Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[SiH](C)O[SiH](C)C.C(OC(=O)C)(=O)C.FC(F)(F)S(O[Si](C(C)C)(C(C)C)C(C)C)(=O)=O.[CH2:41]([Si:49]([CH3:55])([CH3:54])[O:50][SiH:51]([CH3:53])[CH3:52])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>[Pt].C1(C)C=CC=CC=1>[CH2:1]([Si:51]([CH3:52])([CH3:53])[O:50][Si:49]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:55])[CH3:54])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C[SiH](C)O[Si](C)(C)CCc1ccccc1
Agent: [Pt]
Agent: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: C[SiH](C)O[SiH](C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: C[Si](C)(CCc1ccccc1)O[Si](C)(C)CCc1ccccc1
Yield: 58 %

Procedure:
380 mg Of styrene and 240 mg of 1,1,3,3-tetramethyldisiloxane were placed in a glass tube to which 20 μL (21.6 mg) of acetic anhydride and 2 μL (2.3 mg) of triisopropylsilyl trifluoromethanesulfonate (i-Pr3SiOSO2CF3) were added by microsyringe. 5 μL (platinum weight: 0.0017 mg) Of a toluene solution (platinum content: 0.04 wt %) of zero-valent platinum complexed with divinylsiloxane were added to this. The tube was put in a 60° C. oil bath and heated for 8 hours. After cooling, the tube contents were analyzed by gas chromatography, which revealed that the styrene conversion rate was 55%, 1-phenethyl-1,1,3,3-tetramethyldisiloxane had been produced at a yield of 58% (based on 1,1,3,3-tetramethyldisiloxane) and 1,3-bis(phenethyl)-1,1,3,3-tetramethyldisiloxane at a yield of 21%, and the ratio of alpha addition to beta addition of phenethyl groups was 1:49.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:20]([O:22][C:23](=[O:29])[C@H:24]([CH:26]([CH3:28])[CH3:27])[NH2:25])[CH3:21]>C(Cl)(Cl)Cl.CO>[CH2:20]([O:22][C:23](=[O:29])[C@H:24]([CH:26]([CH3:28])[CH3:27])[NH:25][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:21]
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(C)C

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and L-valine ethyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.2 in 97:3 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13](OC)=[O:14])[CH:8]=[CH:7][C:6]=1[CH:18]1[CH2:23][CH2:22][CH:21]([CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]1>C(O)C>[Cl:4][C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13]([NH:2][NH2:3])=[O:14])[CH:8]=[CH:7][C:6]=1[C@H:18]1[CH2:23][CH2:22][C@H:21]([CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]1
Reactant: NN
Reactant: CCOC(=O)C(C)C1CCC(c2ccc(NC(=O)C(=O)OC)cc2Cl)CC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of hydrazine hydrate (86 mg, 1.73 mmol) in ethanol (1 mL) was added dropwise to a stirred solution of ethyl 2-[4-(2-chloro-4-{[methoxy(oxo)acetyl]amino}phenyl)cyclo-hexyl]propanoate (0.58 g, 1.44 mmol) in ethanol (14 mL) and the reaction mixture was stirred at room temperature for 18 h. The mixture was filtered to leave a solid, which was washed with ethanol to give the title compound (Intermediate 106) (0.45 g, 81%) as a white solid; 1H NMR δ 1.14 (3H, d), 1.16-1.28 (2H, m), 1.27 (3H, t), 1.4-1.58 (2H, m), 1.6-1.7 (1H, m), 1.71-1.93 (4H, m), 2.29-2.39 (1H, m), 2.82-2.94 (1H, m), 4.15 (2H, dq), 4.7 (2H, s), 7.4 (1H, d), 7.8 (1H, dd), 8.01 (1H, d), 10.4 (1H, s), 10.8 (1H, s); MS m/e MH+ 396.
Reaction SMILES: F[C:2]1[C:3]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>CC(N(C)C)=O.CCOC(C)=O>[OH:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][OH:25])[C:2]1[C:3]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: OCCNCCO
Reactant: COC(=O)c1cc(F)c(S(C)(=O)=O)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(N(CCO)CCO)c(S(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 30 °C
Yield: 72.9 %

Procedure:
A mixture of 4 (1.48 g, 5.34 mmol) and diethanolamine (1.40 g, 13.3 mmol) in DMA (6 mL) was stirred at 30° C. for1 h, and then diluted with EtOAc (60 mL). The solution was washed with brine (2×) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with EtOAc/MeOH, followed by recrystallization from EtOAc/iPr2O, to give methyl 5-[bis(2-hydroxyethyl)amino]-4-(methylsulfonyl)-2-nitrobenzoate (5) (1.41 g, 73%): mp 99-100° C.; 1H NMR [(CD3)2SO] δ 8.56 (s, 1 H), 7.73 (s, 1 H), 4.62 (t, J=4.9 Hz, 2 H), 3.89 (s, 3 H), 3.59-3.49 (m, 8 H), 3.45 (s, 3 H). Anal. (C13H18N2O8S) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH:15]=O)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.[N:17]1[C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([CH2:27][N:28]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[N:17]1[C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([CH2:27][N:28]([CH:36]2[CH2:41][CH2:40][N:39]([CH2:15][CH2:14][N:9]3[C:7]4=[N:8][C:3]([O:2][CH3:1])=[CH:4][N:5]=[C:6]4[CH:12]=[CH:11][C:10]3=[O:13])[CH2:38][CH2:37]2)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(nn1)OCCO2)C1CCNCC1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(nn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A suspension of [3-(methyloxy)-6-oxopyrido[2,3-b]pyrazin-5(6H)-yl]acetaldehyde (240 mg, assuming 191 mg of aldehyde) and 1,1-dimethylethyl (6,7-dihydro[1,4]dioxino[2,3-c]pyridazin-3-ylmethyl)-4-piperidinylcarbamate (305 mg) in chloroform (10 mL) and methanol (1.5 mL) was stirred at room temperature under argon for 1 h before addition of sodium triacetoxyborohydride (553 mg). The reaction was stirred at rt overnight. A saturated solution of sodium bicarbonate (20 mL) was added to the reaction and the aqueous was extracted with 10% MeOH/DCM (3×50 mL). The combined organic phases were dried (MgSO4), evaporated and the residue was subjected to column chromatography on silica gel eluting with 0-10% methanol-DCM to afford 358 mg of the title compound (60%).
Reaction SMILES: CC1(C)[O:6][C:5](=O)[C@H:4]([C@@H:8]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=3)[CH2:17][C@H:16]2[CH3:31])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[O:3]1.[NH2:33][OH:34]>CO.CO.C(#N)C>[OH:34][NH:33][C:5](=[O:6])[C@@H:4]([OH:3])[C@@H:8]([C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:24]=[CH:23][N:22]=2)[CH2:17][C@H:16]1[CH3:31])=[O:14])[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: NO
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2cc(C(F)(F)F)ccn2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O
Solvent: CO
Solvent: CC#N
Product: CC(C)C[C@H](C(=O)N1CCN(c2cc(C(F)(F)F)ccn2)C[C@H]1C)[C@H](O)C(=O)NO
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 29.8 %

Procedure:
To a solution of (5S)-2,2-dimethyl-5-[(1S)-3-methyl-1-({(2R)-2-methyl-4-[4-(trifluoro methyl)pyridin-2-yl]piperazin-1-yl}carbonyl)butyl]-1,3-dioxolan-4-one (142 mg; 0.31 mmol; 1.0 eq.) in MeOH (5.0 mL) was added an aqueous solution of hydroxylamine (50%; 0.046 mL; 1.55 mmol; 5.0 eq.) and the resulting reaction mixture was stirred at RT for 4.5 h. Evaporation of the solvents gave an oil. This residue was taken up in MeOH/ACN (2 mL/1 mL) and purified by reverse-phase chromatography to give the title product (3) as a white powder (40 mg; 29.8%) as a single diastereoisomer. M−(ESI): 431.0; M+(ESI): 433.6. HPLC (condition C): Rt: 10.8 min (HPLC purity: 98.7%).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:16][CH:17]=O.[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:30]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCl>[C:33]([O:32][C:31]([N:30]([CH2:29][C:27]1[CH:26]=[CH:25][C:24]2[O:19][CH2:20][CH2:21][O:22][C:23]=2[CH:28]=1)[CH:38]1[CH2:43][CH2:42][N:41]([CH2:17][CH2:16][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:2]2=[O:1])[CH2:40][CH2:39]1)=[O:37])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)c1cc(=O)n(CC=O)c2ccccc12
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To 24 mL of dichloromethane suspension containing 0.8 g of methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxylate and 1.1 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.24 mL of acetic acid was added, at room temperature and stirred at room temperature for 1 hour. To the reaction mixture, 1.0 g of sodium triacetoxyborohydride was added, and stirred at room temperature for 1 hour. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; ethyl acetate], to give 1.25 g of methyl 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-4-carboxylate as a slight yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1N
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)OCc2ccccc2)cc1N
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 70 %

Procedure:
After dissolving 1-methyl 2-aminoterephthalate (8.00 g, 41.1 mmol) in dimethylformamide (80 ml), anhydrous potassium carbonate (6.25 g, 45.1 mmol) and benzyl bromide (4.12 ml, 43.1 mmol) were added and the mixture was stirred at room temperature for 15.5 hours. An excess of triethylamine was added, and after stirring for an additional 10 minutes at room temperature, ice water was added and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and brine and then dried over anhydrous magnesium sulfate. Filtration was performed with silica gel-alumina and the solvent was distilled off under reduced pressure. IPE was added to the obtained oil for crystallization, and the crystals were filtered off. The filtrate was concentrated and then the same procedure was repeated twice to yield the title compound (8.21 g) as a light yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.Cl.[NH2:15][OH:16].O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[N:15][OH:16]
Reactant: COc1cccc2c1CCCC2=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc2c1CCCC2=NO
Temperature: 80 °C
Yield: 94 %

Procedure:
A solution of 5-methoxy-1-tetralone (5.0 g) in ethanol (100 mL) was treated with hydroxylamine hydrochloride (2.1 g) and sodium carbonate monohydrate (3.6 g). The reaction mixture was heated overnight at 80° C. with a condenser. Cooled to room temperature after approximately seventeen hours, transferred to another flask and concentrated. The residue was triturated in water and filtered to yield the title product as a beige solid (5.1 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[OH-].[Na+].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(OCC)C>[OH:1][C@H:2]1[CH2:6][N:5]([S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2C[C@H](O)C[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
35.6 g (0.27 mol) of (2S,4R)-4-hydroxyproline were dissolved in 300 ml (0.60 mol) of 2N sodium hydroxide in a 750 ml sulphonation flask which was provided with stirrer, dropping funnel, thermometer and condenser. Thereupon, within 10 minutes there was added dropwise thereto a solution of 63 g (0.33 mol) of p-toluenesulphonyl chloride in 180 ml of diethyl ether. The temperature was held at 16°-20° C. by means of a water bath. After intensive stirring at room temperature for 16 hours, the reaction has finished. The aqueous phase (pH about 7) was separated and back-washed with 250 ml of diethyl ether. The ether phases were back-washed a further twice with 100 ml of deionized water each time. The combined aqueous phases were acidified to pH 2 with 25 ml of concentrated hydrochloric acid (27%) while cooling with ice at 5° C. and stirred for 1.5 hours at 5° C. The separated crystals were filtered off under suction, washed with 1 liter of deionized water and dried for 16 hours in a vacuum drying oven at 40° C./17 mbar. The resulting product (76.2 g of white crystals of melting point (142°-145° C.) was, for purification, dissolved in 200 ml of hot ethanol/water (1:4, v/v) and recrystallized while stirring and slowly cooling to 5° C. The white crystals obtained after drying (73.4 g) were again recrystallized from 150 ml of ethanol/water (1:4, v/v) as previously described and dried in a vacuum drying oven at 50° C./17 mbar. There were obtained 69.4 g (89.6%) of (2S,4R)-4-hydroxy-1-(p-tolylsulphonyl)-2-pyrrolidinecarboxylic acid of melting point 146°-147° C. [α]D20 =-87.6° (c=1 in ethanol).
Reaction SMILES: O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]([NH:35][NH:36][C:37](=O)[CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]1[O:34][C:37]([CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[N:36][N:35]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
(CF3SO2)2O (1.0 mL) was slowly added to a −10° C. solution of tert-butyl (3-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-3-oxopropyl)carbamate (1.0 g, 2.17 mmol) and pyridine (1.0 mL) in dry DCM (10 mL). The reaction mixture was allowed to warm to rt and then was stirred at rt for 1 h. Then saturated NaHCO3 was added at 0° C. very slowly. The organic layer was separated and the aqueous layer was exacted with EtOAc (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 10:1 to 4:1 petroleum ether/EtOAc) to give tert-butyl (2-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)ethyl)carbamate (0.40 g, 42%) as a slight yellow solid. ESI-MS (EI+, m/z): 444 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 7.48-7.46 (m, 2H), 7.45-7.37 (m, 3H), 6.99 (t, J=5.5 Hz, 1H), 4.99-4.94 (m, 2H), 4.59 (d, J=7.0 Hz, 1H), 3.73 (br s, 1H), 3.32-3.26 (m, 2H), 2.96-2.92 (m, 2H), 2.85-2.81 (m, 2H), 2.19-2.15 (m, 1H), 2.05-1.99 (m, 2H), 1.86-1.83 (m, 1H), 1.34 (s, 9H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:12][CH2:11][C:10]2=[O:21].CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[O:21]=[C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([O:6][C:1](=[O:4])[CH2:2][CH3:3])[CH:8]=2)[N:13]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:12][CH2:11]1
Reactant: CCC(=O)N1CCC(=O)c2cc(O)ccc21
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCC(=O)Oc1ccc2c(c1)C(=O)CCN2C(=O)CC
Yield: 110.3 %

Procedure:
A solution of propionyl chloride (1.018 g) in chloroform (5 ml) was added dropwise to a solution of 6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.09 g), N,N-dimethylaniline (1.513 g), and 4-dimethylaminopyridine (0.061 g) in chloroform (20 ml) with stirring and ice cooling over a period of 10 minutes After being stirred overnight at ambient temperature, the mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed successively with 5% hydrochloric acid, water, aqueous sodium bicarbonate, and water, dried over magnesium sulfate, and evaporated in vacuo to give an oil of 4-oxo-1-propionyl-6-propionyloxy-1,2,3,4-tetrahydroquinoline (1.51 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]1.C(Br)(Br)(Br)[Br:34]>C1COCC1>[Br:34][CH:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Br)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Triphenylphosphine (727 mg, 2.77 mmol) was added to a stirred solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (173 mg, 0.924 mmol) and carbon tetrabromide (919 mg, 2.77 mmol) in THF (3.00 mL) at 0° C., and the resulting mixture was allowed to warm slowly to rt. After 20 h, the reaction was filtered and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 10%-40% EtOAc/hexanes as eluent) afforded the title compound i-5a m/z (ES) 250 (MH)+. 1H NMR (500 MHz, CDCl3): δ 4.49 (m, 1H), 3.81 (m, 2H), 3.63 (m, 1H), 3.53 (m, 1H), 2.33 (m, 1H), 2.26 (m, 1H), 1.49 (s, 9H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH:15]([CH2:18][OH:19])[O:14][C:13]=2[CH:20]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH:15]([CH2:18][OH:19])[O:14][C:13]=2[CH:20]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)OC(CO)CO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)OC(CO)CO2
Temperature: 25 °C
Reaction time: 15 h
Yield: 46 %

Procedure:
Acetic anhydride (0.24 g, 2.4 mmol) was added to a stirred mixture of the title compound from Step 1 above (0.30 g, 1.66 mmol) and Et3N (0.70 g, 6.9 mmol) in CH2Cl2 (30 mL). The reaction was stirred at room temperature for 15 h. More acetic anhydride (0.10 g, 1.0 mmol) was added and the mixture was stirred for a further 5 h at room temperature. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/isohexane (1:3 to 2:3) as eluent to give 170 mg (46%) of the title product as an oil.
Reaction SMILES: [Mg].[CH3:2]I.[CH3:4][N:5]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=[O:17])=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl-].[NH4+]>CCOCC>[CH3:2][CH:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:5]([CH3:4])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:15]=1)[OH:17]
Reactant: CI
Reactant: CN1CCCCc2cc(C=O)ccc21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)c1ccc2c(c1)CCCCN2C
Reaction time: 2 h

Procedure:
The Grignard reagent was prepared from 1.04 g of magnesium shavings and 2.30 ml of methyl iodide under argon in 40 ml of absolute ether. To this Grignard solution was slowly added dropwise at room temperature a solution of 4.38 g of 2,3,4,5-tetrahydro-1-methyl-1H-1-benzazepine-7-carboxaldehyde in 10 ml of ether. The reaction mixture was stirred for 2 hours. Thereafter, the mixture was hydrolyzed with saturated ammonium chloride solution, extracted with ether, washed with water and dried. After evaporation, there were obtained 4.47 g of 2,3,4,5-tetrahydro-α-methyl-1-methyl-1H-1-benzazepine-7-methanol as a yellow oil.
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.OC1(C2C=CC(C#N)=CC=2)CCC(=O)CC1>>[OH:1][C:2]1([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[CH2:11][CH2:10][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(C2(O)CCC3(CC2)OCCO3)nc1
Agent: N#Cc1ccc(C2(O)CCC(=O)CC2)cc1
Product: N#Cc1ccc(C2(O)CCC(=O)CC2)nc1

Procedure:
The title compound was synthesized from 6-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)nicotinonitrile using the sane typical deprotection procedure as for 4-(1-hydroxy-4-oxocyclohexyl)benzonitrile.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH:17][C:18]3[CH:37]=[CH:36][C:21]([O:22][C:23]4[C:28]([C:29]5[C:30]([C:34]#[N:35])=[N:31][NH:32][CH:33]=5)=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:20][CH:19]=3)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-:39].[K+].[K+].OO>CS(C)=O>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:22][C:23]4[C:28]([C:29]5[C:30]([C:34]([NH2:35])=[O:39])=[N:31][NH:32][CH:33]=5)=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:36][CH:37]=3)=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1n[nH]cc1-c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1n[nH]cc1-c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
In a 20-mL sealed tube was dissolved 4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1-H-pyrazole-3-carbonitrile (0.070 g, 0.145 mmol) in DMSO (1.0 mL). To this was added potassium carbonate (0.024 g, 0.174 mmol) and hydrogen peroxide (0.445 mL, 14.5 mmol) and the mixture was stirred at 20° C. for 3 days and quenched with water. The product was extracted into EtOAc, washed 1× saturated NaHCO3, 1×H2O, dried over Na2SO4, filtered through fritted funnel and concentrated. The title compound was purified using a Gilson reverse phase liquid chromatography system. The product fractions were extracted into CH2Cl2. The organic layers were washed organics 1× saturated NaHCO3, 1×H2O, dried with Na2SO4, filtered through fritted funnel and concentrated to yield 4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1-H-pyrazole-3-carboxamide as light yellow solid. MS m/z=500 [M+1]+. Calc'd for C29H21N7O2: 499.52.