Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[CH3:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[N:37][CH:38]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:36]3[CH:35]=[CH:34][C:33]([CH3:32])=[CH:38][N:37]=3)(=[O:41])=[O:40])=[O:31])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: Cc1ccc(S(N)(=O)=O)nc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
A mixture of phenyl 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylcarbamate (203 mg, 0.50 mmol), 5-methylpyridine-2-sulfonamide (86 mg, 0.50 mmol) and DBU (82 μL, 0.55 mmol) in acetonitrile (5 mL) was stirred for overnight at ambient temperature. Then, the volatile components were removed by evaporation and the residue was dissolved in dichloromethane. The organic phase was washed with water, dried (MgSO4) and concentrated. The residue was purified by TLC with dichloromethane/methanol (10:1) to afford 145 mg (60%) of the title compound as white solids: MS (ESI) m/z 490 [M+H]+, 488 [M−H]−, 1H-NMR (DMSO-d6) δ 1.18 (3H, t, J=7.5 Hz), 2.37 (3H, s), 2.72-2.90 (4H, m), 3.23 (2H, q, J=6.0 Hz), 6.69 (1H, br), 7.40-7.59 (6H, m), 7.85-7.93 (4H, m), 8.24 (1H, s), 8.55 (1H, s).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:11][OH:12])[CH:7]=[C:8]([F:10])[CH:9]=1.CI.N[C@H:16](C(O)=O)CCSC>CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([CH2:11][O:12][CH3:16])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: CSCC[C@H](N)C(=O)O
Reactant: OCc1cc(F)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COCc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 231.1 %

Procedure:
NaH (60% dispersion in mineral oil, 245 mg, 6.12 mmol) was added to a solution of (3-bromo-5-fluorophenyl)methanol (1.195 g, 5.83 mmol) in 2-Me THF (20 mL). After gas evolution had ceased, MeI (0.455 mL, 7.29 mmol) was added and the resulting mixture was stirred at r.t. for 16 h. Another portion of NaH (50 mg, 2.1 mmol) and Met (0.10 mL, 1.6 mmol) were added and the mixture was heated to 60° C. for 2 h. The cooled mixture was diluted with EtOAc, washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (gradient of 0-15% EtOAc in heptane) to give 0.810 g (63% yield) of the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.30 (s, 3H), 4.38-4.46 (m, 2H), 7.18 (m, 1H), 7.37 (s, 1H), 7.44-7.50 (m, 1H); MS (EI) m/z 218 M′.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[CH:12]=[C:11]([O:20]S(C(F)(F)F)(=O)=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O.Cl>[C:1]([O:5][C:6](=[O:28])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[CH:12]=[C:11]([OH:20])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cc(OS(=O)(=O)C(F)(F)F)cc2c1CCCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)COc1cc(O)cc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
To a solution of (5-oxo-3-trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (XXIX, 140 mg, 0.33 mmol) in tetrahydrofuran (5 mL) was added a 1.0 M solution of tetrabutylammonium fluoride (660 μL, 0.66 mmol) in tetrahydrofuran at room temperature under nitrogen. The resulting light yellow solution was stirred for 5 h at room temperature, and then diluted with water (10 mL) and 1.0N hydrochloric acid (5 mL). The mixture was extracted with ethyl acetate (2×35 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by ISCO (40 g) column chromatography (gradient elution with 5-50% ethyl acetate in hexanes) to provide (3-hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (82 mg, 85%) as a yellow solid: ES(+)-HRMS m/e calcd. for C16H20O5 (M+H)+293.1384, obsd. 293.1383.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)(=[O:13])/[CH:10]=[CH:11]/[CH3:12].CS(O)(=O)=O>O>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:8][CH:11]([CH3:12])[CH2:10][C:9]2=[O:13]
Reactant: Oc1ccc(F)cc1
Reactant: C/C=C/C(=O)O
Agent: CS(=O)(=O)O
Solvent: O
Product: CC1CC(=O)c2cc(F)ccc2O1
Temperature: 92 °C

Procedure:
A mixture of 56.1 g (0.5 mol) 4-fluorophenol, 172 g (2 mol) crotonic acid and 1120 ml methane sulfonic acid was heated at 92° C. for 20 hours. The reaction was cooled to 0° C., poured onto 2 liters ice and 2 liters water and extracted with 3×800 ml diethyl ether. The combined organic layers were washed with 3×500 ml water, 4×500 ml 1N sodium hydroxide, 2×500 ml water and 500 ml brine, dried over magnesium sulfate and concentrated in vacuo to give 48.5 g crude solid. The latter was purified by flash chromatography on 1000 cc silica gel using diethyl ether:hexane (1:10) as eluant. The title compound was obtained as a yellow solid, 37 g (41%); m.p. 65°-68° C. The Chemical Abstracts Registry Nos. for this compound are 88754-96-5 and 82320-16-9.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]([N:12]1[C:20]2[C:15](=[C:16]([CH2:21]O)[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C([O-])(O)=O.[Na+]>CCOCC.C(Cl)Cl>[Br:2][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]2[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: BrP(Br)Br
Reactant: CC(C)(C)OC(=O)n1ccc2c(CO)cccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ccc2c(CBr)cccc21
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
PBr3 (2.4 mL. 25.8 mmol) was added dropwise at 0° C. under nitrogen to a stirred solution of tert-butyl 4-(hydroxymethyl) 1H-1-indolecarboxylate 6 (6.0 g, 24.3 mmol) in ether (80 mL) and CH2Cl2 (20 mL) under nitrogen. The reaction was completed 30 minutes after the addition. The mixture was poured into a cold aqueous NaHCO3 solution (100 mL) and extracted with ethyl acetate (3×80 mL). The combined extract was washed sequentially with water (80 mL), and brine (80 mL), then dried (MgSO4), filtered, and finally concentrated to provide tert-butyl 4-(bromomethyl)-1H-1-indolecarboxylate 7 (6.3 g, 84%) as an oil which was immediately taken to the next step.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][O:13][CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][O:13][CH3:14])[CH:3]=2)=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26]
Reactant: COCc1cc(F)ccc1C(=O)OC
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Product: COCc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)ccc1C(=O)OC
Yield: 33 %

Procedure:
Prepared according to Preparation 1 using methyl 4-fluoro-2-(methoxymethyl)benzoate (Preparation 35) and 4-chloro-3-(trifluoromethyl)phenol at 120° C. for 48 hours. The title compound was isolated after purification using silica gel column chromatography eluting with 0-10% EtOAc in heptane as a colourless oil (0.140 g, 0.000374, 33% yield).
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH:19]1[CH2:24][CH2:23][CH:22]=[CH:21][O:20]1>C1C=CC=CC=1>[CH3:17][O:18][C:19]1([O:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: COC1CCC=CO1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: c1ccccc1
Product: COC1(OC(C(=O)c2ccccc2)c2ccccc2)CCCCO1
Yield: 87.4 %

Procedure:
85 parts of benzoin are reacted with 68.4 parts (50% molar excess) of 2-methoxy-2,3-dihydro-4H-pyran in 120 parts by volume of benzene, analogously to Example 1. The resulting benzoin 2-methoxy-tetrahydropyranyl ether, obtained in a yield of 87.4% of theory, boils at 195° to 200° C/0.3 mm Hg and has the following structure: ##STR7## NMR spectrum (in CDCl3): δ = 1.0 -2.4 (multiplet, 6 protons)
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:9][C:10]1[C:11](=[O:18])[CH:12]=[C:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:18][C:11]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:12]=[C:13]([CH3:17])[C:14](=[O:16])[CH:15]=[C:10]1[CH3:9]
Reactant: CCOC(=O)C[Zn]Br
Reactant: CC1=CC(=O)C(C)=CC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C=C(C)C(=O)C=C1C
Yield: 87 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.45 g (3.33 mmol) of 2,5-dimethyl-p-benzoquinone in 3 mL of THF was added dropwise while stirring at. 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3, 1/2) afforded 0.65 g of the desired product (yield 87%).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=O)[C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[CH:16]=[CH:17][C:18]=3[O:19][C:10]=2[CH:9]=[CH:8][N:7]=1.[CH3:29][Mg]Br.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1.C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:28][C:2]([CH3:1])([CH3:27])[CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[CH2:29])[C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[CH:16]=[CH:17][C:18]=3[O:19][C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: CC(C)(C)CCOc1nccc2oc3ccc(-c4cncnc4)cc3c(=O)c12
Reactant: C[Mg]Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C=C1c2cc(-c3cncnc3)ccc2Oc2ccnc(OCCC(C)(C)C)c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-(3,3-dimethylbutoxy)-8-(pyrimidin-5-yl)-10H-chromeno[3,2-c]pyridin-10-one (0.320 g, 0.852 mmol) in THF (8.00 mL) was cooled to 0° C. and methylmagnesium bromide (3.0 M in diethyl ether) (0.483 mL, 1.449 mmol) was added dropwise. The mixture stirred at 0° C. for 1 h. The mixture was quenched at 0° C. with saturated aqueous ammonium chloride solution and diluted with EtOAc. The aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow film. This material was dissolved in chloroform (8.00 mL), pyridinium p-toluenesulfonate (10.71 mg, 0.043 mmol) was added, and the mixture was heated at reflux for 2 h. The reaction mixture was diluted with DCM and the solution was partitioned between DCM and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1-(3,3-dimethylbutoxy)-10-methylene-8-(pyrimidin-5-yl)-10H-chromeno[3,2-c]pyridine as a yellow solid. MS m/z=374.2 [M+H]+. Calcd for C23H23N3O2: 373.4.
Reaction SMILES: CN(C)C=O.O[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]1[C:16]([F:19])([F:18])[F:17].S(Cl)([Cl:22])=O>>[Cl:22][C:13]1[CH:14]=[C:15]2[NH:7][C:8]([C:16]([F:19])([F:18])[F:17])=[N:9][C:10]2=[N:11][CH:12]=1
Reactant: On1c(C(F)(F)F)nc2ncccc21
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: FC(F)(F)c1nc2ncc(Cl)cc2[nH]1

Procedure:
Dimethylformamide (2 milliliters) was added to 4 grams of 1-hydroxy-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine in 10 milliliters of thionyl chloride. The resulting reaction mixture was heated on a steam bath overnight. Solvent was removed and the residue shaken with 50 milliliters of water and filtered. The residue was then taken up in sodium hydroxide solution, filtered and acidified to pH 3, shaken with three 150-milliliter portions of diethyl ether, and dried over magnesium sulfate. Solvent was evaporated, yielding the desired 6-chloro-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine, m.p., 290°-2° C., with sublimation from 260° C.
Reaction SMILES: [OH:1][C@@:2]([CH2:51][CH2:52][CH3:53])([C@@H:10]([C:28](N1[C@@H](C(C)C)C(C2C=CC=CC=2)(C2C=CC=CC=2)OC1=S)=[O:29])/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH2:54][C@@H:55]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([O:67][CH2:68][C:69]#[C:70][CH3:71])=[CH:63][CH:62]=1)[C:56]([O:58][CH3:59])=[O:57]>ClCCl>[CH2:68]([O:67][C:64]1[CH:63]=[CH:62][C:61]([CH2:60][C@H:55]([NH:54][C:28]([C@@H:10](/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])=[O:20])[C@@:2]([OH:1])([CH2:51][CH2:52][CH3:53])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:29])[C:56]([O:58][CH3:59])=[O:57])=[CH:66][CH:65]=1)[C:69]#[C:70][CH3:71]
Reactant: CCC[C@@](O)(C(=O)OC(C)(C)C)[C@H](/C=C/CCCCCNC(=O)OCC[Si](C)(C)C)C(=O)N1C(=S)OC(c2ccccc2)(c2ccccc2)[C@@H]1C(C)C
Reactant: CC#CCOc1ccc(C[C@H](N)C(=O)OC)cc1
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCNC(=O)OCC[Si](C)(C)C)[C@@](O)(CCC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 40 °C
Yield: 8.1 %

Procedure:
tert-Butyl (E)-(2S,3S)-2-hydroxy-3-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidine-3-carbonyl)-2-propyl-10-(2-trimethylsilanyl-ethoxycarbonylamino)-dec-4-enoate (582 mg, 0.759 mmol) and methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate (376 mg, 1.52 mmol) were dissolved in dichloromethane (10 mL), and dichloromethane was then distilled off under reduced pressure. The obtained mixture was warmed at 40° C. for 41 hours. The reaction mixture was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 443 mg (0.0618 mmol, 81% yield) of tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-propyl-10-(2-trimethylsilanyl-ethoxycarbonylamino)-dec-4-enoate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:10](=[O:26])[CH:11]=[CH:12][N:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[C:14]3[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:4]([F:27])[CH:3]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.CCO.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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:8][C:6]1[CH:7]=[C:2]([C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)[CH:3]=[C:4]([F:27])[C:5]=1[C:9]1[C:10](=[O:26])[CH:11]=[CH:12][N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: O=c1ccn2c(-c3ccc(F)cc3)cccc2c1-c1c(F)cc(Br)cc1F
Reactant: OB(O)c1cncnc1
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: CCO
Solvent: Cc1ccccc1
Product: O=c1ccn2c(-c3ccc(F)cc3)cccc2c1-c1c(F)cc(-c2cncnc2)cc1F
Temperature: 90 °C

Procedure:
To a solution of 1-(4-bromo-2,6-difluorophenyl)-6-(4-fluorophenyl)-2H-quinolizin-2-one Example 44, 74 mg, 0.17 mmol) in toluene (5 mL) was added pyrimidin-5-ylboronic acid (42 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium (196 mg, 0.017 mmol), EtOH (0.5 mL) and 2N Na2CO3 (0.5 mL), and heated to 90° C. for 12 h. After cooling the reaction to room temperature, the mixture was concentrated. The crude residue was dissolved in EtOAc and washed with water, brine, dried over MgSO4, and concentrated. The crude material was purified using silica gel chromatography (CH2Cl2/EtOAc/MeOH) to give title compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[C:17]([Br:19])[N:16]=[CH:15][C:14]=1[NH:20][C@@H:21]([CH3:24])[CH2:22][OH:23]>N1C=CC=CC=1>[Br:19][C:17]1[CH:18]=[C:13]([NH:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:14]([NH:20][C@@H:21]([CH3:24])[CH2:22][OH:23])=[CH:15][N:16]=1
Reactant: C[C@@H](CO)Nc1cnc(Br)cc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(Br)ncc2N[C@@H](C)CO)cc1
Temperature: 0 °C
Yield: 48.2 %

Procedure:
p-Toluenesulfonyl chloride (0.022 g, 0.114 mmol) was added to a 0° C. solution of (S)-2-(4-amino-6-bromopyridin-3-ylamino)propane-1-ol (0.028 g, 0.114 mmol) in pyridine (2.0 mL). The reaction mixture stirred at 0° C. and was allowed to warm to room temperature over 16 h. A second portion of p-toluenesulfonyl chloride (0.022 g, 0.114 mmol) was added, and the mixture stirred at room temperature overnight. The mixture was concentrated and the residue was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford a purple solid. This material was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 0-5% methanol-ethyl acetate) to afford (S)-N-(2-bromo-5-(1-hydroxypropan-2-ylamino)pyridin-4-yl)-4-methylbenzenesulfonamide (0.022 g, 48%) as a purple solid. MS (ESI, pos. ion) m/z 400, 402.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:9][OH:10].C([O-])(=O)C.[Na+]>C(O)C>[CH:1](=[N:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1cccnc1

Procedure:
Nicotinaldehyde oxime was prepared in quantitative yield by the reaction of nicotinaldehyde with hydroxylamine and sodium acetate in ethanol as for 20.
Reaction SMILES: C([O:3][C:4](=[O:22])[C@H:5]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])C>C(O)C>[NH:6]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:5]([C:4]([OH:22])=[O:3])[CH2:17][CH2:18][C:19](=[O:20])[OH:21]
Reactant: CCOC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Solvent: CCO
Product: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O

Procedure:
N-Benzyloxycarbonyl-glutamic acid-α-ethyl ester. 113 g (0.43 mol) of Z-glu anhydride is dissolved in one liter of anhydrous ethanol and refluxed for 15 hours. The α- and γ-monoethyl esters of Z-Glu are thus formed successively in a ratio of 1:2. The reaction solution is concentrated in vacuo, the oily residue dissolved with 250 ml of anhydrous ether, 78 g of distilled dicyclohexylamine is added, and the mixture is let stand for 2 days in the refrigerator. The crystallizate of the α- and γ-ester.dicyclohexyl ammonium salts is removed with a suction filter and the mother liquor is concentrated in vacuo to recover Z-glu and saponified for 5 hours with 2N NaOH in dioxane at pH 10.5 on the autotitrator. The dicyclohexylammonium salt mixture is dissolved in 300 ml of ethanol to recover the alpha ester, and approximately 1.5 liters of petrol ether (40° C.) is added until turbidity is produced. It is desirable to add a small amount of previously prepared α-ester.dicyclohexylammonium salt as seed crystals. The α-ester.DCA salt crystallizes uniformly (virtually pure on tlc) at 20° C. in the time period from 0.5 to 4 hours, and is recrystallized two more times from ethanol to which petrol ether (40° C.) is added in a ratio of 1:5 until turbidity occurs. All of the mother liquors are worked up as described above for the recovery of Z-Glu. Yield of Z-Glu-α-ethyl ester.DCA salt 34 g (30%) m.p. 154° C. (from a mixture of ethanol and petrol ether (40° C.). RF value in a 7:1 mixture of benzene and glacial acetic acid: 0.50.
Reaction SMILES: O.O.O.C([O-])(=O)C.[Na+].[CH2:9]([O:12][N:13]=[C:14]([C:42]1[N:43]=[C:44]([NH:47]C(=O)C(F)(F)F)[S:45][CH:46]=1)[C:15]([NH:17][CH:18]1[C:40](=[O:41])[N:20]2[C:21]([C:37]([OH:39])=[O:38])=[C:22]([CH2:25][S:26][C:27]3[N:31]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[N:30]=[N:29][N:28]=3)[CH2:23][S:24][C@H:19]12)=[O:16])[C:10]#[CH:11].Cl>O>[CH2:9]([O:12][N:13]=[C:14]([C:42]1[N:43]=[C:44]([NH2:47])[S:45][CH:46]=1)[C:15]([NH:17][CH:18]1[C:40](=[O:41])[N:20]2[C:21]([C:37]([OH:39])=[O:38])=[C:22]([CH2:25][S:26][C:27]3[N:31]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[N:30]=[N:29][N:28]=3)[CH2:23][S:24][C@H:19]12)=[O:16])[C:10]#[CH:11]
Reactant: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCC(=O)O)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCC(=O)O)CS[C@H]12)c1csc(N)n1
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A solution of sodium acetate trihydrate (5.97 g) in water (25 ml) was added to 7-[2-(2-propynyloxyimino)-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (3.0 g) and the mixture was stirred overnight. The reaction mixture was adjusted to pH 3 with 10% hydrochloric acid under ice-cooling and precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.80 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:4]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:5]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[N:4]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)nc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 2-(methoxy)-6-(4-chlorophenyl)-5-(phenyl)pyridine-3-carboxylate (150 mg, 0.42 mmol) from Example 5 in methanol (5 mL) was added 5N sodium hydroxide (0.42 mL, 2.1 mmol). The reaction was stirred at rt for 72 h and was then diluted with water and acidified with 2N hydrochloric acid. The mixture was extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title product as a white solid.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[C:9](=[O:18])[NH:8][C:7]1=[O:19].Cl>O1CCCC1>[CH3:17][C:15]1[N:16]=[C:12]([C:10]2[C:9](=[O:18])[NH:8][C:7](=[O:19])[N:6]([CH2:5][CH2:4][CH:3]=[O:2])[CH:11]=2)[S:13][CH:14]=1
Reactant: COC(CCn1cc(-c2nc(C)cs2)c(=O)[nH]c1=O)OC
Agent: Cl
Solvent: C1CCOC1
Product: Cc1csc(-c2cn(CCC=O)c(=O)[nH]c2=O)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-[3,3-bis(methyloxy)propyl]-5-(4-methyl-1,3-thiazol-2-yl)-2,4(1H,3H)-pyrimidinedione (Pre 44, 34 mg, 0.109 mmol) in Tetrahydrofuran (THF) (1.5 ml) 1M aqueous HCl (0.546 ml, 0.546 mmol) was added and the mixture was stirred at rt for 5 hrs. Other 1M aqueous HCl (0.273 ml, 0.273 mmol) was added and the mixture was stirred at rt overnight. Volatiles were evaporated (rotary, cold bath) and the residue was taken up with TEA (0.122 ml, 0.874 mmol) and THF (3 mL). The slurry was evaporated to dryness (rotary) to afford a crude that was used in the next reaction step assuming quantitative conversion to target compound (0.109 mmol) without any further purification