Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([CH:13](O)[CH3:14])[N:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>C(Cl)Cl.O>[N:30]([CH:13]([C:9]1[N:8]=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1)[CH3:14])=[N+:31]=[N-:32]
Reactant: CC(O)c1nccc(Oc2ccc(F)cc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1nccc(Oc2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.4 %

Procedure:
Under N2 atmosphere, 1-(4-(4-fluorophenoxy)pyrimidin-2-yl)ethanol (140 mg, 0.598 mmol) was dissolved in 3 mL anhydrous DCM. Triethylamine (0.175 mL, 1.26 mmol) was added, and the mixture was cooled to 0° C. MsCl (0.070 mL, 0.897 mmol) was added, and the mixture was stirred 15 minutes. Maintaining 0° C., DCM solvent was removed under N2 stream. Residue was taken up in 2 mL dry DMF. NaN3 (78 mg, 1.19 mmol) added, and the reaction was stirred at rt for 24 h. Mixture was poured into 20 mL water, and extracted with 20 mL EtOAc. Organic layer was washed with 20 mL brine and dried over Na2SO4. Filtered and concentrated to give 120 mg (77%) 2-(1-azidoethyl)-4-(4-fluorophenoxy)pyrimidine as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=5.7 Hz, 1H), 7.16-6.90 (m, 4H), 6.70 (d, J=5.7 Hz, 1H), 4.34 (q, J=6.9 Hz, 1H), 1.55-1.46 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:6][C:7]=1[N+:16]([O-:18])=[O:17]
Reactant: CC(=O)NC(C)(C)Cc1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)NC(C)(C)Cc1ccc(Br)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 98 %

Procedure:
An ice-cooled solution of 3.3 g (12 mmol) of N-[2-(4-bromophenyl)-1,1-dimethylethyl]-acetamide in 3 ml of concentrated sulfuric acid was treated dropwise with a mixture of 3 ml of concentrated sulfuric acid and 6 ml of 90% nitric acid. After 1 hour the mixture was cautiously added to 200 ml of ice/water and the precipitated product extracted with 150 ml of dichloromethane. The organic solution was dried over magnesium sulfate, filtered and evaporated to give 3.7 g (98%) of N-[2-(4-bromo-3-nitrophenyl)-1,1-dimethyl-ethyl]acetamide as a white solid. [Mass spectrum (ESI) MH+ =315].
Reaction SMILES: C([O:3][C:4](=[O:11])[C:5](=[O:10])[C@@H:6]([CH3:9])[CH2:7][CH3:8])C.N([O-])=O.[Na+].C([O-])(O)=O.[Na+].[Na+].[Cl-]>OS(O)(=O)=O.O>[OH:10][C@@H:5]([C@@H:6]([CH3:9])[CH2:7][CH3:8])[C:4]([OH:11])=[O:3]
Reactant: CCOC(=O)C(=O)[C@@H](C)CC
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CC[C@H](C)[C@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of L-isoleucine(+) [1] (11.73 g, 89.4 mmol, [α]D20 =+40° (5% in 6M HCl)) in 300 ml of 1N aq. H2SO4 at 2° was slowly added (ca. 12 h) a solution of NaNO2 (19.5 g, 0.28 mol) in 300 ml of demineralised water. After stirring overnight at room temperature, 7.7 g of powdered NaHCO3 were added to bring the pH above 2. The solution was saturated with NaCl and extracted 6 times with ethyl acetate, maintaining the pH between 2 and 3 (1N aq. H2SO4, pH meter). After drying (Na2SO4), the organic layer was concentrated and the crude product (10.73 g, 91%) was recrystallised from hexane/ethyl acetate 9/1 at -30° to give pure (+)-(2S, 3S)-2-hydroxy-3-methylpentanoic acid [2].
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][CH:9]=1)=O.[OH:22][CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24][NH2:25].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:10]1([C:7]2[N:6]=[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]([CH2:2][CH:1]=[N:25][CH2:24][CH:23]([OH:22])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:9][N:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)c1cnc(-c2ccccc2)nc1-c1ccccc1
Reactant: NCC(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: OC(CN=CCc1cnc(-c2ccccc2)nc1-c1ccccc1)c1ccccc1
Yield: 82.1 %

Procedure:
A mixture of 61.2 g (0.223 mole) of 2,4-diphenyl-5-pyrimidyl methyl ketone, 30.6 g (0.223 mole) of β-hydroxyphenethylamine and 3.0 g p-toluenesulfonic acid monohydrate in 750 ml toluene was stirred and refluxed using a Dean-Stark apparatus for 11.0 hours, amt. H2O evolved: 4:10 ml; theoretical amt.: 4.0 ml. The toluene was removed in vacuo and the residue was dissolved in 1000 ml chloroform. The solution was washed with 300 ml H2O, dried (MgSO4), and concentrated to dryness in vacuo. Recrystallization of the residue from ethanol gave in three crops 72 g (82%) of the product, m.p. 140°-144°.
Reaction SMILES: B.O1CCCC1.[CH3:7][C:8]([O:11][C:12](=[O:23])[NH:13][CH2:14][CH2:15][C:16](=[O:22])[C:17]1[S:18][CH:19]=[CH:20][N:21]=1)([CH3:10])[CH3:9].CO.C(OCC)(=O)C>O1CCCC1.CCCC(C)C>[CH3:10][C:8]([O:11][C:12](=[O:23])[NH:13][CH2:14][CH2:15][C@@H:16]([OH:22])[C:17]1[S:18][CH:19]=[CH:20][N:21]=1)([CH3:7])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCC(=O)c1nccs1
Agent: B
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCC(C)C
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1nccs1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
To a solution of (S)-3-methyl-CBS-oxazaborolidine (1M solution in toluene, 0.43 ml) in dry tetrahydrofuran (30 ml) at −10° C. under nitrogen, was added borane-tetrahydrofuran complex (1M in tetrahydrofuran, 2.58 ml) and stirred at −10° C. for 15 minutes. A solution of [3-oxo-3-(2-thiazolyl)propyl]carbamic acid 1,1-dimethylethyl ester (1.1 g, 4.3 mmol) in dry tetrahydrofuran (20 ml) was added dropwise over 45 minutes and the resulting mixture was allowed to warm up to room temperature over 16 h. Methanol (10 ml) was added and the mixture was stirred at room temperature for 15 minutes before the solvent was removed at reduced pressure. Methanol (10 ml) was again added and removed at reduced pressure to leave a crude yellow oil. Flash chromatography (silica, 25 to 100% ethyl acetate in isohexane) gave 0.75 g of a clear gum (67%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[C:24]1([NH2:31])[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1>C(OCCO)C.C(OCC)(=O)C>[C:9]1([S:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([NH2:31])[CH:25]=3)[N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1nccc(Sc2ccccc2)n1
Reactant: Nc1cccc(N)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCCO
Product: Nc1cccc(Nc2nccc(Sc3ccccc3)n2)c1
Temperature: 25 °C
Yield: 42 %

Procedure:
To a stirred mixture of 2-chloro-4-(phenylthio)pyrimidine (300 mg, 1.35 mmol) and diisopropylethylamine (0.35 mL, 2.02 mmol) in 2-ethoxyethanol (2 mL), was added 1,3-phenylenediamine (291 mg, 2.70 mmol) in one portion. The whole was heated under reflux for 20 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), washed with water and brine. The organic solution was dried (Na2SO4), concentrated in vacuo. The residue was flash chromatographed on silica gel using ethyl acetate:petroleum ether (20:80→50:50) as eluant to give the product (167 mg, 42%).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2Br)=[CH:3][CH:2]=1.[Li]CCCC.CCCCCC.[C:27]([N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)([O:29][CH2:30][CH3:31])=[O:28].Cl>CCCCCCC.C1COCC1>[OH:38][C:35]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:4]2[CH:5]=[CH:6][C:1]([CH3:15])=[CH:2][CH:3]=2)[CH2:34][CH2:33][N:32]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:37][CH2:36]1
Reactant: Cc1ccc(Sc2ccccc2Br)cc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCCCCCC
Product: CCOC(=O)N1CCC(O)(c2ccccc2Sc2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a stirred reactor under nitrogen cover 2-(4-tolylsulfanyl)-phenyl bromide (600 g, 2.15 mol) was suspended in heptane (4.5 L). At room temperature 10M BuLi in hexane (235 mL, 2.36 mol) was added over 10 minutes. Only a small exotherm was noticed. The suspension was stirred for 1 hour at ambient temperature and then cooled down to −40° C. 1-Carbethoxy-4-piperidone (368 g, 2.15 mol) dissolved in THF (1.5 L) was added at a rate not faster than the reaction temperature was kept below −40° C. When the reaction has gone to completion, it was warmed to 0° C. and 1M HCl (1 L) was added keeping the temperature below 10° C. The acid aqueous phase was separated and extracted with ethyl acetate (1 L). The organic phases were combined and extracted with sodium chloride solution (15%, 1 L). The organic phase was dried over sodium sulphate and evaporated to a semi crystalline mass. It was slurried with ethyl ether (250 mL) and filtered off. Dried in an vacuum oven at 40° C. until constant weight.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].N1CCCC1.C1C=CC=CC=1.C1(C[OH:47])C=CC=CC=1>C(O)(=O)C>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[C:15](=[O:47])[CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: OCc1ccccc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
4-Cholesten-3,6-dione was prepared using 4-cholesten-3-one (Aldrich Co.) as a starting material by reference to the method of Hevl and Herr (F. W. Hevl and M. E. Herr, J. Am. Chem. Soc., 75: 1918, 1953) and that of Malhotra et al. (S. K. Malhotra, J. J. Hostynek and A. F. Lundin, J. Am. Chem. Soc., 90: 6565, 1968). Stated specifically, pyrrolidine (2.85 g) was added to a benzene solution (50 ml) of 4-cholesten-3-one (3.84 g) and the mixture was refluxed under heating for 24 hours. After cooling, the solvent and the excess pyrrolidine were distilled off under vacuum. Upon recrystallization from methanol, a colorless crystal of dienamine (4.16 g) was obtained. Cupric acetate (100 mg) was added to a benzene-methanol (500:10) solution of the dienamine (4.16 g) and air was introduced into the mixture for 24 hours. Then, a 2% aqueous solution (20 ml) of acetic acid was added and the mixture was stirred for 30 minutes and washed successively with water, a 1% sodium carbonate solution and a saturated saline solution. The resulting residue was dried, filtered and subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to yield a colorless crystal of 4-cholestene-3,6-dione (3.23 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[S:7][C:8]([C:10]#N)=[CH:9][C:5]=2[CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.C[OH:27].Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[S:7][C:8]([CH:10]=[O:27])=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1cc2cc(C#N)sc2cc1OC
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1cc2cc(C=O)sc2cc1OC
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
5,6-Dimethoxy-benzo[b]thiophene-2-carbonitrile (2.0 g) was suspended in dry toluene (40 ml) under an atmosphere of nitrogen. The reaction mixture was cooled to -5° C. and treated dropwise with a solution of diisobutylaluminium hydride in toluene (1.5M, 13 ml). After 30 minutes the solution was treated with methanol (5 ml) then poured into hydrochloric acid (1M, 200 ml) and stirred for 15 minutes. The resultant solution was extracted into dichloromethane (4×100 ml) then the organic extracts were combined, washed with brine, dried over magnesium sulphate and evaporated to dryness. The orange residue (1.6 g) was crystallised from dichloromethane:ether to give 5,6-dimethoxy-benzo[b]thiophene-2-carboxaldehyde as a white solid, m.p. 155°-156° C.
Reaction SMILES: [CH3:1][CH:2]([CH:12]=O)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].Cl.[CH3:15][O:16][C:17](=[O:21])[C@@H:18]([CH3:20])[NH2:19].C(=O)([O-])[O-].[K+].[K+].C([BH3-])#N.[Na+]>C(O)C>[C:7]([O:6][C:5]([NH:4][CH2:3][CH:2]([CH3:1])[CH2:12][NH:19][C@@H:18]([C:17]([O:16][CH3:15])=[O:21])[CH3:20])=[O:11])([CH3:8])([CH3:9])[CH3:10]
Reactant: COC(=O)[C@@H](C)N
Reactant: CC(C=O)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: CCO
Product: COC(=O)[C@@H](C)NCC(C)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of tert-butyl (2-methyl-3-oxopropyl)carbamate (2.0 g, 8.9 mmol) in ethanol was added D-Alanine methyl ester hydrochloride (1.25 g, 8.9 mmol), followed by potassium carbonate (0.62 g, 4.5 mmol). The resulting mixture was stirred at room temperature for 3 hr. Sodium cyanoborohydride (0.63 g, 10 mmol) was added in one portion. The reaction mixture was stirred at room temperature overnight. The solvent was removed on a rotavap, and the residue was taken up into water and extracted with ethyl acetate (3×). The combined organic extract was washed with brine, dried over sodium sulfate and evaporated to yield methyl N-{3-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-D-alaninate as colorless viscous oil, which was used without further purification. MS (M+1−Boc): 175.3
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[N-:35]=[N+:36]=[N-:37].[Na+]>CCOC(C)=O>[N:35]([CH2:24][CH2:23][O:22][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[N+:36]=[N-:37]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCOS(C)(=O)=O)c2cccc(F)c2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN=[N+]=[N-])c2cccc(F)c2)C1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
(R)-tert-Butyl 3-((R)-(3-fluorophenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (13.8 g, 32 mmol) was dissolved into anhydrous DMF (150 mL), solid NaN3 (6.1 g, 96 mmol, 3 eq) was added and the reaction mixture was heated to 80° for overnight. The reaction mixture was cooled to rt and then was added with EtOAc (500 mL), the organic phase was washed with water (3×100 mL) and brine (2×80 mL), dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-((R)-(2-azidoethoxy)(3-fluorophenyl)methyl)piperidine-1-carboxylate (12 g), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:16]([OH:19])([CH3:18])[CH3:17])[CH:11]=3)[N:6]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:23][CH:22]=1
Reactant: CCCCc1nc(=O)c2cc(C(C)(C)O)ccc2[nH]1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1nc2ccc(C(C)(C)O)cc2c(=O)n1Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.37 g of 2-butyl-6-(1-hydroxy-1-methylethyl)-4(1H)-quinazolinone in 115 ml of acetone is added 1.58 g of 4-bromobenzyl bromide and 2.18 g of anhydrous potassium carbonate. The resulting suspension is heated to reflux for 16 hours. The reaction mixture is then allowed to cool to room temperature, filtered and the filtrate is concentrated vacuo. The residue is purified by HPLC eluting with ethyl acetate/hexanes (1:3) to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])[CH:5]=[CH:4][N:3]=1.OO.NC(N)=[O:35].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])[CH:5]=[CH:4][N+:3]=1[O-:35]
Reactant: NC(N)=O
Reactant: O=c1c2cc(Cc3ccnc(Cl)c3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c2cc(Cc3cc[n+]([O-])c(Cl)c3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-[(2-chloropyridin-4-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 15, 54.5 mg, 0.129 mmol) in 2 mL of dichloromethane was added urea hydrogen peroxide (60.8 mg, 0.646 mmol), triethylamine (0.090 mL, 0.65 mmol), and trifluoroacetic anhydride (0.036 mL, 0.26 mmol). After 30 min, additional urea hydrogen peroxide (36.5 mg, 0.388 mmol), and triethylamine (0.18 mL, 1.3 mmol), and trifluoroacetic anhydride (0.146 mL, 1.03 mmol) were added. After 3 h, the reaction was cooled to −78° C., treated with 10% aqueous sodium carbonate, and extracted 3× with dichloromethane. The combined organic solutions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was suspended in methanol, and the slurry was filtered and washed with additional methanol to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 438.1214 for [M+H]+ [Calc'd for C23H21ClN3O4, [M+H]+=438.1215]: 1H NMR (400 MHz, d6-DMSO) δ 9.01 (d, J=1.1 Hz, 1H), 8.73 (s, 1H), 8.32 (d, J=6.8 Hz, 1H), 8.14 (d, J=7.7 Hz, 1H), 8.06 (s, 1H), 7.82-7.74 (m, 3H), 7.22-7.20 (m, 1H), 5.31 (d, J=5.5 Hz, 1H), 4.67 (br s, 1H), 4.56 (s, 2H), 4.18 (br s, 1H), 4.00-3.93 (m, 2H), 3.46 (t, J=11.0 Hz, 1H), 3.15 (t, J=10.5 Hz, 1H), 2.24 (br s, 1H), 1.92-1.90 (m, 1H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.[C:20]([NH:23][NH:24][C:25](=O)[CH2:26][C@@:27]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:32][C:31](=[O:33])[N:30]([C@H:34]([C:36]2[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][CH:37]=2)[CH3:35])[CH2:29][CH2:28]1)(=[O:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>>[Br:42][C:39]1[CH:38]=[CH:37][C:36]([C@@H:34]([N:30]2[CH2:29][CH2:28][C@:27]([CH2:26][C:25]3[O:22][C:20]([CH3:21])=[N:23][N:24]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:32][C:31]2=[O:33])[CH3:35])=[CH:41][CH:40]=1
Reactant: CC(=O)NNC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Cc1nnc(C[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(Br)cc3)C(=O)O2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.2 %

Procedure:
A suspension of P2O5 (73 mg, 0.52 mmol) and methanesulfonic acid (500 mg, 5.25 mmol) was stirred for 1 hour at room temperature. Then N′-acetyl-2-((S)-3-((S)-1-(4-bromo phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetohydrazide (50 mg, 0.105 mmol) was added. After heating at 70-80° C. for 4 h, the mixture was neutralized with aqueous sodium carbonate. The resulting mixture was extracted with EtOAc, and the combined organic layer was concentrated to give the crude product, which was purified by preparative HPLC to afford (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one (2.5 mg, 5%). 1H NMR (400 MHz, CDCl3): δ=1.51 (d, 3H), 2.32-2.41 (m, 2H), 2.48 (s, 3H), 2.73 (m, 2H), 3.16 (m, 2H), 5.49 (m, 1H), 6.78 (d, 2H), 7.24 (m, 2H), 7.32 (m, 2H), 7.41 (m, 3H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1>[Cl-].C([N+](CCCC)(CCCC)CC1C=CC=CC=1)CCC.O>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:1]#[N:2])=[CH:7][CH:6]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CCc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
196 g (4 mol) of sodium Cyanide, 12.5 g (40 mmol) of tributylbenzylammonium chloride and 660 mL of water are initially introduced into a 2 l multineck apparatus with reflux condenser, internal thermometer and dropping funnel, and the mixture is heated to 90° C. At the same temperature, 644 g (4 mol) of molten 4-chlorobenzyl chloride are added dropwise in 1 h, and the mixture is then stirred for 2 h. After having been cooled to about 35° C., the organic phase is separated off, washed with water and fractionated over a short column. 552 g of 4-chlorobenzyl cyanide (91% of theory) are obtained.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[CH3:25][C:26]([CH3:31])=[CH:27][C:28](O)=[O:29].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:25][C:26]([CH3:31])=[CH:27][C:28]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:29]
Reactant: CC(C)=CC(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=C(C)C
Yield: 76.3 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 3-methylcrotonic acid (1.4 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (2.7 g, 77%) as crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[CH:10]=[N:9][N:8]([CH:11]3[CH2:14][O:13][CH2:12]3)[C:6]=2[N:7]=1.[CH3:28][C:29]1([CH3:46])[CH2:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]([CH3:45])([CH3:44])[NH:30]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]3[CH2:14][O:13][CH2:12]3)[C:6]=2[N:7]=[C:2]([C:33]2[CH2:32][C:31]([CH3:45])([CH3:44])[NH:30][C:29]([CH3:46])([CH3:28])[CH:34]=2)[CH:3]=1)=[O:16]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2COC2)c(=O)[nH]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2COC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(oxetan-3-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) solution was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (44% yield). LCMS: 491.50 (M+1)+; HPLC: 98.99% (@ 254 nm) (Rt;4.678); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (bs, 1H), 8.93 (t, 1H), 8.43 (s, 1H), 7.83 (s, 1H), 6.84 (s, 1H), 6.21-6.14 (m, 1H), 5.89 (s, 1H), 5.08-5.02 (m, 4H), 4.38 (d, 2H, J=4.4 Hz), 2.42 (s, 2H), 2.23 (s, 3H), 2.12 (s, 3H), 1.24 (s, 6H), 1.14 (s, 6H).