Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6].[C:13]([O-:16])(O)=[O:14].[Na+].[CH2:18]1[CH2:22]OC[CH2:19]1>>[F:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][C:13]([O:16][CH2:22][CH:18]=[CH2:19])=[O:14]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(F)c(N)c1
Reactant: O=C([O-])O
Agent: [Na+]
Product: C=CCOC(=O)Nc1cc(C(=O)OC)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of methyl 3-amino-4-fluorobenzoate (109 g, 644 mmol) in THF (2000 mL), saturated NaHCO3 (68 g, 805 mmol) was added. Then 2-propen-1-yl chloridocarbonate (93 g, 773 mmol) was added dropwise at 0° C. The mixture was stirred at rt for 2 h. The solution was extracted with EtOAc (500 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product (160 g, 98%), which was used in the next step directly. 1H NMR (400 MHz, CDCl3) δ ppm 8.72-8.81 (m, 1H), 7.71-7.79 (m, 1H), 7.09-7.16 (m, 1H), 6.87-6.94 (br, 1H), 5.91-6.03 (m, 1H), 5.41 (d, J=17.1 Hz, 1H), 5.28 (d, J=10.5, 1H), 4.70 (d, J=10.5 Hz, 1H), 4.70 (d, J=5.5 Hz, 2H), 3.90 (s, 3H).
Reaction SMILES: F[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:5](=[O:14])[NH:6]2.C(N(C(C)C)CC)(C)C.C[Si]([N:36]=[N+:37]=[N-:38])(C)C.Cl>C1COCC1.C(O)C>[N:36]([C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:5](=[O:14])[NH:6]2)=[N+:37]=[N-:38]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(F)c21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(N=[N+]=[N-])c21

Procedure:
(Z)-1,3-Dihydro-4-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (6.60 g, 21.8 mmol)(from Example 13) was suspended in 330 mL of THF and 165 mL of ethanol. To this mixture was added diisopropylethylamine (56.9 ml, 326 mmol) and trimethylsilyl azide (28.6 mL, 218 mmol)(Aldrich). The reaction mixture was heated at reflux overnight, and then poured into 2 L mixture of ice and 1N HCl solution. The solid precipitate was filtered, washed with water and dried at 50° C. under high vacuum to give (Z)-4-azido-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one as a dark red solid. (Yield 6.44 g, 90%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18](OS(C(F)(F)F)(=O)=O)=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:30]([O-:33])(=[S:32])[CH3:31].[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:16]=[CH:17][C:18]([S:32][C:30](=[O:33])[CH3:31])=[CH:19][CH:20]=2)[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)C1
Reactant: CC([O-])=S
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)Sc1ccc(C2CN(CCC(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.2 %

Procedure:
To a degassed solution of 3-[2-(4-trifluoromethanesulfonyloxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (2.55 g; 5.80 mmol) in toluene (50 mL) was added Pd2dba3 (0.27 g; 0.29 mmol) and (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]-ethyl]-2-(dicyclohexylphosphino)ferrocene (0.32 g; 0.58 mmol), followed, after 5 min. by, potassium thioacetate (1.33 g; 11.6 mmol). The resulting mixture was heated under reflux overnight. After cooling to RT the mixture was diluted with CH2Cl2, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/acetone 95:5) to afford 3-[2-(4-Acetylsulfanyl-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (1.70 g)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[F:23])[CH:8]=[C:9]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)[CH:10]=1)=[O:4].O[Li].O>C1COCC1.O>[F:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[C:7]1[CH:8]=[C:9]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1
Reactant: COC(=O)c1cc(-c2cncs2)cc(-c2ccc(C)cc2F)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3cncs3)c2)c(F)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of 2′-fluoro-4′-methyl-5-thiazol-5-yl-biphenyl-3-carboxylic acid methyl ester (0.327 g, 1 mmol) in THF (10 mL) was added a solution of LiOH—H2O (1.2 mmol) in H2O (15 mL) at 0° C. The reaction was allowed to warm to room temperature and THF was removed under reduced pressure. The aqueous solution was acidified to pH=2, and the solid was collected by filtration and dried to yield 2′-Fluoro-4′-methyl-5-thiazol-5-yl-biphenyl-3-carboxylic acid as awhite solid (75%), MS (M+H)=314.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.FC(F)(F)S(O[C:26]1[C:34]([Si](C)(C)C)=[CH:33][C:29]2[O:30][CH2:31][O:32][C:28]=2[CH:27]=1)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[O:17][CH:2]3[CH:3]=[CH:4][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=4[N:1]3[C:26]3[CH:27]=[C:28]4[O:32][CH2:31][O:30][C:29]4=[CH:33][C:34]2=3)=[CH:14][CH:13]=1
Reactant: c1ccc2ncccc2c1
Reactant: C[Si](C)(C)c1cc2c(cc1OS(=O)(=O)C(F)(F)F)OCO2
Reactant: O=Cc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc(C2OC3C=Cc4ccccc4N3c3cc4c(cc32)OCO4)cc1
Yield: 88 %

Procedure:
Following the general procedure, treatment of quinoline (0.064 g, 59 μL, 0.50 mmol) and 4-chlorobenzaldehyde (0.105 g, 0.75 mmol) with 6-(trimethylsilyl)benzo[d][1,3]dioxol-5-yl trifluoromethanesulfonate (0.205 g, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=70/30) of the crude reaction mixture afforded 8-(4-chlorophenyl)-6aH,8H [1,3]dioxolo[4″,5″:4′,5′]benzo[1′,2′:4,5][1,3]oxazino[3,2-a]quinoline as inseparable mixture of diastereomers as a white solid (0.171 g, 88% yield, dr determined by 1H NMR analysis of crude reaction mixture is >20:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([CH:25](O)[CH3:26])[CH:22]=[CH:23][CH:24]=3)[N:15]=2)=[CH:10][C:9]=1[C:28]([F:31])([F:30])[F:29].[NH2:32][C@@H:33]([CH3:41])[C:34]([O:36]C(C)(C)C)=[O:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=3)[CH2:25][CH2:26][NH:32][C@@H:33]([CH3:41])[C:34]([OH:36])=[O:35])[N:15]=2)=[CH:10][C:9]=1[C:28]([F:31])([F:30])[F:29]
Reactant: Cc1ccccc1-c1ccc(-c2nc(-c3cccc(C(C)O)c3)no2)cc1C(F)(F)F
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Product: Cc1ccccc1-c1ccc(-c2nc(-c3cccc(CCN[C@@H](C)C(=O)O)c3)no2)cc1C(F)(F)F

Procedure:
The title compound was prepared following the protocol used for Example 91, Steps 2 and 3, but starting from (3-(5-(2′-methyl-2-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol (84 mg, 0.2 mmol) and (S)-tert-butyl 2-aminopropanoate (87 mg, 0.6 mmol). It was isolated as a white solid (133 mg, 96%). 1H NMR: (DMSO-d6, 400 MHz) δ 8.57 (s, 1H), 8.53 (d, J=8.1 Hz, 1H), 8.07-8.03 (m, 2H), 7.69 (d, J=8.0 Hz, 1H), 7.65-7.53 (m, 2H), 7.44-7.37 (m, 2H), 7.33 (td, J=4.0, 2.1 Hz, 1H), 7.20 (d, J=7.6 Hz, 1H), 3.31 (q, J=7.2 Hz, 2H), 3.18-3.02 (m, 3H), 2.06 (s, 3H), 1.33 (d, J=7.0 Hz, 3H). LC/MS (Method B): 496 (M+H)+. HPLC (Method G) Rt 3.24 min (Purity: 99.1%).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8][Br:9])=[CH:5][CH:4]=1)#[N:2].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Br-:9].[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8][N+:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: c1ccncc1
Solvent: CC#N
Product: N#Cc1ccc(C(=O)C[n+]2ccccc2)cc1
Product: [Br-]
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 4-cyanophenacyl bromide (10) (5.02 g, 22.2 mmol) in anhydrous acetonitrile (300 mL) was added pyridine (3.6 mL, 45.3 mmol) at room temperature. The mixture was stirred for 30 minutes. The precipitate was filtrated, washed with acetonitrile (20 mL) and dried under vacuum to give 1-(2-(4-cyano-phenyl)-2-oxo-ethyl)-pyridinium bromide (11) as a white powder (100%). 1H NMR (DMSO-d6) δ 6.56 (s, 2H), 8.21 (m, 6H), 8.76 (t, J=7.8, 1H), 9.03 (d, J=6.6, 2H).
Reaction SMILES: B.O1[CH2:6][CH2:5][CH2:4]C1.[N:7]1[CH:12]=[CH:11]C=[CH:9][CH:8]=1.B.B.[CH3:15]SC.S(C)C.[B]>N1C=CC=CC=1.C1COCC1>[CH3:11][CH2:12][N:7]([CH:8]([CH3:9])[CH3:15])[CH:5]([CH3:6])[CH3:4]
Reactant: C1CCOC1
Reactant: c1ccncc1
Reactant: CSC
Agent: B
Agent: [B]
Product: CCN(C(C)C)C(C)C

Procedure:
As the phosphorous atom of the H-phosphinate intermediate does not present a pair of free electrons and is not a good donor for the introduction of the BH3 group, the boronation procedure requires an in situ intermediate activation of the H-phosphinate with a silylation agent to obtain a disilyl-phosphonite. The H-phosphinates 5 and 10 are activated in situ in anhydrous THF with N,O-bis(trimethylsilyl)acetamide (BSA) for 1 hr. in their corresponding disilyl-phosphonite intermediates. Various boron complexes have been tested in different solvents to optimise the boronation conditions. A rapid and effective boronation was finally obtained with the complex borane-N,N-diisopropylethylamine (BH3:DIPEA). The complexes borane-tetrahydrofuran (BH3:THF), borane-pyridine (BH3:Pyridine), and borane-dimethylsulfide (BH3:Me2S) require significant reduction times and do not improve the yield. In addition, in order to reduce the formation of diboranated products, the quantity of boron complexes was reduced to a maximum of 2 equivalents to obtain the best compromise between consumption of initial material and the appearance of by-products. In situ boronation of the disilyl phosphonites of 5 and 10 with 2 equivalents of BH3:DIPEA results in the formation of -boranophosphonate intermediates. Without isolation, the intermediates obtained were treated with 30% concentrated ammonium hydroxide in methanol (1:1, v/v) to cleave the trimethylsilyl groups thus making it possible to obtain α-boranophosphonates 6a and 6b. The presence of the P—B bond was confirmed by 31P NMR showing a typical peak at 83 ppm and 98 ppm respectively. α-boranophosphonates 6a and 6b are purified by reverse-phase chromatography with a yield of 28% and 32% respectively.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:30])[CH:3]=1.[H-].[Na+].[CH3:33]I>CN(C=O)C>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:33])[S:24]([CH3:27])(=[O:26])=[O:25])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:30])[CH:3]=1
Reactant: CI
Reactant: COc1cc2c(Oc3ccc(Br)cc3F)ncnc2cc1OCCCNS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(Br)cc3F)ncnc2cc1OCCCN(C)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
4-(4-Bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methylsulphonylamino)propoxy)quinazoline (1.0 g, 2 mmol) was taken up in DMF (10 ml), treated with sodium hydride (60% dispersion in mineral oil, 0.11 g, 2.7 mmol) and stirred, under nitrogen for 30 minutes. Methyl iodide (0.16 ml, 2.6 mmol) was added and the mixture stirred for 18 hours. The solvent was removed by evaporation and the residue taken up in water and extracted with dichloromethane (3×30 ml). The organic solution was then washed with water, brine, dried (MgSO4) and evaporated to dryness. The crude product was purified by silica column chromatography eluting with methanol (2.5 to 5%) in dichloromethane to give 4-(4-bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methyl N-methylsulphonylamino) propoxy)quinazoline (0.86 g, 83%).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[ClH:17]>O1CCOCC1>[ClH:17].[ClH:17].[CH:1]1([N:4]2[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C1CN(C2CC2)CCN1
Temperature: 45 °C

Procedure:
A solution of tert-butyl 4-cyclopropylpiperazine-1-carboxylate (92 g) in 1,4-dioxane (200 mL) was treated with HCl (4 M in 1,4-dioxane, 500 mL) over 10 min while maintaining the temperature below 40° C. After the addition was complete, the mixture was heated at 45° C. for 9 h and then was cooled to room temperature. The thick suspension was diluted with hexanes (400 mL) and was cooled to 10° C. The resulting solid was collected by filtration, washed with hexanes, and dried to yield the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:60]1[CH:65]=[CH:64][CH:63]=[C:62]([CH2:66][NH2:67])[CH:61]=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:67][CH2:66][C:62]4[CH:61]=[N:60][CH:65]=[CH:64][CH:63]=4)=[O:23])=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Benzoic acid 29 (150 mg, 0.34 mmol) was dissolved in anhydrous DMF (5 mL), DIEA (0.12 mL, 0.69 mmol) and HBTU (171 mg, 0.45 mmol) were successively added and the reaction mixture was stirred at 20° C. for 10 min. 3-Pyridinylmethanamine (0.14 mL, 1.4 mmol) was subsequently added and the reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was diluted with EtOAc (150 mL), washed with H2O (3×50 mL), washed with brine (50 mL) and dried. The solvent evaporated and the residue was purified by column chromatography, eluting with a gradient (0-10%) MeOH/EtOAc, to afford benzamide 30 (170 mg, 94%) as a white solid: mp (EtOAc) 225-226° C.; spectroscopically identical to the sample prepare above.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[N:13][N:12]=2)=[CH:8][CH:7]=1.C[Si]([C:27]#[N:28])(C)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl.O>[C:29]([N:13]1[N:12]=[C:11]([NH:10][C:9]2[CH:8]=[CH:7][C:6]([Cl:5])=[CH:22][CH:21]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]1[C:27]#[N:28])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Clc1ccc(Nc2nncc3ccccc23)cc1
Reactant: C[Si](C)(C)C#N
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: N#CC1c2ccccc2C(Nc2ccc(Cl)cc2)=NN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under N2 atmosphere, first 164 mg (1.2 mmol) anhydrous aluminium chloride is added to 12.6 g (49.3 mmol) 1-(4-chloroanilino)phthalazine in 90 ml dichloromethane, followed by 12.3 ml (98.6 mmol) trimethylsilyl cyanide. Finally, 11.5 ml (98.6 mmol) benzoyl chloride is added under ice cooling and stirred for 3 h at RT. The suspension is poured onto 0.6 ml water, filtered off, washed with water, and dried. Mixing in 150 ml boiling ethanol yields pure title compound: m.p.: 201-202° C.; Anal. calc.(C22H15N4ClO) C, 68.31%; H, 3.91%; N, 14.48%, Cl, 9.16%; found C, 68.03%; H, 3.89%; N, 14.22%; Cl, 9.42%.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]=[C:37]=[O:38])=[CH:31][CH:30]=1>CN(C=O)C.Cl>[ClH:28].[NH2:3][C:4]([CH:15]1[CH2:16][CH2:17][N:18]([C:37](=[O:38])[NH:36][CH2:35][C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)[CH2:19][CH2:20]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6]
Reactant: NC(CCCCB(O)O)(C(=O)O)C1CCNCC1
Reactant: O=C=NCc1ccc(Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(CCCCB(O)O)(C(=O)O)C1CCN(C(=O)NCc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
A stirred solution of crude 2-amino-6-borono-2-(piperidin-4-yl)hexanoic acid dihydrochloride (Example 26-A, Step 1, 0.240 g, 0.594 mmol) in dry DMF (12 mL) under nitrogen was treated with triethylamine (0.662 mL, 4.75 mmol) to give a white slurry. 1-chloro-4-(isocyanatomethyl)benzene (0.177 mL, 1.34 mmol) was added dropwise, and the resulting opaque mixture was stirred at room temperature for 1 h. The mixture was diluted with 1 N HCl (15 mL) and washed with ethyl acetate (2×20 mL), and the aqueous layer was concentrated under reduced pressure to give the crude product which was purified by reverse phase HPLC [Phenomenex Luna 250×30.00 mm, 10 micron column. 40 mL/min flow rate. Gradient: solvent A is 0.07% TFA in acetonitrile; solvent B is 0.10% TFA in water; 5% to 50% A over 24 min, then 50% to 100% A over 1 min]. Product fractions were pooled and concentrated, and the residue was taken up in 0.5N HCl (5 mL)/acetonitrile (8 mL) and concentrated. The residue was once again treated with 0.5N HCl (5 mL)/acetonitrile (8 mL) and concentrated and dried under high vacuum overnight to give 2-amino-6-borono-2-{1-[(4-chlorobenzyl)carbamoyl]-piperidin-4-yl}hexanoic acid hydrochloride (92 mg, 34%) as an off-white solid. 1H NMR (D2O, 400 MHz) δ 7.26 (m, 2H), 7.15 (m, 2H), 4.19 (s, 2H), 3.95 (bt, J=14.6 Hz, 2H), 2.75 (bt, J=12.8 Hz, 2H), 2.06 (bt, J=12.4 Hz, 1H), 1.81 (m, 3H), 1.53 (bd, J=12.8 Hz, 1H), 1.32 (m, 4H), 1.11 (m, 2H), 0.69 (t, J=7.6 Hz, 2H). ESI+ MS found for C19H29BClN3O5 m/z 408.4 (M−18+H); ESI− MS m/z 424.4 (M−H), 406.4 (M−18−H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]12([OH:16])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]([O:16][C:6]12[CH2:13][CH:12]3[CH2:11][CH:10]([CH2:9][CH:8]([CH2:14]3)[CH2:7]1)[CH2:15]2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: OC12CC3CC(CC(C3)C1)C2
Solvent: ClC(Cl)Cl
Product: O=C(CCl)OC12CC3CC(CC(C3)C1)C2

Procedure:
There was added slowly at 10° C. and under nitrogen 24 ml of chloracetyl chloride to 30.5 g (0.2 mole) of 1-adamantanol and 12 g of magnesia in suspension in 400 ml of chloroform; it was then brought under reflux for some hours. It was cooled, the inorganic material was filtered off and the solvent evaporated. The crude product was crystallized in hexane. 90% of the product melting 79° C. (capillary) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)([CH:13]=O)[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CN.CO.[C:28]([BH3-])#[N:29].[Na+]>CO>[C:1]([O:5][C:6](=[O:23])[N:7]([C:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)([CH2:13][NH:29][CH3:28])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: C=CCC(C=O)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Agent: CN
Agent: [Na+]
Solvent: CO
Product: C=CCC(CNC)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 68 %

Procedure:
tert-Butyl[1-(3,4-dichlorophenyl)-1-formyl-3-butenyl]methylcarbamate (35 g) was dissolved in methanol (350 mL), and 40% methylamine-methanol solution (44 mL) was added thereto, followed by refluxing for 15 hours. The reaction mixture was cooled to room temperature, and sodium cyanoborohydride (12.5 g) was added thereto, followed by refluxing for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (sequentially through use of n-hexane:ethyl acetate=2:1 and chloroform:methanol=10:1 to 5:1), to thereby give the title compound (24.8 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:13]O)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].S(Cl)([Cl:17])=O>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:3]([CH2:13][Cl:17])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cnc(CO)c(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1cnc(CCl)c(Cl)c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 193.3 %

Procedure:
To a solution of ethyl 5-chloro-6-(hydroxymethyl)nicotinate (990 mg, 4.59 mmol, Step-2) in DCM (20 mL) is added thionyl chloride (0.80 mL, 9.2 mmol) at 0° C. After stirring at rt for 2 hours, the solvent is removed in vacuo to give 1.20 g (97% yield) of the title compound as brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:13]Br>C(O)(=O)C>[Br:13][CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:12]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1cccc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of 1-(3-nitrophenyl)ethanone (50 g, 303.03 mmol, 1.00 equiv) in acetic acid (300 mL), Br2 (53.5 g, 331.6 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 60° C. in an oil bath. The reaction was then quenched by the addition of ice and the solids were collected by filtration. The crude product was re-crystallized from ethyl acetate/petroleum ether in the ratio of 1:10. This resulted in 25 g (34%) of 2-bromo-1-(3-nitrophenyl)ethanone as a white solid.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[H][H].[C]=O.O.[CH2:9]([OH:12])[CH2:10][CH3:11]>>[CH:9](=[O:12])[CH2:10][CH3:11].[C:9]([O:3][CH2:1][CH3:2])(=[O:12])[CH2:10][CH3:11]
Reactant: CCO
Reactant: [H][H]
Reactant: CCCO
Agent: [C]=O
Solvent: O
Product: CCC=O
Product: CCOC(=O)CC
Temperature: 190 °C
Reaction time: 4 h

Procedure:
Absolute ethanol (78.43 g.) and cobaltous trifluoroacetate tetrahydrate (4.30 g.) were charged to a 300 ml. autoclave system as described in Examples 3-7. The autoclave was pressurized to 3000 psig with a 1:1 mole ratio mixture of hydrogen and carbon monoxide at room temperature and then heated to 190° C. At 190° C. the pressure was brought to 5000 psigg with the same gas mixture and the reaction was carried out under these conditions for four hours. After cooling to room temperature the mixture was vented and the liquid product mixture removed from the autoclave. A total weight of 86.79 g. of product was obtained or a yield of 82.49 g. of volatiles. The volatile product mixture was analyzed via gas chromatography using the procedure described in Examples 3-7. The run had an ethanol conversion of 14% and produced water (6.1 g.), propionaldehyde (0.7 g.), n-propanol (3.7 g.), ethyl propionate (0.1 g.) and a total weight of unknown compounds (3.6 g.).