Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:35])=[C:4]([N:8]([CH2:22][C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[O:24])[S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO.C1COCC1>[Cl:1][C:2]1[C:3]([CH3:35])=[C:4]([N:8]([CH2:22][C:23]([NH:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[O:24])[S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(OC)cc2)c2cccc(Cl)c2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CNC(=O)CN(c2cccc(Cl)c2C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
220 mg of methyl 4-{[(3-chloro-2-methylphenyl)amino]sulfonyl}benzoate was dissolved in 1.10 mL of DMF, and 168 mg of 2-bromo-N-(4-methoxybenzyl)acetamide and 100 mg of potassium carbonate were added thereto, followed by stirring at room temperature for 7 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3 to 4:6) to obtain 270 mg of methyl 4-[((3-chloro-2-methylphenyl)-{2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]benzoate. The obtained methyl 4-[((3-chloro-2-methylphenyl)-{2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]benzoate was dissolved in 2.00 mL of methanol and 1.50 mL of THF, and 1.05 mL of a 1 M aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 2 days. The reaction liquid was acidified by addition of 1 M hydrochloric acid, and then extracted with a mixed solvent of chloroform/methanol (5/1), and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform:methanol=100:0 to 90:10) to obtain 204 mg of 4-[((3-chloro-2-methylphenyl) {2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]benzoic acid.
Reaction SMILES: [OH:1][C:2]([CH3:40])([CH3:39])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([N:24](CC3C=CC(OC)=CC=3)[C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])[CH:19]=[CH:20][C:12]1=2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]([CH3:40])([CH3:39])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:22])=[O:23])[CH:19]=[CH:20][C:12]1=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2OCC(C)(C)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)COc1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a solution of 4-(2-(2-hydroxy-2-methylpropoxy)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (600 mg, 0.585 mmol) in DCM (5 mL) was added TFA (1.4 mL, Spectrochem) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL) and extracted with DCM (2×10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by prep HPLC purification to obtain 4-(2-(2-hydroxy-2-methylpropoxy)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (120 mg, 26.0%) as a white solid. m/z (ESI) 461.8 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.50 (s, 1H), 7.38-7.24 (m, 2H), 7.20 (d, J=4.6 Hz, 1H), 7.16-6.95 (m, 4H), 6.76 (d, J=4.3 Hz, 1H), 6.23-6.00 (m, 1H), 4.46 (s, 1H), 4.31 (d, J=3.9 Hz, 2H), 3.61-3.58 (m, 4H), 0.83 (s, 6H).
Reaction SMILES: C([O:3][C:4]1(OCC)[CH2:11][C:10]2[C:5]1=[CH:6][C:7]([O:14][CH3:15])=[C:8]([O:12][CH3:13])[CH:9]=2)C.Cl.O>C1COCC1.O>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:14][CH3:15])[C:4](=[O:3])[CH2:11]2
Reactant: CCOC1(OCC)Cc2cc(OC)c(OC)cc21
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
7,7-Diethoxy-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene (1.76 g, 6.98 mmol) is stirred in a mixture of THF/water (6/1) at ambient temperature. 815 mg of an aqueous 11N HCl solution (1.1 eq, 7.7 mmol) are then added. The reaction mixture is stirred for 2 hours ambient temperature. Water is added to facilitate two extractions with ethyl acetate (2×30 mL). The organic phases are dried over MgSO4 and then subjected to drying. There are obtained 1.01 g of the title product in the form of a grey powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.[C:37]([S:40][CH2:41][CH2:42][N:43]([CH2:52][CH2:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1)[C:44](=[O:51])[NH:45][C@@H:46]([CH3:50])[C:47]([OH:49])=O)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([S:40][CH2:41][CH2:42][N:43]([CH2:52][CH2:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1)[C:44](=[O:51])[NH:45][C@@H:46]([CH3:50])[C:47]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:49])(=[O:39])[CH3:38]
Reactant: CC(=O)SCCN(CCC1CCCCC1)C(=O)N[C@@H](C)C(=O)O
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)SCCN(CCC1CCCCC1)C(=O)N[C@@H](C)C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
In anhydrous methylene chloride (5 ml) are dissolved (2S)-2-[3-[2-(acetylthio)ethyl]-3-(2-cyclohexylethyl)ureido]propionic acid (Compound No. 7-1, 826 mg), N-methylpiperazine (0.27 ml) and 1-hydroxybenzotriazole (357 mg) under a nitrogen atmosphere. To the solution are added N-methylmorpholine (0.29 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (506 mg) successively under ice cooling, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, a 5% aqueous sodium hydiogencarbonate solution (30 ml) is added to the resulting oily matter, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 801 mg (78%) of the titled compound (Compound No. 13-1).
Reaction SMILES: [OH-].[Ca+2].[OH-].[CH2:4]([O:7][C:8]([N:10]1[CH2:14][C@H:13](OS(C)(=O)=O)[CH2:12][C@H:11]1[CH2:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:9])[CH:5]=[CH2:6].[C:26]([SH:29])(=[O:28])[CH3:27]>CC(C)CC(=O)C>[C:26]([S:29][C@@H:13]1[CH2:14][N:10]([C:8]([O:7][CH2:4][CH:5]=[CH2:6])=[O:9])[C@H:11]([CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH2:12]1)(=[O:28])[CH3:27]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cn1ccnc1
Reactant: CC(=O)S
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1Cn1ccnc1
Temperature: 82.5 °C

Procedure:
To a solution of calcium hydroxide (2.25 g) and (2S,4R)-1-allyloxycarbonyl-2-(imidazol-1-yl)methyl-4-methanesulfonyloxypyrrolidine (10 g) in 4-methyl-2-pentanone (60 ml) was added dropwise thioacetic S-acid (4.38 ml) with stirring below 45° C. The solvent (18 ml) of the mixture was removed under reduced pressure at 40-45° C. The resulting suspension was heated at 80-85° C. for 2 hours. After cooling, water (20 ml) and ethyl acetate (20 ml) was added to the reaction mixture. The insoluble material was filtered off and washed with ethyl acetate (30 ml). The filtrate and washing were combined. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(imidazol-1-yl)methylpyrrolidine (7.94 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.[CH:9](OCC)=[O:10]>>[CH:9]([NH:1][CH2:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)=[O:10]
Reactant: CCOC=O
Reactant: NCCc1ccco1
Product: O=CNCCc1ccco1

Procedure:
Here, 2-(2-amino-ethyl)furan (10.0 g, 0.090 mol) is refluxed with ethyl formate (80 ml, 1.0 mol) for 12 hours. The reaction product is concentrated by evaporation and distilled in vacuo.
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].[CH3:6][N:7]([P:9](Cl)[N:10]([CH3:12])[CH3:11])[CH3:8].P(Cl)(Cl)Cl.C[N-]C.[Li+]>C(OCC)C.CCCCCC.CN(P(N(C)C)N(C)C)C>[C:1]([P:9]([N:10]([CH3:12])[CH3:11])[N:7]([CH3:8])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]C(C)(C)C
Reactant: CN(C)P(Cl)N(C)C
Agent: CN(C)P(N(C)C)N(C)C
Agent: C[N-]C
Agent: [Li+]
Solvent: ClP(Cl)Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(C)P(N(C)C)C(C)(C)C
Temperature: 0 °C
Yield: 69 %

Procedure:
Tertiarybutylbis(dimethylamino)phosphine was prepared according to Reaction Scheme #2 by reaction of tertiarybutyllithium with bis(dimethylamino)phosphoruschloride which had been prepared from the reaction of neat trisdimethylaminophosphine and phosphorustrichloride. Trisdimethylaminophosphine was prepared from the reaction of phosphorus trichloride with three equivalents of lithium dimethylamide in diethylether at 0° C. A solution of 88.4 g (0.64 mol) PCl3 in 50 ml diethylether was added dropwise to a stirred suspension of 105 g (2.06 mol) LiNMe2 in 1.5 liters diethylether at 0° C. The resulting mixture was filtered and the P(NMe2)3 product, 0.444 mol, 72.5 g (69% yield based on PCl3), was fractionally distilled from the filtrate at 45° C./9.5 torr. PCl3, 0.222 mol (30.5 g) was added slowly to the purified P(NMe2)3 with stirring at 0° C. The resulting P(NMe2)2Cl compound was heated to 35° C. for one hour then diluted with 1 liter of hexane and cooled to -78° C. A 400 ml aliquot (0.68 mol) of tertiarybutyl lithium, ((CH3)3C)Li, in hexane was added dropwise over a two hour period with stirring. The mixture was allowed to warm, filtered and the tertiarybutyl-bis(dimethylamino)phosphine, ((CH3)3C)P(NMe2)2, product, 55 g, 0.31 mol (45% yield based on P(NMe2)2Cl), was purified by repeated fractional distillation of the filtrate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.C[Al](C)C.C[O:19][C:20]([C:22]1[N:23]=[C:24]([CH2:68][CH2:69][CH3:70])[N:25]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[N:48]([C:49]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[N:47]=[N:46][N:45]=3)=[CH:34][CH:33]=2)[C:26]=1[C:27]([O:29][CH3:30])=[O:28])=O>C(Cl)Cl.CCOCC.C1(C)C=CC=CC=1>[CH3:30][O:29][C:27]([C:26]1[N:25]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[N:48]([C:49]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[N:47]=[N:46][N:45]=3)=[CH:36][CH:37]=2)[C:24]([CH2:68][CH2:69][CH3:70])=[N:23][C:22]=1[C:20]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[O:19])=[O:28]
Reactant: CCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCc1nc(C(=O)N2CCN(c3ccccn3)CC2)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
To a solution of 0.72 g (4.4 mmol) of 1-(2-pyridyl)piperazine in 10 mL of anhydrous CH2Cl2 under N2 was added 4.4 mL (4.4 mmol) of a 1 N solution of HCl in ether. After 15 min., the suspension was cooled to 10° C. and treated with 2.2 mL (4.4 mmol) of 2.0 M Me3Al in toluene. Slow gas evolution was noted. After 30 min., a solution of 2.81 g (4.00 mmol) of 4,5-bis(methoxycarbonyl)-2-propyl-1-[(2'-(N-trityltetrazol-5-yl)biphen-4-yl)methyl]imidazole in 12 mL of CH2Cl2 was added. The reaction mixture was allowed to warm to room temperature and stir for 2 h, then partitioned between EtOAc and H2O. The water layer was washed with EtOAc and the combined organic extracts were washed with water and brine, then dried over MgSO4. After removal of solvents at reduced pressure, the residual tan foam (4.08 g) was purified using flash chromatography (eluent: 50/50 EtOAc-hexane to 1% MeOH-EtOAc) to give 2.36 g (71%)of the title compound as a white foam. 1H NMR (300 MHz, CDCl3): δ 0.88 (t, J=7.5 Hz, 3H, CH3); 1.70 (sextet, J=7.5 Hz, 2H, CH2); 2.52 (t, J=7.5 Hz, 2H, CH2); 3.45 (m, 2H, piperazine); 3.54 (m, 2H, piperazine); 3.63 (m, 2H, piperazine); 3.71 (s, 3H, CO2CH3); 3.93 (m, 2H, piperazine); 5.46 (s, 2H, benzyl); 6.67 (m, 2H, aromatic); 6.82 (d, J=8.0 Hz, 2H, p-disubstituted aromatic); 6.94 (d, J=7.5 Hz, 6H, trityl); 7.11 (d, J=8.0 Hz, 2H, p-disubstituted aromatic); 7.2-7.4 (m, 10H, aromatic); 7.4-7.5 (m, 3H, aromatic); 7.91 (dd, J= 7.0, 6.0 Hz, 1H, tetrazolyl-phenyl); 8.19 (approx. dd, J=5.5, 2 . 0 Hz, 1H, pyridyl).
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][C:21](=[N:35][NH:36][C:37]([NH2:39])=[O:38])[CH2:22][C@H:23]([NH:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH2:29])[CH:24]=[O:25])([CH3:19])([CH3:18])[CH3:17].O.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NC(N)CC(C)C)C>CN1CCCC1=O.C(Cl)Cl>[C:16]([O:20][C:21](=[N:35][NH:36][C:37]([NH2:39])=[O:38])[CH2:22][C@H:23]([NH:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:29][C:13](=[O:15])[CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH:24]=[O:25])([CH3:18])([CH3:19])[CH3:17]
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Reactant: O=C(O)COc1cccc2ccccc12
Agent: CCN=C=NC(N)CC(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@H](NC(=O)COc1cccc2ccccc12)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.7 %

Procedure:
To a solution of (1-naphthyloxy)acetic acid (0.150 g, 0.74 mmol) and (3S)-3-(leucinyl)amino-4-oxobutanoic acid tert-butyl ester semicarbazone (0.360 g, ca 0.83 mmol) in N-methylpyrrolidone(2.0 mL)-CH2Cl2(2.0 mL) at 0° C. (ice bath) under nitrogen was added hydroxybenzotriazole hydrate (0.130 g) followed by 1-ethyl-3-(3′,3′-dimethyl-1′-aminopropyl)carbodiimide hydrochloride (0.195 g, 1.02 mmol). After stirring at 0° C. for 1 hrs and at room temperature for 5 hrs, the mixture was partitioned between EtOAc-water. The organic phase was washed with water, 5% KHSO4, saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography eluting with MeOH-CH2Cl2 (2:100 then 5:100) to give the title compound (0.366 g, 94%) as a colorless foam. TLC(MeOH-CH2Cl2; 5:95) Rf=0.20.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([O:16]C(OC(C)(C)C)=O)[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][CH:4]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:40]=[CH:39][C:38]([CH2:41][C:42]([O:44][CH2:45][CH:46]=[CH2:47])=[O:43])=[CH:37][N:36]=2)=[CH:31][CH:30]=1>>[CH2:45]([O:44][C:42]([CH2:41][C:38]1[CH:37]=[N:36][C:35]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH2:2][C:3]3[C:8]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[C:7]([OH:16])[C:6]([C:24]([F:26])([F:25])[F:27])=[CH:5][CH:4]=3)=[CH:34][CH:33]=2)=[N:40][CH:39]=1)=[O:43])[CH:46]=[CH2:47]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: C=CCOC(=O)Cc1cnc(-c2ccc(O)cc2)nc1
Product: C=CCOC(=O)Cc1cnc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)nc1
Yield: 28 %

Procedure:
According to a method similar to Example (2-3) and Example (33-5), from tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (412 mg, 0.92 mmol) obtained in Example (28-5) and allyl [2-(4-hydroxyphenyl)-5-pyrimidinyl]acetate (250 mg, 0.92 mmol), tert-butyl 6-{[4-(5-{[(allyloxy)carbonyl]methyl}-2-pyrimidinyl)phenoxy]methyl}-2-hydroxy-3-(trifluoromethyl)benzoate was obtained (140 mg, two-step total yield: 28%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:6]([O:18][CH3:19])[CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[CH3:19][O:18][C:6]1[CH:5]=[C:4]([CH:17]=[CH:16][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)[NH2:1]
Reactant: COc1cc([N+](=O)[O-])ccc1OC1CCN(C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1OC1CCN(C)CC1
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 4-[4-nitro-2-methoxyphenoxy]-1-methylpiperidine (2.17 g, 8.15 mmol, in ethanol (150 mL) was added 10% palladium on cabon (400 mg). The mixture was subjected to 1 atm hydrogen with stirring overnight. Removal of the catalyst by filtration and evaporation of the solvent yielded the product (1.75 g, 91%). 1H NMR (CDCl3) δ 1.81-2,04 (4H, m), 2.34 (5H, m), 2.81 (2H, m), 3.56 (2H, br s), 3.80 (3H, s), 4.04 (1H, s), 6.20 (1H, dd, J=2.7 Hz, J′=8.4 Hz), 6.29 (1H,d, J=2.5 Hz), 6.77 (1 H, d, J=8.3 Hz). LCMS m/z=237 (m+H+).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[CH:19]1([CH2:22][CH2:23][CH2:24][CH2:25]O)[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][CH2:23][CH2:24][CH2:25][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=2)[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Reactant: OCCCCC1CC1
Product: O=C(O)CNC(=O)c1ccc(OCCCCC2CC2)cc1
Yield: 88 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (251 mg, 1.00 mmol) prepared in Example 1 (1a) and 4-cyclopropylbutan-1-ol (which is the compound disclosed in J. Med. Chem., (1998), 41, 1112-1123, 137 mg, 1.20 mmol) to give 257 mg of the title compound (white powder, yield: 88%).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:10]([CH:12]([CH2:16][CH3:17])[C:13](=[S:15])[NH2:14])[CH3:11]>C(O)C>[CH3:11][CH2:10][CH:12]([C:13]1[S:15][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:14]=1)[CH2:16][CH3:17]
Reactant: CCC(CC)C(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(C(CC)CC)n1

Procedure:
Ethyl 3-bromo-2-oxopropanoate (2.5 mL) was added dropwise to a solution of 2-ethylbutanethioamide (example 71, step b) (3.8 g) in ethanol (100 mL) and the resulting mixture heated at reflux overnight. The solvent was evaporated and the residue partitioned between ethyl acetate (100 mL) and saturated sodium hydrogen carbonate solution (100 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2×100 mL). The combined organic solutions were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 20:1 isohexane:ethyl acetate. The fractions containing product were combined and evaporated to give the subtitled compound as a yellow oil. Yield 2.8 g.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:11]([Cl:14])=[N:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.[CH2:25]([O:32][CH2:33][C:34](Cl)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:19]1([S:16]([NH:15][C:10]2[CH:9]=[C:8]([C:4]3[S:3][C:2]([NH:1][C:34](=[O:35])[CH2:33][O:32][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:6][C:5]=3[CH3:7])[CH:13]=[N:12][C:11]=2[Cl:14])(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Cc1nc(N)sc1-c1cnc(Cl)c(NS(=O)(=O)c2ccccc2)c1
Product: Cc1nc(NC(=O)COCc2ccccc2)sc1-c1cnc(Cl)c(NS(=O)(=O)c2ccccc2)c1

Procedure:
Using an analogous method to that described in Example 51, N-[5-(2-amino-4-methyl-1,3-thiazol-5-yl)-2-chloropyridin-3-yl]benzenesulfonamide was reacted with 2-benzyloxyacetyl chloride. The reaction product was purified by preparative HPLC (Method A) to give the title product (retention time 9.6 minutes); 1H NMR Spectrum: (DMSOd6+D2O) 8.56 (1H, d); 8.09 (1H, d); 8.03 (2H, br d); 7.83 (1H, t); 7.70 (2H, t); 7.31-7.26 (3H); 7.26-7.24 (2H); 4.41 (2H, AB system); 4.12 (1H, d); 3.86 (1H, d); 2.24 (3H, s); Mass Spectrum: M+H+ 529.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH3:31])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(OC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1cc2c(cc1OC1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Yield: 87.3 %

Procedure:
A mixture of 3-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (Example #82, Step A, 0.032 g, 0.066 mmol), 2,4,6-trimethyl-cyclotriboroxane (0.025 g, 0.199 mmol), K2CO3 (0.018 g, 0.133 mmol) and Pd(dppf)Cl2.CH2Cl2 (0.006 g, 0.007 mmol) in dioxane (3 mL) and water (0.5 mL) was stirred at 110° C. for 4 h. The solvent was removed in vacuo and the residue was purified by preparative TLC (eluting with 30% EtOAc in petroleum ether) to give 3-(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester as a white solid (0.024 g, 87%). LC/MS (Table 1, Method 2) Rt=1.160 min.; MS m/z: 417 [M+H]+.
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-])([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:20]([N+:27]([O-:29])=[O:28])=[CH:19][CH:18]=[CH:17][C:16]2=[CH:15][C:14]=1[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cccc([N+](=O)[O-])c3nc2-1

Procedure:
Japanese Kokai Patent Application No. 59-51288 provides one method of making 9-nitro-camptothecin by treating camptothecin with a slight excess of concentrated nitric acid in concentrated sulfuric acid. However, when following this procedure, a yield of about 3% to about 7% of the 9NC product which is capable for medicinal use is obtained. Further, this procedure results in unwanted byproducts such as the inactive isomer, 12-nitrocamptothecin (12NC), in a ratio of about 1 to 3 of 9NC to 12NC. The following scheme shows the reaction from the use of nitric acid and sulfuric acid.