Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:30][CH3:31])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:9]([C:27]([OH:29])=O)[CH2:8]2)=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:49][C@:50]1([C:55]([NH:57][S:58]([CH:61]2[CH2:63][CH2:62]2)(=[O:60])=[O:59])=[O:56])[CH2:52][C@H:51]1[CH:53]=[CH2:54].O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:30][CH3:31])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])[C:14]([CH3:16])([CH3:17])[CH3:15])[C@H:9]([C:27](=[O:29])[NH:49][C@:50]3([C:55](=[O:56])[NH:57][S:58]([CH:61]4[CH2:63][CH2:62]4)(=[O:60])=[O:59])[CH2:52][C@H:51]3[CH:53]=[CH2:54])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: CS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@](SC)(c2ccc(-c3ccccc3)cc2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To an iced slurry of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxylic acid (26 mg, 0.049 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide, p-toluenesulfonate salt, H2O (24.85 mg, 0.059 mmol), and HATU (28.1 mg, 0.074 mmol) in DCM (1 mL) was added N,N-diisopropylethylamine (0.026 mL, 0.148 mmol). The formed colorless slurry was stirred at room temperature overnight (it became light yellow solution). Diluted with DCM, quenched with 5% citric acid. The separated organic layer was washed with sat. sodium citrate and brine, dried over MgSO4, filtered, evaporated in vacuo. The residue was purified by prep-HPLC to afford the desired product tert-butyl (S)-1-((2S,4R)-4-(biphenyl-4-yl)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(methylthio)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (18 mg, 0.024 mmol, 49.3% yield) as a white solid. 1H NMR (500 MHz, MeOD) ppm 1.03-1.12 (m, 11H), 1.25 (d, J=3.36 Hz, 2H), 1.43-1.48 (m, 1H), 1.50 (s, 9H), 1.88 (dd, J=8.09, 5.34 Hz, 1H), 1.92 (s, 3H), 2.16-2.27 (m, 1H), 2.38 (t, J=11.29 Hz, 1H), 2.82 (dd, J=11.90, 6.10 Hz, 1H), 2.90-2.99 (m, 1H), 3.97-4.04 (m, 2H), 4.48-4.53 (m, 1H), 5.03 (d, J=10.99 Hz, 1H), 5.13 (d, J=10.68 Hz, 1H), 5.30 (d, J=17.40 Hz, 1H), 5.70-5.81 (m, 1H), 7.37 (t, J=7.02 Hz, 1H), 7.46 (t, J=7.48 Hz, 2H), 7.57-7.64 (m, 4H), 7.64-7.73 (m, 2H). LC-MS (retention time: 3.28 min, method B), MS m/z 739 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:11])[CH:3]=1.[CH2:12]([N:14](CC)[CH2:15][CH3:16])[CH3:13].N1CCCC1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]2[CH2:15][CH2:16][CH2:13][CH2:12]2)=[O:8])=[C:4]([Cl:11])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: O=C(c1ccc(Br)cc1Cl)N1CCCC1
Reaction time: 1 h
Yield: 96.3 %

Procedure:
4-Bromo-2-chloro-benzoic acid (30 g, 127.4 mmol) was placed in a 3 L round bottom flask and 1.5 L of EtOAc was transferred into it. Triethylamine (25.8 g, 255 mmol), pyrrolidine (18 g, 255 mmol), and T3P (48.6 g, 152.9 mmol, 50 wt % in EtOAc) were then added. After 1 hr, the reaction was quenched with 200 mL of 1N NaOH and stirred for 10 min. The layers were separated and after 2 more extractions of the aqueous phase with EtOAc (2×500 ml), the combined organic extracts were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a viscous oil. Flash chromatography using a 330 g ISCO™ column and 50%, 80% EtOAc/Hexanes yielded the title compound as a light yellow colored viscous oil (35.4 g. 96% yield) Rf=0.25 (50% EtOAc/Hexanes), LRMS m/z Calcd for C11H11BrClNO, 288.6, found, 289.9 (M+H) APCI; 1H-NMR (CDCl3) δ 7.56 (d, J=1.7 Hz, 1H), 7.43 (dd, J=1.7, 8.3 Hz, 1H) 7.17 (d, J=8.3 Hz, 1H), 3.63 (b apt t, J=6.6 Hz, 2H), 3.17 (B apt t, J=6.6 Hz, 2H), 2.00-1.84 (m, 4H). 13C-NMR (CDCl3) δ 166.0, 13.6, 132.6, 131.3, 130.7, 128.9, 123.3, 48.0, 45.8, 261, 24.7.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([OH:17])=[O:16]>>[N+:6]([C:13]1[CH:12]=[C:11]([C:15]([OH:17])=[O:16])[S:10][CH:14]=1)([O-:9])=[O:7]
Reactant: O=C(O)c1cccs1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])cs1
Reaction time: 1 h
Yield: 73.9 %

Procedure:
Sulfuric acid (3.0 mL, 5.505 g, 56.17 mmol) was added to nitric acid (2.0 mL, 2.98 g, 49.6 mmol) slowly at 0-10° C. After completion of the addition, thiophene-2-carboxylic acid (2.8 g, 21.87 mmol) was added to the above nitration mixture slowly for 15 min at the same temperature and stirred the mixture for 1 h. The reaction mixture was poured into ice cold water and stirred for 30 min. The precipitated solid was filtered, washed with cold water and dried. The filtrate was extracted with ethyl acetate. The combined ethyl acetate layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The combined product was stirred with hexane (2×50 mL) and filtered the solid and dried to give the product as an off-white solid (2.8 g, 75%), mp 110-118° C. The product was a mixture of two compounds by HPLC and 1H NMR and was proceeded to the next step.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([O:46]C)=[O:45])=[CH:40][CH:39]=4)[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:39]=[CH:40][C:41]([C:44]([OH:46])=[O:45])=[CH:42][CH:43]=4)[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:4]=[C:3]([C:2]([F:1])([F:50])[F:49])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
Methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (10 mg, 0.014 mmol), aqueous potassium hydroxide (150 μL, 3M, 0.45 mmol) and ethanol (1 mL) were stirred at 20° C. for 2 hours and 30 minutes to complete the hydrolysis. The reaction mixture was acidified by HCl (aq., 1N) and then basified by sodium bicarbonate. Volatiles were removed under reduced pressure. The resulting mixture was worked up with ethyl acetate, washed with brine. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to an oil. This oil was purified by preparative TLC on SiO2 (eluted with 50% EtOAc in hexanes) to afford 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS calc.=697.15; found=698.03 (M+1)+. 1H NMR signals are doubled because of atropisomerism 1H NMR (CDCl3, 500 MHz), 8.16-8.11 (m, 2H), 7.83 (d, J=8.0 Hz, 1H), 7.74-7.69 (m, 2H), 7.69-7.65 (m, 2.5H), 7.65-7.61 (m, 1.5H), 7.57 (s, 1H), 7.48-7.42 (m, 2.0H), 7.11 (dd, J=8.8, 2.5 Hz, 1H), 5.57 (d, J=8.0 Hz, 0.5H), 5.17 (d, J=8.0 Hz, 0.5H), 4.97 (d, J=15.5 Hz, 0.5H), 4.93 (d, J=15.5 Hz, 0.5H), 4.16 (d, J=16 Hz, 0.5H), 3.95 (d, J=16.0 Hz, 0.5H), 3.88, 3.87 (s, 3H), 3.80-3.72 (m, 1H), 0.55 (d, J=6.5 Hz, 1.5H), 0.41 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[NH:17][C:18]([C:20]1[S:21][C:22]2[CH2:23][N:24]([C:29](SC)=[N:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:25][CH2:26][C:27]=2[N:28]=1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:39]#[C:40][NH2:41]>C1COCC1>[C:40]([NH:41]/[C:29](=[N:30]\[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)/[N:24]1[CH2:25][CH2:26][C:27]2[N:28]=[C:20]([C:18]([NH:17][C:10]3[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])[S:21][C:22]=2[CH2:23]1)#[N:39]
Reactant: COc1ccc(NC(=O)c2nc3c(s2)CN(C(=Nc2ccccc2)SC)CC3)c(NC(=O)OC(C)(C)C)c1
Reactant: N#CN
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2nc3c(s2)CN(/C(=N/c2ccccc2)NC#N)CC3)c(NC(=O)OC(C)(C)C)c1

Procedure:
A solution of methyl 2-({2-[(tert-butoxycarbonyl)amino]-4-methoxyphenyl}carbamoyl)-N-phenyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carbimidothioate (1 eq) obtained in step I, cyanamide (10 eq) in very small quantity of THF was heated at reflux temperature for 15 h.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]12[CH2:15][CH:14](O)[CH2:13][C@@H:12]1[C:11](=[O:17])[N:10]([C@@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCN(S(F)(F)[F:36])CCOC>C(Cl)Cl>[C:1]([O:5][C:6]([C@:8]12[CH2:15][CH:14]([F:36])[CH2:13][C@H:12]1[C:11](=[O:17])[N:10]([C@@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CC(O)C[C@@H]2C1=O
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C[C@@]2(C(=O)OC(C)(C)C)CC(F)C[C@H]2C1=O
Reaction time: 1 h
Yield: 71 %

Procedure:
(1S,5S)-7-Hydroxy-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octan-1-ylcarboxylic acid tert-butyl ester (1.0 g, 2.89 mmol) was dissolved in methylene chloride (15 mL). Bis(2-methoxyethyl)aminosulfur trifluoride (BAST) (0.59 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for one hour. The reaction solution was washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1→4:1→1:1) to give 711 mg (71%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:27])=[C:15](OS(C(F)(F)F)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:40]([OH:43])[CH:41]=[CH2:42].C(N(C(C)C)CC)(C)C>ClCCl>[OH:43][CH2:40][C@@H:41]1[C@H:16]2[C:15](=[C:14]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:27])[N:13]3[C@H:12]([S:17]2)[C@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:38]3=[O:39])[CH2:42]1
Reactant: C=CCO
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C3C[C@H](CO)[C@@H]3S[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a mixture of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3-(trifluoromethylsulphonyloxy)ceph-3-em-4-carboxylate (20 mg, 0.0341 mmol), allyl alcohol (11.6 μl, 0.171 mmol) and dichloromethane (0.5 ml) was added diisopropylethyl-amine (6 μl, 0.034 mmol). After stirring at room temperature for 30 min the mixture was chromatographed to give the title compound (12 mg, 71%), (Found: M+, 4.94.1528. C26H26N2O6S requires M, 494.1512); νmax (CH2Cl2) 1787, 1722, 1687 cm-1 ; δH (CDCl3) 2.89 (1H, m), 2.96 (1H, dt, J 16.8 , 3.0), 3.22 (1H, ddd, J 16.2, 8.9, 1.2), 3.62 (2H, ABq, J 15.7), 3.65 (2H, d, J 7.2), 3.79 (3H, s), 4.44 (1H, m), 4.92 (1H, d, J 5.0), 5.17 (2H, ABq, J 12.0), 5.76 (1H, dd, J 8.9, 5.0), 6.32 (1H, d, J 8.9), 6.86 (2H, d, J 8.6), 7.28 (7H, m).
Reaction SMILES: [Br:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[C:10]([OH:26])=[C:11]([C:23](=[O:25])[CH3:24])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1.C(OCC)(=O)C.Cl>N1C=CC=CC=1>[C:23]([C:11]1[C:10]([OH:26])=[C:9]([NH:8][C:3](=[O:4])[C:2]([Br:1])([CH3:7])[CH3:6])[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(N)c1O
Reactant: CC(C)(Br)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(OCc2ccccc2)cc(NC(=O)C(C)(C)Br)c1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4.64 g (25 mmol) 2-bromo-2-methyl-propionyl chloride are added dropwise at 5 to 20° C. to a solution of 5.15 g (20 mmol) 1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone in 20 mL pyridine. After the addition has ended the mixture is stirred for 15 minutes, combined with ice water and 100 mL ethyl acetate and acidified with conc. hydrochloric acid. The organic phase is separated off, washed with water and dried with sodium sulphate. After the solvent has been distilled off the residue is crystallised from a diethyl ether/petroleum ether mixture.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH2:9].CCO[C:13]([S-:15])=[S:14].[K+].Cl>CN(C=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[S:14][C:13]([SH:15])=[N:9][C:3]=2[CH:4]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc(F)ccc1F
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc2sc(S)nc2c1
Temperature: 120 °C
Yield: 67 %

Procedure:
A mixture of 2,5-difluoro-phenylamine (129 mg, 1 mmol) and potassium o-ethyl dithiocarbonate (352 mg, 2.2 mmol) in DMF (5 mL) was heated to 120° C. for 15 min in microwave. The reaction mixture was cooled, diluted with 10 mL of ice water, and acidified with 3 mL of HCl solution (1 mol/L). Then the mixture was extracted with EtOAc (3×50 mL), washed with brine and dried over Na2SO4. The dried organic layers were concentrated to give 5-fluorobenzo[d]thiazole-2-thiol (120 mg, 0.67 mmol, 67%). ESI-MS (M+1): 185 calc. for C7H4FN4S2 184.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:17]=[C:16](F)[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:17]=[C:16]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cc(Cl)cc(Cl)c1
Reactant: C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(Nc1cc(N2CCNCC2)ccc1[N+](=O)[O-])c1cc(Cl)cc(Cl)c1
Yield: 19 %

Procedure:
N-(1-(3,5-dichlorophenyl)ethyl)-5-fluoro-2-nitrobenzenamine (1.62 mmol), piperazine (8.1 mmol), N,N-diisopropylethylamine (0.58 mmol) were stirred at 60° C. in dry acetonitrile (20 mL) for 3 days. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 20% ethyl acetate in hexanes to afford the title compound (19% yield). 1H NMR (400 MHz, CDCl3): δ 9.31 (d, 1H), 7.63 (d, 1H), 7.25 (s, 1H), 7.22 (s, 2H), 6.18 (d, 1H), 5.53 (s, 1H), 4.48 (m, 1H), 3.48 (m, 4H), 3.25 (m, 4H), 1.60 (d, 3H), 1.47 (s, 9H); MS (ESI) m/z: Calculated for C18H20O2N4O2: 395.28; Observed: 396.3 (M++1).
Reaction SMILES: C[Si](C)(C)[O:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[B-](F)(F)(F)[F:22].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:22][CH:9]1[C:4](=[O:3])[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:8]1
Reactant: C[Si](C)(C)OC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1F
Reaction time: 4 h
Yield: 95 %

Procedure:
The mixture of 4-(4-trimethylsilyloxy-piperidin-1-yl)-nitrobenzene (101 mmol), selectfluor (101 mmol) in acetonitrile (100 ml) was stirred for 4 hours. The solvent was removed under reduced pressure and to the residual mass was extracted into ethyl acetate water mixture. The combined organic layer was dried and removal of the solvent afforded title compound in 95% yield.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH:1](=[N:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: ON=Cc1ccccc1
Reaction time: 5 h
Yield: 99.2 %

Procedure:
10.6 g of benzaldehyde, 7.0 g of hydroxylamine hydrochloride and 14.0 g of sodium carbonate were added to 200 ml of methanol and then stirred for 5 hours at normal temperature. The reaction mixture was filtered and then methanol was distilled off under reduced pressure from the filtrate to obtain 12.0 g (Yield 99%) of the title compound (III-1) as a white solid.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]=2[C:4]([NH:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][CH:17]=2)=[N:3][CH:2]=1.Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1>>[C:18]([C:15]1[N:14]=[CH:13][C:12]([NH:11][C:4]2[C:5]3[CH2:10][N:9]([C:23]4[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:8][CH2:7][C:6]=3[N:1]=[CH:2][N:3]=2)=[CH:17][CH:16]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccc(Nc2ncnc3c2CNCC3)cn1
Reactant: Clc1cccnc1Cl
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CN(c2ncccc2Cl)CC3)cn1

Procedure:
The title compound was prepared according to the procedure given for Compound 1C by reacting (5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-(6-tert-butyl-pyridin-3-yl)-amine with 2,3-dichloropyridine to give the desired compound as an off-white powder.
Reaction SMILES: C([O:3][C:4](=O)[C:5](=[O:30])[CH:6]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:16]=1[N+:27]([O-])=O)[CH2:7][C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])C.C(O)(=O)C>C1COCC1.C(Cl)Cl.[Cl-].[Na+].O.[Zn]>[CH2:12]([O:11][C:9]([C:8]1[O:30][C:5]2[C:4](=[O:3])[NH:27][C:16]3[C:17]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:18][CH:19]=[CH:20][C:15]=3[C:6]=2[CH:7]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)C(=O)CC(C(=O)C(=O)OCC)c1cccc(N2CCCCC2)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(o1)c(=O)[nH]c1c(N3CCCCC3)cccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-(2-nitro-3-piperidin-1-yl-phenyl)-2,5-dioxo-hexanedioic acid diethyl ester (iii) in THF is treated with acetic acid (“HOAc”) and is stirred at room temperature for 4 h. The reaction is treated with zinc dust (10 eq) and is stirred for an additional 2 h. The reaction is diluted with DCM, half saturated brine, and partitioned. The organic layer is washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated. Chromatography gives 4-oxo-6-piperidin-1-yl-4,5-dihydro-furo[2,3-c]quinoline-2-carboxylic acid ethyl ester (iv).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.CCOP(OCC)([CH2:18][C:19]#[N:20])=O.CC(C)([O-])C.[K+].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:18]/[C:19]#[N:20])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C#N)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
7 g of 3,4-dimethoxybenzaldehyde (42.1 mmoles) are dissolved in 84 mL of THF and the solution is cooled to 0° C. 8.2 g of diethyl cyanomethyl phosphonate (7.5 mL, 46.3 mmoles, 1.1 eq.) and subsequently 5.2 g of potassium tert-butoxide (46.3 mmoles, 1.1 eq.) are added little by little. The mixture is stirred for one hour at 0° C. and then overnight at ambient temperature. The reaction mixture is hydrolysed using 175 mL of water and extracted twice with dichloromethane. The organic phases are collected and the solvent is evaporated off under reduced pressure to yield 7.69 g of the title product in the form of a beige solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1.C(N(CC)CC)C.[C]=O.[C:25]([O:28][CH2:29]C)(=[O:27])C>CO.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:29][O:28][C:25](=[O:27])[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C]=O
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 25 °C

Procedure:
The mixture consisting of 1-bromo-3-(methylsulfonyl)-5-(trifluoromethyl)benzene (0.20 g, 0.66 mmol, Combi-Blocks, Inc.), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (20.4 mg, 0.025 mmol, CAS RN 72287-26-4) and triethylamine (0.134 g, 0.184 mL, 1.32 mmol) in ethyl acetate (2 mL) and methanol (2 mL) was stirred at 110° C. under a 70 bar carbon monoxide atmosphere for 20 h. After cooling to room temperature silica gel was added and the brown suspension evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50). Light brown oil (0.156 g; 83%). MS (GC_MS (EI)): m/z=282.0 [M].
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].ClCl.S(Cl)([Cl:14])(=O)=O>>[Cl:14][C:6]1[CH:5]=[C:3]([OH:4])[C:1](=[CH:8][CH:7]=1)[OH:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1ccccc1O
Agent: ClCl
Product: Oc1ccc(Cl)cc1O

Procedure:
For example, chlorination of catechol with either chlorine or sulfuryl chloride, Berichte 44, 2182 (1911), C.A. 5, 3433 (1911) gives 4-chlorocatechol as the major product, whereas excess halogen yields the 4,5-dichlorocatechol. ##STR14##
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3]C.[CH3:6][CH2:7][C@@:8]1([OH:31])[C:13](=[O:14])[O:12][CH2:11][C:10]2[C:15]([N:17]3[C:29](=[CH:30][C:9]1=2)[C:28]1[N:27]=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]2)=[CH:20][C:19]=1[CH2:18]3)=[O:16].S(=O)(=O)(O)O.OO>O>[CH3:1][CH2:2][CH2:3][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:27]=[C:28]2[C:19]=1[CH2:18][N:17]1[C:15](=[O:16])[C:10]3[CH2:11][O:12][C:13]([C@:8]([OH:31])([CH2:7][CH3:6])[C:9]=3[CH:30]=[C:29]12)=[O:14]
Reactant: CCCCO
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: CCCc1c2c(nc3ccccc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Ferrous sulfate heptahydrate (2.8 g, 10.1 m-mol) and 1-butanol (3 ml, 43 m-mol) were dissolved in water (30 ml). Camptothecin (500 mg, 1.43 m-mol) was suspended in the solution and dissolved therein by addition of concentrated sulfuric acid (15 ml). To this solution was added dropwise under ice-cooling and agitation a 30% aqueous solution of hydrogen peroxide (1.1 ml, 10.1 m-mol) in small portions. The agitation was continued for 4 hours at room temperature. The reaction mixture was diluted with ice water (1.5 l) and extracted with chloroform (2 l). The chloroform layer was dried with magnesium sulfate, filtered and evaporated until dryness under reduced pressure. The residue was subjected to column chromatography (chloroform) through silica gel (15 g) to effect separation and purification of the product which was then recrystallized from n-hexane-chloroform whereby 110 mg (21.0%) of the objective compound were obtained as light yellow white needle crystals. M.P. 260°-261° C.