Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:42]=[CH:41][C:17]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)[CH2:30][CH2:29]3)=[O:27])[CH:20]=2)=[C:16]([F:43])[CH:15]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:43][C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:12])[CH:42]=[CH:41][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]([N:28]2[CH2:29][CH2:30][CH:31]([N:34]3[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]3)[CH2:32][CH2:33]2)=[O:27])[CH:20]=1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)CC1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)ccn3)CC2)CC1
Reaction time: 0.42 h
Yield: 25 %

Procedure:
After adding a solution of 2-phenylacetyl isothiocyanate in toluene (0.2 M, 2.0 ml) to a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (85 mg) and (+)-10-camphorsulfonic acid (92 mg) in ethanol (2.0 ml) at room temperature, the mixture was stirred for 25 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=98:2 to 95:5) to provide the title compound (30.5 mg, 25%) as white powder.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[F:14][C:15]1[CH:16]=[C:17]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:18]=[CH:19][C:20]=1[CH:21]=O.Cl>CN(C=O)C>[CH2:26]([O:25][C:24]([NH:23][C:17]1[CH:18]=[CH:19][C:20](/[CH:21]=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])=[C:15]([F:14])[CH:16]=1)=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=Cc1ccc(NC(=O)OCc2ccccc2)cc1F
Reactant: COC(=O)CP(=O)(OC)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(NC(=O)OCc2ccccc2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
Sodium hydride (0.513 g of a 60% dispersion, 12.8 mmol) was placed in a flask and washed three times with hexane. The resulting solid was suspended in DMF (10 mL) and cooled to 0° C. Trimethyl phosphonoacetate (2.2 mL, 13.5 mmol) was added dropwise to this suspension to give a clear homogeneous solution. After stirring for another 15 minutes at 0° C., a solution of benzyl 3-fluoro-4-formylphenylcarbamate (3.5 g, 12.8 mmol) in DMF (10 mL) was added dropwise. The resulting orange suspension was allowed to warm slowly to room temperature and stirred for 16 hours. The reaction mixture was poured into 0.5 N HCl and extracted with three portions of dichloromethane. Combined organic phases were washed with saturated NaHCO3, H2O, brine, and dried (MgSO4) filtered and concentrated. The resulting orange solid was washed sequentially with hexane and then 30% ethyl acetate-hexane to provide the title compound as a yellow-orange solid (2.7 g). The washings were concentrated and purified by column chromatography (0-30% ethyl acetate-hexane) to provide an additional 0.95 g of the product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH3:9].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](Cl)=[O:26]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:9])[C:25](=[O:26])[C:24]1[CH:23]=[C:22]([C:21]([F:36])([F:35])[F:20])[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=1
Reactant: CNc1cnccc1Br
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of (4-bromo-pyridin-3-yl)-methyl-amine (1 g, 5.376 mmol) in THF (8 mL) was added LiHMDS (1M solution in THF, 10.7 mL, 10.7 mmol, CAS RN 4039-32-1) dropwise at −78° C., and stirred for 15 minutes before 3,5-bis-trifluoromethyl-benzoyl chloride (1.5 mL, 8.06 mmol, CAS RN 785-56-8) was added to the reaction mixture. After stirring at −78° C. for 1 h the reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL) and diluted with EtOAc (40 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and evaporated off in vacuo. The residue was purified by column chromatography over silica gel (15% EtOAc in n-hexane) to afford the title compound. Pale yellow solid (985 mg, 43%). MS (ESI): m/z=427.2 [M+H]+.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[C:10]([CH3:30])=[C:11]([CH2:28]O)[C:12]2[O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:13]=2[C:26]=1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.CCCCCC>C(Cl)(Cl)Cl>[C:1]([NH:5][C:6]([NH:8][C:9]1[C:10]([CH3:30])=[C:11]([CH3:28])[C:12]2[O:16][CH2:15][C@H:14]([C:17]3[CH:18]=[CH:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[C:13]=2[C:26]=1[CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(CO)c2c(c(C)c1NC(=O)NC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1c(C)c2c(c(C)c1NC(=O)NC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Yield: 57 %

Procedure:
Using (+)-N-(tert-butyl)-N′-((3R)-7-(hydroxymethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)urea obtained in Example 49, the title compound was synthesized in the same manner as in Example 45. Yield: 57%. Melting point: 209-210° C. (ethyl acetate-hexane). [α]D20=+53.2° (c=0.47, chloroform).
Reaction SMILES: C[C@@H]1C2NC=CC=2C(=O)N1.C(O[C:16]([NH:18][C@H:19]([CH2:23][O:24][CH3:25])[C:20](O)=O)=[O:17])(C)(C)C.C[C@@H]1C2[NH:32][C:33]([B:35]3[O:39][C:38]([CH3:41])([CH3:40])[C:37]([CH3:43])([CH3:42])[O:36]3)=[CH:34][C:30]=2C(=O)N1>>[CH3:25][O:24][CH2:23][CH:19]1[C:20]2[NH:32][C:33]([B:35]3[O:39][C:38]([CH3:41])([CH3:40])[C:37]([CH3:43])([CH3:42])[O:36]3)=[CH:34][C:30]=2[C:16](=[O:17])[NH:18]1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C[C@H]1NC(=O)c2cc[nH]c21
Product: COCC1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21

Procedure:
6-(Methoxymethyl)-5,6-dihydropyrrolo[3,4-b]pyrrolo-4(1H)-one (485a) was prepared in a manner similar to that described for Intermediate 702, starting from (R)-2-((tert-butoxycarbonyl)amino)-3-methoxypropanoic acid (prepared according to the procedure in WO 2012/051551). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.32 (br. s., 1H), 7.58 (s, 1H), 6.83 (d, J=2.74 Hz, 1H), 6.09 (d, J=2.74 Hz, 1H), 4.50 (ddd, J=6.75, 5.58, 1.37 Hz, 1H), 3.37-3.49 (m, 2H), 3.30 (s, 3H). m/z (ES, +ve) 167.0 (M+H)+. 6-(Methoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (485b) was prepared in a manner similar to that described for Intermediate 705, using 6-(methoxymethyl)-5,6-dihydropyrrolo[3,4-b]pyrrolo-4(1H)-one (485a) as the starting material. 1H NMR (400 MHz, CDCl3) δ ppm 6.93 (d, J=1.76 Hz, 1H), 5.85 (s, 1H), 4.56-4.65 (m, 1H), 3.55 (dd, J=8.61, 7.04 Hz, 1H), 3.40-3.47 (m, 4H), 1.30-1.36 (m, 12H). m/z (ES, +ve) 293.1 (M+H)+.
Reaction SMILES: O.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH3:13].Br[CH:15]1[CH2:20][CH2:19][O:18][C:16]1=[O:17].CC1C=CC=C(C)N=1>CC(C)=O>[CH3:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[NH:2][CH:20]1[CH2:19][O:18][C:16](=[O:17])[CH2:15]1
Reactant: O=C1OCCC1Br
Reactant: Cc1ccc2ccccc2c1N
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: CC(C)=O
Product: Cc1ccc2ccccc2c1NC1COC(=O)C1
Reaction time: 7 h
Yield: 60.5 %

Procedure:
A 200-ml round-bottom flask equipped with a heating mantle and connected to a water aspirator vacuum system was charged with 15.0 g (0.1 mol) 1-amino-2-methylnaphthalene, 16.4 g (0.1 mol) alpha-bromo-gamma-butyrolactone and 10.7 g (0.1 mol) 2,6-dimethylpyridine. The reaction mixture was maintained at about 94°-101° C. and 160 mm of Hg for about 7 hours. The reaction mixture was cooled, diluted with 100 ml acetone and filtered. The filtrate was evaporated under reduced pressure to give an oily residue which was eluted through a silica gel column with 15% acetone/85% petroleum ether to give 14.6 g of 3-(N-2-methylnaphth-1-ylamino)-gamma-butyrolactone, m.p. 92°-94° C. Elemental analysis for C15H15NO2 showed: %C, calc. 75.0, found 74.5; %H, calc. 5.9, found 5.6; %N, calc. 5.8, found 5.6.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[CH2:15][C:16]1[N:20]=[CH:19][O:18][N:17]=1.C(N(CC)CC)C>C(Cl)Cl>[O:18]1[CH:19]=[N:20][C:16]([CH2:15][N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[N:17]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClCc1ncon1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ncon2)CC1
Temperature: 50 °C
Reaction time: 22 h
Yield: 67.4 %

Procedure:
To a solution of Boc-piperazine (571 mg, 3.07 mmol) and 3-(chloromethyl)-1,2,4-oxadiazole (400 mg, 3.37 mmol) in CH2Cl2 (30 mL) was added triethylamine (1.70 mL, 12.3 mmol). The reaction was stirred for 22 h at 50° C. before concentrated in vacuo to give a crude oily white solid. Purification was accomplished by flash chromatography on silica gel (4×12) eluting with MeOH/CH2Cl2 (5%) to yield the title compound (555 mg, 67%) as a white solid. 1H-NMR (500 MHz, CDCl3) 1.43 (s, 9H, C(CH3)3), 2.52 (app t, J=4.9 Hz, 4H, CH2), 3.45 (app t, J=4.9 Hz, 4H, CH2), 3.78 (s, 2H, CH2C—), 8.71 (s, 1H, CHar); LC-MS (ESI, m/z): Rt=1.67 min-213 (M-tBu)+, 169 (M-Boc)+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]([CH3:31])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]4[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:10]2)=[N:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.O>CN1C(=O)CCC1>[CH3:31][N:8]([C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10]1)[C:5]1[CH:4]=[N:3][C:2]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:7][N:6]=1
Reactant: C1COCCN1
Reactant: CN(c1cnc(Br)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(c1cnc(N2CCOCC2)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 25 °C

Procedure:
A solution of (R)-5-bromo-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine (0.099 mmol) and morpholine (1.5 mL) in NMP (0.5 mL) was stirred at 195° C. for 2 hours in a microwave reactor. After cooling to the ambient temperature, it was poured into water, and extracted with EtOAc. The combined organic extracts were concentrated and the residue was purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: [CH2:1]([CH:4]([CH2:9][C:10]#[CH:11])[C:5]([O:7]C)=[O:6])[C:2]#[CH:3].[OH-].[Na+].Cl>O>[CH2:1]([CH:4]([CH2:9][C:10]#[CH:11])[C:5]([OH:7])=[O:6])[C:2]#[CH:3]
Reactant: C#CCC(CC#C)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCC(CC#C)C(=O)O

Procedure:
Methyl 2-(2-propynyl)-4-pentynoate (27.5 g) was saponified with sodium hydroxide (22 g) in refluxing water (250 ml). The solution was cooled and acidified with 12 N HCl to pH 3, and then extracted with t-butyl methyl ether. The organic layer was washed with brine and dried over sodium sulfate. Solvent removal afforded the title compound.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1>C1(C)C=CC=CC=1.CO.C(Cl)Cl>[CH3:8][N:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:22][CH3:1])=[O:21])=[CH:18][CH:17]=2)[CH2:13][CH2:14]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.2 %

Procedure:
A solution of (trimethylsilyl)diazomethane ((0.611 mL, 3.84 mmol) 2.0M in diethyl ether) was added dropwise to a stirred suspension of 4-((4-methylpiperazin-1-yl)methyl)benzoic acid (0.75 g, 3.20 mmol) in toluene (21 mL) and methanol (7 mL) over a period of 10 mins under nitrogen. The resulting suspension was stirred at room temperature for 3 h. A further aliquot of (trimethylsilyl)diazomethane (1.222 mL, 7.68 mmol) was added dropwise and the solution was stirred at room temperature for a further 18 h. The reaction mixture was evaporated to dryness to afford the crude product (0.723 g) as a white solid. This was taken up in DCM and the insolubles were filtered off. The filtrate was evaporated to dryness to afford the crude product. This was taken up in DCM again and more insolubles were filtered off to afford methyl 4-((4-methylpiperazin-1-yl)methyl)benzoate (0.351 g, 44.2%), which was used without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]=[CH:17][CH2:18][CH3:19])=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:25]([O:24][C:22](=[O:23])[C:21]([O:15][C:13]1[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:11][C:12]=1[CH:16]=[CH:17][CH2:18][CH3:19])([CH3:28])[CH3:27])[CH3:26]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCC=Cc1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC=Cc1ccc(OCc2ccccc2)cc1OC(C)(C)C(=O)OCC
Temperature: 55 °C
Yield: 76 %

Procedure:
5-Benzyloxy-2-but-1-enylphenol (0.70 g, 2.75 mmol) was dissolved in anhydrous DMF (12 mL), followed by the addition of ethyl bromoisobutyrate (1.62 mL, 11.0 mmol), and cesium carbonate (3.58 g, 11.0 mmol). The mixture was then heated for 18 h (55° C.). The reaction mixture was then cooled and concentrated in vacuo. The crude residue was partitioned between EtOAc (70 mL) and water (40 mL). The organic layer was washed with brine, dried (Na2SO4), and removed in vacuo. The crude residue was purified using radial chromatography, eluting with 5% EtOAc/Hex to give 0.77 g (76%) of a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.41-7.28 (m, 6H), 6.65-6.59 (m, 2H), 6.40 (d, J=2.4 Hz, 1H), 6.14-6.07 (m, 1H), 4.99 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 2.22 (quintet, J=7.6 Hz, 2H), 1.56 (s, 6H), 1.26 (t, J=7.1 Hz, 3H), 1.08 (t, J=7.6 Hz, 3H), MS (ES) m/e 369 (M+1).
Reaction SMILES: N1(C2C=CC(NC3C4N(C=CN=4)C(C4C=CNC(=O)C=4)=CN=3)=CC=2)CCOCC1.[CH2:30]([N:32]([CH2:55][CH3:56])[CH2:33][CH2:34][NH:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45]2[C:46]3[N:47]([CH:52]=[CH:53][N:54]=3)[C:48](Br)=[CH:49][N:50]=2)=[CH:40][N:39]=1)=[O:37])[CH3:31].CC1(C)C(C)(C)OB([C:65]2[CH:66]=[N:67][NH:68][CH:69]=2)O1.CC([O-])(C)C.[Na+]>CN(C=O)C.O.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>[CH2:30]([N:32]([CH2:55][CH3:56])[CH2:33][CH2:34][NH:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45]2[C:46]3[N:47]([CH:52]=[CH:53][N:54]=3)[C:48]([C:65]3[CH:66]=[N:67][NH:68][CH:69]=3)=[CH:49][N:50]=2)=[CH:40][N:39]=1)=[O:37])[CH3:31]
Reactant: CCN(CC)CCNC(=O)c1ccc(Nc2ncc(Br)n3ccnc23)cn1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: O=c1cc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3nccn23)cc[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1ccc(Nc2ncc(-c3cn[nH]c3)n3ccnc23)cn1
Yield: 18.3 %

Procedure:
In the same way as described for Compound 85, step 1, using 5-(5-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-pyridine-2-carboxylic acid (2-diethylamino-ethyl)-amide (169 mg, 0.39 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (91 mg, 0.47 mmol), Pd(PPh3)4 (45 mg, 0.039 mmol) and NaOtBu (150 mg, 1.56 mmol) in DMF:water (3:1, 9 mL). The crude residue is purified by reverse phase preparative HPLC to give the title compound (30 mg, 18%). LCMS: Rt 1.81 min (97.6%); m/z (APCI) 420 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm). 1.02 (6H, t), 2.36-2.71 (4H, m), 3.09-3.40 (4H, m), 7.73 (1H, s), 7.84 (1H, s), 8.04 (1H, d), 8.24 (3H, m), 8.56 (1H, m), 8.79 (1H, d), 9.28 (1H, s), 10.24 (1H, s), 13.40 (1H, br s).
Reaction SMILES: N(S([O-])(=O)=O)(S([O-])(=O)=[O:4])[O].[K+].[K+].[CH3:13][C:14]1([CH3:25])[CH2:22][C:21]2[C:16](=[C:17]([CH3:24])[CH:18]=[CH:19][C:20]=2[CH3:23])[NH:15]1>P([O-])([O-])([O-])=O.CO>[CH3:13][C:14]1([CH3:25])[CH2:22][C:21]2[C:16]([C:17]([CH3:24])=[CH:18][C:19](=[O:4])[C:20]=2[CH3:23])=[N:15]1
Reactant: Cc1ccc(C)c2c1CC(C)(C)N2
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1=CC(=O)C(C)=C2CC(C)(C)N=C12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.7 %

Procedure:
To a solution of 65% potassium nitrosodisulfonate (10.4 g, 25.2 mmol) in pH 6.86 phosphate buffer (320 ml) was added a solution of 2,3-dihydro-2,2,4,7-tetramethyl-1H-indole (2.21 g, 12.6 mmol) in methanol (50 ml) and stirred at room temperature for 1.5 hours. The reaction mixture was extracted three times with toluene. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to a column chromatography on a silica gel (hexane:ethyl acetate=5:1) and recrystallized from ethyl acetate-hexane to obtain 1.71 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH:11][C:12](=[O:31])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]34[CH2:30][CH:25]5[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]5)[CH2:22]3)[CH2:28]4)=[CH:17][CH:16]=2)[CH:5]=1.[OH-].[K+].Cl>O1CCOCC1.O>[C:21]12([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:12]([NH:11][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=4[OH:10])[C:3]([OH:32])=[O:2])=[O:31])=[CH:16][CH:17]=3)[CH2:28][CH:27]3[CH2:29][CH:23]([CH2:24][CH:25]([CH2:26]3)[CH2:30]1)[CH2:22]2
Reactant: COC(=O)c1ccc(O)c(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)O)ccc1O
Yield: 74.8 %

Procedure:
3-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester (151.8 mg, 0.35 mmol) in 1,4-dioxane/H2O (10 ml) was treated with KOH (290.7 mg, 5.18 mmol) at 60° C. for 3 h. The reaction mixture was then acidified with 10% HCl to PH 2, and then partitioned between ethyl acetate and brine. The organic phase was washed with water, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CH2:MeOH 4:1) to give 3-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid as a white solid (110.4 mg, 75.10% yield).
Reaction SMILES: C[C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3]CC(O)=O.[O:29]=[CH:30][C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[N+]([O-])([O-])=O.[NH4+].P([O-])(O)(O)=O.[K+].P([O-])([O-])(O)=O.[K+].[K+].O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Mg+2]>O>[OH:27][C@@H:13]1[C@@:12]2([CH3:28])[C@@H:11]([CH2:10][CH2:9][C@@H:8]2[CH:2]([CH:30]=[O:29])[CH3:3])[C@H:16]2[C@@H:15]([C@:20]3([CH3:26])[C:19]([CH2:18][CH2:17]2)=[CH:24][C:23](=[O:25])[CH2:22][CH2:21]3)[CH2:14]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CC(C=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
Pseudomonas putida D4014-A357 (FERM BP-206) was cultivated in the followingmanner. A medium was prepared by adding 50 ml of tap water to 0.2 g of deoxycholic acid, 0.1 g of glucose, 0.2 g of ammonium nitrate, 0.1 g of potassium dihydrogen phosphate, 0.6 g of dipotassium hydrogen phosphate, 0.02 g of magnesium sulfate heptahydrate and 0.02 g of yeast extract, adjusting the solution to pH 8.4 with 1N sodium hydroxide and further adding water to make the volume 100 ml. This medium was placed in a 500 mlSakaguchi flask and steam-sterilized at 120° C. for 15 minutes. Separately and in advance, the above microbe was grown in the same medium as above on a test tube shaker for one day and a 10 ml portion of the seedculture was added to the above 500 ml Sakaguchi flask, followed by shake culture at 30° C. for 2 days. The precipitate which had formed during the cultivation and the cells were collected by centrifugation and washed with water, and 50 ml of methanol was added thereto to dissolve theprecipitate to a satisfactory extent. Recentrifugation gave a supernatant methanol solution. The methanol was distilled off with a rotary evaporatorto give 65 mg of 12α-hydroxypregna-4-en-3-one-20-carbaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Brc1ccc(OCc2ccccc2)cc1
Reaction time: 24 h

Procedure:
4-Bromophenol (3.9 g, 22.41 mmol), benzyl bromide (4.6 g, 26.9 mmol), and cesium carbonate (89.6 mmol) were combined in DMSO (30 mL) under nitrogen at room temperature. The reaction was stirred for 24 h, filtered to remove the solids, and then partitioned between ethyl acetate and water. The organic layer was washed with water, 1 N HCl, and brine; dried over magnesium sulfate; and, concentrated to give a semi-solid. The product was crystallized from hexanes to give 1-bromo-4-benzyloxy-benzene as an off white powder (4.3 g, 75%). MS found: (M+H)+=263, 265.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([OH:15])[CH:14]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]>CC(C)=O>[CH3:16][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=2)=[CH:14][C:13]=1[O:15][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]
Reactant: Cc1ccc(Nc2nccc(N)n2)cc1O
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cc(Nc2nccc(N)n2)ccc1C
Yield: 28 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 5-(4-aminopyrimidin-2-ylamino)-2-methylphenol (52 mg, 0.24 mmol) and Cs2CO3 (78 mg, 0.24 mmol) in acetone (3.0 mL) was treated with 4-bromo-2-methyl-2-butene (28 μL, 0.24 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 28% yield (19 mg).