Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10](S(C2SC(Cl)=CC=2)(=O)=O)[C:11]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#N)[CH:25]=3)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[OH-:41].[Na+].Cl.C[OH:45]>>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:23][C:24]3[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=3)[C:30]([OH:45])=[O:41])[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COc1cc(F)cc2c1c(N(S(=O)(=O)c1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C#N)c1
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1cc(F)cc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C(=O)O)c1
Temperature: 60 °C
Yield: 65 %

Procedure:
A solution of 5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-N-[1-[(3-cyanophenyl)methyl]-6-fluoro-4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 53) (53 mg, 0.08 mmol) in methanol (10 mL) was treated with 2M NaOH solution (1 mL) was heated to 60° C. under nitrogen overnight. More 2M NaOH solution (0.5 mL) was added and the mixture was heated to 71° C. over the weekend. The mixture was allowed to cool to RT and then treated with 2M HCl solution to pH 0. The mixture was extracted with ethyl acetate and the organic solution was washed with 2M HCl, brine, dried (MgSO4) and evaporated to a gum 54 mg. The residue was dissolved in 1:1 MeOH-DMSO 1 mL and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A) collecting fractions with RT=7.77 min 19% and 8.73 min, 81%). The solvent was evaporated in vacuo from the major fraction (RT=8.73 min) to give 3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-6-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}benzoic acid (26 mg, 65%), as a white solid: LCMS (System A) RT=1.04 min, ES+ve m/z 496/498 (M+H)+ for carboxylic acid product. The minor component (RT=7.77 min) was evaporated under reduced pressure to give the title compound (6.2 mg, 15%) as a white solid: LCMS (System A) RT=0.97 min, ES+ve m/z 495/497 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](Cl)=[O:11])=[CH:6][CH:5]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[NH2:31])[N:24]([CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)[N:23]=2)=[CH:18][C:17]=1[O:39][CH3:40].FC(F)(F)C1C=CC(C(Cl)=O)=CC=1>ClCCl.N1C=CC=CC=1>[NH2:31][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:24]([CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)[N:23]=[C:22]([C:19]3[CH:20]=[CH:21][C:16]([NH:15][C:10](=[O:11])[C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=4)=[C:17]([O:39][CH3:40])[CH:18]=3)[C:30]=12
Reactant: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Agent: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
4-(Trifluoromethoxy)-1-benzenecarbonyl chloride (38 mg, 0.170 mmol) in dichloromethane (0.3 mL) was added to a solution of 3-(4-amino-3-methoxyphenyl)-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (60 mg, 0.17 mmol) in pyridine (1.2 mL) at 0° C. After 5 minutes, the ice-water bath was removed and the reaction mixture was stirred at room temperature for 1 hours then, more 4-(trifluoromethyl)-1-benzenecarbonyl chloride (19 mg, 0.085 mmol) was added. After 2 hours, the solvent was evaporated and the residue was purified by flash column chromatography using dichloromethane/methanol (95:5 to 70:30) as mobile phase to give N1-{4-[4-amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-4-(trifluoromethoxy)benzamide (70 mg, 76%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[C:6](O)(=O)[CH3:7].[CH2:10]1[CH2:14]OC[CH2:11]1>>[CH2:2]([C:7]1[CH2:6][CH:11]=[CH:10][CH:14]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CC(=O)O
Reactant: CCCCBr
Reactant: C1CCOC1
Product: CCCCC1=CC=CC1
Temperature: 62.5 °C
Yield: 70 %

Procedure:
A solution of bromobutane (0.98 mol) in 28 grams of THF is heated to 60-65° C. A warm solution of CpMgCl in THF (1.0 mol) as produced in Example 1 is added to the bromobutane solution while maintaining a pot temperature between 60-65° C. After the addition and the consequent reaction are complete by GC analysis, the reaction mixture is cooled to ambient temperature, 25% by weight of aqueous acetic acid is added, and the organic layer is separated, washed with 10% by weight of aqueous sodium carbonate, and dried over anhydrous sodium sulfate. The organic layer is filtered, and fractionally distilled under reduced pressure to recover 70 to 80% yield of n-butyl cyclopentadiene.
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:5]2[N:6]=[C:7]([O:12][CH3:13])[CH:8]=[C:9]([O:10][CH3:11])[N:4]2[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[S:23](Cl)(=[O:25])=[O:24].N1C=CC=CC=1.CS(C)=O>C(#N)C>[CH3:13][O:12][C:7]1[CH:8]=[C:9]([O:10][CH3:11])[N:4]2[N:3]=[C:2]([NH:1][S:23]([C:17]3[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=3[Cl:15])(=[O:25])=[O:24])[N:14]=[C:5]2[N:6]=1
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: COc1cc(OC)n2nc(N)nc2n1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1cc(OC)n2nc(NS(=O)(=O)c3c(Cl)cccc3Cl)nc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.8 %

Procedure:
2-Amino-5,7-dimethoxy[1,2,4]triazolo[1,5-a]-pyrimidine (0.75 g, 3.8 mmol) and 2,6-dichlorobenzene-sulfonyl chloride (1.86 g, 7.6 mmol) were mixed in dry acetonitrile (15 mL). To this mixture was added dry pyridine (0.61 mL) and dry DMSO (54 μL, 0.7 mmol). The mixture was allowed to stir at room temperature. After 24 hours, the solvent was removed in vacuo, the residue was partitioned between CH2Cl2 (300 mL) and 2N HCl and the solids were collected by vacuum filtration to give a white solid A. The CH2Cl2 was dried (MgSO4) and removed in vacuo to give a white solid B. Both HPLC and NMR indicated that solid A and B are product. The solids were combined to afford the product as a white powder (1.41 g, 92%). mp 211-213° C. Anal: Cacld for C13H11Cl2N5O4S: C, 38.63; H, 2.74; N, 17.33; S, 7.93; found: C, 38.11; H, 2.68; N, 16.83; S, 7.77. 1H NMR (DMSO-d6): δ 12.4 (bs, 1H); 7.64-7.54 (m, 3H); 6.26 (s, 1H); 4.07 (s, 3H); 3.88 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C:16]1[CH:21]=[C:20]([OH:22])[C:19]([OH:23])=[CH:18][C:17]=1[Cl:24])[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:31](OC(=O)C)(=[O:33])[CH3:32].C1C[O:41][CH2:40][CH2:39]1>O>[CH2:1]([O:8][C:9]([N:11]([C:16]1[CH:21]=[C:20]([O:22][C:31](=[O:33])[CH3:32])[C:19]([O:23][C:40](=[O:41])[CH3:39])=[CH:18][C:17]=1[Cl:24])[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CN(C(=O)OCc1ccccc1)c1cc(O)c(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Oc1cc(Cl)c(N(CC(=O)O)C(=O)OCc2ccccc2)cc1OC(C)=O

Procedure:
N-Benzyloxycarbonyl 2-chloro-4,5-dihydroxyphenylglycine (1.76 g, 5 mmole) in water (30 ml) and THF (20 ml) was adjusted to pH 7.5 with saturated sodium carbonate solution. Acetic anhydride (1.2 ml) was added and pH 6.5 maintained with saturated sodium carbonate solution, after 15 minutes and again after a further 15 minutes more acetic anhydride (0.6 ml) was added. After another 15 minutes the solution was washed with ether (2×25 ml), acidified to pH 2.5 and extracted with ethyl acetate (3×30 ml). The extracts were washed with water (2×25 ml) and brine (20 ml) dried and evaporated to a foam, 1.87 g 86%, δ[(CD3)2CO] 2.20(6H, s, 2×OCOCH3), 5.03(2H, s, OCH2), 5.80(1H, d, J8 Hz, CHNH), 7.12(1H, d, J8 Hz, CHNH), 7.23(5H, s, Ph), 7.33 and 7.35(2H, 2×s, Ar), 9.57(1H, s, CO2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[K].[CH:16](=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[O:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[CH:16]=[O:24])([O-:14])=[O:13]
Reactant: O=Cc1ccccc1O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: [K]
Solvent: O
Product: O=Cc1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
200 parts of 4-chloro-3-nitrobenzotrifluoride is heated to 160° C. and stirred and 160 parts of the potassium salt of salicylaldehyde is added over a period of 30 minutes. After the addition is complete, an exothermic reaction takes place and the temperature rises to about 195° C. Heating is then discontinued until the reaction subsides and the mixture is then heated for 1 hour at 150° C. The mixture is cooled, ice and water are added, and it is then extracted with ether. The ether layer is filtered to remove insoluble material and the resultant solution is dried over sodium sulfate. The ether solvent is then evaporated and the residual oil is recrystallized from a mixture of hexane and benzene to give 2-(2-nitro-4-trifluoromethyl-phenoxy)benzaldehyde melting at about 79°-81° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH2:14][CH2:15][CH2:16][CH:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19]>>[N+:8]([C:7]1[C:2]([NH:14][CH2:15][CH2:16][CH:17]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:18]([O:20][CH3:21])=[O:19])=[N:3][CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: COC(=O)C(CCN)c1ccccc1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Product: COC(=O)C(CCNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-])c1ccccc1
Yield: 77.7 %

Procedure:
A procedure similar to the method described in step C.1 is carried out, starting from 0.8 g (3.93 mmol) of 2-chloro-3,5-dinitropyridine and 1 g (4.32 mmol) of methyl 4-amino-2-phenylbutyrate. This gives 1.1 g of expected product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([NH2:9])=O)[CH3:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]#[N:9])[CH3:2]
Reactant: CCOc1cc(C(N)=O)ccc1OC
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc(C#N)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a solution of 3-ethoxy-4-methoxybenzamide (3.30 g) in pyridine (33 mL) was added phosphorus oxychloride (1.73 mL) under ice-water cooling, and the mixture was stirred for 2 hours at ambient temperature. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water under ice-water cooling. The separated organic layer was washed with 1N-hydrochloric acid, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (5:1 to 4:1) to give 3-ethoxy-4-methoxybenzonitrile as colorless powders (2.83 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]([NH2:10])[C@H:2]1[OH:11].CCN(CC)CC.Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[O:11]1[C@H:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C@H:3]2[NH:10][C:20]1=[O:22]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1N[C@@H]2c3ccccc3C[C@@H]2O1
Temperature: -60 °C

Procedure:
(1R,2S)-cis-1-amino-2-indanol (0.980 g, 6.569 mmol) was placed in a round-bottomed flask and a dry Ar atmosphere was established. Dry CH2Cl2 (50 mL) and Et3N (1.9 mL, 13.63 mmol) were added, and the resulting solution was cooled to −60° C. On addition of triphosgene (0.64 g, 2.157 mmol), the cooling bath was removed, and the reaction was allowed to warm to 20° C. over one hour. The reaction was then poured into CH2Cl2 (100 mL) and H2O (50 mL) and the aqueous phase was extracted with CH2Cl2 (3×100 mL). After drying with MgSO4, the organic layer was evaporated under reduced pressure to give (3aR-cis)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]-oxazol-2-one, (R)-24 (1.15 g, quantitative) as white crystals, which was of sufficient purity for the next step in the reaction sequence. An analytical sample was recrystallized from CH2Cl2/hexanes. mp 205.5-206.5° C.; [Ghosh et al. (1992) J. Chem. Soc. Chem. Commun. 1673-1674 for enantiomer mp 205° C.]; [α]25D=+107.7 (c 1.25, CHCl3); [Id. for enantiomer [α]25D=−79.4 (c 1.4, CHCl3)]. IR (KBr) 3255, 1752, 1707 cm−1; 1H NMR (acetone-d6) δ 7.24-7.43 (4H, m), 5.39 (1H, t, J=7.5 Hz), 5.21 (1H, d, J=7.0 Hz), 3.42 (1H, dd, J=17.7, 6.2 Hz), 3.20 (1H, d, J=17.9 Hz), 2.90 (1H, br s); 13C NMR (acetone-d6) δ 159.1, 142.5, 141.0, 129.7, 128.3, 126.2, 125.8, 80.8, 61.7, 39.3; HRMS (FAB+) m/z: calcd for C10H9NO2+H, 176.0771; found, 176.0681.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10]C(=O)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[C:7](=[O:24])[C:6]=2[CH:25]=1.C(O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:25]=[C:6]([C:7]([NH:8][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:24])[C:5]([OH:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCCCCn1c(=O)oc2ccc(Cl)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCCCNC(=O)c1cc(Cl)ccc1O
Temperature: 40 °C

Procedure:
Ethyl 8-(6-chloro-2H-1,3-benzoxazine-2,4(3H)-dionyl)octanoate (641 g, 1.7 mol) and ethyl alcohol (3200 ml) were added to a 22 liter, five neck flask. In a separate 5 liter flask, sodium hydroxide (NaOH) (288.5 g, 7.2 mol) was dissolved in deionized water (3850 ml). This mixture was added to the reaction mixture contained in the 22 liter flask. A temperature increase to 40° C. was noted. Heating of the reaction mixture was started and when the reaction temperature had increased to 50° C. it was noted that all of the solids in the reaction mixture had dissolved. A temperature of 50° C. was maintained in the reaction mixture for a period of 1.5 hours. The reaction flask was then set up for vacuum distillation. 2200 ml of distillate were collected at a vapor temperature of 55° C. (10 mm Hg) before the distillation was discontinued. The reaction flask was then placed in an ice/water bath and concentrated hydrochloric acid (HCl) (752 ml) was added over a period of 45 minutes. During this addition the reaction mixture was noted to have thickened somewhat and an additional 4 liters of deionized water was added to aid the stirring of the reaction mixture. The reaction mixture was then vacuum filtered and the filter cake was washed with 3 liters of deionized water. After drying in vacuo at room temperature 456.7 g (83.5%) of N-(5-chlorosalicyloyl)-8-aminocaprylic acid was isolated.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[OH:19])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[OH:40]O.[Cl-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N+:12]2([O-:40])[CH2:13][CH2:14][CH:15]([C:18]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:34][CH:35]=3)([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=3)[OH:19])[CH2:16][CH2:17]2)=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: OO
Reactant: CCCOc1ccc(CN2CCC(C(O)(c3ccc(C(F)(F)F)cc3)c3ccc(C(F)(F)F)cc3)CC2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCCOc1ccc(C[N+]2([O-])CCC(C(O)(c3ccc(C(F)(F)F)cc3)c3ccc(C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.1 %

Procedure:
To a stirred solution of 1.5 grams (0.003 mole) of N-(4-propoxyphenylmethyl)-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine in 25.0 mL of absolute methanol was added 1.4 mL (0.014 mole) of 30% aqueous hydrogen peroxide in one portion. Upon completion of the addition the reaction mixture was stirred at ambient temperature for five hours and then analyzed by thin layer chromatography (TLC), which indicated the reaction was not complete. An additional 3.0 mL (0.029 mole) of 30% aqueous hydrogen peroxide was added, and the reaction mixture was stirred for about 18 hours. At the conclusion of this period the reaction mixture was poured into 100 mL of an aqueous saturated sodium chloride solution. The mixture was extracted with three 100 mL portions of ethyl acetate, and the combined extracts were washed with one 100 mL portion of an aqueous saturated sodium chloride solution. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.5 grams of N-(4-propoxyphenylmethyl)-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine N-oxide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].I[CH2:15][CH3:16].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:15][CH3:16])[CH3:2]
Reactant: CCOC(=O)CCNC1CCCC1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)CNC1CCCC1
Reaction time: 1 h
Yield: 44.5 %

Procedure:
To a mixture of 1.0 g (0.0054 mole) of 3-cyclopentylamino-propanoic acid ethyl ester, 0.842 g (0.00542 mole) of iodoethane and 15 mL of dry tetrahydrofuran, at −78 degrees, was added 11.4 mL (0.0114 mole) of a 1M solution of lithium bis(trimethylsilyl)amide in hexanes over 5 minutes. The mixture was stirred for one hour at −78 degrees, then the cooling bath was removed and the mixture stirred overnight at room temperature, and then poured into ice water containing 5 mL of 1M sodium hydroxide solution. The mixture was extracted with ether, and the ether extract washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.5125 g of (rac)-2-cyclopentylaminomethyl-butanoic acid ethyl ester, which was used without further purification in subsequent steps.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[CH:11]=2)[N:4]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[Cl:16][C:12]1[CH:11]=[C:10]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:24][C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)[N:4]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Oc1ccc(F)cc1
Reactant: ClCc1cccc(Oc2ccnc(Cl)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Fc1ccc(OCc2cccc(Oc3ccnc(Cl)c3)n2)cc1
Yield: 69.8 %

Procedure:
A mixture of 2-(chloromethyl)-6-[(2-chloro-4-pyridyl)oxy]pyridine (1.66 g, 6.5 mmol), 4-fluorophenol (0.89 g, 8 mmol), and potassium carbonate (1.1 g, 8 mmol) in N,N-dimethylformamide (5 mL) is refluxed for 90 minutes, cooled, and diluted with a 1:1 hexane/ethyl acetate solution (100 mL). The organic mixture is then filtered through a layer of silica gel using a 1:1 hexane/ethyl acetate solution as eluent. The resultant solution is concentrated in vacuo to obtain an oil. Flash column chromatography of the oil using silica gel and a 8:2 hexane/ethyl acetate solution gives the title product as colorless crystals (1.5 g, 70%, mp 103° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22][OH:23])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2nc(CO)cc2-c2ccc(Cl)c(Cl)c2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(COS(C)(=O)=O)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a stirred solution of [5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-methanol (7.2 g, 0.021 mol) in THF (125 mL) and triethylamine (TEA) (4.6 mL, 0.033 mol) was added methanesulfonyl chloride (2.5 mL, 0.031 mol). The reaction mixture was stirred at 45° C. for 4 h. The reaction mixture was cooled to rt, quenched with H2O (75 mL) then washed with EtOAc (3×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to oil. This crude pyrazole mesylate was used in the next step without further purification. HPLC: Rt=10.03 (Method E). MS (ES+): mass calculated for C18H18Cl2N2O4S, 427.30; m/z found 428.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCCC1>CO>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])/[C:24]/2=[CH:16]\[C:13]1[NH:12][C:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])[C:6](=[O:18])[C:7]=2[C:14]=1[CH3:15]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Temperature: 25 °C
Yield: 75.1 %

Procedure:
5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c (53 mg, 0.2 mmol) was dissolved in 1 ml of methanol under stirring, and added with 5-chloro-1,3-dihydro-indol-2-one (34 mg, 0.2 mmol) and piperidine (0.1 ml) to the solution. Upon the completion of the addition, the mixture was stirred to mix well in dark, heated to reflux for 2 hours and lots of precipitate was formed. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature, and filtered. The filter cake was washed with ethanol and dried to obtain the title compound (Z)-2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-dimethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 23 (62 mg, yield 75%) as an orange powder.
Reaction SMILES: [CH2:1]([C:3]1([OH:26])[C:23]2[CH:22]=[C:21]3[N:9]([CH2:10][C:11]4[C:12]3=[N:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=4)[C:8](=[O:24])[C:7]=2[CH2:6]OC1=O)[CH3:2].C(#N)C.Cl([O-])(=O)(=O)=O>CN(C)C=O.O>[CH3:6][C:7]1[C:8](=[O:24])[N:9]2[C:21](=[CH:22][C:23]=1[C:3](=[O:26])[CH2:1][CH3:2])[C:12]1=[N:13][C:14]3[C:19]([CH:20]=[C:11]1[CH2:10]2)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCC(=O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2

Procedure:
A sample of 4.6 g of 4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-3,14(4H,12H)-dione [(20 S) camptothecin] was stirred with 46 ml of N,N-dimethylformamide. The suspension was heated at reflux, and the disappearance of starting material was monitored by HPLC (C18 reverse phase column, 20-25% acetonitrile:water mobile phase, perchlorate buffer at pH approximately 3.0). The reaction was monitored by UV detection at a wavelength of 228 nm. The only responses detected under these conditions were a peak for N,N-dimethylformamide near the solvent front, a peak for the starting material and a peak for the desired product with a retention time of approximately 3.2 relative to the starting material. The reaction was heated until consumption of the starting material was complete (approximately 8 days). After cooling to ambient temperature the solid product was collected by filtration, and washed with methanol. After drying under vacuum to a constant weight 3.48 g (87%) of product, m.p. 233°-234° C. was obtained.