Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29](OC(N1CCN(C(=O)C2C=CC(C=O)=CC=2)CC1)=O)([CH3:32])(C)[CH3:30].N1CCOCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[CH:32]1([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)=[O:28])[CH2:10][CH2:9]2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCN1
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCN(C2CC2)CC1
Reaction time: 3 h
Yield: 48 %

Procedure:
4-(4-Morpholin-4-ylmethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester. A solution of 4-(4-formyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (2.06 g) in methanol (100 mL) was treated with morpholine (4 mL) and NaB(OAc)3H (6.98 g, in portions over 1 h). After 3 h, the mixture was diluted with satd. aq. NaHCO3 and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2) to give the title compound (1.22 g, 48%). MS (ESI): mass calcd. for C21H31N3O4, 389.23; m/z found, 390.4 [M+H]+. 1H NMR (CDCl3): 7.39-7.33 (m, 4H), 3.75-3.66 (m, 6H), 3.50 (s, 2H), 3.51-3.33 (m, 6H), 2.45-2.41 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[CH:25]=[C:26]4[C:32](=[O:33])[N:31]([CH2:34][CH2:35][CH2:36][C:37]#[N:38])[C:30](=[S:39])[N:27]4[C:28]=3[CH:29]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]>COCCOC>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[O:23][C:24]3[CH:25]=[C:26]4[C:32](=[O:33])[N:31]([CH2:34][CH2:35][CH2:36][C:37]5[N:1]=[N:2][NH:3][N:38]=5)[C:30](=[S:39])[N:27]4[C:28]=3[CH:29]=2)=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCCN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: O=C1c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C(=S)N1CCCc1nn[nH]n1
Temperature: 25 °C

Procedure:
Sodium azide (76 mg, 1.17 mmol) and triethylamine hydrochloride (161 mg, 1.17 mmol) are added to a solution of Compound 35 (462.5 mg, 1.25 mmol) dissolved in DME (15 ml) and the suspension is refluxed for 48 hours. The mixture is then cooled to room temperature and the solvent is removed under reduced pressure. Water (30 ml) and ethyl acetate (30 ml) are added thereto and the aqueous phase is extracted three more times with ethyl acetate. The combined organic extracts are dried over Na2SO4 and the solvent is evaporated under reduced pressure. The crude product is recrystallized from ethanol to give Compound 36.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([OH:28])[CH:22]=2)=[O:18].[O:29]1[CH2:32][CH:31](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:30]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([O:28][CH:31]1[CH2:32][O:29][CH2:30]1)[CH:22]=2)=[O:18]
Reactant: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccc(O)cc5[nH]4)c3N)ccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccc(OC6COC6)cc5[nH]4)c3N)ccc2[nH]1
Temperature: 80 °C
Reaction time: 144 h
Yield: 28.8 %

Procedure:
[5-Amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(6-hydroxy-1H-indol-2-yl)-methanone (21 mg, 0.056 mmol), toluene-4-sulfonic acid oxetan-3-yl ester (19 mg, 0.084 mmol), and potassium carbonate (13 mg, 0.095 mmol) were dissolved in anhydrous N,N-dimethylformamide (DMF), and heated at 80° C. with stirring under a nitrogen atmosphere for six days. After cooling to room temperature, the reaction mixture was combined with water, and extracted with an ethyl acetate/methanol (10/1) solution. The organic layer was isolated, washed with water, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=100/3) to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[6-(oxetan-3-yloxy)-1H-indol-2-yl]-methanone as a yellow solid (6.9 mg, 29%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:6](O)=[O:7].C[N:16](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.N>CN(C)C=O.O>[Br:12][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:11]=1)[C:6]([NH2:16])=[O:7]
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution (18 mL) of 3-trifluoromethyl-5-bromobenzoic acid (5.0 g, 19 mmol) in N,N-dimethylformamide were added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (4.3 g, 22 mmol), 1-hydroxybenzotriazole (3.4 g, 22 mmol) and 28% aqueous ammonia (1.7 mL, 28 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was to recrystallized (hexane-ethyl acetate) to give the title compound (3.7 g, 74%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[C:8]2[C:3]=1[CH:4]=[N:5][C:6](Cl)=[N:7]2.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:30]([Cl:40])[CH:29]=1>C(O)(C)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:17][CH2:18]2)=[C:8]2[C:3]=1[CH:4]=[N:5][C:6]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[C:30]([Cl:40])[CH:29]=1)=[N:7]2
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)c3cnc(Cl)nc23)CC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)c3cnc(Nc4ccc(N5CCOCC5)c(Cl)c4)nc23)CC1
Temperature: 110 °C

Procedure:
A mixture of tert-butyl 4-(5-bromo-2-chloroquinazolin-8-yloxy)piperidine-1-carboxylate (1 eq) and N-(4-amino-2-chlorophenyl) morpholine (1 eq) in isopropanol was heated in a sealed tube at 110° C. for overnight. The reaction mixture was concentrated and proceeds for next step. ES/MS m/z 618.0 (MH+).
Reaction SMILES: IC.[C:3]([O:7][C:8]([NH:10][C@H:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:12][C:13]([OH:15])=[O:14])=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:23](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:3]([O:7][C:8]([NH:10][C@H:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:12][C:13]([O:15][CH3:23])=[O:14])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 127.9 %

Procedure:
Iodomethane (1.038 mL, 16.68 mmol) was added in one portion to (S)-3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (1 g, 3.34 mmol) and potassium carbonate (0.922 g, 6.67 mmol) in DMF (15 mL). The resulting suspension was stirred at 80° C. for 24 hours. The reaction mixture was concentrated and diluted with EtOAc (50 mL) with water (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford (S)-methyl 3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoate (1.340 g, 128%) as a orange solid. 1H NMR (399.9 MHz, DMSO-d6) δ 1.36 (9H, s), 2.71-2.74 (1H, m), 2.74-2.80 (1H, m), 3.57 (3H, s), 4.91 (1H, d), 7.33 (2H, d), 7.39 (2H, d), 7.49 (1H, d). m/z (ESI−) (M−H)−=312; HPLC tR=2.57 min.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[C:12]1([C:18]2[C:19]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[C:20]3[CH:26]=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[C@H:45]([C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)[C:46](O)=[O:47])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:55][C:52]1[CH:51]=[CH:50][C:49]([C@@H:45]([C@@H:41]2[CH2:42][CH2:43][CH2:44][N:40]2[C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[C:46](=[O:47])[N:30]2[CH2:29][CH2:28][N:27]([C:19]3[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:23][N:22]=[C:21]4[NH:24][CH:25]=[CH:26][C:20]=34)[CH2:32][CH2:31]2)=[CH:54][CH:53]=1
Reactant: c1ccc(-c2cnc3[nH]ccc3c2N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.103 mL, 0.592 mmol) was added to 5-phenyl-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine dihydrochloride (0.052 g, 0.15 mmol, see Example 19), (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (0.0503 g, 0.148 mmol, see Example F) and TBTU (0.0570 g, 0.178 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The mixture was directly loaded onto a column and purified by chromatography (1:1 hexane:ethyl acetate) to give (S)-tert-butyl 2-((S)-1-(4-chlorophenyl)-2-oxo-2-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)ethyl)pyrrolidine-1-carboxylate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (0.5 mL), and 2M HCl in ether (1 mL) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone dihydrochloride (0.062 g, 63%). MS ESI (+) m/z 500 detected.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)=[CH:54][CH:53]=1)[CH3:50]>CN(C=O)C>[CH2:49]([O:51][C:52]1[CH:53]=[CH:54][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=2)=[CH:56][CH:57]=1)[CH3:50]
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: CCOc1ccc(-c2cccc(N)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc1
Temperature: 25 °C
Yield: 42.7 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.015 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-ethoxy-biphenyl-3-ylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.012 g of product in 41% yield: LCMS (ESI) m/z 402 (MH+).
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:20]N1C(=O)CCC1=O>ClCCl>[C:1]([NH:8][C:9]1[S:10][C:11]([Cl:20])=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1sccc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1sc(Cl)cc1-c1ccccc1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
To 2-(N-Boc-amino)-3-phenyl-thiophene (89 mg, 0.32 mmol) in dichloromethane (4 ml) at 0° C. was slowly added N-chlorosuccinimide (48 mg, 0.36 mmol), and the mixture allowed warm to ambient temperature for 16 hr. The mixture was diluted with dichloromethane, washed with water, and the organic phase concentrated in vacuo. Flash chromatography on silica gel (ethyl acetate/hexanes) yielded 2-(N-Boc-amino)-5-chloro-3-phenyl-thiophene (66 mg, 66%).
Reaction SMILES: [F:1][C:2]1[C:26](/[N:27]=[CH:28]\[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[C:6](=[O:22])[O:7][C:8]2[CH:15]=[C:14]([O:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11].[Br:35]N1C(=O)CCC1=O.O>C1COCC1>[Br:35][CH2:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]([O:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)=[CH:15][C:8]=2[O:7][C:6](=[O:22])[C:5]=1[CH2:4][C:3]1[CH:23]=[CH:24][CH:25]=[C:26](/[N:27]=[CH:28]\[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:2]=1[F:1]
Reactant: Cc1c(Cc2cccc(/N=C\c3ccccc3)c2F)c(=O)oc2cc(Oc3nccs3)ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: O=c1oc2cc(Oc3nccs3)ccc2c(CBr)c1Cc1cccc(/N=C\c2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
THF (4.5 mL) was added to 3-(2-fluoro-3-{[1-phenyl-meth-(Z)-ylidene]-amino}-benzyl)-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran (compound 6a-3-4-1P) (226 mg), and the mixed solution was stirred at −78° C. for 20 minutes, and further stirred at 0° C. for 1 hour to yield a dark brown solution. This solution was added over 10 minutes to a solution of N-bromosuccinimide (178 mg) in THF (3.0 mL) (which had been prepared in advance in a separate container), and the mixture was further stirred at 0° C. for 1 hour. The reaction solution was added to water (5 mL) to complete the reaction, and the solution was extracted with ethyl acetate. The resultant organic layer extraction liquid was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was then distilled away under reduced pressure, and a residue (320 mg) containing the title compound was obtained.
Reaction SMILES: [ClH:1].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.[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C=O)C.Cl>[ClH:1].[NH2:3][C:4]([CH:15]1[CH2:16][CH2:17][N:18]([C:28](=[O:30])[CH3:29])[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: CC(=O)OC(C)=O
Reactant: NC(CCCCB(O)O)(C(=O)O)C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(C(N)(CCCCB(O)O)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52.9 %

Procedure:
To a stirring solution of crude 2-amino-6-borono-2-(piperidin-4-yl)hexanoic acid dihydrochloride (Example 26-A, Step 1, 250 mg, 0.618 mmol) in dry DMF (13 mL) under nitrogen was added triethylamine (0.69 mL, 4.95 mmol) to give a white slurry. The resultant slurry was treated with acetic anhydride (0.131 mL, 1.39 mmol), added dropwise, and the reaction mixture was stirred at room temperature for 2.5 h. The mixture was then diluted with ice water (10 mL) and 3 N HCl (5 mL) prior to extraction with ethyl acetate (2×25 mL). 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; 2% A for 2 min, 2% to 20% A over 23 min, then 20% to 100% A over 1 min.] Product fractions were pooled and concentrated, and the residue was taken up in 0.25N HCl (3 mL)/acetonitrile (8 mL) and concentrated. The residue was once again treated with 0.25N HCl (3 mL)/acetonitrile (8 mL) and concentrated and dried under high vacuum overnight to give 2-amino-6-borono-2-[1-acetylpiperidin-4-yl]hexanoic acid hydrochloride (110 mg, 53%) as a white solid. 1H NMR (D2O, 400 MHz) δ 4.38 (bt, J=12 Hz, 1H), 3.92 (bt, J=12 Hz, 1H), 3.03 (m, 1H), 2.55 (m, 1H), 2.11 (m, 1H), 2.00 (s, 3H), 1.87-1.78 (m, 3H), 1.55 (m, 1H), 1.50-1.00 (m, 6H), 0.68 (t, J=7.2 Hz, 2H). ESI+ MS found for C13H25BN2O5 m/z 583.3 (2M−18+H), 565.6 (2M−2×18+H), 283.4 (M−18+H), 265.3 (M−2×18+H); ESI− MS m/z 581.6 (2M−18−H), 299.4 (M−H), 281.4 (M−18−H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Cl)=[C:6]([CH3:10])[CH:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[OH:15].C(N(CC)CC)C.[SH2:23]>O1CCCC1>[CH3:1][C:2]1[C:7]([CH2:8][SH:23])=[C:6]([CH3:10])[CH:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[OH:15]
Reactant: S
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CS

Procedure:
This material was synthesized according to the procedure of Song (Song, J. U.S. Pat. No. 3,810,929) using 2,4-dimethyl-3-chloromethyl-6-t-butylphenol (160.8 g, 0.71 m), triethylamine (80 g), tetrahydrofuran (200 ml) and excess hydrogen sulfide. This afforded upon work-up a slightly yellow odorous oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](Cl)=[CH:4][C:3]=1[OH:12].[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[OH:12][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([S:23][C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:13](=[O:15])[CH3:14])=[CH:22][CH:21]=2)[CH:4]=1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Sc2cc(O)c(C)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 98.2 %

Procedure:
A mixture of 2-methyl-4-nitro-5-chloro phenol (1.5 g, 8.0 mmol), 4-Acetamido thiophenol (1.6 g, 8.8 mmol) and cesium carbonate (5.74 g, 17.6 mmol) in DMF (10 mL) was heated 2.5 h at 100° C. The mixture was cooled, diluted with ethyl acetate (100 mL) and the organic layer was washed with water and aqueous 10% sodium chloride solution, then, dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent removed under vacuum leaving N-[4-(5-Hydroxy-4-methyl-2-nitro-phenylsulfanyl)-phenyl]-acetamide as a solid (2.5 g, 81%). A solution of N-[4-(5-Hydroxy-4-methyl-2-nitro-phenylsulfanyl)-phenyl]-acetamide (2.5 g, 6.45 mmol), iron powder (1.79 g, 32 mmol) and ammonium chloride (0.514 g, 9.6 mmol) in a methanol (10 mL), tetrahydrofuran (10 mL), and water (5 mL) solution was heated to reflux for 1.5 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide N-[4-(2-Amino-5-hydroxy-4-methyl-phenylsulfanyl)-phenyl]-acetamide (1.7 g, 91%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[CH3:26][C:27]([O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=1[C:36]([OH:38])=[O:37])=[O:28]>>[C:27]([O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=1[C:36]([O:38][C:4]1([N:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:37])(=[O:28])[CH3:26]
Reactant: ON=C1CCOCC1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CC(=O)Oc1ccccc1C(=O)OC1(N=O)CCOCC1

Procedure:
4-Nitrosotetrahydro-2H-pyran-4-yl 2-(acetyloxy)benzoate was prepared from tetrahydro-pyran-4-one oxime, lead tetraacetate and Aspirin using conditions of General Method 3. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.15 (1H, dd, 7.8, 1.5 Hz), 7.65 (1H, td, 7.8, 1.5 Hz), 7.40 (1H, t, 7.6 Hz), 7.17 (1H, d, 8.1 Hz), 4.08 (2H, dt, 11.6, 4.1 Hz), 3.79 (2H, td, 11.5, 2.4 Hz), 2.21-2.29 (5H, m), 1.96-1.99 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([C:27]2([O:33][CH2:34][CH3:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([C:27]2([O:33][CH2:34][CH3:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: CCOC1(c2ccc(I)cc2)CCOCC1
Product: CCOC1(c2ccc(/C=C/CC(NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)CCOCC1
Yield: 68.1 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (60.4 mg) was reacted with tetrahydro-4-(4-iodophenyl)-4-ethoxy-2H-pyran (66.4 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(4-ethoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid methyl ester (68.9 mg). Column chromatography (silica gel, eluent: cyclohexane/chloroform=2/1 cyclohexane/ethyl acetate=4/1) was used for purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][O:32][CH2:31]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH:30]3[CH2:34][CH2:33][O:32][CH2:31]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: BrCCCC1CCOC1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCC1CCOC1

Procedure:
Prepared similarly to Intermediate 216 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(3-bromopropyl)tetrahydrofuran.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[C@H:10]([C:12]([OH:14])=O)[CH3:11])=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21])#[N:2].[CH2:24]([NH2:26])[CH3:25]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][C:16]([F:18])([F:17])[F:19])[C@H:10]([C:12]([NH:26][CH2:24][CH3:25])=[O:14])[CH3:11])=[CH:5][C:4]=1[C:20]([F:22])([F:21])[F:23])#[N:2]
Reactant: CCN
Reactant: C[C@@H](C(=O)O)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Product: CCNC(=O)[C@H](C)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)alanine and ethylamine: 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=8.8 Hz, 1H), 7.10 (d, J=2.7 Hz, 1H), 6.96 (dd, J=8.8, 2.8 Hz, 1H), 5.95 (bs, 1H), 4.26 (q, J=7.1 Hz, 1H), 4.10 (m, 2H), 3.28 (m, 2H), 1.58 (d, J=7.1 Hz, 3H), 1.06 (t, J=7.4 Hz, 3H).