Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:17][O:18][C:19](=[O:22])[CH2:20]Br.O>CC(C)=O>[CH3:17][O:18][C:19](=[O:22])[CH2:20][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)COc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Initially charge 50 g (359.4 mmol) of 3-nitrophenol and 175.67 g (539 mmol) of caesium carbonate in 1.0 liter of acetone and add 71.5 g (467.3 mmol) of bromoacetic acid methyl ester. Stir the mixture at 50° C. for 1 h and, after cooling, pour onto 7.5 liters of water. Stir the suspension for 30 min, then filter off with suction and wash the filter residue with water. Dry the solid in a drying cabinet at 50° C. and 100 mbar. 64.3 g (84.7% of theory) of the target compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][N:31]3[CH2:32][CH2:33][CH:28]([C:24]4[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=4)[CH2:29][CH2:30]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(Cl)cc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
A solution of 4-(4-chlorophenoxy)benzaldehyde (0.119 g, 0.510 mmol) and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (0.126 g, 0.510 mmol) in 1,2-dichloroethane (5.00 mL) was treated with sodium triacetoxyborohydride (0.424 g, 2.00 mmol) and HOAC (0.0300 mL, 0.500 mmol) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was neutralized with saturated NaHCO3 aqueous solution (10 mL) and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo and purified by preparative TLC plates using 5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product (53.0 mg, 23.0%): 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.34-7.19 (m, 7H), 6.98-6.87 (m, 5H), 3.50 (s, 2H), 2.98 (d, 2H, J=11.8 Hz), 2.58-2.44 (m, 2H), 2.10-1.98 (m, 2H), 1.83-1.76 (m, 4H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 463.2 (M+H)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][CH2:7][C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[N:12]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=[C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:22]=2)[CH:11]=1)=[O:9].Cl>O1CCCC1.CO.O>[Cl:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=[C:23]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:22]=1)[CH:11]=[C:10]2[C:8](=[O:9])[CH2:7][CH2:6][C:5]([OH:39])=[O:4]
Reactant: COC(=O)CCC(=O)c1cn(Cc2cc(-c3ccccc3)nc(-c3ccccc3)c2)c2ccc(Cl)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1cn(Cc2cc(-c3ccccc3)nc(-c3ccccc3)c2)c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 97 %

Procedure:
2N Sodium hydroxide solution (1.45 mL, 2.9 mmol) was added dropwise to a stirred solution of methyl-4-[5-chloro-1-(2,6-diphenyl-pyridin-4-ylmethyl)-1H-indol-3-yl]-4-oxobutyrate (254 mg, 0.5 mmol) in tetrahydrofuran (10 mL) and methanol (2 mL). The clear reaction mixture was stirred at room temperature until the reaction was complete (TLC control), and then diluted with water (10 mL), and acidified to pH 3 with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×20 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5-10% methanol in methylene chloride as eluent, afforded the title compound as a white solid (240 mg, 98%): Rf: 0.45 (10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 12.09 (1H, s, COOH), 8.80 (1H, s, ArH), 8.15 (1H, d, J=2 Hz, ArH), 8.09 (4H, m, ArH), 7.83 (2H, s, ArH), 7.69 (1H, d, J=8 Hz, ArH), 7.46 (6H, m, ArH), 7.24 (1H, dd, J=8, 2 Hz, ArH), 5.66 (2H, s, CH2N), 3.17 (2H, t, J=7 Hz, CH2CO), 2.59 (2H, t, J=7 Hz, CH2CO); ESI-LCMS e/z calculated for C30H23ClN2O3 494.976, found 495 [M+H (35Cl)]+, 497 [M+H (37Cl)]+, 517 [M+Na (35Cl)]+, 519 [M+Na (37Cl)]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH2:6][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([F:11])[CH:3]=1
Reactant: O=Cc1c(F)cc(Br)cc1F
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Fc1cc(Br)cc(F)c1CN1CCOCC1
Temperature: 59 °C
Yield: 37 %

Procedure:
A mixture of 4-bromo-2,6-difluorobenzaldehyde, available from Sigma-Aldrich, (500 mg, 2.26 mmol) and morpholine (0.198 ml, 2.26 mmol) was prepared in chloroform (10 ml) at room temperature and heated to 58-60° C. in a sealed tube for 1 h. The mixture was then cooled to room temperature and sodium triacetoxyborohydride (719 mg, 3.39 mmol) was added and the mixture heated again to 58-60° C. in a sealed tube for 60 h. The mixture was allowed to cool down to room temperature and then washed with water (5 ml), filtered through a phase separator and concentrated in vacuo. Crude 1HNMR (CDCl3) suggested an 8:2 mixture of the desired amine to the imine product. After initial chromatography (1-5% methanol/dichloromethane) which did not separate products, mixture was purified by preparative HPLC to afford 4-(4-bromo-2,6-difluorobenzyl)morpholine as a colourless oil (247 mg, 0.85 mmol, 37%).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:1][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:17])=[CH:14][CH:13]=1
Reactant: NC1CCc2ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Product: O=C(NC1CCc2ccccc21)c1ccc(F)cc1

Procedure:
The title compound was prepared from (rac)-1-aminoindan (1.7 g, 12.85 mmole) and 4-fluorobenzoyl chloride (2.24 g, 14.1 mmole) as in Ex. 52; 1.71 g(6.7 mmole, 52%), mp: 109-10° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH2:7][CH:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:9]1=[O:15].[C-:20]#[N:21].[Na+].Cl>CS(C)=O>[C:20]([CH2:2][CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH2:7][CH:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:9]1=[O:15])#[N:21]
Reactant: [C-]#N
Reactant: O=C1CCCC(=O)C1Cc1ccccc1CCCCl
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCc1ccccc1CC1C(=O)CCCC1=O
Temperature: 95 °C
Reaction time: 3 h

Procedure:
A mixture of 22 g (0.079 mol) of 2-[2-(3-chloropropyl)benzyl]-1,3-cyclohexanedione 3 and 15.5 g (0.316 mol) of NaCN in 250 ml of dry dimethyl sulfoxide was stirred at 95° C. for 3 hours. The reaction was filtered while hot to remove NaCl, and the dimethyl sulfoxide was distilled out under high vacuum. The residue was dissolved in 400 ml H2O, filtered through a diatomaceous earth filter aid (celite) to give a red solution and neutralized by the rapid addition of 40 ml concentrated HCl. The precipitate was recrystallized twice from ethyl acetate to give 16 g of the cyanodione, IIa, mp 143° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:9][C:8](N)=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].N([O-])=O.[Na+].[ClH:19]>O.[Cu]Cl>[Cl:19][C:8]1[S:9][C:10]2[C:2]([CH3:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Cc1c([N+](=O)[O-])ccc2nc(N)sc12
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc2nc(Cl)sc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Suspend 7-methyl-6-nitro-benzothiazol-2-ylamine (5.17 g, 24.7 mmol) in conc. HCl (70 mL) and water (70 mL). Add copper (1) chloride (542 mg, 5.47 mmol) followed by slow addition of sodium nitrite (17.4 g, 252 mmol). Stir at rt for 2 h and then add water (100 mL). Filter the solid and dry in a vacuum oven at 40° C. overnight to yield 4.45 g (79%) of the title compound: 1H NMR δH (400 MHz, DMSO) 8.16 (d, J=9.2 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 2.71 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:23])=[CH2:22]>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:21]([CH3:23])=[CH2:22])[CH2:31][CH2:32]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Reactant: C=C(C)c1ccccc1N1CCNCC1
Product: C=C(C)c1ccccc1N1CCN(C(=O)Nc2cc(C)c(C)nc2OC)CC1
Yield: 62 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(2-isopropenylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]3[N:22]=[C:23]4[C:29]([C:30]([OH:32])=O)=[CH:28][N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:24]4=[N:25][CH:26]=3)=[N:16][N:17]2[CH3:20])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:72][C@H:73]([CH3:80])[C:74]([NH:76][CH2:77][CH2:78][OH:79])=[O:75]>CN(C=O)C>[OH:79][CH2:78][CH2:77][NH:76][C:74]([C@H:73]([NH:72][C:30]([C:29]1[C:23]2[C:24](=[N:25][CH:26]=[C:21]([C:15]3[C:14]4[C:18](=[CH:19][C:11]([F:10])=[CH:12][CH:13]=4)[N:17]([CH3:20])[N:16]=3)[N:22]=2)[N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[CH:28]=1)=[O:32])[CH3:80])=[O:75]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@@H](N)C(=O)NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(=O)NCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
In a round-bottomed flask, (R)-2-amino-N-(2-hydroxy-ethyl)-propionamide trifluoroacetate (crude from Step 2) was dissolved in DMF (2 ml) and N,N-diisopropylethylamine (0.70 ml, 4.0 mmol) was added. Then 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (170 mg, 0.39 mmol) was added followed by HATU (161 mg, 0.42 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and diluted with petroleum ether. The resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-100% EtOAc) and MeOH/EtOAc (gradient 0-10% MeOH) to give 127 mg (59%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(2-hydroxy-ethylcarbamoyl)-ethyl]-amide as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][C:27]([OH:29])=O)[CH:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:36]N(C=O)C>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][CH:36]=[C:26]([C:22]1[CH:21]=[C:20]([C:14]3[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=3)[CH:25]=[CH:24][CH:23]=1)[C:27]2=[O:29]
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: COc1ccc(-c2cccc(CC(=O)O)c2)cc1OC
Reactant: CN(C)C=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COc1ccc(-c2cccc(-c3coc4cc(O)c(Cl)cc4c3=O)c2)cc1OC

Procedure:
This compounds was synthesised in the same manner as described above. 4-Chlororesorcinol (0.15 g, 1.0 mmol), (3′,4′-dimethoxy-biphenyl-3-yl)-acetic acid (0.28 g, 1 mmol), BF3Et2O (5 ml), PCl5 (0.32 g, 1.5 mmol), DMF (6 ml and 4 ml). The white precipitate formed was shown to contain the required compound and was taken directly onto the next stage.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]([CH3:14])[C:12]#N)=[CH:5][NH:6]2.[OH-:15].[K+].Cl.C([OH:20])C>C(O)CO>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]([CH3:14])[C:12]([OH:20])=[O:15])=[CH:5][NH:6]2
Reactant: CCO
Reactant: CC(C#N)c1c[nH]c2cccc(Br)c12
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: OCCO
Product: CC(C(=O)O)c1c[nH]c2cccc(Br)c12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
The compound prepared in Example 51, namely, 2-(4-bromo-1H-indol-3-yl)propanenitrile (184 mg) was dissolved in a mixture of ethanol (1 mL) and ethylene glycol (1 mL) and an aqueous 20% potassium hydroxide solution (0.5 mL) was added, and then the mixture was stirred overnight at 120° C. The reaction mixture was ice-cooled and then neutralized with 2M hydrochloric acid. The precipitated crystal was collected by filtration to obtain the titled compound having the following physical properties (155 mg).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.CO[C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Br:20].[NH4+].[Cl-]>C1COCC1>[OH:21][C:12]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Br:20]
Reactant: COC(=O)CCCCCCCBr
Reactant: Fc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCCCCCCBr)(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
7.65 g (313.8 mmol) magnesium shavings are placed under protective gas atmosphere and 55.1 g (314.8 mmol) 4-bromofluorobenzene dissolved in 250 ml abs. THF are added dropwise so that the reaction mixture boils gently. After complete addition, the mixture is heated for 30 minutes under reflux, and, afterwards, the suspension is cooled. While cooling in an ice bath, a solution of 25.0 g (105.4 mmol) 8-bromoctanoic acid methyl ester in 100 ml abs. THF is added dropwise. Subsequently, the mixture is heated for a further 30 minutes under reflux. After cooling, NH4Cl-solution is added to the reaction and this is extracted by diisopropyl ether by shaking. The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with petroleum ether/acetic acid ethyl ester (20/1 to 10/1): Yield 36.4 g (87%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:12]1[CH:28]=[CH:27][C:15]([CH2:16][C:17]2[C:22]([O:23]COC)=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:14][CH:13]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[CH2:8]([C:12]1[CH:28]=[CH:27][C:15]([CH2:16][C:17]2[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:14][CH:13]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCc1ccc(Cc2ncccc2OCOC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1ccc(Cc2ncccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of the compound of Example B229 (256 mg, 0.849 mmol) in methylene chloride (5 ml), and this reaction mixture was stirred at room temperature overnight. After a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate were added, the reaction mixture was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (182 mg).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[O:21]=[C:22]1[C:27](C(Cl)=O)=[CH:26][CH:25]=[C:24]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:23]1.[N:36]1[C:45]2[C:40](=[CH:41][C:42]([NH2:46])=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([C:27]2[C:22](=[O:21])[O:23][C:24]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:26]=2)=[O:13])[C@H:8]([C:18]([NH:46][C:42]2[CH:41]=[C:40]3[C:45](=[CH:44][CH:43]=2)[N:36]=[CH:37][CH:38]=[CH:39]3)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: Nc1ccc2ncccc2c1
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=CCON=C1C[C@@H](C(=O)Nc2ccc3ncccc3c2)N(C(=O)c2ccc(CCCCC)oc2=O)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinamine the title compound was obtained in 67% purity by LC/MS. MS(ESI+): m/z=503.2.
Reaction SMILES: [I:1][Si](C)(C)C.[CH3:6][Si:7]([O:10][C:11]([C:13]1[N:18]2[C:19](=[O:26])[CH:20]([NH:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C@H:17]2[S:16][CH2:15][C:14]=1[CH:27]=[CH:28][CH2:29]OC=O)=[O:12])([CH3:9])[CH3:8]>ClCCl>[CH3:6][Si:7]([O:10][C:11]([C:13]1[N:18]2[C:19](=[O:26])[CH:20]([NH:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C@H:17]2[S:16][CH2:15][C:14]=1[CH:27]=[CH:28][CH2:29][I:1])=[O:12])([CH3:9])[CH3:8]
Reactant: C[Si](C)(C)I
Reactant: C[Si](C)(C)NC1C(=O)N2C(C(=O)O[Si](C)(C)C)=C(C=CCOC=O)CS[C@H]12
Solvent: ClCCl
Product: C[Si](C)(C)NC1C(=O)N2C(C(=O)O[Si](C)(C)C)=C(C=CCI)CS[C@H]12

Procedure:
2.5 ml of iodotrimethylsilane are added at 0° to the solution of 7-trimethylsilylamino-3-(3-formyloxy-1-propen-1-yl)-3-cephem-4-carboxylic acid trimethylsilyl ester obtained in Example 2a) in dichloromethane, and the solution is stirred for 4½ hours at 0°. The NMR-spectroscopic data are identical to the data given in Example 1.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH2:12][CH2:13][C:14]1([OH:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>O.C(OCC)(=O)C>[O:4]=[C:3]1[NH:12][CH2:13][C:14]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]2)[O:27][CH2:2]1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)CO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Chloroacetyl chloride (4.88 mL) was added dropwise to a vigorously stirred mixture at 0° C. of potassium carbonate (17.43 g) in water (78 mL) and tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (10.4 g) in ethyl acetate (92 mL). After 30 minutes at 0° C. the mixture was extracted with ethyl acetate and the organic layer dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The residue was dissolved in THF (200 mL) and added dropwise over 3 hours to a stirred solution under nitrogen and heated at reflux of potassium tert-butoxide (1M in tert-butanol, 75 mL) and THF (250 mL). The mixture was cooled to room temperature and allowed to stir for 18 hours. Most of the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and brine, the aqueous layer was re-extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by trituration with a mixture of ether (30 mL) and isohexane (20 mL) to afford the subtitled product. Yield 8.20 g.
Reaction SMILES: C[Si]([Cl:5])(C)C.[Br-].C([NH3+])(C)(C)C.[CH:12]1([C:15](=[O:22])[CH2:16][C:17]([CH:19]2[CH2:21][CH2:20]2)=[O:18])[CH2:14][CH2:13]1.CS(C)=O>C(#N)C.O>[Cl:5][CH:16]([C:17]([CH:19]1[CH2:20][CH2:21]1)=[O:18])[C:15]([CH:12]1[CH2:13][CH2:14]1)=[O:22]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(CC(=O)C1CC1)C1CC1
Agent: CC(C)(C)[NH3+]
Agent: [Br-]
Solvent: CC#N
Solvent: O
Solvent: CS(C)=O
Product: O=C(C1CC1)C(Cl)C(=O)C1CC1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
Trimethylsilyl chloride (16.6 ml, 130 mmol) was added to a solution of tert-butylammonium bromide (0.70 g, 2.17 mmol) in acetonitrile (50 ml) under nitrogen at 0° C. 1,3-Dicyclopropyl-propane-1,3-dione (ref: WO98155438) (6.62 g, 43.5 mmol) in acetonitrile (15 ml) was then added followed by dimethylsulfoxide (9.25 ml, 130 mmol) dropwise, and the reaction was allowed to warm to room temperature over 4 hours. The mixture was diluted with water (75 ml), extracted with diethylether (3×35 ml) and the combined organic extracts dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with pentane:diethylether (95:5, by volume) to provide the title compound (3.76 g) as an oil, which was an 80:20 mixture of enol:keto forms.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Cl[C:19]1[C:20]([C:33]#[N:34])=[N:21][CH:22]=[C:23](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[CH:25](/[C:23]1[CH:22]=[N:21][C:20]2[C:19]([CH:24]=1)=[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]1=[N:8][C:33]=2[NH2:34])=[CH:26]\[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N#Cc1ncc(/C=C/c2ccccc2)cc1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: Cc1ccccc1
Product: Nc1nc2ccccc2c2cc(/C=C/c3ccccc3)cnc12
Temperature: 25 °C

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and (E)-3-chloro-5-styrylpicolinonitrile (from step 1) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give (E)-2-styrylbenzo[f][1,7]naphthyridin-5-amine as a brown solid. 1H NMR (dmso-d6): δ 9.22 (d, 1H), 9.06 (d, 1H), 8.51 (d, 1H), 7.78 (d, 1H), 7.66 (d, 2H), 7.46-7.56 (m, 3H), 7.70 (t, 2H), 7.26-7.32 (m, 2H), 7.08 (bs, 2H). LRMS [M+H]=298.2.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22]>CC(C)=O.O>[C:1]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(c1ccccc1)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzoyl chloride (18.5 ml) and an aqueous (50 ml) solution of sodium carbonate (17.0 g) were added dropwise to a solution of (S)-2-pyrrolidinemethanol (12.0 g) in a mixture of acetone (70 ml) and water (14 ml). After addition, the reaction mixture was stirred for 30 mins at room temperature. The reaction mixture was filtered. Water was added to the filtrate. The mixture was extracted with methylene chloride. The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica-gel (hexane-EtOAc) to give the title compound (24.1 g) having the following physical data: