Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCS3
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCS3
Yield: 46.9 %

Procedure:
The tert-butyl(6bR,10aS)-5-(2,4-dichlorophenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (136 mg, 47%) was prepared via coupling of the appropriate tert-butyl(6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (250 mg, 0.608 mmol) with 2,4-dichlorophenyl boronic acid (116 mg, 0.608 mmol) using the procedure described in Example 450 Step A.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.[NH2:12][C:13]1[CH:14]=[C:15]([C@H:19]([OH:23])[CH2:20][C:21]#[N:22])[CH:16]=[CH:17][CH:18]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][NH:12][C:13]3[CH:14]=[C:15]([C@H:19]([OH:23])[CH2:20][C:21]#[N:22])[CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#CC[C@@H](O)c1cccc(N)c1
Reactant: O=Cc1ccc2cc[nH]c2c1
Product: N#CC[C@@H](O)c1cccc(NCc2ccc3cc[nH]c3c2)c1

Procedure:
Reaction between 1H-indole-6-carbaldehyde and (R)-3-(3-aminophenyl)-3-hydroxypropanenitrile gives (R)-3-(3-(((1H-indol-6-yl)methyl)amino)phenyl)-3-hydroxypropanenitrile.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23]>>[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[C:21]3[S:17][C:18](=[O:23])[NH:19][C:20]3=[O:22])=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CNc1cccc(-c2ccc(C=O)cc2)c1
Reactant: O=C1CSC(=O)N1
Product: CNc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 91.7 %

Procedure:
In a manner similar to that of Example 1(f), starting with 2.9 g (13.7 mmol) of 3′-methylaminobiphenyl-4-carboxaldehyde and 1.6 g (13.7 mmol) of 2,4-thiazolidine dione, 3.9 g (91%) of the expected product are obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[CH:11]3[O:16][CH:10]3[C:9]=2[CH:17]=1)(=[O:3])[CH3:2].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]O)=[CH:20][CH:19]=1.S(=O)(=O)(O)[OH:28].C(OCC)(=O)C>C(#N)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:14])([CH3:15])[C@@H:11]([OH:28])[C@H:10]([O:16][CH2:25][CH2:24][C:21]3[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=3)[C:9]=2[CH:17]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)Nc1ccc2c(c1)C1OC1C(C)(C)O2
Reactant: OCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)Nc1ccc2c(c1)[C@@H](OCCc1ccccc1)[C@H](O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
To a solution of 6-acetylamino-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (0.50 g, 2.1 mmol) and 2-phenethyl alcohol (0.50 mL, 4.2 mol) in acetonitrile (2.5 mL), a catalytic amount of concentrated sulfuric acid was added at the room temperature and stirred at the room temperature for 5 hours. Thereto, ethyl acetate was added, and the formed organic phase was washed with water, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After the solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform: ethyl acetate=1:1), the obtained pink amorphous substance was recrystallized from hexane-ethyl acetate, to obtain the intended substance as pink crystals (yield; 40%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]Cl)([O-:3])=[O:2].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][CH2:20][C:21]1[N:25]=[CH:24][O:23][N:22]=1>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][CH2:20][C:21]1[N:25]=[CH:24][O:23][N:22]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1SCc1ncon1
Reactant: O=[N+]([O-])c1ccccc1SCl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1SNc1ccccc1SCc1ncon1
Reaction time: 8 h

Procedure:
A solution of 2-nitrophenylsulphenyl chloride (1.44 g, 7.5×10-3 mol) in chloroform was added dropwise to a solution of 3-(2-aminophenylthiomethyl)-1,2,4-oxadiazole in chloroform (20 ml). The yellow mixture was stirred overnight, the crude product collected by filtration and recrystallised from ethyl acetate/hexane to give 3-[2-(2-nitrophenylsulphenylamino)phenyl]thiomethyl-1,2,4-oxadiazole, m.p. 90° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH2:15][CH:16]2[CH2:18][O:17]2)=[CH:12][C:6]2[CH:7]=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CO.C(O)C.C(O)(C)C>[CH3:1][O:2][C:3]1[C:13]([O:14][CH2:15][CH:16]([OH:17])[CH2:18][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)=[CH:12][C:6]2[CH:7]=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc2oc(=O)ccc2cc1OCC1CO1
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Solvent: CO
Product: COc1cc2oc(=O)ccc2cc1OCC(O)CN1CCN(c2ccccc2)CC1
Yield: 99 %

Procedure:
Method C (5 d at 40° C.); starting materials: 7-methoxy-6-(oxiranylmethoxy)-2H-1-benzopyran-2-one and 1-phenylpiperazine; yield 99%; fusion point 160°-162° C. (from isopropanol and ethanol). Hydrochloride: method F; yield 78%; fusion point 222°-225° C. (from isopropanol, ethanol and methanol).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[OH:9])[CH:5]=[CH:4][CH:3]=1.C(O)C.O>C(O)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1C(O)c1cccc(Br)n1
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1ccccc1C(=O)c1cccc(Br)n1
Yield: 66.2 %

Procedure:
By the same procedure of Ex. 22, and reacting 3.3 g 6-bromo-α-(2-methoxyphenyl)-2-pyridinemethanol (obtained as in Ex. 19) in 20 ml glacial acetic acid with CrO3 (1 g in 5 ml water), there is obtained 2.17 g title product, m.p. 97°-8° C. (ethanol:water); UV (ethanol): λmax. 278 nm, ε: 12,480; Br 27.67 (27.36).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8]([O:11]S(C)(=O)=O)(=[O:10])=[O:9].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[C:27]1[C:28](=[O:46])[NH:29][C:30](=[O:45])[C:31]=1[C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]([CH2:41][CH2:42][CH2:43]O)[N:33]=1.Cl>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[C:27]1[C:28](=[O:46])[NH:29][C:30](=[O:45])[C:31]=1[C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]([CH2:41][CH2:42][CH2:43][O:11][S:8]([CH3:7])(=[O:10])=[O:9])[N:33]=1
Reactant: Cn1cc(C2=C(c3nn(CCCO)c4ccccc34)C(=O)NC2=O)c2cc(Cl)ccc21
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1cc(C2=C(c3nn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2cc(Cl)ccc21
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Pyridine (0.37 g, 4.62 mmol) and methanesulfonic anhydride (0.54 g, 3.08 mmol) were added to Compound 74 (0.67 g, 1.54 mmol) in THF (10 mL). The mixture was heated at 50° C. for 2 h, then cooled to rt. Another portion of THF (5 mL) was added, followed by 1 N HCl (5 mL). The mixture was stirred for another 15 min, then extracted with EtOAc several times. The combined EtOAc layers were washed once with 1 N HCl (10 mL), water (2×20 mL) and saturated NaCl (20 mL), then dried (Na2SO4) and evaporated in vacuo to obtain 3-(5-chloro-1-methyl-1H-indol-3-yl)-4-[1-[3-[(methylsulfonyl)oxy]propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione as Compound 26a (0.73 g, 92%) as a reddish solid. ES-MS m/z 513 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:42][S:43]([CH2:46][CH2:47][CH2:48][C:49](Cl)=[O:50])(=[O:45])=[O:44]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8](=[NH:9])[C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:25]([NH:31][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][S:43]([CH3:42])(=[O:45])=[O:44])=[CH:26][CH:27]=[CH:28][C:29]=3[CH3:30])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)CCCC(=O)Cl
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
{[4-(6′-Amino-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.500 g, 2.020 mmol), (Example 25: step c), triethylamine (0.153 g, 3.030 mmol), and DCM [30 mL] were added to a flask containing a stirbar. 4-Methanesulfonyl-butyryl chloride (0.013 g, 0.611 mmol) was added slowly while monitoring reaction. Reaction was concentrated in vacuo followed by chromatography (50%–80% EtOAc/Hx). Material was dissolved in a solution of trifluoroacetic acid/dichloromethane (1:1), [4 mL]. This solution stirred at room temperature for 2 hours. Reaction was concentrated in vacuo followed by reverse-phase HPLC [acetonitrile/water (0.01% TFA)] to yield title compound (0.138 g, 88%). ESI-MS (m/z): Calcd. for C24H27N3O5S4: 566.75; found 566.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>COCCOC.O.[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>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]=1
Reactant: OB(O)c1ccccc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C)cc1
Yield: 89 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.30 mmol), benzeneboronic acid (110 mg; 0.901 mmol) and tetrakis(triphenylphosphine) palladium(0) (34.7 mg; 0.030 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-Diisopropylethylamine (0.185 mL; 1.202 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 1 h. The reaction mixture was partitioned between brine and ethyl acetate, the phases were separated and the water layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (1-10%) in heptane to give 100 mg (89%) of the title compound. ESI/APCI(+): 375 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][C:15]#[CH:16])=[O:12])=[CH:4][CH:3]=1.[N:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27](OC2C=CC=CC=2)[CH:26]=1)=[N+:22]=[N-:23].O.[O:39]=[C:40]1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[N:23]=[N:22][N:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:39][CH3:40])=[CH:29][CH:30]=3)[CH:16]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: C#CCNC(=O)c1cccnc1Nc1ccc(F)cc1
Reactant: [N-]=[N+]=NCc1cccc(Oc2ccccc2)c1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(Cn2cc(CNC(=O)c3cccnc3Nc3ccc(F)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 740 %

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-fluoroaniline (9b, 111 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide 10b as pure product. To a solution of 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (10b, 150 mg, 0.55 mmol) and 1-(azidomethyl)-4-methoxybenzene (12c, 99 mg, 0.61 mmol)) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 5b (192 mg, 80%); mp: 201-204° C.; 1H NMR (300 MHz, CDCl3) δ 10.57 (s, 1H), 8.45 (brs, 1H), 8.25 (dd, J=4.7, 1.4 Hz, 1H), 7.94 (dd, J=7.7, 1.4 Hz, 1H), 7.62-7.57 (m, 3H), 7.41 (s, 1H), 7.23 (s, 1H), 6.98 (t, J=8.4 Hz, 2H), 6.88 (t J=8.4 Hz, 2H), 6.69-6.65 (m, 1H), 5.44 (s, 2H), 4.63 (d, J=5.5 Hz, 2H), 3.78 (s, 3H); MS (ESI m/z): 433 [M+H]+. Yield: 80%
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][N:14]([C:16]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[C@H:13]([C:25]([OH:27])=O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][O:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[C:35]([O:34][C:33]([NH:32][CH2:31][CH2:30][O:29][NH:28][C:25]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]([NH:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][N:14]1[C:16]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:22])[CH3:23])=[O:17])=[O:27])=[O:39])([CH3:38])([CH3:36])[CH3:37]
Reactant: C[Si](C)(C)CCOC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)NCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)OCC[Si](C)(C)C
Yield: 53.6 %

Procedure:
(2S,5R)-5-(Benzyloxyamino)-1-((2-(trimethylsilyl)ethoxy)carbonyl)piperidine-2-carboxylic acid (601 mg, 1.52 mmol) described in Example 101 and tert-butyl 2-(aminooxy)ethylcarbamate (303 mg, 1.72 mmol) of Reference Example 9 were dissolved in N,N-dimethylformamide (5.8 mL), to which was added 1-hydroxybenzotriazole.monohydrate (264 mg), followed by ice cooling. To this was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (330 mg), a temperature was elevated to room temperature, followed by reaction for 5 h. Water was added to the reaction mixture and extracted with ethyl acetate. After the organic layer was washed with 10% citric acid aqueous solution, water, 6.5% sodium bicarbonate aqueous solution and saturated brine sequentially, the organic layer was dehydrated over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting oil residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/2) to afford 450 mg of the title compound (yield 54%).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11]>C(O)(=O)C.[Pt]=O>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[CH:23]1[CH:14]([CH2:15][C:16]2[C:21]([NH:22]1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CC2Cc3ccccc3NC12
Yield: 76.7 %

Procedure:
Camptothecin (500 mg, 1.43 m-mol) is suspended in acetic acid (100 ml). Platinum oxide (100 mg) is added to the suspension and the mixture is subjected to catalytic reduction (1.5 hours, absorption of about 140 ml of hydrogen) at room temperature under atmospheric pressure. After removing the catalyst by filtration, the reaction mixture is evaporated until dryness under reduced pressure. The residue is taken up in chloroform (200 ml) and washed with a 5% aqueous solution of sodium hydrogen carbonate (100 ml) and then with a saturated solution of edible salt (100 ml). The chloroform phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure until dryness. The residue is purified by column chromatography (chloroform) on silica gel (20 g) whereby 285 mg (conversion rate: 56.3%; yield: 76.7%) of the title compound is obtained as yellowish white crystals. Unreacted starting material (113 mg in crude state) is recovered. M.P. (dec.) 240°-242° C. (from methanol)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[CH:3][C:2]1=[O:7].[CH2:8]([N:10](CC)CC)C.[N:15]1[O:16][N:17]=[C:18]2[CH:23]=[C:22]([C:24](Cl)=[O:25])[CH:21]=[CH:20][C:19]=12>CN.C(O)C.ClCCl>[CH3:8][N:10]([CH:4]1[CH2:5][CH2:6][O:1][C:2](=[O:7])[CH2:3]1)[C:24]([C:22]1[CH:21]=[CH:20][C:19]2=[N:15][O:16][N:17]=[C:18]2[CH:23]=1)=[O:25]
Reactant: O=C(Cl)c1ccc2nonc2c1
Reactant: CCN(CC)CC
Reactant: O=C1C=CCCO1
Agent: CN
Solvent: ClCCl
Solvent: CCO
Product: CN(C(=O)c1ccc2nonc2c1)C1CCOC(=O)C1
Temperature: 55 °C
Reaction time: 0.75 h

Procedure:
5,6-Dihydro-2H-pyran-2-one (1.0 g, 10.2 mmol) was dissolved in 3 ml of a 33% solution of methylamine in ethanol and heated to 55° C. overnight. The solvent was evaporated, the residue dissolved in methanol (20 ml) and conc. HCl (20 ml) and the mixture heated at 95° C. for 2.5 h. The mixture was evaporated to dryness, the residue dissolved in THF (20 ml), dichloromethane (20 ml) and triethylamine (3 ml) and a solution of [2,1,3]-benzoxadiazole-5-carboxylic acid chloride (2.0 g, 11 mmol), in dichloromethane (5 ml), added. After stirring the mixture for 0.75 h, the mixture was washed with 1N HCl and conc. NaHCO3 solution, dried over sodium sulfate, and concentrated under vacuum. The residue was purified on a silica gel column using ethyl acetate/hexane/dichloromethane (70:20:10), to give N-methyl-N-(2-oxotetrahydro-2H-pyran-4-yl)-[2,1,3]-benzoxadiazole-5-carboxamide as white solid after crystallization from dichloromethane/methanol (0.21 g). Mp=169-171° C., 1H NMR (300 MHz, CDCl3, rotamers) δ 7.97 (d, J=9.0 Hz, 1H); 7.90 (s, 1H); 7.40 (d, J=9.0 Hz, 1H); 5.10-4.40 (m, 3H); 3.01 (s, 3H); 3.00-2.74 (m, 2H) and 2.60-2.10 ppm (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:12](OC)(OC)OC>CO.C1(C)C=CC=CC=1>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: COC(OC)OC
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1cccc(Br)c1
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
A solution of (3-bromo-phenyl)-acetic acid (10.4 g, 48.5 mmol), in methanol (80 mL), was treated with trimethyl orthoformate (6.5 mL, 59.4 mmol). HCl gas was bubbled through the stirred solution for 10 minutes. The HCl addition was exothermic. After stirring for 15 minutes HPLC analysis of the solution showed complete conversion to product. After stirring for 16 hrs at ambient temperature the solution was diluted with toluene (100 mL) and concentrated under reduced pressure to afford a biphasic mixture. This liquid was diluted with toluene and concentrated under reduced pressure to afford (3-bromo-phenyl)-acetic acid methyl ester (11.2 g, quantitative yield) as a pale yellow liquid. 1H-NMR (400 MHz, CDCl3): δ 7.46-7.38 (2H, m), 7.23-7.18 (2H, m), 3.71 (3H, m), 3.60 (2H, m).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[CH:4][NH:3]1.[H-].C([Al+]CC(C)C)C(C)C.CO.O>C1COCC1>[OH:9][CH2:8][C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:1])[CH:7]=1
Reactant: COC(=O)c1cc[nH]c(=O)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=c1cc(CO)cc[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a stirred solution of methyl 2-oxo-1,2-dihydropyridine-4-carboxylate (300 mg, 1.96 mmol) in THF (20 mL) was added diisobutylaluminium hydride (1.0 M in THF, 20 mL, 20 mmol). The mixture was stirred at RT for 3 h, then MeOH (2 mL) and H2O (1 mL) were added. The mixture was stirred at RT for 20 minutes and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (DCM:MeOH=8:1) to afford 4-(hydroxymethyl)pyridin-2(1H)-one as a white solid (150 mg, 61.2%). MS (ES+) C6H7NO2 requires: 125. found: 126 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[CH2:15](O)[CH2:16][OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:16]1[O:17][C:12]([CH3:13])([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:6][CH:7]=2)[O:14][CH2:15]1
Reactant: OCCO
Reactant: COC(=O)c1ccc(CC(C)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(CC2(C)OCCO2)cc1

Procedure:
A mixture of 1-(4-carbomethoxyphenyl)propan-2-one (17.3 g), ethan-1,2-diol (5.6 g) and p-toluenesulphonic acid (200 ml) in benzene (150 ml) was refluxed under a Dean and Stark head until the theoretical amount of water had been collected (ca. 4 hours). The solvent was evaporated and the residue was partitioned between sodium bicarbonate solution and ether. The ethereal extract was washed with water, dried, evaporated and distilled to give 15.7 g (74%), bp 136-140/1.5 mm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(OCC)=O)=O)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[NH:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24].Cl.[OH-].[Na+]>CN(C=O)C>[S:3]1[CH:4]=[CH:5][S:1][C:2]1=[C:6]([C:13]([N:21]1[CH2:28][CH2:27][CH2:26][CH:22]1[C:23]([OH:25])=[O:24])=[O:15])[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8]
Reactant: CCOC(=O)OC(=O)C(C(=O)OC(C)C)=C1SC=CS1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(C(=O)N1CCCC1C(=O)O)=C1SC=CS1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.1 %

Procedure:
Isopropyl 2-(1,3-dithiol-2-ylidene)-2-(ethoxycarbonyloxy-carbonyl)acetate (13.2 g) and proline (4.6 g) was dissolved in DMF (60 ml). The mixture was stirred at room temperature for 24 hrs, thereto was added conc-HCl (20 ml) and stirred for a further 2 hrs. The reaction mixture was poured into ice water and basified to pH=12 with aqueous sodium hydroxide solution. The mixture was washed with methylene chloride and the aqueous layer was acidified to pH=2 with dil-HCl. The solid formed was filtered and recrystallized from ethyl acetate and n-hexane to obtain the pure product (12.5 g, 91%).