 18 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride and saturated sodium bicarbonate was added. The mixture was cooled to 0° C. and methanol was added dropwise. After stirring for 30 min, the mixture was stirred at room temperature for 1 h. The solvent was removed, and the residue dissolved in methylene chloride, washed with water, saturated sodium bicarbonate (15 mL), and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:20, ethyl acetate/hexanes) provided 440 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.52, 7.19, 3.88, 3.18, 1.65, 1.46, 0.97.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([OH:26])=O)[CH2:21][N:22]=1)=[CH:14]2.Cl.C[N:40](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>C(OCC)(=O)C.CO>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:30][CH:29]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([NH2:40])=[O:26])[CH2:21][N:22]=1)=[CH:14]2
Reactant: Cn1ccnc1COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ccnc1COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.9 %

Procedure:
A mixture of (2-{7-[(1-methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (210 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (150 mg), 1-hydroxybenzotriazole ammonium salt (118 mg) and N,N-dimethylformamide was stirred at room temperature for 5 hr. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was washed with diisopropyl ether. Sodium chloride was added to the aqueous layer to give a saturated solution, and the mixture was subjected to extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (methanol:ethyl acetate=0:100 to 25:75, volume ratio), and the obtained amorphous solid was crystallized from diethyl ether to give the title compound (50 mg, yield 24%) as colorless crystals. melting point 130-131° C. MS 540 (MH+).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[C:26]([CH3:34])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:34][C:26]1[CH:25]=[C:24]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)[CH:29]=[CH:28][C:27]=1[S:30]([NH2:33])(=[O:32])=[O:31]
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: Cc1cc(Br)ccc1S(N)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)ccc1S(N)(=O)=O
Temperature: 80 °C
Yield: 45.9 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.2 g, Example 33), 4-bromo-2-methylbenzenesulfonic acid amide (1.7 g, Example 79a), ethanol (3 ml), 2M aqueous sodium carbonate (0.7 ml) and tetrakis(triphenylphosphine)palladium (0) (0.03 g) with heating at 80° C. for 3 hours. After work-up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as a foam (0.13 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[CH:16]1([N:21]=[C:22]=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:22](=[O:23])[NH:21][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CO
Product: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)NC1CCCC1

Procedure:
Prepared according to the procedure described in Example 19, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and cyclopentyl isocyanate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20](C(O)=O)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:24])[N:12]2[CH3:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:24])[N:12]2[CH3:25])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C(=O)c2ccccc2C(C(=O)O)C1c1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1C(=O)c2ccccc2CC1c1ccc(C(C)(C)C)cc1
Yield: 75.6 %

Procedure:
To 50 ml of a solution containing 9.00 g of 3-(4-t-butylphenyl)-4-hydroxycarbonyl-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline in dimethylsulfoxide, 4.20 g of sodium carbonate was added and the mixture was allowed to react at 150° C. for 1 hour. After the reaction, the solvent was evaporated under reduced pressure, and 800 ml of water was added thereto, followed by extraction with ethyl acetate (100 ml×5). The combined organic layers were washed with water (300 ml×6) and then with brine, and were dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography [hexane/ethyl acetate (2/1)] to obtain 5.92 g of 3-(4-t-butylphenyl)-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]2[NH:11][C:12]([C:14]3[N:15]([CH3:27])[CH:16]=[C:17]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:18]=3)=[N:13][C:8]2=[CH:7][CH:6]=1)=[O:4].Cl>[OH-].[Na+].O.O1CCOCC1>[C:23]([O:22][C:20]([NH:19][C:17]1[CH:18]=[C:14]([C:12]2[NH:11][C:9]3=[N:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[C:8]3[N:13]=2)[N:15]([CH3:27])[CH:16]=1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1ccc2nc(-c3cc(NC(=O)OC(C)(C)C)cn3C)[nH]c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(NC(=O)OC(C)(C)C)cc1-c1nc2ccc(C(=O)O)nc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.5 %

Procedure:
Compound 8 (60 mg, 0.6 mmol) was dissolved in 0.2 M NaOH in H2O/dioxane 1:1 (7 mL) and stirred for 5 h at r.t. while the solution turned orange. The solution was cooled to 0° C. and 1N HCl was added dropwise until pH 1-2, while an orange precipitate developed. The product was separated by centrifugation, the supernatant removed, and the formed precipitate washed with cold H2O (2×2 mL). Lyophilization afforded 46 mg (81%) of 9 as an orange solid. Data of 9: UV (MeOH): λmax 359. 1H NMR (300 MHz, DMSO-d6): δ 1.46 (s, 9H), 4.05 (s, 3H), 7.01 (brs, 1H, D2O exchange), 7.15 (s, 1H), 7.98 (m, 3H), 9.30 (s, 1H, D2O exchange). 13C NMR (75 MHz, DMSO-d6): δ 28.96, 37.47, 79.21, 106.38, 118.65, 119.93, 120.44, 122.32, 124.99, 141.58, 150.32, 153.38, 166.53. MS (ESI): m/z (rel intensity) 358 (100). HRMS (FAB): m/z calcd for C17H20N5O4, 358.1515; found, 358.1506.