Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:17](O)=[O:18])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:41]([S:60][CH2:61][C@@H:62]([C:64]([NH2:66])=[O:65])[NH2:63])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][C@@H:16]([CH2:20][CH2:21][NH:22][C:23](=[O:24])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:17](=[O:18])[NH:63][C@H:62]([C:64](=[O:65])[NH2:66])[CH2:61][S:60][C:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:30][CH:31]=1)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCNC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
3.00 g (5.30 mmol) of the compound from example 13A was dissolved in 120 ml dichloromethane. 1.92 g (5.30 mmol) S-Trityl-L-cysteinamide, 0.92 ml (5.30 mmol) N,N-diisopropylethylamine and 2.02 g (5.30 mmol) HATU were added. The reaction mixture was split into 6 portions. The portions were heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 800 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 4.91 g (3.73 mmol, 70% of theory, 69% purity) of the desired product.
Reaction SMILES: [Cl-].[Na+:2].Cl[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])(=[O:6])=[O:5].[OH2:16]>>[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([O-:12])=[O:11])([OH:16])(=[O:6])=[O:5].[Na+:2]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: O
Agent: [Cl-]
Agent: [Na+]
Product: O=C([O-])c1cccc(S(=O)(=O)O)c1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 90.9 %

Procedure:
360 g of 26.4% strength sodium chloride solution, prepared from 95.0 g of sodium chloride and 265.0 g of water, and 332 g of crude 3-(chlorosulfonyl)benzoic acid (water content: 39.2%) (corresponding to 201.8 g (0.92 mol) of 100% 3-(chlorosulfonyl)benzoic acid) are introduced into a 1 l four-neck flask fitted with stirrer, internal thermometer and reflux condenser. The reaction mixture is heated to 100° C. and stirred for a further 45 minutes at this temperature. The mixture is then allowed to cool over about 1 hour to 40° C. Subsequently it is cooled with an ice bath to <5° C. and stirred for a further 30 minutes at this temperature. The precipitated product is filtered off with suction and washed with 256 g of 5% strength sodium chloride solution, prepared from 12.8 g of sodium chloride and 243.2 g of water and cooled to 5° C., in two portions. The filter cake is dried at 100° C./100 torr (13.16 kPa). 196.3 g of sodium 3-sulfobenzoate are obtained with a purity of 95% and a sodium chloride content of 3.9% (corresponding to 186.5 g (0.83 mol) of 100% sodium 3-sulfobenzoate). The yield is 90.9% of theoretical. 345 g of mother liquor and 318 g of wash liquor are produced.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[O-:16]C1C=C2C(C=CC(S([O-])(=O)=O)=C2)=CC=1.[Na+].[Na+]>>[OH:16][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc2ccc(I)cc2c1
Reactant: O=S(=O)([O-])c1ccc2ccc([O-])cc2c1
Agent: [Na+]
Product: NS(=O)(=O)c1ccc2ccc(O)cc2c1
Yield: 5 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 11, sodium 7-oxidonaphthalene-2-sulfonate (Pfaltz and Bauer, 1.00 g, 3.73 mmol) was converted to the title compound (40 mg, 5%) after purification using preparative HPLC. 1H NMR (DMSO-d6) δ 8.17 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.87 (d, J=8.8 Hz, 2H), 7.62 (dd, J=8.6, 1.8 Hz, 1H), 7.35 (s, 2H), 7.28 (d, J=2.2 Hz, 1H), 7.23 (dd, J=8.9, 2.3 Hz, 1H); MS(ESI−) m/z 236.3 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:11][CH2:10]2)=[C:4]([Cl:12])[CH:3]=1.[Cl-].[C:14]([O:18][C:19](=[O:22])[CH2:20][Zn+])([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([O:18][C:19](=[O:22])[CH2:20][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:11][CH2:10]2)=[C:4]([Cl:12])[CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Clc1cc(Br)ccc1OC1CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Cc1ccc(OC2CC2)c(Cl)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 4-bromo-2-chloro-1-cyclopropoxy-benzene (610 mg, 2.46 mmol, 1.00 eq.) in dioxane (20 mL), bis(tri-t-butylphosphine)palladium (0) (193 mg, 0.37 mmol, 0.15 eq.) and 2-tert-butoxy-2-oxoethylzinc chloride (0.5M in diethyl ether) (8.9 mL, 4.44 mmol, 1.80 eq.) were added in sequence. The resulting mixture was stirred at r.t. for 18 hours and further at 60° C. for 4 hours. The mixture was allowed to cool down to r.t. and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, Heptane to Heptane+5% AcOEt) to yield the title compound as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([NH:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH3:12])[CH3:11])[CH:7]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:11][CH:10]([CH3:12])[CH:9]([NH:8][C:6]1[CH:7]=[C:2]([N:32]2[CH2:31][CH2:30][N:29]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:34][CH2:33]2)[CH:3]=[CH:4][C:5]=1[N+:19]([O-:21])=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)C(Nc1cc(F)ccc1[N+](=O)[O-])c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)C(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])c1ccccc1
Yield: 86.9 %

Procedure:
A solution of 5-fluoro-N-(2-methyl-1-phenylpropyl)-2-nitrobenzenamine (1.79 g, 6.2 mmol), N-Boc-piperazine (1.16 g, 6.2 mmol) and N,N-diisopropylethylamine (2.2 mL, 12.4 mmol) in acetonitrile was stirred at reflux for 24 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo to yield 2.45 g of the crude aniline. The crude product was purified by PTLC (15% ethyl acetate in hexanes) to yield 1.75 g (62%) of tert-butyl 4-(3-(2-methyl-1-phenylpropylamino)-4-nitrophenyl)piperazine-1-carboxylate: 1H NMR (400 MHz, CD3OD): δ 9.01 (br d, 1H), 7.96 (dd, 1H), 7.33-7.32 (m, 4H), 7.25-7.24 (m, 1H), 6.27 (br d, 1H), 5.72 (s, 1H), 4.40 (t, 1H), 3.42-3.34 (m, 4H), 3.27-3.23 (m, 2H), 3.16-3.11 (m, 2H), 2.13 (m, 1H), 1.07 (d, 3H), 0.96 (d, 3H). MS (ESI) m/z: Calculated: 454.26; Observed: 477.3 (M++Na).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[CH2:9][C:10]1[CH:44]=[CH:43][C:13]([C:14]([NH:16][C:17]2[C:18]3[CH:31]=[C:30]([C:32]([NH:34][N:35]([CH3:42])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[S:29][C:19]=3[N:20](C(OC(C)(C)C)=O)[N:21]=2)=[O:15])=[CH:12][CH:11]=1.ClCC1C=CC(C(NC2C3C=C(C(NN(C4C=CC(Cl)=CC=4)C)=O)SC=3N(C(OC(C)(C)C)=O)N=2)=O)=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:42][N:35]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH:34][C:32]([C:30]1[S:29][C:19]2[NH:20][N:21]=[C:17]([NH:16][C:14](=[O:15])[C:13]3[CH:43]=[CH:44][C:10]([CH2:9][N:6]4[CH2:5][CH2:4][NH:3][CH:2]([CH3:1])[CH2:7]4)=[CH:11][CH:12]=3)[C:18]=2[CH:31]=1)=[O:33]
Reactant: CC1CNCCN1
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccc(C(=O)Nc3n[nH]c4sc(C(=O)NN(C)c5ccccc5)cc34)cc2)CCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
27 mg (74 μmol) of tetrabutylammonium iodide, followed by 111 mg (1.11 mmol) of 2-methylpiperazine, are added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours, and then treated with ice. It is then extracted with ethyl acetate and then twice with dichloromethane. The organic extracts are combined and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 3 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography on a cartridge of 12 g of silica gel (0.035-0.060 mm), eluting first with a gradient of a dichloromethane/methanol mixture (100/0 to 98/2 by volume), and then with a dichloromethane/methanol/28% aqueous ammonia mixture (12/3/0.5 by volume) at a flow rate of 20 mL/min. The fractions containing the expected product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 85 mg of N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-(3-methylpiperazin-1-ylmethyl)benzamide are thus obtained in the form of a yellow powder melting from 176 to 186° C. LC-MS-DAD-ELSD: 504(+)=(M+H)(+).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N:14]([CH3:24])[C:15](=[O:19])[O:16][CH2:17][CH3:18])=[CH:20][CH:21]=1
Reactant: CCOC(=O)Nc1c(Oc2ccc(N)cc2)ccnc1N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(C)c1c(Oc2ccc(N)cc2)ccnc1N
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 52.9 %

Procedure:
Method O1. Ethyl 4-(4-aminophenoxy)-2-aminopyridin-3-yl-carbamate (72 mg, 0.25 mmol) was dissolved in dry THF (3 mL) and cooled at 0° C. Sodium hydride (11 mg, 0.28 mmol) was added, and the reaction mixture was stirred for 25 minutes. Methyl iodide (18 μL, 0.25 mmol) was added. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1.5 hours. The solvent was evaporated and the residue extracted between DCM and saturated Na2CO3. The organic layer was dried and evaporated, and the residue purified by column chromatography (eluent AcOEt) to afford the title compound (40 mg, 53%). 1H-NMR (δ, ppm, DMSO-d6): 1.10 (t, 3H, CH3,Et, J=7.04 Hz), 3.01 (s, 3H, CH3N), 3.90-4.10 (m, 2H, CH2,Et), 5.06 (s, 2H, NH2,Ph), 5.78 (d, 1H, HPy,5, J=6.68 Hz), 5.97 (s, 2H, NH2,Py2), 6.59 (d, 2H, Harom,Ph,3+5, J=8.76 Hz), 6.73 (d, 2H, Harom,Ph,2+6, J=8.79 Hz), 7.67 (d, 1H, HPy,6, J=5.73 Hz). LC-MS (m/z): 302 (M+, 100). Acc. mass (C15H19N4O3): calculated 303.1457, found 303.1453.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[O:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][OH:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][O:18][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: OCc1ncco1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(OCc2ncco2)cn1
Temperature: 40 °C
Reaction time: 24 h
Yield: 26.4 %

Procedure:
To a flask was added methyl 5-chloropyrazine-2-carboxylate (1.5179 g, 8.80 mmol), oxazol-2-ylmethanol (0.697 ml, 8.80 mmol), and cesium carbonate (0.845 ml, 10.56 mmol) in DMF (25.1 mL) to stir at 40° C. for 24 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, brine, and dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (100 g), eluting with a gradient of 10-100% EtOAc/hexane, to provide methyl 5-(oxazol-2-ylmethoxy)pyrazine-2-carboxylate (0.547 g, 2.327 mmol, 26.5% yield). MS m/z=236.0 [M+H]+. Calculated for C10H9N3O4: 235.059
Reaction SMILES: [CH3:1][CH2:2][CH:3]1[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[C:14](=[CH:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11].CNC.CN(C=[O:33])C>O=O.[Cu](Cl)Cl>[CH3:1][CH2:2][C@@:3]1([OH:33])[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]
Reactant: CN(C)C=O
Reactant: CCC1C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: Cl[Cu]Cl
Agent: CNC
Agent: O=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Yield: 91 %

Procedure:
To a solution of 18 (47.8 mg, 0.144 mmol), copper(II) chloride (80 mg) and dimethylamine (100 μl) in DMF (16 mL) was bubbled in oxygen for 7 h. The reaction mixture was concentrated in vacuum to about 5 mL, and was then diluted with water. A solution of saturated ammonium chloride was used to adjusted the pH of the above mixture to about 6, and the resulting mixture was extracted with chloroform (10 mL×10). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was flash chromatographed with 2% methanol in chloroform to give dl-camptothecin (45.5 mg, 91%).
Reaction SMILES: C(OC(CNC(=O)COC1C=C2C(C3C(CC)(C2)CCC(=O)C=3)=C(Cl)C=1Cl)=O)(C)(C)C.C([O:36][C:37]([CH2:39][CH2:40][NH:41][C:42](=[O:63])[CH2:43][O:44][C:45]1[CH:57]=[C:56]2[C:48]([C:49]3[C:54]([CH2:58][CH3:59])([CH2:55]2)[CH2:53][CH2:52][C:51](=[O:60])[CH:50]=3)=[C:47]([Cl:61])[C:46]=1[Cl:62])=[O:38])(C)(C)C>>[C:37]([CH2:39][CH2:40][NH:41][C:42](=[O:63])[CH2:43][O:44][C:45]1[CH:57]=[C:56]2[C:48]([C:49]3[C:54]([CH2:58][CH3:59])([CH2:55]2)[CH2:53][CH2:52][C:51](=[O:60])[CH:50]=3)=[C:47]([Cl:61])[C:46]=1[Cl:62])([OH:38])=[O:36]
Reactant: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)NCCC(=O)OC(C)(C)C)c(Cl)c1Cl)C2
Agent: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)NCC(=O)OC(C)(C)C)c(Cl)c1Cl)C2
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)NCCC(=O)O)c(Cl)c1Cl)C2

Procedure:
By carrying out the reaction as described in Example 107, Step B, except that the N-(t-butoxycarbonylmethyl)-[(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetamide is replaced by an equimolar amount of N-[2-(t-butoxycarbonyl)ethyl]-[(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetamide. There is obtained N-(2-carboxyethyl)-[(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetamide.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8](C=O)[CH2:7][CH2:6]1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](N)[CH2:25][NH2:26]>>[NH:26]1[CH2:25][CH2:24][N:2]=[C:1]1[CH2:3][CH2:4][CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: NCCN
Reactant: N#CCCC1CCN(C=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C1CNC(CCC2CCNCC2)=N1
Temperature: 200 °C

Procedure:
A mixture containing 4-(2-cyanoethyl)-1-piperidinecarboxaldehyde (10 g, 0.06 M) and ethylenediamine p-toluenesulfonate (30 g, 0.129 M) were heated at 200° C. for 41/2 hours. Crystallization of the crude reaction mixture from isopropanol (70 ml) yielded the desired product as the di-p-toluenesulfonate salt (14 g). The salt was then basified with 2 equivalents of MeONa and distilled (0.2 mmHg, 170° C.) to give 4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]piperidine (4.1 g, 37% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][O:41][CH2:42][C@@H:43]([CH3:47])[CH2:44][O:45][CH3:46])=[CH:36][CH:35]=2)[C@H:13]([CH2:48][OH:49])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:50](Cl)(=[O:52])[CH3:51]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][O:41][CH2:42][C@@H:43]([CH3:47])[CH2:44][O:45][CH3:46])=[CH:36][CH:35]=2)[C@H:13]([CH2:48][O:49][C:50](=[O:52])[CH3:51])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CO)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](COC(C)=O)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21

Procedure:
Analogously to Example 2a, (3S,4R,5R)-3-hydroxymethyl-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H -benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (Example 1a) and acetyl chloride are used to afford the title compound as a colorless oil. Rf=0.20 (EtOAc-heptane 1:1); Rt=5.69 (gradient I).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.S([O-])(OC)(=O)=O>CN(C=O)C.O>[CH3:16][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CNC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)Cc1ccc(OC)c([N+](=O)[O-])c1
Yield: 82 %

Procedure:
To a solution of 4.2 g (19.8 mmol) of 4-hydroxy-N-methyl-3 -nitrobenzeneacetamide in 50 mL of DMF containing 5.5 g of anhydrous potassium carbonate was added 5.6 mL of dimethyl sulfate. The mixture was heated at 60°-70° C. for 45 min, treated with an additional 3.0 mL of methyl sulfate, and heated for another 30 min. The mixture was cooled, poured into 200 mL water, and extracted with dichloromethane. The extracts were washed with water, dried and evaporated to give a solid which was recrystallized from ethanol-water to afford 3.7 g of a yellowish solid (82%). 1H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.47 (d, 1H, J =9.0 Hz), 7.25 (d, 1H, J =8.4 Hz), 5.71 (brs, 1H), 3.90 (s, 3H) 3.47 (s, 2H), 2.75 (d, 3H, J=4.8 Hz).
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][C@@H:18]3[O:23][N+:24]([O-:26])=[O:25])([CH3:16])[C@@H:14]([O:27]C(=O)C)[CH2:13][CH2:12]4)[C@H:9]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][S:40]([CH2:43][CH2:44][CH2:45][C:46]([F:52])([F:51])[C:47]([F:50])([F:49])[F:48])(=[O:42])=[O:41])[CH2:8][C:7]=2[CH:6]=1)(=O)C.[OH-].[K+]>CO>[N+:24]([O:23][C@H:18]1[CH2:17][C@@:15]2([CH3:16])[C@@H:11]([CH2:12][CH2:13][C@@H:14]2[OH:27])[C@H:10]2[C@H:19]1[C:20]1[CH:21]=[CH:22][C:5]([OH:4])=[CH:6][C:7]=1[CH2:8][C@H:9]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][S:40]([CH2:43][CH2:44][CH2:45][C:46]([F:52])([F:51])[C:47]([F:48])([F:49])[F:50])(=[O:41])=[O:42])([O-:26])=[O:25]
Reactant: CC(=O)Oc1ccc2c(c1)C[C@@H](CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)[C@@H]1[C@@H]2[C@@H](O[N+](=O)[O-])C[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[C@]12C[C@H](O[N+](=O)[O-])[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 4 h

Procedure:
For saponification, 1.0 g of 3,17β-diacetyloxy-11β-nitrooxy-7α-(9-[4,4,5,5,5-pentafluoropentane-sulfonyl]-nonyl)-estra-1,3,5(10)-triene is dissolved in 50 ml of methanol, mixed with 20 ml of 3% methanolic potassium hydroxide solution and allowed to stand for 4 hours at room temperature.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH3:12][C:13]1C=[CH:17][C:16](S(OCCCCC#C)(=O)=O)=[CH:15][CH:14]=1>>[CH2:17]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH2:16][CH2:15][CH2:14][C:13]#[CH:12]
Reactant: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C=O)cc1O
Product: C#CCCCCOc1cc(C=O)ccc1OC
Yield: 57 %

Procedure:
Isovanillin (0.78 g, 5.2 mmol) was alkylated using hex-5-ynyl 4-methylbenzenesulfonate (1.95 g, 7.73 mmol according to Procedure 4. The crude product was recystallised from EtOAc/petrol to provide 3-(hex-5-ynyloxy)-4-methoxybenzaldehyde (0.68 g, 57%) as a colourless crystalline solid; mp 66-67° C.; δH (400 MHz, CDCl3) 1.74 (p, J=7.2 Hz, 2H, CH2), 1.96-2.0 (m, 3H, CH2, C≡CH), 2.30 (td, J=7.2, 2.8 Hz, 2H, CH2C≡CH), 3.95 (s, 3H, OCH3), 4.11 (t, J=7.2 Hz, 2H, OCH2), 6.97 (d, J5,6=8.0 Hz, 1H, H5), 7.40 (d, J2,6=1.6 Hz, 1H, H2), 7.44 (dd, J5,6=8.0 Hz, J2,6=1.6 Hz, 1H, H6), 9.84 (s, 1H, CHO); δC (100 MHz, CDCl3) 18.1, 25.0, 28.0, 56.2, 68.4, 68.7, 83.9, 110.3, 110.6, 126.7, 130.1, 149.0, 154.9, 190.9; vmax 1018, 1263, 1582, 1679, 2933, 3238 cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][CH2:16][NH:17]2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Ca+2].[I:26](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[I:26][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[CH2:9][CH2:8][NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[NH:17][CH2:16][CH2:15][CH2:14]2
Reactant: CC(C)(C)OC(=O)NCCc1ccc2c(c1)NCCC2
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1cc2c(cc1I)CCCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a mixed solution of 770 mg of t-butyl[2-(1,2,3,4-tetrahydroquinolin-7-yl)ethyl]carbamate in 15 ml of dichloromethane and 3 ml of MeOH were added 420 mg of calcium carbonate and 970 mg of benzyltrimethylammonium dichloroiodate, followed by stirring at room temperature for 2 hours. The insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 595 mg of t-butyl [2-(6-iodo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]carbamate as a reddish brown viscous substance.