Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[CH3:7].CN(C(ON1N=[N:31][C:26]2C=[CH:28][CH:29]=[N:30][C:25]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC[N:42]([CH2:45][CH3:46])[CH2:43][CH3:44]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:46][C:45]([N:42]2[C:43]3[CH2:44][CH2:28][CH2:29][N:30]([C:9](=[O:11])[CH2:8][N:5]4[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4]4)[C:25]=3[CH:26]=[N:31]2)=[CH:7][CH:6]=1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(CC)CC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(Cl)cc1

Procedure:
The regioisomer mixture obtained above (66 mg, approx 0.25 mmol total) was combined with 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid (67 mg, 0.275 mmol), HATU (114 mg, 0.3 mmol), and Et3N (52 μL, 0.38 mmol) in THF (1 mL). After 90 minutes the reaction slurry was diluted with EtOAc, washed with H2O, and concentrated. The residue was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide two regioisomers. First eluting, Compound A: 1-[1-(4-chlorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]ethanone was isolated as a white solid (1.7 mg). 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.36 (s, 0.8H), 7.59 (s, 0.2H), 7.43 (s, 4H), 5.24 (s, 0.4H), 5.13 (s, 1.6H), 3.92 (m, 0.4H), 3.85 (m, 1.6H), 2.90 (m, 1.8H), 2.77 (m, 0.2H), 2.34 (s, 2.4H), 2.32 (s, 0.6H), 2.13 (m, 1.5H), 2.05 (m, 0.5H); MS: (ES) m/z calculated for C19H17Cl2F3N5O [M+H]+ 458.1, found 458.0. Second eluting, Compound B: 1-(2-(4-chlorophenyl)-6,7-dihydro-2H-pyrazolo[4,3-b]pyridin-4(5H)-yl)-2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanone was isolated as a white solid (31.0 mg). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.56 (m, 2H), 7.36 (m, 2H), 5.16 (s, 2H), 3.84 (s, 2H), 2.93 (t, J=6.6 Hz, 2H), 2.32 (s, 3H), 2.19 (m, 2H); MS: (ES) m/z calculated for C19H17Cl2F3N5O [M+H]+ 458.1, found 458.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=1.Cl.CN(C)CCCN=C=NCC.N1(C2C=CN=CC=2)CCCC1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:17][C:13]1[N:12]=[C:11]([NH:10][C@H:8]([C:4]2[CH:3]=[C:2]([NH:1][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([CH3:18])=[N:20][CH:21]=3)[CH:7]=[CH:6][CH:5]=2)[CH3:9])[CH:16]=[N:15][CH:14]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2cccc([C@H](C)Nc3cncc(Cl)n3)c2)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.1 %

Procedure:
A mixture of N-[(1S)-1-(3-aminophenyl)ethyl]-6-chloropyrazin-2-amine (300 mg, 1.2 mmol), 6-methylnicotinic acid (182 mg, 1.32 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (277 mg, 1.45 mmol), 4-pyrrolidinopyridine (36 mg, 0.24 mmol) and triethylamine (0.34 mL, 2.4 mmol) in dichloromethane (6 mL) was stirred at room temperature for 72 hours. After this time the mixture was diluted with ethyl acetate (20 mL), washed successively with saturated aqueous sodium hydrogen carbonate (2×15 mL) and brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure to give a yellow oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give N-(3-{(1S)-1-[(6-chloropyrazin-2-yl)amino]ethyl}phenyl)-6-methylnicotinamide (380 mg, 86%) as a white solid.
Reaction SMILES: [CH3:1][OH:2].C(N(CC)CC)C.[C:10]([C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:17]([O:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:18])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:17]([O:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:2][CH3:1])=[O:26])=[CH:23][CH:22]=1)=[O:18])([CH3:13])([CH3:12])[CH3:11]
Reactant: CO
Reactant: COc1ccc(C(=O)OCc2ccc(C(=O)Cl)cc2)cc1C(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(COC(=O)c2ccc(OC)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5 ml of methanol, 460 μl of triethylamine and 50 ml of THF are introduced into a round-bottomed flask. A solution of 1.2 g (3.3 mmol) of 4-(3-tert-butyl-4-methoxybenzoyloxymethyl)benzoyl chloride dissolved in 30 ml of THF is added dropwise and the mixture is stirred at room temperature for 4 h.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:13]=[C:14](/[CH:19]=[CH:20]/[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([CH2:29][OH:30])[CH2:25][CH2:24]2)=[O:22])[CH:15]=[C:16]([F:18])[CH:17]=1>C(Cl)Cl>[F:18][C:16]1[CH:15]=[C:14](/[CH:19]=[CH:20]/[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([CH:29]=[O:30])[CH2:27][CH2:28]2)=[O:22])[CH:13]=[C:12]([F:11])[CH:17]=1
Reactant: O=C(/C=C/c1cc(F)cc(F)c1)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CC1CCN(C(=O)/C=C/c2cc(F)cc(F)c2)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A 2-L round bottom flask was charged with DCM (900 mL) and oxalylchloride (25.36 g, 0.20 mole, 1.3 eq.) and cooled to −78° C. Dimethylsulfoxide (DMSO, 31.22 g, 0.40 mole, 2.6 eq.) was added dropwise and the mixture was stirred at −78° C. for 10 min. Then, {1-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}methanol (43.2 g, 0.15 mole, 1.0 eq, dissolved in 100 mL of DCM and a few mL DMSO) was added slowly. After stirring for another 30 min at −78° C., TEA (93.14 g, 0.92 mole, 6.0 eq.) was added slowly. The suspension was then stirred at −78° C. for 30 min, then warmed to room temperature over 2 h. The mixture was diluted with 300 mL DCM and washed with 2×200 mL 2M HCl, 1×100 mL saturated NaHCO3, and then dried over MgSO4, and concentrated to afford 1-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinecarbaldehyde (35.4 g, 82%) as a brown oil. The material was used in the next step without further purification. MS (ES) m/e 280 [M+H]+. 1HNMR (CDCl3) δ(ppm): 9.72 (s, 1H), 7.56 (d, 1H), 7.04 (m, 2H), 6.90 (d, 1H), 6.82 (m, 1H), 4.40 (m, 1H), 4.00 (m, 1H), 3.36 (m, 1H), 3.22 (m, 1H), 2.56-2.64 (m, 1H), 2.02 (m, 2H), 1.67 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10][OH:11].N1C=CC=CC=1.[C:19](Cl)([Cl:21])=[O:20].Cl.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[CH:3]2[CH2:8][CH:7]1[CH2:6][CH:5]=[CH:4]2.[Cl:21][C:19]([O:11][CH2:10][CH3:9])=[O:20]
Reactant: O=C(Cl)Cl
Reactant: CC1(C)C2CC=C(CCO)C1C2
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)C2C=CCC1C2
Product: CCOC(=O)Cl
Reaction time: 1 h

Procedure:
16.6 G. (0.1 mole) of 6,6-dimethylbicyclo-[3.1.1]hept-2-ene-2-ethanol and 7.9 g. (8.1 ml., 0.1 mole) of pyridine are thoroughly mixed and added dropwise at 10° C to 125 ml. (0.2 moles) of 17.2% phosgene and benzene over a period of 20 minutes. A white precipitate of pyridine hydrochloride forms immediately. The reaction mixture is stirred in the cold for one hour and at room temperature overnight. A stream of nitrogen is passed through the mixture to remove the excess phosgene and the solution is filtered. The filtrate is evaporated to dryness in vacuo affording 23.4 g. (quantitative yield) of 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-ethyl chloroformate which infrared analysis indicates to be pure material.
Reaction SMILES: N([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[N:5]([CH3:7])[CH3:6])=O.C[N:13](C)C1C=CC=CC=1.N([O-])=O.[ClH:24]>>[NH2:13][C:10]1[CH:9]=[CH:8][C:4]([N:5]([CH3:7])[CH3:6])=[CH:3][CH:11]=1.[ClH:24]
Reactant: CN(C)c1ccccc1N=O
Reactant: CN(C)c1ccccc1
Agent: Cl
Agent: O=N[O-]
Product: CN(C)c1ccc(N)cc1

Procedure:
In step (a), nitrosodimethylaniline is prepared from dimethylaniline by treatment with nitrite (NaNO2) in aqueous acid (HCl) solution. In step (b), the nitroso compound is reduced to form p-aminodimethylaniline in aqueous acid (HCl) solution using zinc dust solution. In steps (c), (d), and (e), the p-aminodimethylaniline is oxidized in aqueous acid solution with another molecule of dimethylaniline, and simultaneously a thiosulfonic acid group is introduced; the ring is then closed using manganese dioxide or copper sulfate. More specifically, a clear neutral solution of p-aminodimethylaniline is acidified (H2SO4), and a non-reducing zinc chloride solution is added (ZnCl2 with Na2Cr2O7). Aluminium thiosulfate (Al2(S2O3)3) and sodium thiosulfate (Na2S2O3) are added. Sodium dichromate (Na2Cr2O7) is added. The mixture is heated and aerated. Dimethylaniline is added. Sodium dichromate (Na2Cr2O7) is added. The mixture is heated, and becomes dark greenish-blue in colour due to the formation of the thiosulfonic acid of Bindschedler green. Manganese dioxide or copper sulfate is added, and the mixture heated, and the dye precipitates from the concentrated zinc chloride solution.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20].Cl>C(Cl)Cl.O>[C:19]([O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Br:1])(=[O:21])[CH3:20]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OC(C)=O)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a stirred suspension of methyl 3-bromo-4-hydroxybenzoate (270 g, 1168 mmol) in DCM (1.5 L) was added pyridine (150 mL). Acetyl chloride (87 mL, 1227 mmol) was then added dropwise at room temperature and under nitrogen. The mixture was left to stir for 2 hrs at room temperature. Water (1 L) was then added followed by HCl 2N until pH 1. The organic layer was then washed with water, brine, dried over magnesium sulfate, filtered and evaporated to dryness to afford methyl 4-acetoxy-3-bromobenzoate (300 g, 94%) as a white powder. NMR Spectrum: (DMSOd6) 2.34 (s, 3H), 3.87 (s, 3H), 7.47 (d, 1H), 8.01 (dd, 1H), 8.20 (d, 1H).
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH:13]1[CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C.[CH2:29]([N:31]([CH2:35][CH3:36])[C:32](Cl)=[O:33])[CH3:30].[Cl-].[Ca+2].[Cl-]>O1CCCC1.O>[CH2:29]([N:31]([CH2:35][CH3:36])[C:32]([N:15]1[CH2:16][CH:13]([O:12][C:11]2[CH:17]=[CH:18][CH:19]=[C:9]([C:8]([F:7])([F:20])[F:21])[CH:10]=2)[CH2:14]1)=[O:33])[CH3:30]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: CCN(CC)C(=O)Cl
Agent: O=C(O)C(=O)O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(CC)C(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 15 h
Yield: 60.1 %

Procedure:
A stirred slurry of 5 g (0.0163 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate in 50 ml of tetrahydrofuran was treated with 5 ml of triethylamine and after 1 hr, 2.5 g (0.018 mole) of diethylcarbamoyl chloride was added. After stirring an additional 15 hr, the reaction was treated with 10 ml of water and saturated with calcium chloride. The tetrahydrofuran was decanted from the solid residue and concentrated in vacuo to an oil. The crude oil was chromatographed on a Water's Prep-LC using 50% ethyl acetate/toluene as the eluent. After concentration of the main fractions 3.1 g (60.1%) of pale yellow oil was obtained.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[N:5]=[N:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]3[O:34][CH2:33]3)[C:27]([O:29]C)=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]([OH:34])[CH2:33][S:1][C:2]3[N:6]([CH3:7])[N:5]=[N:4][N:3]=3)[C:27]([OH:29])=[O:28])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: Cn1nnnc1S
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nnnn3C)C(=O)O)cc2)cc1

Procedure:
Example 30 is prepared from 5-mercapto-1-methyltetrazole and 1d using the procedure described for compound 20.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][O:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C(N)(=[S:16])C.O>FC(F)(F)C(O)=O>[NH2:2][C:1](=[S:16])[CH:3]1[CH2:8][O:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(N)=S
Reactant: CCOC(=O)N1CCC(C#N)CO1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)N1CCC(C(N)=S)CO1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
A mixture of ethyl 5-cyanotetrahydro-2H-1,2-oxazine-2-carboxylate (i.e. the product of Step H) (0.63 g, 0.0034 mol) and thioacetamide (0.72 g, 0.0096 mol) in trifluoroacetic acid (about 2 mL) was stirred at 50° C. for 20 h. The reaction mixture was poured into water (10 mL) and extracted with diethyl ether (3×10 mL). The combined organic extracts were washed with water (10 mL), dried over magnesium sulfate, filtered and concentrated to provide an orange oil (about 0.76 g). The resulting oil was adsorbed onto Celite® (diatomaceous filter aid), and then purified by silica gel column chromatography (25% to 50% gradient of ethyl acetate in petroleum ether as eluant) to provide the title compound (0.19 g).
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH3:21][C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.[CH2:32]=O.[OH-].[Na+]>C(O)C>[CH3:2][S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:32][CH2:21][C:22]3[CH:31]=[N:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:19][CH:20]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Reactant: C=O
Reactant: Cc1cnc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(C(=O)C2CCN(CCc3cnc4ccccc4n3)CC2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
5.0 g (15.7 mmol) of 4-(4-methylsulfonylaminobenzoyl)piperidine hydrochloride was suspended in 5 ml of ethanol. 2.49 g of 2-methylquinoxaline and 7.0 ml of formalin were added to the suspension and the mixture was stirred at 90° C. for 1 h. After cooling, the mixture was neutralized with a 20% aqueous sodium hydroxide solution and the formed crystals were recrystallized from ethyl acetate to obtain 0.32 g (yield: 5%) of the intended compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1.[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][CH:11]1[C:10](=[O:15])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH2:12]1
Reactant: BrBr
Reactant: CCCC1(c2cccc(OC)c2)CCCCC1=O
Solvent: ClC(Cl)Cl
Product: CCCC1(c2cccc(OC)c2)CCCC(Br)C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
2-(3-Methoxy-phenyl)-2-propyl-cyclohexanone (100 mg, 0.41 mmol) was dissolved in chloroform (1 mL). To this solution bromine (68.1 mg, 0.43 mmol) in chloroform (0.5 mL) was added drop wise at −11° C. The reaction was stirred at 5° C. for 1½ hours, at room temperature for 1 hour and at 50° C. for 1 hour. The solvent was removed under reduced pressure to yield the crude title compound (126 mg) which was used directly in the next step without further purification.
Reaction SMILES: [C:1](#[N:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[ClH:7].[CH2:8]([OH:10])[CH3:9]>>[ClH:7].[C:1](=[NH:6])([O:10][CH2:8][CH3:9])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)C#N
Agent: Cl
Product: CCOC(=N)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Pivalonitrile (1.3 mL, 12.0 mmol) was dissolved in anhydrous ethanol (28 mL) under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 54 h. The solvent was removed in vacuo to afford ethyl pivalimidate hydrochloride (2.0 g, 100%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.19 (br s, 1H), 4.42 (q, J=6.9 Hz, 2H), 1.33 (t, J=6.8 Hz, 3H), 1.24 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:12](=[O:13])[O:11][C:9](=[O:10])[C:6]2=[N:7][CH:8]=1.[CH3:14][OH:15].[OH-:16].[Na+]>>[CH3:14][O:15][CH2:2][C:3]1[CH:4]=[C:5]([C:12]([OH:11])=[O:13])[C:6]([C:9]([OH:16])=[O:10])=[N:7][CH:8]=1
Reactant: CO
Reactant: [OH-]
Reactant: O=C1OC(=O)c2ncc(CCl)cc21
Agent: [Na+]
Product: COCc1cnc(C(=O)O)c(C(=O)O)c1
Reaction time: 5 h

Procedure:
7.0 g (35 mmol) 5-chloromethyl-2,3-pyridinedicarboxylic acid anhydride were dissolved in 165 g (5.16 mol) methanol at room temperature, causing formation of monoesters. 14 g (350 mmol) NaOH (50% in water) were slowly added whereupon the temperature rose to 50° C. and carboxylate started to precipitate. Stirring was continued for additional 5 hrs at 65° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([NH:10][C@H:11]([C:19]([OH:21])=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9].OC(C(O)(C)C)(C)C.[BH:30]([OH:32])[OH:31].[NH2:33][C@H:34](C(O)=O)[CH2:35][CH:36]([CH3:38])[CH3:37].CC(C)CB(O)O>CO.CCCCCCC>[B:30]([OH:32])([OH:31])[C@@H:34]([NH:33][C:19]([C@@H:11]([NH:10][C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][N:2]=1)=[O:9])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:21])[CH2:35][CH:36]([CH3:38])[CH3:37]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cnccn1
Reactant: OBO
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: CC(C)(O)C(C)(C)O
Agent: CC(C)CB(O)O
Agent: Cl
Solvent: CO
Solvent: CCCCCCC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B(O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1N HCl (37.1 mL) was added dropwise into a mixture of pinacol N-(pyrazine-2-yl-carbonyl)-L-phenylalanine-L-leucine boronate ([8]; 5.77 g, 12.4 mmol as a 22.0 (R,S)-[8])/(S,S)-[8] diastereomeric mixture) and 2-methylpropaneboronic acid (1.89 g, 18.5 mmol) in MeOH (57.7 mL) and n-heptane (57.7 mL). The reaction mixture was stirred at room temperature overnight. The water layer was separated and washed twice with n-heptane (30 mL each). The water layer was concentrated at 35° C. and DCM (30 mL) was added into the residue. 2 N NaOH (36.9 mL) was added dropwise into the reaction mixture. The water layer was separated and washed twice with DCM (30 mL each). After dilution with DCM (30 mL) 1N HCl was added dropwise until the pH of the aqueous phase was about 6. The water layer was extracted twice with DCM (30 mL each). The DCM portions were collected together and concentrated at 35° C. Ethyl acetate (46 mL) was added into the residue and concentrated. Ethyl acetate (16 mL) was added into the residue and concentrated until approximately 10% of the original volume remained. n-Heptane (46 mL) was added and the resulting solid was then filtered, washed with n-heptane (20 mL) and dried under vacuum at 35° C. The crude bortezomib was obtained as yellow solid (3.7 g, 9.63 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)[C:6]=2[CH:21]=1.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:13][C@H:10]([C:8]2[N:7]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)[C:6]3[CH:21]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH2:11][CH3:12])[N:26]=[CH:25][N:24]=1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 90 °C
Yield: 63.8 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]propylamine (88 mg, 0.32 mmol), 4-amino-6-chloro-5-cyanopyrimidine (49 mg, 0.32 mmol) and DIPEA (0.11 mL, 0.64 mmol) in IPA (1 mL) was heated for 5.5 h at 90° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PPC, gradient 0-5% 2M NH3/MeOH in EtOAc) to afford 350 as a pale yellow solid (83 mg, 64%). LCMS (Method K): RT 3.67 min [M+H]+ 407.0. 1H NMR (CDCl3, 400 MHz): δ 8.68 (1H, d, J=2.7 Hz), 8.60 (1H, br s), 8.01 (1H, s), 7.70 (1H, dd, J=9.0, 4.9 Hz), 7.67 (1H, br s), 7.06 (1H, app. td, J=9.2, 2.4 Hz), 6.79 (1H, dd, J=8.3, 2.4 Hz), 6.00 (1H, d, J=8.0 Hz), 5.40 (2H, s), 5.31 (1H, dt, J=8.0, 7.3 Hz), 2.05 (1H, dqd, J=14.7, 7.4, 7.3 Hz), 1.97 (1H, dqd, J=14.7, 7.4, 7.3 Hz), 0.86 (3H, t, J=7.4 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].ClCCl.Cl[CH2:17]/[CH:18]=[CH:19]\[CH2:20]Cl.CCCCCC>CCCCCC.C(OCC)(=O)C>[C:6]1([C@H:5]([N:12]2[CH2:20][CH:19]=[CH:18][CH2:17]2)[C:3]([O:2][CH3:1])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@H](N)c1ccccc1
Reactant: ClC/C=C\CCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)[C@H](c1ccccc1)N1CC=CC1
Yield: 65.2 %

Procedure:
From L-phenylglycine methyl ester (808 mg, 4.89 mmol), dichloromethane (0.1 ml) and cis-1,4-dichloro-2-butene (170 mg, 1.39 mmol). Flash chromatography: silica gel, gradient neat hexane to hexane:ethyl acetate (1:2) afforded the product (197 mg, 65%) as colourless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C@H:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:16][C:17]([O:19][C@@H:20]3[CH:25]4[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]4)[CH2:21]3)=[O:18])[CH:10]=2)=[CH:5][C:4]([C:34](O)=[O:35])=[N:3]1.C(N(CC)CC)C.[CH2:44]([O:46][CH:47]([O:52][CH2:53][CH3:54])[CH2:48][CH2:49][CH2:50][NH2:51])[CH3:45].CCN=C=NCCCN(C)C.OC1C=CC=C[N+]=1[O-]>CN(C=O)C.C(OCC)(=O)C>[CH2:53]([O:52][CH:47]([O:46][CH2:44][CH3:45])[CH2:48][CH2:49][CH2:50][NH:51][C:34]([C:4]1[CH:5]=[C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C@@H:15]([NH:16][C:17](=[O:18])[O:19][C@@H:20]3[CH:25]4[CH2:24][CH2:23][N:22]([CH2:27][CH2:26]4)[CH2:21]3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:12]=[CH:13][CH:14]=2)[N:2]([CH3:1])[N:3]=1)=[O:35])[CH3:54]
Reactant: Cn1nc(C(=O)O)cc1COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Reactant: CCOC(CCCN)OCC
Agent: CCN=C=NCCCN(C)C
Agent: [O-][n+]1ccccc1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(CCCNC(=O)c1cc(COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)n(C)n1)OCC
Temperature: 25 °C
Reaction time: 90 h
Yield: 56.9 %

Procedure:
To a stirred solution of 1-methyl-5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)-1H-pyrazole-3-carboxylic acid (0.30 g, 0.61 mmol) in DMF (6 mL) was added triethylamine (0.2 mL, 1.53 mmol), 4-aminobutyraldehyde diethyl acetal (0.20 mL, 1.22 mmol), EDCI (0.18 g, 0.91 mmol) and 2-hydroxypyridine-N-oxide (0.09 g, 0.91 mmol). The reaction mixture stirred at RT for 90 h. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate, brine, dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure to afford the crude target material (0.22 g, 57%) which was used directly without further purification.