Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([NH:8][CH2:9][P:10](=[O:17])([O:14]CC)[O:11]CC)=[O:7])=[O:5])[CH3:2].C[Si](Br)(C)C.C(O)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]([NH:8][CH2:9][P:10](=[O:11])([OH:17])[OH:14])=[O:7])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=O)NCP(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCP(=O)(O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.6 %

Procedure:
Diethyl N-(ethoxycarbonylcarbonyl)aminomethylphosphonate (15.0 g prepared as described in Example 1) in dry dichloromethane (90 ml) was placed in a flask which was sealed with a rubber septum. Trimethylsilyl bromide (28 ml); ca. 3.8 molar proportions was added by syringe through the septum and the mixture stirred for four hours at room temperature. The solution was then evaporated under reduced pressure to give a yellow oil. This was taken up in dry dichloromethane (ca. 100 ml) and treated with ethanol (20 ml) to decompose the intermediate trimethylsilyl ester. The solution was then evaporated under reduced pressure to leave a yellowish semi-solid residue. Trituration of this with ethanol (ca. 8 ml) gave N-(ethoxycarbonylcarbonyl)aminomethylphosphonic acid as a white solid (6.82 g). A sample of acid prepared in this way (40 g) was taken up in ethanol (1500 ml) to give a slightly cloudy solution. To this isopropylamine (10.8 g, one molar proportion) was added dropwise with stirring. When addition was complete, the mixture was stirred for 2 hours and then evaporated under reduced pressure. The remaining viscous brown oil was taken up in warm ethanol (50 ml) and the solution diluted with ether until slightly cloudy. On standing, a white solid separated. This was collected and washed with ethanol (ca. 50 ml) and then ether, giving Compound no. 6 Table 1 (48.7 g). A sample recrystallised from ethanol (50 ml) plus water (3 ml) had a melting point of 158°-160°.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:19]([O:21]C)=O)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al](CC)(CC)[CH2:24][CH3:25].CNCCNC>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:19](=[O:21])[CH2:24][CH3:25])=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[Al](CC)CC
Reactant: COC(=O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: CNCCNC
Solvent: Cc1ccccc1
Product: CCC(=O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure O, methyl 5,6-diphenyl-pyrazine-2-carboxylate (Compound 93) (92 mg, 0.32 mmol), Et3Al (0.9 ml, 1M in hexane), DMEDA (38 mg, 0.35 mmol) in toluene was reacted to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].[C:22](Cl)(=[O:24])[CH3:23]>O1CCCC1>[C:22]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: Nc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-amino-7-chloro-3-phenyl-2(1H)-quinolone (Example 2) (0.3 g) in tetrahydrofuran (30 ml) was treated with sodium hydride (0.2 g, 80% disp. in oil). After 1 h, acetyl chloride (0.7 ml) was added and the reaction mixture was stirred for 2 h at room temperature then heated under reflux for 14 h. The reaction was partitioned between water and ethyl acetate. The organic phase was dried (MgSO4) and the solvent was removed in vacuo. The residue was suspended in 1N NaOH, and placed in an ultrasound bath for 5 mins. The aqueous phase was extracted with diethyl ether, acidified to pill and the precipitate produced was collected by filtration to give the title compound (0.080 g); mp 275°-277° C. (DMF-water). Found: C, 58.39; H, 4.83; N, 8.02. C17H13ClN2O2.2H2O requires C, 58.54; H, 4.91; N, 8.03%; δ (360 MHz, DMSO-d6) 1.88 (3H, s, CH3CO), 7.22-7.58 (8H, m, aromatics), 9.69 (1H, br s, NH), 12.06 (1H, br s, NH); m/z (EI) 312 (M+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C([C@@H:38]1COC(=O)[N:39]1C([C@@H](C(C)C)CS(N1CCN(C2N=CC(C3C=CC(C#N)=CC=3)=CN=2)CC1)(=O)=O)=O)C1C=CC=CC=1>>[C:38]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:28]([CH3:29])[CH3:30])[C:25]([OH:27])=[O:26])(=[O:21])=[O:22])[CH2:16][CH2:15]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:39]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C#N)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C#N)cc3)cn2)CC1)C(=O)O
Yield: 14 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-flurophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid, from 4-(2-{4-[2-(R)-(4-(R)-benzyl-2-oxooxazolidine-3-carbonyl)-3-methylbutane-1-sulfonyl]piperazin-1-yl}pyrimidin-5-yl)benzonitrile (0.70 g), to give the title compound as a white solid (0.70 g, 14%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:11]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[O:28])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(NCCCCCCO)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=CCCCCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
0.32 ml (4.40 mmol) of dimethyl sulfoxide is added dropwise under nitrogen to a solution of 0.19 ml (2.20 mmol) of oxalyl chloride in 10 ml of methylene chloride which is being stirred at -50°. The mixture is stirred for 15 minutes, and then 0.5 g (2 mmol) of 6-(N-benzyloxycarbonylamino)hexan-1-ol is added. Stirring is continued at -50° for 25 minutes, 1.78 ml (10 mmol) of N-ethyl-N,N-diisopropylamine are added dropwise and the mixture is poured into 10 ml of ice-water. The organic phase is separated off and the aqueous phase is extracted with 10 ml of methylene chloride. The organic phases are combined, washed twice with 5 ml of N-hydrochloric acid each time and once with 10 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness by evaporation. The resulting oil is purified by chromatography on silica gel with hexane/ethyl acetate (1:1) as eluant. 6-(N-benzyloxycarbonylamino)hexanal is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([OH:48])[CH:36]=[CH:37][C:38]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>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.CCOC(C)=O.CCCCCCC>[OH:48][C:35]1[CH:36]=[CH:37][C:38]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)(=[O:14])=[O:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[C:33]([O:32][CH3:31])[CH:34]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: COc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(O)cc4OC)nccc3c2)cc1
Temperature: 80 °C
Yield: 63.9 %

Procedure:
A vial was charged with 1-chloro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (INTERMEDIATE ZZZZ, 122 mg, 0.277 mmol), 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (138 mg, 0.553 mmol), potassium carbonate (191 mg, 1.384 mmol), and Pd(PPh3)4 (32.0 mg, 0.028 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (1038 μl) and water (346 μl) were added. The vial was sealed and heated to 80° C. for 2 h in a Biotage Initiator microwave reactor. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (25-g Interchim column, 35-85% EtOAc/Heptane, then with 85-100% EtOAc/Heptane) to give 1-(4-hydroxy-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (93.6 mg, 0.177 mmol, 64.0% yield) as an off-white solid. m/z (ESI) 529.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:18]>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][Br:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(OCc2ccccc2)cc1
Solvent: CCOCC
Product: BrCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of (4-(benzyloxy)phenyl)methanol (21.4 g, 100 mmol) in diethyl ether (250 mL) at 0° C. was added phosphorous tribromide (10.8 g, 40 mmol) and stirred at 0° C. for minutes and at room temperature for 3 hours. The reaction was quenched with water and the layers were separated. The organic layer was washed with water (2×400 mL), saturated sodium bicarbonate (2×400 mL), and brine. The ether layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford 1-(benzyloxy)-4-(bromomethyl)benzene (746).
Reaction SMILES: N[C:2]12[CH2:8][C:5]([C:9]([OH:11])=[O:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(O)(=[O:14])C.N([O-])=O.[Na+].[OH-].[K+]>O.CO.CO.C(OCC)(=O)C>[OH:14][C:2]12[CH2:8][C:5]([C:9]([OH:11])=[O:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: NC12CCC(C(=O)O)(CC1)C2
Reactant: CC(=O)O
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C(O)C12CCC(O)(CC1)C2
Temperature: 10 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A 2-L, 3-neck, round bottom flask was equipped with a mechanical stirrer, a reflux condenser, a J-KEM temperature controller, and a nitrogen inlet. The flask was charged with 4-aminobicyclo[2.2.1]heptane-1-carboxylic acid (56.3 g, 363 mmol) and 10% aqueous acetic acid (340 mL). The reaction mixture was cooled to 10° C. and was slowly treated over 45 min with sodium nitrite (75.0 g, 1.088 mol) in water (125 mL) via addition funnel. A significant amount of gas evolution was observed and the reaction mixture was stirred at 65° C. overnight. The reaction was cooled to 5° C. and slowly treated over 30 min with potassium hydroxide (183 g, 3.265 mol) in methanol (400 mL) via addition funnel. The reaction was stirred at 65° C. for 5 h when TLC analysis (10% methanol/ethyl acetate) indicated a complete reaction. The reaction mixture was concentrated to remove methanol and the remaining aqueous mixture was extracted with ethyl acetate (2×400 mL). The aqueous layer was acidified to pH 3 using concentrated hydrochloric acid (210 mL) while cooling in ice/water bath. The resulting solids (impurities) were filtered and washed with water (2×30 mL). The filtrate was extracted with ethyl acetate (10×400 mL), dried over sodium sulfate, and concentrated to dryness to provide 53 g (94%) of 4-hydroxybicyclo[2.2.1]heptane-1-carboxylic acid; MS (ESI) m/z 155.2 [M+1]−
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCN
Product: CN(C)CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Prepared from 1-chloro-2,4-dinitro-benzene and N,N-dimethyl-ethylenediamine
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([C:18]([F:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[Br:28])=[O:6].S(=O)(=O)(O)O.[CH2:38]=O.[OH-].[Na+]>>[Br:28][C:9]1[CH:10]=[C:11]([C:18]([F:27])([C:19]([F:20])([F:21])[F:22])[C:23]([F:24])([F:25])[F:26])[CH:12]=[C:13]([C:14]([F:16])([F:17])[F:15])[C:8]=1[NH:7][C:5](=[O:6])[C:4]1[CH:29]=[CH:30][CH:31]=[C:2]([NH:1][CH3:38])[C:3]=1[F:32]
Reactant: C=O
Reactant: Nc1cccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)c1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CNc1cccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)c1F
Temperature: 0 °C
Yield: 72 %

Procedure:
0.930 g (1.71 mmol) of 3-amino-N-(2-bromo-4-(heptafluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluorobenzamide was added to 5 ml of concentrated sulfuric acid, and 10 ml of a 37% aqueous formaldehyde solution was charged dropwise thereto at 40° C. The reaction mixture was poured into ice-water, adjusted to pH 10 using an aqueous sodium hydroxide solution, and extracted with the addition of ethyl acetate. The organic layer was washed with a 20% aqueous sodium hydroxide solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=8:1) to prepare 0.690 g (yield 72%) of a target compound.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:29]=[CH:28][C:9]([O:10][C:11]2[C:12]([N+:25]([O-:27])=[O:26])=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([O:22]CC)=[O:21])=[CH:14]3)=[C:8]([O:30][CH3:31])[CH:7]=1)C.O[Li].O.Cl>C1COCC1.CO.O>[C:4]([CH2:5][C:6]1[CH:29]=[CH:28][C:9]([O:10][C:11]2[C:12]([N+:25]([O-:27])=[O:26])=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([OH:22])=[O:21])=[CH:14]3)=[C:8]([O:30][CH3:31])[CH:7]=1)([OH:32])=[O:3]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc3[nH]c(C(=O)OCC)cc3c2[N+](=O)[O-])c(OC)c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(CC(=O)O)ccc1Oc1ccc2[nH]c(C(=O)O)cc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 15.3 (0.62 g, 1.40 mmol) in a mixture of THF/CH3OH/H2O (10 mL, ratio=2/2/1), was added LiOH.H2O (1.17 g, 28 mmol). The mixture was stirred at room temperature overnight. The reaction was neutralized with 1N HCl to PH=2, extracted with ethyl acetate twice, the combined organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was used without further purification. MS EST (pos.) m/z: 387.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[C:62]([O:65][CH:66]1[CH2:69][CH:68]([C:70](O)=[O:71])[CH2:67]1)(=[O:64])[CH3:63]>CN(C=O)C.O>[C:62]([O:65][CH:66]1[CH2:69][CH:68]([C:70](=[O:71])[NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[N:13][C:12]([NH:15][C:16]([C:18]4[C:19](=[O:31])[N:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:21]([CH3:24])[C:22]=4[CH3:23])=[O:17])=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:67]1)(=[O:64])[CH3:63]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: CC(=O)OC1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CC(C(=O)Nc2cc(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)nc3)ccn2)C1
Temperature: 120 °C
Yield: 30 %

Procedure:
To a solution of N-(5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (50 mg, 0.12 mmol), HOAT (19 mg, 0.24 mmol), EDCI (28 mg, 0.14 mmol) and DIPEA (0.1 mL, 0.6 mmol) in DMF (5 mL) was added a solution of 3-acetoxycyclobutanecarboxylic acid in DMF (5 mL) at 0° C. The reaction was heated at 120° C. for 5 hours, then cooled to rt, diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (DCM/EtOAc (v/v)=1/2) to give the title compound as a white solid (20 mg, 30%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].O1[CH2:38][CH2:37]OCC1.O>CCOC(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>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:15]([C:2]4[CH:3]=[N:4][CH:5]=[CH:37][CH:38]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: C1COCCO1
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: O
Solvent: CCOC(C)=O
Product: O=C1C(c2cccnc2)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Temperature: 25 °C
Yield: 64 %

Procedure:
To a microwave reaction vial, 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one (1.0 g, 2.5 mmol) obtained in Step 6,3-pyridinylboronic acid (470 mg, 3.8 mmol, 1.5 eq), Pd(PPh3)4 (180 mg, 6 mol %), Na2CO3 (800 mg, 3.0 eq), and dioxane/H2O (4:1, 5 mL) were sequentially charged. The reaction vial was placed into a microwave reactor and irradiated at 150° C. for 20 min. After cooling to room temperature, the reaction was diluted with EtOAc and dried over MgSO4. The mixture was filtered through a Celite pad while rinsing with EtOAc and then concentrated in vacuo. The residue was purified by prep HPLC (CH3CN/H2O=1:1) to afford the desired product (640 mg, 64%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:29]=[CH:28][C:18]([CH2:19][NH:20]C(=O)OC(C)(C)C)=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.C(Cl)[Cl:31].CO>Cl.O1CCOCC1>[ClH:31].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:29]=[CH:28][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Reaction time: 48 h
Yield: 98 %

Procedure:
A solution of tert-butyl {4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzyl}carbamate (1.17 g; 3.00 mmol; 1.0 eq.) in HCl solution in 1,4-dioxane (7.5 mL, 4N) was stirred at RT. After 48 h, the reaction mixture was concentrated to dryness affording a sticky solid, which was sonicated in a 1:1 mixture of DCM/MeOH. The suspension obtained was concentrated to dryness to afford the title compound as a beige solid (967 mg, 98%). HPLC (Condition A): Rt 2.08 min (purity 95.3%). MS (ESI+): 291.1, MS (ESI−): 289.2. Purification by preparative HPLC of 50 mg of this crude by afforded a pure sample (35 mg): 1H NMR (300 Mz, DMSO-d6) δ: 13.40 (brs, 1H), 9.33 (s, 1H), 8.36 (dt, J=8.2 Hz, J=1.0 Hz, 1H), 8.07 (d, J=8.5 Hz, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.62 (dt, J=8.2 Hz, 1.0 Hz, 1H), 7.47-7.42 (m, 1H), 7.29-7.24 (m, 1H), 4.02 (s, 2H). HPLC (Condition A): Rt 2.06 min (purity 97.5%). MS (ESI+): 291.1, MS (ESI−): 289.1.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][CH:3]=[CH:4][CH3:5].CO>N1C=CC=CC=1>[C:1]([NH:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:6])[CH:2]=[CH:3][CH2:4][CH3:5]
Reactant: CC=CCC(=O)Nc1ccccc1
Solvent: c1ccncc1
Solvent: CO
Product: CCC=CC(=O)Nc1ccccc1

Procedure:
52.6 g of pent-3-enanilide, 19.2 g of methanol, 4.75 g of pyridine and 2.05 g of Co2 (CO)8 were reacted analogously to Example 1 for 1.5 hours at 170° C. At a pentenanilide conversion of 58.3 mol %, C6 -dicarboxylic acid methylesteranilides were formed at a selectivity S of conversion of 37.5 mol % (11 =65.3%).
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:23](O)[CH3:24])[CH:22]=1)[CH2:10][CH2:9]2>C(Cl)Cl>[Br:2][CH:23]([C:21]1[CH:22]=[C:17]([N:11]2[CH2:10][CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([Cl:5])[CH:7]=3)[C:12]2=[O:16])[CH:18]=[N:19][CH:20]=1)[CH3:24]
Reactant: CC(O)c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(Br)c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
PBr3 (541 mg, 2 mmol) was added dropwise into a solution of 6-chloro-2-[5-(1-hydroxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one (example 13) (302 mg, 1 mmol) in 5 mL DCM at 0° C. The reaction was stirred at RT for 2 hours before it was neutralized with satd. aq. NaHCO3 solution and extracted with DCM (10 mL, 2×). The organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to afford a crude product as an oil which was used in the next step without further purification (380 mg, 100%). MS: 365.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([OH:11])=[CH:4][CH:3]=1.FC1C(O)=CC2C[O:19][B:18](O)C=2C=1>>[F:10][C:6]1[C:7]2[CH2:8][O:9][B:18]([OH:19])[C:2]=2[CH:3]=[CH:4][C:5]=1[OH:11]
Reactant: O=Cc1c(Br)ccc(O)c1F
Reactant: OB1OCc2cc(O)c(F)cc21
Product: OB1OCc2c1ccc(O)c2F

Procedure:
4-Fluorobenzo[c][1,2]oxaborole-1,5(3H)-diol was prepared from 6-bromo-2-fluoro-3-hydroxybenzaldehyde in a similar manner to that of Intermediate 2.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:12][C:13]([CH3:18])([CH3:17])[C:14](Br)=[O:15]>C(=S)=S>[Br:12][C:13]([CH3:18])([CH3:17])[C:14]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)=[O:15]
Reactant: Fc1ccccc1
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(C)(Br)C(=O)c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
A slurry of 14 g. (0.105 mole) of anhydrous aluminum chloride in 14.4 g. (0.150 mole) of fluorobenzene and 24 ml. of carbon disulfide is cooled to 15°C. To it is added 23.8 g. (0.100 mole) of α-bromoisobutyryl bromide over 10-15 minutes at 15°-20°C. The reaction is stirred for five minutes at 20°C and then quenched on ice. The product is extracted into chloroform. The chloroform layer is washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to give 2-bromo-4'-fluoro-2-methylpropiophenone.
Reaction SMILES: [I:1][C:2]1[S:6][C:5]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[CH2:17]=[CH:18][CH:19](O)[CH:20]=[CH2:21].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:18]([CH:19]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:5]1[S:6][C:2]([I:1])=[CH:3][CH:4]=1)[CH:20]=[CH2:21])=[CH2:17]
Reactant: C=CC(O)C=C
Reactant: O=C(O)CCCCCOCc1ccc(I)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(C=C)OC(=O)CCCCCOCc1ccc(I)s1
Reaction time: 12 h
Yield: 78.3 %

Procedure:
A mixture of 6-[5-iodo-(2-thienyl)]methoxyhexanoic acid (13.20 g, 37.3 mmol), 1,4-pentadien-3-ol (3.13 g, 37.3 mmol), dicyclohexylcarbodiimide (7.70 g, 37.3 mmol) and 4-dimethylaminopyridine (0.1 g) in DCM (250 mL) is stirred for 12 h under nitrogen. The solid is removed by filtration and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica, eluting with petroleum ether/diethyl ether (90:10), to give the product as a brown oil (12.27 g, 77%) NMR showed the expected signals.