Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](Br)=[C:5]([CH3:7])[N:6]=1.[C:9]1([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][SH:23])[CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:30]>CN(C)C=O.CO>[ClH:30].[NH2:1][C:2]1[S:3][C:4]([S:23][CH2:22][CH2:21][N:18]2[CH2:17][CH2:16][CH:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:20][CH2:19]2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(N)sc1Br
Reactant: SCCN1CCC(c2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1nc(N)sc1SCCN1CCC(c2ccccc2)CC1
Temperature: 0 °C

Procedure:
9.65 g of 2-amino-5-bromo-4-methylthiazole, 11.1 g of 2-(4-phenyl-1-piperidinyl)ethyl mercaptan and 20.7 g of potassium carbonate in 50 ml of dimethylformamide were stirred at 80° C. for 30 minutes. The mixture was poured into ice-water and extracted with methylene chloride, and the organic phase was washed with water, dried and concentrated. The residue was purified by chromatography (SiO2 ; CH2Cl2, CH3OH (0-20%)). The hydrochloride was prepared by dissolving the free base in methanol and adding ethereal HCl.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1Cl.[CH2:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=Cc1ccccc1
Reactant: COC(=O)c1cccnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1C=Cc1ccccc1
Yield: 82.1 %

Procedure:
To a solution of the ester 18 (48.8 g, 0.28 mol) in DMF (450 mL) was added styrene (165 mL, 1.42 mol), palladium acetate (6.5 g, 30 mmol), sodium acetate (47 g, 0.57 mol) and triphenyl phosphine (30 g, 0.11 mol). The mixture was heated under reflux for 22 h. The palladium-catalyst was removed by filtration through a Celite pad. The filtrate was concentrated under reduced pressure, and the residue was dissolved in a minimum amount of ethyl acetate. To the above solution was added hexane. After removal of the precipitate by filtration, the filtrate was concentrated. The resulting crude material was purified by FCC (1:1 v/v ethyl acetate-hexane) to afford the ester 19 (55.0 g, 81%) as a light yellow oil:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1>CO.[C].[Pd]>[NH2:9][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:8]
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(O)c1N
Reaction time: 96 h
Yield: 98.6 %

Procedure:
In methanol (20 ml), 10% palladium-carbon (0.30 g, 20 wt %) was added to 3-methyl-2-nitrophenol (1.50 g, 9.80 mmol) and they were subjected to catalytic hydrogenation for 4 days. From the reaction mixture, an insoluble matter was filtered off through Celite. The filtrate was distilled under reduced pressure to remove the solvent to give 2-amino-3-methylphenol (1.19 g, 99%) as a brown oil.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:5][OH:6].[OH-].[K+].C1C[O:18][CH2:17]C1.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl>O.CCOC(C)=O>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C@H:4]1[CH2:5][O:6][C:17](=[O:18])[NH:3]1
Reactant: C1CCOC1
Reactant: N[C@H](CO)c1ccccn1
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1N[C@@H](c2ccccn2)CO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 21 %

Procedure:
To a solution of (S)-2-amino-2-(pyridin-2-yl)ethanol bis hydrochloride (0.80 g, 5.8 mmol) in water (50 mL) cooled to 0° C. was added potassium hydroxide (2.6 g, 46 mmol) and the reaction stirred at 0° C. for 15 minutes, followed by the addition of THF (100 mL) and the reaction cooled to 0° C. To the reaction was next added bis(trichloromethyl) carbonate (1.7 g, 5.8 mmol) and the reaction stirred at 0° C. for 2 hours. The reaction was diluted with EtOAc (300 mL) and the layers were separated. The organic layer was washed with water (100 mL) and brine (100 mL), dried over MgSO4 and concentrated in vacuo. The crude material was chromatographed using EtOAc as eluent to yield (S)-4-(pyridin-2-yl)oxazolidin-2-one (0.20 g, 21%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH:13][CH2:14]CO)=[N:8][C:7]([CH3:17])=[C:6]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:24][O:25][CH2:26][CH2:27]CN>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH:13][CH2:14][CH2:27][CH2:26][O:25][CH3:24])=[N:8][C:7]([CH3:17])=[C:6]2[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COCCCN
Reactant: COc1ccc2c(NCCO)nc(C)c(-c3ccccc3)c2c1
Product: COCCCNc1nc(C)c(-c2ccccc2)c2cc(OC)ccc12

Procedure:
Following the procedure for 2-[(6-methoxy-3-methyl-4-phenylisoquinolin-1-yl)amino]ethanol, using (in Step B) 3-methoxy-1-aminopropane in place of ethanolamine, the titled compound was synthesized.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][C:6]=2[CH:5]=[C:4]([Cl:21])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)CCC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]2[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][C:6]=2[CH:5]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(Br)c2OC1C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(-c3ccccc3)c2OC1C(F)(F)F
Temperature: 110 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
A mixture of ethyl 6-chloro-8-bromo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 74, Step 1)(2.0 g, 5.2 mmol), tetrakis(triphenylphosphine) palladium(0) (2.15 g, 1.7 mmol), triphenylphosphine (0.013 g, 0.05 mmol), and tributylphenyltin (1.9 mL, 5.7 mmol) in toluene (60 mL) was heated to 110° C. for 3 days. The reaction mixture was allowed to cool to room temperature and filtered through a plug of silica gel eluting with 25% ethyl acetate in hexanes. The filtrate was concentrated in vacua and then purified by flash chromatography (silica gel, ethyl acetate-hexanes, 1:9). The fractions containing desired product were combined and concentrated in vacua. To remove the remaining tin impurities the mixture was taken up in THF (10 mL) and aqueous ammonium fluoride solution (10 wt %, 20 mL) and stirred at room temperature for 2 hours. The solution was extracted with ethyl acetate. The extracts were combined, dried over MgSO4, filtered, and concentrated in vacua to afford the ester as an oil (1.30 g, 65%). 1H NMR(CDCl3/300 MHz) 7.67 (s, 1H),7.47–7.36 (m, 5H), 7.31 (d, 1H, J=2.6 Hz), 7.18 (d, 1H, J=2.4 Hz), 5.69 (q, 1H, J=6.8 Hz), 4.30 (m, 2H), 1.33 (t, 3H, J=7.1 Hz). 19FNMR (CDCl3/282 MHz) d −78.27 (d, J=7.2 Hz). FABLRMS m/z 383 (M+H). ESHRMS m/z 400.0937 (M+NH4, Calc'd 400.0927)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([O:20][CH3:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][CH:7]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:22])[CH:4]([O:20][CH3:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(Cc1ccc(O)cc1)OC
Yield: 86.8 %

Procedure:
3-(4-Benzyloxyphenyl)-2-methoxypropanoic acid methyl ester (1.91 g; 6.36 mmole) was hydrogenated in methanol (30 ml) using Pd/C (5%, wet, 0.9 g) as catalyst. The mixture was filtered through celite and the filtrate was evaporated in vacuo to give 1.16 g (yield 87%) of 3-(4-hydroxyphenyl)-2-methoxypropanoic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18](F)[C:17]([C:21]#[N:22])=[C:16]([F:23])[CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[C:18]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:17]([C:21]#[N:22])=[C:16]([F:23])[CH:15]=2)[CH2:12][CH2:13]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: OCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(F)c(C#N)c(F)c2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(F)c(C#N)c(OCCN3CCOCC3)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
To a solution of 0.10 g (0.30 mmol) of [1-(4-cyano-3,5-difluoro-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 0.040 mL (0.33 mmol) of 4-(2-hydroxyethyl)-morpholine in THF (15 mL), cooled to 0° C., was added 0.60 mL (0.60 mmol) of sodium bis(trimethylsilyl)amide as a 1.0 M solution in THF. The reaction was stirred at 0° C. for 30 min then warmed to 60° C. for 6 h. The reaction was cooled to room temperature and excess base was consumed by the addition of a saturated aqueous solution of NH4Cl. The mixture was diluted with H2O and washed with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash silica gel chromatography to provide 0.081 g (61%) of {1-[4-cyano-3-fluoro-5-(2-morpholin-4-yl-ethoxy)-phenyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as a white foam.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:15])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1.[S:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.C([O-])(=O)C.[K+]>CN(C)C(=O)C.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>[F:14][C:10]1[CH:9]=[C:8]([C:7]2[N:6]=[C:5]([NH2:15])[CH:4]=[N:3][C:2]=2[C:20]2[S:16][CH:17]=[N:18][CH:19]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cnc(Br)c(-c2cccc(F)c2)n1
Reactant: c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1cnc(-c2cncs2)c(-c2cccc(F)c2)n1
Temperature: 150 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
A mixture of 5-bromo-6-(3-fluorophenyl)pyrazin-2-amine (Preparation 1, 100 mg, 0.37 mmol), thiazole (0.06 mL, 0.88 mmol) and potassium acetate (54 mg, 0.56 mmol) in N,N-dimethylacetamide (1 mL) was degassed with argon. The catalyst Pd(PPh3)4 (23 mg, 0.02 mmol, 5 mol %) was added and degassing was repeated. The mixture was heated to 150° C. in a sealed tube and stirred overnight. The mixture was cooled and ethyl acetate and aqueous NH4Cl were added. The aqueous layer was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by flash silica gel chromatography (hexanes/EtOAc 1:1) to give the title compound (15 mg, 15%) as a yellow solid.
Reaction SMILES: [C@H:1]1([O:12][C@H:13]2[C@H:24]([OH:25])[C@@H:23]([CH2:26][OH:27])[O:22][C@H:15]([O:16][CH2:17][CH2:18][N:19]=[N+]=[N-])[C@H:14]2[OH:28])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]>O.CO.[Pd]>[C@H:1]1([O:12][C@H:13]2[C@H:24]([OH:25])[C@@H:23]([CH2:26][OH:27])[O:22][C@H:15]([O:16][CH2:17][CH2:18][NH2:19])[C@H:14]2[OH:28])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: [N-]=[N+]=NCCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: NCCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 50 mL round bottom flask, 2-azidoethyl 3-O-α-D-mannopyranosyl-α-D-mannopyranoside (139 mg, 0.338 mmol) was dissolved in water/CH3OH (v/v 1:1, 5 mL). To the above solution was added Pd/C (10%, 36 mg, 0.034 mmol). The reaction mixture was stirred at 25° C. under H2 balloon for 18 hr. The mixture was filtered through a pad of Celite, and the filtrate was concentrated to give the title compound. LC-MS Method A: m/e=386.08 [M+1]; Rt=0.24 min.
Reaction SMILES: Br[C:2]1([CH2:10][C:11]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:6](=[O:7])[O:5][C:4]([CH3:9])([CH3:8])[O:3]1.N12CCCN=C1CCCCC2>O1CCCC1>[CH3:8][C:4]1([CH3:9])[O:5][C:6](=[O:7])/[C:2](=[CH:10]/[C:11]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])/[O:3]1
Reactant: CC1(C)OC(=O)C(Br)(CC(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OC(=O)/C(=C/C(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldiphenylsilyl ester (˜26 g, 52.4 mmol) in dry tetrahydrofuran (160 ml) was cooled to 0° C. and treated dropwise over 5 minutes with 1,8-diazabicyclo [5,4,0] undec-7-ene (12.7 g, 78.8 mmol) and the resulting mixture was stirred at 5° C. for 1.5 hour. The solid formed was filtered and washed with a small amount of tetrahydrofuran. The filtrate was used as such for the next step.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1[C:13]([OH:14])=CC=CC=1C.C(C1C=C(O)C=CC=1)C.C=O>C([O-])(=O)C.[Zn+2].C([O-])(=O)C.C([O-])=O.[Cd+2].C([O-])=O>[CH:4]1[CH:3]=[CH:2][C:1]([OH:7])=[C:6]([CH2:13][OH:14])[CH:5]=1
Reactant: Cc1cccc(O)c1
Reactant: Oc1ccccc1
Agent: C=O
Agent: CC(=O)[O-]
Agent: CCc1cccc(O)c1
Product: OCc1ccccc1O

Procedure:
Marchand and Grenet U.S. Pat. Nos. 3,290,352 and 3,290,393, patented Dec. 6, 1966, note that British Pat. No. 774,696 condenses phenol, meta-cresol or meta-ethylphenol with formaldehyde in aqueous medium in the presence of zinc acetate or cadmium formate. Starting with phenol, the best yield of pure saligenol obtained is 21%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[C:10]([O-])([O-])=[O:11].[K+].[K+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>O.C1(C)C=CC=CC=1>[C:4]([C@@H:5]1[CH2:7][O:8][C:10](=[O:11])[NH:6]1)([O:3][CH3:2])=[O:9]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1COC(=O)N1
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To (S)-serine methyl ester hydrochloride (20 g, 128.64 mmol) in water (230 ml) was added KHCO3 (14.16 g, 141.52 mmol) and K2CO3 (19.56 g, 141.52 mmol) at room temperature. It was then cooled by an ice bath and triphosgene (19.04 gm, 64.32 mmol) was added in toluene (192 ml) via an addition funnel over 25 minutes. The reaction mixture turned cloudy. After 2 h, reaction phases were separated and the aqueous layer was lyophilized to yield (S)-4-carbomethoxy-2-oxazolidinone as a white solid (16.5 g) in 88% yield.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1.Br[CH2:27][C:28]([O:30]CC)=[O:29].[OH-].[Na+]>CO>[C:28]([CH2:27][NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1)([OH:30])=[O:29]
Reactant: CCOC(=O)CBr
Reactant: N[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 6) in MeOH was added TEA (2.5 eq), followed by ethyl bromoacetate (1.2 eq). The reaction mixture was stirred at RT overnight. To this reaction mixture was then added 1N NaOH and stirred for 6 hr. After concentration in vacuo, 1N HCl was added to adjust pH to 1. The reaction mixture was purified using reverse phase HPLC to afford the title compound. ESI-MS m/z 405 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH3:2].[CH2:20](O)[CH2:21][CH2:22][OH:23]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([C:3]1[CH:4]=[C:5]([C:6]2([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:23][CH2:22][CH2:21][CH2:20][O:7]2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH3:2]
Reactant: OCCCO
Reactant: CCc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C2(c3ccccc3)OCCCO2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A suspension of 3-ethyl-4-nitro-benzophenone (11f) (20.0 g, 78.4 mmol), 1,3-propandiol (7.15 g, 94.0 mmol), p-toluenesulfonic acid monohydrate (50 mg) in toluene (300 mL) was refluxed using a Dean-Stark-trap for 24 hours. The Dean-Stark-trap was then replaced by a Soxhlet-extractor filled with molecular sieve and the mixture was refluxed for an additional 48 hours to achieve complete conversion. The reaction mixture was then cooled to ambient temperature, washed with an aqueous, saturated solution of NaHCO3 and concentrated in vacuo until crystallization started. The suspension was cooled for 0.5 hours in an ice bath and after which the crystalline product was filtered, washed with a small volume of hexane and air dried to give 22.48 g (72 mmol, 91.5%) compound 17 as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-])=O)=[CH:12][C:7]=2[NH:6][C:5](=[O:16])[CH:4]([NH:17][C:18](=[O:20])[CH3:19])[CH2:3]1.[CH3:22][NH:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[NH:31][C:32]1[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=1)=[O:25]>>[CH3:22][NH:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[NH:31][C:32]1[C:37]([Cl:38])=[CH:36][N:35]=[C:34]([NH:13][C:11]2[CH:10]=[CH:9][C:8]3[C:2]([CH3:21])([CH3:1])[CH2:3][CH:4]([NH:17][C:18](=[O:20])[CH3:19])[C:5](=[O:16])[NH:6][C:7]=3[CH:12]=2)[N:33]=1)=[O:25]
Reactant: CC(=O)NC1CC(C)(C)c2ccc([N+](=O)[O-])cc2NC1=O
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1sccc1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(C)=O)CC3(C)C)ncc1Cl

Procedure:
Title compound was prepared from N-(5,5-Dimethyl-8-nitro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-acetamide and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide in an analogous manner to Example 1221d. Title compound was isolated as a brown solid. (51 mg, 36%) MP=205-210, LCMS 530 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 11.70 (s, 1H), 9.80 (s, 1H), 9.63 (s, 1H), 8.47 (d, J=4.8 Hz, 1H), 8.26-8.24 (m, 2H), 8.08 (d, J=8.2 Hz, 1H), 7.76 (d, J=5.6 Hz, 1H), 7.47 (s, 1H), 7.35-7.30 (m, 2H), 4.32-4.29 (m, 1H), 2.78 (d, J=4.1 Hz, 3H), 2.14-2.10 (m, 1H), 1.94-1.90 (m, 1H), 1.87 (s, 3H), 1.38 (s, 3H), 1.27 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].[N:26]1[CH:27]=[C:28]([CH:35]=O)[N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=12>O1CCCC1.C(OCC)(=O)C>[N:26]1[CH:27]=[C:28](/[CH:35]=[CH:6]/[C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=12
Reactant: O=Cc1cnc2ccccn12
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cnc2ccccn12
Temperature: 65 °C
Yield: 51.4 %

Procedure:
(Ethoxycarbonylmethylene)triphenylphosphorane (0.72 g, 2.05 mmol) was added to a solution of imidazo[1,2-a]pyridine-3-carbaldehyde (0.25 g, 1.71 mmol) in anhydrous tetrahydrofuran (THF) (20 mL) at room temperature. The reaction mixture was heated overnight at 65° C. After completion of the reaction as indicated by HPLC, the reaction mixture was diluted with ethyl acetate (EtOAc) (20 mL) and quenched with a saturated solution of ammonium chloride (10 mL). The organic layer was washed with water (3×20 mL) and brine (15 mL). It was dried over anhydrous Na2SO4, filtered and evaporated to get the crude product. This crude was purified by silica gel column chromatography using 50-80% EtOAc in Hexanes to provide pure (E)-ethyl 3-(imidazo[1,2-a]pyridin-3-yl)acrylate (0.19 g) as a white solid. ES+(M+H)+217.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Si]([O:27][CH2:28][CH:29]1[CH2:33][C:32]([CH2:34]Br)=[CH:31][CH2:30]1)(C(C)(C)C)(C)C>>[OH:27][CH2:28][CH:29]1[CH2:33][C:32]([CH2:34][N:7]2[C:8]([S:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:31][CH2:30]1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)OCC1CC=C(CBr)C1
Product: CCc1c(Sc2cc(C)cc(C)c2)n(CC2=CCC(CO)C2)c(=O)[nH]c1=O
Yield: 21.4 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and (4-t-butyl-dimethylsilyloxymethylcyclopent-1-en-1-yl)methyl bromide were reacted by the same way with the example 6 to obtain the titled compound (48 mg).
Reaction SMILES: [CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].COCCOC(N=NC(OCCOC)=O)=O>ClCCl.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCCCCC[C@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCCCCC[C@@H](C)OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1.5 h

Procedure:
After (S)-2-octanol (300 mg, 2.30 mmol), triphenylphosphine (726 mg, 2.76 mmol), 4-nitrobenzoic acid (462 mg, 2.76 mmol), and dichloromethane (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (648 mg, 2.76 mmol) dissolved in dichloromethane (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 1.5 hours. Water (10 mL) was added, and separation was carried out. Then, the aqueous layer was extracted using dichloromethane (10 mL, ×1). The resulting organic layer was collectively washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 5% ethyl acetate-hexane solution) to give (R)-2-(4-nitrobenzoyloxy)octane as a pale yellow liquid substance (572 mg, yield: 89%/(S)-2-octanol).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:23][C@H:24]([CH2:29][OH:30])[CH2:25][CH:26]([CH3:28])[CH3:27]>>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:23][CH:24]([CH2:29][OH:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:9]
Reactant: O=C(O)c1cc(Br)c(OCc2ccccn2)nc1C(F)(F)F
Reactant: CC(C)C[C@H](N)CO
Product: CC(C)CC(CO)NC(=O)c1cc(Br)c(OCc2ccccn2)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1c, using 5-bromo-6-(pyridin-2-ylmethoxy)-2-trifluoromethyl-nicotinic acid and rac-leucinol as starting materials, MS (ISP) 476.1 (M+H)+.