Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.Cl.[F:27][C:28]1([F:33])[CH2:31][CH:30]([NH2:32])[CH2:29]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:32][CH:30]2[CH2:31][C:28]([F:33])([F:27])[CH2:29]2)=[O:11])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: NC1CC(F)(F)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)NC2CC(F)(F)C2)c1
Reaction time: 3 h

Procedure:
To the mixture of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (1.09 g, 3 mmol) and 3,3-difluorocyclobutyl amine hydrochloride (1 g, 7 mmol) in DMF (10 ml), added PyBOP (1.56 g, 3 mmol) then triethyl amine (1.8 ml, 12 mmol). Stirring was kept for 3 hours. Diluted with EtOAc, washed with 1N HCl, water and brine. Dried over anhydrous sodium sulfate. Concentrated, the residue was dissolved in DMSO and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as light yellow powder. MS calcd for (C19H20BF2N3O5S): 451.12. MS found (ESI negative): (M−H)−=450.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.79 (s, 1H), 9.15 (s, 1H), 8.48 (d, J=6.4 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.39 (d, J=2 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.09 (dd, J=8.4 Hz, 1H), 6.40 (d, J=2 Hz, 1H), 6.35 (dd, J=8.4 Hz, 1H), 5.92 (s, 2H), 4.85 (s, 2H), 4.05 (m, 1H), 3.75 (s, 2H), 2.89 (m, 2H), 2.59 (m, 2H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])([CH3:57])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:65][C:66]1[S:67][C:68]2[CH:73]=[CH:72][N:71]=[CH:70][C:69]=2[N:74]=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])([CH3:57])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:65][C:66]4[S:67][C:68]5[CH:73]=[CH:72][N:71]=[CH:70][C:69]=5[N:74]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: Sc1nc2cnccc2s1
Product: COc1ccc(COC(=O)C2=C(CSc3nc4cnccc4s3)CS[C@@H]3C(NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 78.5 %

Procedure:
Using 369 mg of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido}-3-chloromethyl-3-cephem-4-carboxylate in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 74 mg of 2-mercaptothiazolo[4,5-c]pyridine, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 331 mg of the title compound in a yield of 79%.
Reaction SMILES: COC[O:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C@@H:11]2[CH2:13][O:12]2)=[CH:7][CH:6]=1.[C:16]1([C:22]2[C:30]3[C:29]([N:31]4[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]4)=[N:28][CH:27]=[N:26][C:25]=3[S:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:12][C@@H:11]([CH2:13][NH:37][CH:34]1[CH2:35][CH2:36][N:31]([C:29]2[C:30]3[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:23][S:24][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:32][CH2:33]1)[CH2:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:15][CH:14]=1
Reactant: COCOc1ccc(OC[C@@H]2CO2)cc1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Product: Oc1ccc(OC[C@@H](O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)cc1
Yield: 58 %

Procedure:
Synthesis followed SP6 (4 h), using 250 μmol (S)-2-((4-(methoxymethoxy)phenoxy)methyl)oxirane and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-MOM intermediate upon purification by prep. TLC (2 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) with 58% yield. Product was obtained by MOM removal according to SP8 (1.5 eq. TosOH, 10 h) and purification by prep. TLC (1 mm silica gel, CH2Cl2/MeOH 90:10) with 61% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:21])[N:7]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3.C(C1CCN(N)C1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O.C[C:36]([N:38]([CH3:40])C)=[O:37]>>[C:17]([O:16][N:7]1[C:6](=[O:21])[C:5]2[CH:4]=[CH:3][C:2]([N:7]3[CH2:6][CH2:5][CH:40]([NH:38][C:36](=[O:37])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:8]3)=[C:13]3[C:14]=2[C:9](=[CH:10][CH:11]=[CH:12]3)[C:8]1=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)OC(=O)C1CCN(N)C1
Reactant: CC(C)(C)ON1C(=O)c2cccc3c(Br)ccc(c23)C1=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc3c4c(cccc24)C(=O)N(OC(C)(C)C)C3=O)C1
Temperature: 120 °C

Procedure:
A mixture of 6-bromo-2-tert-butyloxy-2,3-dihydro-1H-benzo[de]isoquinoline-1,3-dione (0.5 g, 1.4 mmol, from Example K2) and 3-Boc-aminopyrrolidine (0.8 g, 4.7 mmol) in DMA (4.0 mL) was heated at 120° C. overnight. The mixture was concentrated, and water was added to give a precipitate, which was filtered to yield 0.6 g of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12]C)[C:8](=[O:14])[CH2:7][CH2:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[C:8](=[O:14])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CCc2cc(O)c(O)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 5,6-dimethoxyindan-1-one (Compound 3a) (19 g, 0.094 mole) in 200 mL of methylene chloride was cooled at −78° C. with a dry-ice/iPrOH bath. To this solution was then added 200 mL (0.2 mole) of a 1M solution of BBr3 in CH2Cl2 dropwise. The resulting solution was stirred at −78° C. for 1 hr and then at 0° C. for 1 hr. The solution was then cooled back to −78° C. with a dry-ice/iPrOH bath and quenched with 50 mL of MeOH. The solution was evaporated on a rotary evaporator to dryness, the solid was re-dissolved in MeOH and concentrated again for two more times. The red solid, the title compound, was used in subsequent reactions without further purification. MS m/z 165 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][CH:28]=[CH:27][C:6]=1[O:7][CH2:8][CH:9]([OH:26])[CH2:10][O:11][C:12]1[C:21]2[O:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][C:17](=[O:25])[C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C([OH:33])C.C(=O)(O)[O-:35].[Na+:38]>O>[OH2:7].[C:1]([C:5]1[CH:30]=[CH:29][CH:28]=[CH:27][C:6]=1[O:7][CH2:8][CH:9]([OH:26])[CH2:10][O:11][C:12]1[C:21]2[O:20][C:19]([C:22]([O-:24])=[O:23])=[CH:18][C:17](=[O:25])[C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:2])[CH3:3].[Na+:38].[OH2:33].[OH2:35].[Na+:38].[C:1]([C:5]1[CH:30]=[CH:29][CH:28]=[CH:27][C:6]=1[O:7][CH2:8][CH:9]([OH:26])[CH2:10][O:11][C:12]1[C:21]2[O:20][C:19]([C:22]([O-:24])=[O:23])=[CH:18][C:17](=[O:25])[C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CCO
Reactant: CC(C)(C)c1ccccc1OCC(O)COc1cccc2c(=O)cc(C(=O)O)oc12
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccccc1OCC(O)COc1cccc2c(=O)cc(C(=O)[O-])oc12

Procedure:
To a hot solution of 4.328 parts of 8-(3- 2-t-butylphenoxy -2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid in 250 parts of ethanol was added a solution of 0.882 parts of sodium bicarbonate in 50 parts of water. The resulting solution was filtered and allowed to cool to give 4.0 parts of sodium 8-(3-[2-t-butylphenoxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylate sesquihydrate after collecting and drying over phosphorus pentoxide.
Reaction SMILES: Br[CH:2]([C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[NH2:17][C:18]([NH2:20])=[S:19]>CO>[NH2:20][C:18]1[S:19][C:2]([CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:17]=1
Reactant: NC(N)=S
Reactant: COC(=O)CCC(Br)C(=O)c1ccccc1
Solvent: CO
Product: COC(=O)CCc1sc(N)nc1-c1ccccc1
Yield: 90.6 %

Procedure:
A mixture of methyl 4-bromo-5-oxo-5-phenylpentanoate (15.0 g), thiourea (3.81 g) and methanol (200 ml) was refluxed for 2 hrs. The reaction solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate. The obtained solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 3-(2-amino-4-phenyl-5-thiazolyl)propionate (11.9 g, yield 90%) as pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 130–131° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6].[OH:8][CH:9]([CH3:14])[CH2:10][C:11]([O-:13])=[O:12].C[C:16]1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H:17]1[C:35]([OH:37])=[O:36].C1C([C@@H](O)[C@H](NC(C(Cl)Cl)=O)C[OH:48])=CC=C([N+]([O-])=O)C=1>>[OH:8][CH:9]([CH3:14])[CH2:10][C:11]([O-:13])=[O:12].[OH:1][CH2:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6].[C:35]([O-:37])(=[O:36])[CH:17]([CH3:16])[OH:48]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: O=C(N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1)C(Cl)Cl
Agent: CC(O)CC(=O)[O-]
Agent: O=C([O-])CCCO
Product: CC(O)C(=O)[O-]
Reaction time: 72 h

Procedure:
3-Hydroxybutyrate-4-hydroxybutyrate-lactate terpolymer was prepared according to the method of example 2 except that the collected cells was anaerobically cultured for 3 days in MR medium further containing 2 g/L of 4-hydroxybutyrate (4-HB), 1 g/L of 3-hydroxybutyrate (3-HB), 100 mg/L of ampicillin and 30 mg/L of chloramphenicol instead of MR medium further containing g/L of 4-HB, 100 mg/L of ampicillin and 30 mg/L of chloramphenicol.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH:12](=O)/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH:13](/[CH:12]1[O:1][CH:2]([CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:10][O:11]1)=[CH:14]\[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCC/C=C/C=C/C=O
Reactant: COC(=O)CCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCCCCCC/C=C/C=C/C1OCC(CCCC(=O)OC)O1

Procedure:
Methyl 5,6-dihydroxyhexanoate (0.32 g, 2.0 mmol), 2E,4E-dodecadienal and catalytic pyridinium p-toluenesulfonate (PPTS) were refluxed in 10 ml of benzene for 39 hours with a Dean-Stark trap. Molecular sieves were added after 19 hours. The reaction mixture was cooled, filtered and concentrated. Flash chromatography on silica gel with 25:1 hexane/ethyl acetate as eluent gave the product (0.10 g, 0.31 mmol), 15%.
Reaction SMILES: O.[NH2:2]N.O=C1C2C(=CC=CC=2)C(=O)N1CCN[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)[C:21]([C:32]([NH2:34])=[O:33])=[CH:20][N:19]=1.[CH2:35]([OH:37])[CH3:36]>>[NH2:2][CH2:36][CH2:35][O:37][C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)[C:21]([C:32]([NH2:34])=[O:33])=[CH:20][N:19]=1
Reactant: NN
Reactant: CCO
Reactant: Cc1cccc(Nc2nc(NCCN3C(=O)c4ccccc4C3=O)ncc2C(N)=O)c1
Solvent: O
Product: Cc1cccc(Nc2nc(OCCN)ncc2C(N)=O)c1

Procedure:
A 0.2 ml portion of hydrazine monohydrate was added to a mixture of 350 mg of 2-[2-(1,3-dioxo-2,3-dihydroisoindol-2-yl)ethyl]amino-4-(3-methylanilino)pyrimidine-5-carboxamide with 10 ml of ethanol, followed by heating under reflux for 4 hours. The reaction mixture was concentrated under a reduced pressure. A chloroform-methanol mixed solution was added to the thus obtained residue, followed by washing with water, 1 M sodium hydroxide aqueous solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure, and the resulting residue was recrystallized from ethanol to obtain 140 mg of 2-(2-aminoethoxy)-4-(3-methylanilino)pyrimidine-5-carboxamide (colorless crystals).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:10]([O:12][SiH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH3:11]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.O1CCCC1>[CH2:10]([O:12][Si:13]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[CH2:3][CH2:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH3:11]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: C1CCOC1
Product: CCO[Si](CCC(=O)OC(C)(C)C)(OCC)OCC
Yield: 1000.2 %

Procedure:
Into the 100 ml of dried tetrahydrofuran, were fed 25.8 g (20 mmol) of t-butyl acrylate and 32.8 g (20 mmol) of triethoxysilane, and the mixture was substituted by argon. To the mixture solution, 10 mg of chloroplatinic acid was added and the mixture was heated for 24 hours under reflux. After completion of the reaction, 58.5 g of the objective compound was obtained by removing solvent.
Reaction SMILES: C(O)(=O)C[C:3]([CH2:8][C:9]([OH:11])=O)([C:5]([OH:7])=O)O.OP([O-])([O-])=O.[K+].[K+].Cl.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.[CH2:31]([C:38](O)=O)[C:32](CC(O)=O)=O>O.C(O)(=O)C>[CH2:22]([N:29]1[CH:31]2[CH2:38][C:9](=[O:11])[CH2:8][CH:3]1[CH2:5][O:7][CH2:32]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)CC(=O)CC(=O)O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC2COCC(C1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of C-1 (18 g, 81 mmol) in 40 mL of water and 14 mL acetic acid was heated to 120° C. for 2 h, cooled to room temperature and diluted with 400 mL of pH 4 buffer (160 mL 0.1 M citric acid and 240 mL 0.1 M K2HPO4). After cooling to 0° C., a preformed solution of 9.54 g (66.4 mmol) benzylamine hydrochloride, 100 mL water, and 31 mL concentrated HCl was added dropwise over 10 minutes, keeping the internal temperature below 5° C. Acetonedicarboxylic acid (23.3 g, 160 mmol) was then added in four equal portions, five minutes apart. The pH of the solution was increased to 4 by adding K2HPO4, and the reaction was allowed to warm to room temperature and stir overnight. Solid citric acid was added to return the pH to 4, and the reaction was stirred at room temperature 48 h more, at which time it was cooled to 0° C. and acidified to pH 2 with HCl, and extracted twice with Et2O. The aqueous layer was again cooled to 0° C. and basified to pH 11 with NaOH, and extracted three times with CH2Cl2. The combined organic extracts were washed with 0.1 M citric acid, then with saturated NaHCO3, brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (0 to 100% EtOAc in hexanes) to provide C-2 as a yellowish solid. Data for C-2: 1H NMR (CDCl3, 500 MHz) δ 7.45-7.2 (m, 5H), 3.9 (s, 2H), 3.8 (m, 2H), 3.7 (m, 2H), 3.2 (m, 2H), 2.7 (m, 2H), 2.3 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH3:15])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCNCC1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of EXAMPLE 175B (650 mg) in dichloromethane (6 mL) was added trifluoroacetic acid (6 mL) at 0° C. The reaction mixture was stirred at 0° C. for 50 minutes and concentrated. The concentrate was dissolved in dichloromethane, washed with aqueous NaHCO3 and the organic layer was dried over Na2SO4, and concentrated.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:12][C:8]=1[C:9]([OH:11])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:12][C:8]=1[C:9]([NH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1)=[O:11])[CH:2]=[C:3]([CH3:4])[CH3:5]
Reactant: CC(C)=CCOc1ccc(OCC=C(C)C)c(C(=O)O)c1
Reactant: NCCc1ccncc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)=CCOc1ccc(OCC=C(C)C)c(C(=O)NCCc2ccncc2)c1
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
2,5-diprenyloxybenzoic acid(1.99 g) was dissolved in chloroform(38 ml) and triethylamine(1.91ml), and then diphenylphosphinic chloride(1.31 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 4-(2-aminoethyl)pyridine(0.85 g) added thereto, was stirred for 1 hour at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.41 g of the aimed compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.CC1(C)C(C)(C)[O:21][B:20](B2OC(C)(C)C(C)(C)O2)[O:19]1.C([O-])(=O)C.[K+]>[Pd].O1CCOCC1>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:3][C:2]([B:20]([OH:21])[OH:19])=[CH:7]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cn1cc(Br)nc(Nc2cccnc2)c1=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cc(B(O)O)nc(Nc2cccnc2)c1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
A 250-mL round-bottomed flask equipped with a reflux condenser was charged with 186a (800 mg, 2.86 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.18 g, 8.57 mmol), Pd (dppf) Cl2 (204 mg, 0.28 mmol), potassium acetate (560 mg, 5.71 mmol), and dioxane (60 mL). After bubbling nitrogen through the mixture for 30 minutes, it was stirred at 100° C. for 3 h under nitrogen. The mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduce pressure. The residue solid was washed with petroleum ether (2×30 mL) to afford 186b (406 mg, 58%) as a brown solid. MS-ESI: [M+H]+ 247.3.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[C:13]([C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Br[CH:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C(C)=CC=CC=1.CN(C)C(=O)C>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH:23]([CH3:24])[CH2:25][CH:26]([CH3:28])[CH3:27])[C:13]([C:17]([CH3:20])([CH3:21])[CH2:18][CH3:19])=[CH:12][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: CC(C)CC(C)Br
Reactant: CCC(C)(C)c1cc(C(=O)c2ccccc2)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(C)(C)c1cc(C(=O)c2ccccc2)c(O)cc1OC(C)CC(C)C
Reaction time: 6 h
Yield: 86.8 %

Procedure:
A mixture of 10 g (35 mmol) of 2,4-dihydroxy-5-(1,1-dimethylpropyl)benzophenone, 11 g (66 mmol) of 2-bromo-4-methylpentane and 9.7 g (70 mmol) of potassium carbonate in 50 ml of xylene and 20 ml of N,N-dimethylacetamide is heated with stirring and held at 125° C. for 6 h. The reaction mixture is cooled, then treated with 30 ml of water and extracted with ethyl acetate. The resulting solution is washed with water and then with saturated sodium chloride solution. The residue which remains after drying over MgSO4, filtering and concentrating by evaporation is distilled in a bulb tube (200° C./0. 1 mbar). 11.2 g (86.4%) of the compound are obtained as a yellow liquid.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[OH:19].C([O-])([O-])=O.[Na+].[Na+]>O=S(Cl)Cl.N1C=CC=CC=1.O>[OH:19][C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[NH:12][C:9]([C:7]1[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:11]
Reactant: Nc1cnccc1O
Reactant: O=C(O)c1ccc([N+](=O)[O-])s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1cnccc1O)c1ccc([N+](=O)[O-])s1
Temperature: 10 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A mixture of 5-nitrothiophene-2-carboxylic acid (5.000 g, 28.9 mmol) in SOCl2 (40 mL) was refluxed for 2 h. The excess SOCl2 was evaporated in vacuo and 3-amino-4-hydroxypyridine (2.65 g, 24.1 mmol) in pyridine (150 mL) was added dropwise. The reaction mixture was stirred at 10° C. overnight. Na2CO3 (1.533 g, 14.5 mmol) in water (100 mL) was added and the resultant mixture was stirred for additional 1 h. The precipitate was collected by filtration, washed with 10% Na2CO3 (120 mL), and dried in vacuo to afford N-(4-hydroxypyridin-3-yl)-5-nitrothiophene-2-carboxamide as a yellow powder (5.87 g, yield: 92%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]2)[S:5][CH:6]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C(O)C.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>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:3]=[C:4]([CH2:7][N:8]3[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]3)[S:5][CH:6]=2)=[CH:21][C:20]=1[C:28]([F:29])([F:30])[F:31]
Reactant: CCOC(=O)c1cnn(Cc2nc(Br)cs2)c1
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
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: COCCOC
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnn(Cc2nc(-c3ccc(Cl)c(C(F)(F)F)c3)cs2)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 69.4 %

Procedure:
Under a nitrogen atmosphere, to a mixed solution of the compound (300 mg, 0.95 mmol) obtained in Example 30c and 4-chloro-3-(trifluoromethyl)phenylboronic acid (260 mg, 1.1 mmol) in 1,2-dimethoxyethane/ethanol (v/v=3/1, 4 mL) were added 2N aqueous sodium carbonate solution (0.57 mL, 1.1 mmol) and tetrakistriphenylphosphinepalladium (55 mg, 0.048 mmol), and the mixture was stirred at 100° C. for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give the title compound (274 mg, 69%) as pale-yellow crystals.