Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.[S:46]1[CH:50]=[CH:49][N:48]=[C:47]1[C@H:51]([NH2:53])[CH3:52]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([NH:53][C@@H:51]([C:47]2[S:46][CH:50]=[CH:49][N:48]=2)[CH3:52])=[O:44])=[C:18]([C:23]([F:25])([F:26])[F:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C(F)(F)F)c3)c2cc1OC
Reactant: C[C@@H](N)c1nccs1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4nccs4)c(C(F)(F)F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-(trifluoromethyl)aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (30 mg, yield 71%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=O)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].O[NH:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1)=[NH:29].CC[O-].[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[O:22][N:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=3)[N:27]=2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: N=C(NO)c1cccc(O)c1
Reactant: CCCCn1c(=O)n(CCCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCCc2nc(-c3cccc(O)c3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 180 °C

Procedure:
A mixture of ethyl 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (50 mg, 0.13 mmol), N,3-dihydroxybenzenecarboximidamide (25 mg, 0.16 mmol), 21% solution of NaOEt in EtOH (55 μl, 0.15 mmol) and EtOH (1.5 ml) was heated in the microwave at 180° C. for 10 min. Another aliquot of 21% solution of NaOEt in EtOH (55 μl, 0.21 mmol) was added and the mixture heated in the microwave at 175° C. for 30 min. After cooling the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, concentrated and purified by the MDAP. The title compound was obtained as an off-white solid (20 mg, 32%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:43]>C1COCC1>[CH2:37]([C:29]1[N:28]([C:17]2[N:16]=[C:15]3[C:20]([N:21]=[C:13]([C:10]4([O:12][CH3:43])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]4)[N:14]3[CH3:39])=[C:19]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:18]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1)[CH3:38]
Reactant: CI
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Reaction time: 16 h
Yield: 57.5 %

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (208 mg, 0.39 mmol) in THF (3 mL) was added NaH (19 mg, 0.47 mmol, 60% dispersion in mineral oil) and the mixture allowed to stir for 5 min before the addition of iodomethane (29 μL, 66 mg, 0.47 mmol). The resulting mixture was allowed to stir for 3.5 h before further iodomethane (29 μL, 66 mg, 0.47 mmol) was added. The mixture was stirred for 16 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 40-80%) affording 714 as an oil (123 mg, 57%). LCMS (method I): RT 4.49 min, [M+H]+ 549.2. 1H NMR (CDCl3, 400 MHz): δ 7.99-7.90 (1 H, m), 7.74-7.64 (1 H, m), 7.25-7.16 (2 H, m), 4.60-4.40 (4 H, brd m), 4.18 (2 H, d, J=9.17 Hz), 3.82-3.81 (6 H, m), 3.71 (3 H, s), 3.29 (2 H, t, J=7.54 Hz), 3.07 (3 H, s), 1.42-1.33 (12 H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:12]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[C-:37]#[N:38].[K+].CN(C=O)C.C(OCC)(=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][C:37]#[N:38])[CH:12]([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: [C-]#N
Reactant: COc1ccc(C2C(COS(=O)(=O)c3ccc(C)cc3)c3ccc(OC)cc3C3CCCCC32)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C2C(CC#N)c3ccc(OC)cc3C3CCCCC32)cc1
Reaction time: 2 h
Yield: 87.4 %

Procedure:
Combine toluene-4-sulfonic acid 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-ylmethyl ester (0.224 g, 0.44 mmol), KCN (0.172 g, 2.65 mmol), and DMF (4 mL), and stir under nitrogen atmosphere at 100° C. After 2 hours, add ethyl acetate and water. Separate the organic phase and wash with brine. Dry the organic phase with anhydrous sodium sulfate and flash chromatograph using 0% to 20% ethyl acetate/hexanes to yield the titled compound (0.139 g, 87%) as a white foam. TLC Rf=0.46 in 4:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.31 (m, 1H), 7.24 (d, 2H, J=8.8 Hz), 6.96 (m, 3H), 6.84 (dd, 1H, J=8.4, 2.6 Hz), 3.86 (m, 6H), 3.59 (m, 1H), 3.34 (s, 1H), 3.18 (dd, 1H, J=12.3, 3.1 Hz), 2.90 (dd, 1H, J=17.2, 4.4 Hz), 2.51 (m, 2H), 1.98 (m, 1H), 1.66 (m, 2H), 1.48 (m, 2H), 1.14 (m, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][C:26]=1[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9].C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:24]=[CH:25][C:26]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[C:5]([O:4][CH2:3][CH2:2][N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)[CH:6]=2)=[CH:12][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCBr
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCN1CCNC(=O)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (50 mg, 0.095 mmol) was dissolved in DMF (1.0 ml) and treated with potassium carbonate (18 mg, 0.13 mmol) and piperazin-2-one (11 mg, 0.11 mmol) for 18 hours. The reaction was heated for 2.0 hours at 50° C., then additional potassium carbonate (18 mg, 0.13 mmol) and piperazin-2-one (11 mg, 0.11 mmol) was added. After 2 hours, the reaction was quenched in 5% NaOH and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO4, and purified by reverse phase HPLC to yield 16 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(3-oxopiperazin-1-yl)ethoxy)benzamide. MS (Q1) 558 (M)+.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[C:13]([CH:36]=1)[C:14]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:15])(=O)C.C(O)(=O)C>CO.O1CCOCC1>[CH2:38]([O:37][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][OH:6])=[CH:36][C:13]=1[C:14]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:15])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(=O)OCCc1ccc(OCc2ccccc2)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(CCO)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (0.37 mL) was added to a solution mixture of tert-butyl 2-(5-(2-acetoxyethyl)-2-(benzyloxy)benzamido)-4-phenylbenzoate (0.38 g) in methanol (1.9 mL) and dioxane (1.9 mL), followed by stirring at room temperature for 2 hours. Acetic acid (0.012 mL) was added to the reaction mixture. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 0.35 g of tert-butyl 2-(2-(benzyloxy)-5-(2-hydroxyethyl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [P:1]([O-:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(C)C(C)=CC=CC=1.[CH3:25][C:26](=[O:29])[CH2:27][CH3:28]>>[CH3:3][OH:2].[O:2]([P:1]([C:26]([OH:29])([CH2:27][CH3:28])[CH3:25])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [O-]P(Oc1ccccc1)Oc1ccccc1
Reactant: CCC(C)=O
Solvent: Cc1ccccc1C
Product: CCC(C)(O)P(=O)(Oc1ccccc1)Oc1ccccc1
Product: CO
Temperature: 70 °C

Procedure:
To a one liter four-inlet flask equipped with a temperature controller, a reflux condenser, a nitrogen feed and a mechanical stirrer, 1 mole (234 g) diphenyl phosphite (DPP) and 500 ml xylene were added. The mixture was heated to 70° C. and then stirred. The mixture was heated to a temperature of 90° C. and the stirring was continued until DPP was dissolved completely. To this solution was added slowly 1.0 mole (72 g) 2-butanone within two hours, and the temperature thereof was increased to 120–1258° C. and maintained at that temperature for six hours after the addition of 2-butanone was completed. The mixture was then cooled to room temperature to obtain solid, which was then filtered, and purified with THF to yield 2-(diphenoxy phosphoryl) butan-2-ol methanol [DPOB; (II)]. Yield, 96%; m.p. 52–54° C. Anal. Calcd. for C16H19PO4: C, 62.75; H, 6.21; O, 20.91; P, 10.13. Found: C, 62.61; H, 6.27; O, 20.81; P, 10.31. EIMS, m/z: 306 (92. M+).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:16])[NH2:15])=[N:6]1.[F:21][CH:22]([C:28](=O)[CH3:29])[C:23](OCC)=[O:24]>>[F:21][C:22]1[C:23]([OH:24])=[N:16][C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=3[F:1])[N:6]=2)=[N:15][C:28]=1[CH3:29]
Reactant: CCOC(=O)C(F)C(C)=O
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Product: Cc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(O)c1F

Procedure:
The compound is prepared in analogy to example I, step 6. Starting from 650 mg (2.41 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide (example I, step 5) and ethyl 2-fluoro-3-oxobutanoate, 520 mg (60% of theory) of the product are obtained.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2([S:25][CH2:26][CH3:27])[S:23][CH3:24])[C@H:15]2[C@@:6]1([F:30])[C@:7]1([CH3:29])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:28])[CH:9]=[CH:8]1)(=O)C.[OH-].[Na+].C(O)(=O)C>CO.O1CCCC1>[CH2:26]([S:25][C:19]1([S:23][CH3:24])[CH2:18][CH2:17][C@H:16]2[C@H:15]3[C@:6]([F:30])([C@@H:5]([OH:4])[CH2:22][C@:20]12[CH3:21])[C@:7]1([CH3:29])[C:12](=[CH:11][C:10](=[O:28])[CH:9]=[CH:8]1)[CH2:13][CH2:14]3)[CH3:27]
Reactant: CCSC1(SC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCSC1(SC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Yield: 97.8 %

Procedure:
A solution of 11β-acetyloxy-17-(ethylthio)-9-fluoro-17-(methylthio)androsta-1,4-diene-3-one (620 mg) in a mixture of methanol (20 ml) and tetrahydrofuran (10 ml) is stirred under nitrogen with 3 M aqueous sodium hydroxide (1.5 ml). After eighteen hours, a slight excess of acetic acid is added. The mixture is concentrated in vacuo, diluted with water and extracted with chloroform. The chloroform solution is washed with water, dried, evaporated and chromatographed over a column of silica gel (10 g) eluting the column successively with chloroform-hexane (4:1), chloroform and chloroform-ethyl acetate (95:5) to isolate the title compound (550 mg). Crystallization of this from ethyl acetate-hexane and drying (110° C., 0.3 mm of Hg, 7 hours) gives the analytical specimen, melting point 275° C., dec. (contracts from approximately 200° C., discoloration starts from approximately 220° C. and becomes deeper until spontaneous melting at 275° C. with decomposition) with consistent spectral data. The nmr spectrum shows that this is an essentially 1:1 mixture of the two 17-stereoisomers.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:23]([C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30])([CH3:26])([CH3:25])[CH3:24].C(OC(N1CCN(C2C=CC(C(=O)NC3C=CC=C(C(C)(C)C)C=3)=CC=2)CC1)=O)(C)(C)C>>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:28]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1

Procedure:
4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was prepared from N-Boc-4-(4-carboxyphenyl)piperidine and 3-tert-butyl aniline in a manner similar to the one described in the synthesis of 4-[4-(3-tert-butyl-phenylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester, above. The product was isolated after silica gel column purification with 10-50% Et2O in hexanes. HRMS m/z calcd for C26H35N3O3I [M+H]+: 437.2799. Found: 437.2796.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH3:8])N=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.[CH2:13](N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:1][C:2]1[N:7]=[C:6]([CH3:13])[CH:8]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1)(=[O:23])=[O:22]
Reactant: Cc1nc(O)nc(C(Cl)(Cl)Cl)n1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(Cl)(Cl)Cl)nc(OS(C)(=O)=O)n1
Reaction time: 1 h

Procedure:
To a solution of 2-hydroxy-4-methyl-6-trichloromethyl-[1,3,5]triazine (1.14 g, 5.0 mmol; J. Amer. Chem. Soc. 1956, 78, 2447) and triethylamine (0.51 g, 5.5 mmol) in dichloromethane was added methanesulfonyl chloride (0.57 g, 5.0 mmol) at 0° C. and stirred for 1 h then quenched in saturated aqueous sodium bicarbonate. The separated organic layer was washed once with saturated sodium chloride, dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound of Example 242, Step A as an orange oil, 0.98 g (65%) which was used directly without any further purification. MS (Cl) 291,293 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23]O)[CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([O:12][CH2:23][CH2:22][N:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Reactant: CN1CCN(CCO)CC1
Product: COc1cc2ncnc(Cl)c2cc1OCCN1CCN(C)CC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-6-hydroxy-7-methoxy-quinazoline and 2-(4-Methyl-piperazin-1-yl)-ethanol. LC/ESI-MS: m/z=337 [M+H].
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:6]12)=[O:4].[N:26]1([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>O1CCCC1>[C:24]([C:23]1[CH:22]=[N:21][N:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[CH:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:29]3[CH2:28][CH2:27][N:26]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:31][CH2:30]3)[C:6]=12)#[N:25]
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cnn2c1N(C(=O)CN1CCN(C(=O)OCc3ccccc3)CC1)CC=C2c1cccc(C(F)(F)F)c1
Yield: 48.6 %

Procedure:
A mixture of 6.3 g of 4-(chloroacetyl)-4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 4.2 g of 1-piperazinecarboxylic acid, phenylmethyl ester and 4.1 g of triethylamine in 250 ml of tetrahydrofuran was stirred under reflux for 18 hours, then cooled and filtered. The filtrate was evaporated, the residue taken up in chloroform, washed with water, dried, filtered and concentrated. The residual oil was triturated three times with ether:hexane (1:1), then with hexane. The solid was collected, washed with hexane and dried. The solid was heated to solution in 25 ml of ethyl acetate, filtered, diluted with 25 ml of hexane and cooled, giving 4.6 g of the desired product, mp 113°-115° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][N:30]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f21) and commercially propionyl chloride the title compound is obtained as colorless solid.
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].[N+:27]([O-:30])([OH:29])=[O:28]>S(=O)(=O)(O)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)[C:23]1[N:22]=[C:21]2[C:16](=[CH:15][C:14]=1[CH2:13]3)[C:17]([N+:27]([O-:29])=[O:28])=[CH:18][CH:19]=[CH:20]2)=[O:11].[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:20]([N+:27]([O-:30])=[O:28])=[CH:19][CH:18]=[CH:17][C:16]2=[CH:15][C:14]=1[CH2:13]3)=[O:11]
Reactant: O=[N+]([O-])O
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: O=S(=O)(O)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c([N+](=O)[O-])cccc3nc2-1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cccc([N+](=O)[O-])c3nc2-1

Procedure:
It was also found that when camptothecin in sulfuric acid was treated carefully with nitric acid under ice-cooling and agitation, new 9-nitrocamptothecin could be obtained in a yield of 30-40% together with the known 12-nitrocamptothecin. This new 9-nitrocamptothecin is then reduced to 9-aminocamptothecin which can be converted into various 9-substituted camptothecin derivatives according to the methods known per se as in the case of 10-nitrocamptothecin (Japanese Laid-open Patent Appln. No. 59-51289). For example, 9-aminocamptothecin can be converted into the corresponding 9-halogeno or 9-cyano derivative by once converting the 9-amino derivative into 9-diazonium salt and then treating the salt with cuprous halide or cyanide according to the Sandmayer reaction. Further, 9-diazonium salt can be converted into 9-hydroxy, 9-alkoxy and 9-acyloxy derivatives in the manner known per se.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:3]1[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1.[Cl:32][CH2:33][C:34](Cl)=[O:35]>O1CCOCC1>[Cl:32][CH2:33][C:34]([O:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:3]1[CH:18]=[CH:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:35]
Reactant: COC(=O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Reactant: O=C(Cl)CCl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)CCCCCCC1=C(C=Cc2ccccc2)C(OC(=O)CCl)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6.8 parts of methyl 3-hydroxy5-oxo-2-styrylcyclopent-1-eneheptanoate and 2 parts of pyridine in 80 parts of dioxane is added, at 0°-5°, a solution of 2.4 parts of chloroacetyl chloride in 20 parts of dioxane. The resulting reaction mixture is stirred at that temperature for about 30 minutes, then at room temperature for about 5 hours. At the end of that reaction period the mixture is poured carefully into ice water and the resulting aqueous mixture is extracted with ether. The ether solution is washed successively with dilute hydrochloric acid and dilute aqueous sodium bicarbonate, then dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure. The resulting product is purified by dry column chromatography on silica gel containing 8% of water, using 18% ethyl acetate in benzene, to afford pure methyl 3-chloroacetoxy-5-oxo-2-styrylcyclopent-1-eneheptanoate. This compound is represented by the following structural formula ##SPC7##
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18].C(N(CC)CC)C.[C:26](O)(=[O:28])[CH3:27]>ClCCl>[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:26](=[O:28])[CH3:27])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18]
Reactant: NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Reactant: CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
4-Chloro-5-(3-aminopropoxy)-7-iodoisoindolinone hydrochloride (84.0 mg, 0.208 mmol) was suspended in dichloromethane, and the suspension was added with triethylamine (0.090 mL, 0.648 mmol) and anhydrous acetic acid (0.031 mL, 0.324 mmol), followed by stirring at room temperature for 12 hours. The solvent was evaported under reduced pressure and the residue was purified by slurry using water and acetonitrile to obtain 4-chloro-5-[3-(acetylamino)propoxy]-7-iodoisoindolinone (78.6 mg, yield 92%).