Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C:11](=O)[CH2:10]2.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[C:2]1([NH:1][CH:11]2[CH:12]3[CH2:15][CH2:16][N:9]([CH2:14][CH2:13]3)[CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: c1ccc(NC2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
(Method 1A) To a mixture of 9.3 g (0.1 mol) of aniline and 16.1 g (0.1 mol) of 1-azabicyclo[2.2.2]octan-3-one hydrochloride in 250 mL of dichloroethane (DCE) was added 31.8 g (0.15 mol) of Na(OAc)3BH and the mixture was stirred overnight at room temperature. The reaction was quenched with 3 N NaOH. The layers were separated and the aqueous layer was extracted with an additional portion of CHCl3. The organic layers were combined, dried over NaSO4, and then filtered and the solvent was evaporated in vacuo. Th residue was chromatographed on silica (95/5 CHCl3/10% NH4OH in MeOH) to give N-Phenyl-1-azabicyclo[2.2.2]octan-3-amine (6.0 g 30%) as an off-white solid. MH+=203. 1H NMR (CDCl3) 1.46 (m, 1H), 1.75 (m, 3H), 2.0 (m, 1H), 2.55 (m, 1H), 2.95 (m, 4H), 3.4 (m, 2H), 3.8 (s, 1H), 6.6 (d, 2H), 6.75 (t, 1H), 7.2 (t, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([CH3:19])=[N:14]3)=[N:7][NH:6][C:5]1=[S:20].Br[CH2:22][CH2:23][CH2:24][Cl:25]>>[Cl:25][CH2:24][CH2:23][CH2:22][S:20][C:5]1[N:4]([CH3:3])[C:8]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([CH3:19])=[N:14]3)=[N:7][N:6]=1
Reactant: ClCCCBr
Reactant: Cc1ccc2c(-c3n[nH]c(=S)n3C)cccc2n1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Temperature: 0 °C

Procedure:
Sodium hydride (2.65 g, 60% in oil) was added portionwise to stirred absolute ethanole at 0° C., under a nitrogen atmosphere. Then 4-methyl-5-(2-methyl-5-quinolinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (21.8 g) (intermediate 7) was added portionwise and the reaction mixture was allowed to reach room temperature. Then 1-bromo-3-chloropropane (12.6 ml) was added over 10 min and the reaction mixture was brought to 80° C. and left to react an additional hour after which time the reaction mixture was allowed to reach room temperature and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel with 90% ethyl acetate-acetone to give the title compound (14.18 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:17])[NH:14][CH:13]([C:15]#[N:16])[CH2:12][O:11][CH2:10]2)=[CH:5][CH:4]=1>[Ni].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH3:17])[NH:14][CH:13]([CH2:15][NH2:16])[CH2:12][O:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C)COCC(C#N)N2)cc1
Agent: [Ni]
Solvent: CCO
Product: COc1ccc(C2(C)COCC(CN)N2)cc1
Reaction time: 12 h

Procedure:
A mixture of 40.1 mmol of 5-(4-methoxyphenyl)-5-methylmorpholine-3-carbonitrile and 2 g of Raney nickel (activated by washing with water to pH 7 and subsequent washing with ethanol) in 200 ml of ethanol is hydrogenated under a pressure of 500 psi for 12 hours. The reaction mixture is filtered through Hyflo and the filtrate is evaporated. The crude title compound is identified from the residue on the basis of the Rf. The title compound is employed without further purification in the next stage.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH:19]=[CH:20]2)[CH:15]=[CH:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(OC(C)=C)(=O)C.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>CO.C(O)C.C(O)(=O)C>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][CH:18]([OH:28])[CH:19]=[CH:20]2)=[CH:15][CH:14]=3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: C=C(C)OC(C)=O
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4CC(O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 6 h
Yield: 62.5 %

Procedure:
To a mixture of 38 g (0.1 mol) of cholesta-1,4,6-trien-3-one and 17 g (0.1 mol) of paratoluenesulfonic acid were added 400 g (4 mol) of isopropenyl acetate, and the mixture was heated under reflux for 3 hours. The reaction solution was thoroughly washed with water until it was neutral, and dried over sodium sulfate A solution of the thus obtained concentrate in 600 ml of ether was added dropwise at a temperature of -5° C. to -10° C. to a reducer solution and stirred at 0° C. for 6 hours, said reducer solution being prepared by cooling a solution of 90 g of calcium chloride in 1,500 ml of methanol to a temperature of -5° C. to -10° C., then adding dropwise thereto a solution of 45 g of sodium borohydride in 2,000 ml of ethanol, and stirring the reaction solution at a temperature of -5° C. to -10° C. for 60 minutes. After completion of the reaction, 50% acetic acid was added to the reaction mixture and the resultant solution was extracted with ether. The ethereal layer separated was washed with water and then sodium bicarbonate solution, dried over sodium sulfate and distilled under reduced pressure to remove ether therefrom. The residue was recrystallized from acetone to yield 23.9 g of cholesta-1,5,7-trien-3-ol (IV), m.p. 126°-127° C. The yield was 63%.
Reaction SMILES: [N:1]([CH:4]1[CH2:7][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:5]1)=[N+]=[N-]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C>[NH2:1][CH:4]1[CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(N=[N+]=[N-])C2)C1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC(N)C2)C1
Reaction time: 5 h

Procedure:
1.50 g (7.27 mmol) of Lindlar catalyst (PdCaCO3) are added to a solution of 3.67 g (14.54 mmol) of tert-butyl 2-azido-6-azaspiro[3.4]octane-6-carboxylate, obtained in step 6.3., in 60 mL of ethanol. The reaction medium is placed in a Parr flask under a hydrogen atmosphere at 20 psi, at room temperature for 5 hours. The resulting mixture is filtered through Celite and the filtrate is then concentrated under reduced pressure. After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 95/5/0.5 mixture of dichloromethane, methanol and 28% aqueous ammonia.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([N:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(F)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1

Procedure:
To 2,4-difluoroaniline (40.0 g, 0.31 mol) in N,N-dimethylformamide (400 mL) were added potassium carbonate (120 g, 0.92 mol, 3 eq) and benzyl bromide (112 mL, 0.71 mmol, 2.3 eq). The reaction was stirred with mechanical stirring at room temperature overnight. In order to quench the benzyl bromide in excess, NH4OH (90 mL) was added and the reaction was stirred overnight. The mixture was filtered and DMF was evaporated under reduced pressure. Ethyl acetate was added and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the oily crude was crystallized in methanol, obtaining after drying 71 g of dibenzyl-(2,4-difluoro-phenyl)-amine as a white solid (74%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:24]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:22][CH3:23])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Reactant: CCCNCCC
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A mixture of 2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.01845 mole) and 1,1'-carbonyldiimiazole (2.99 g, 0.01845 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for three hours with a stream of nitrogen bubbling through it. A solution of dipropylamine (5.6 g, 0.0554 mole) in tetrahydrofuran (7 ml) was added and the reaction mixture was refluxed overnight under nitrogen. The solvents were removed under reduced pressure and the residue was triturated in 100 ml of water, the solid was collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, cooled to room temperature, and water was added to the cloud point. The resulting solid was collected by filtration, rinsed with water, and dried under high vacuum at 42° C. overnight to give 2.22 g (34%) of title compound, mp. 135°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=2)[CH:6]=1.N[C:19]1([C:31]#[N:32])[CH:24]=[CH:23][C:22](C2C=CC=CC=2)=[CH:21][CH2:20]1.COC1C(CC(OC)=O)CC(OC)O1>CCOC(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:22]3[CH:23]=[CH:24][C:19]([C:31]#[N:32])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1ccn(-c2ccc(F)cc2)c1
Reactant: N#CC1(N)C=CC(c2ccccc2)=CC1
Agent: COC(=O)CC1CC(OC)OC1OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1
Yield: 60 %

Procedure:
According to the procedure described in Example 14(a) for the preparation of 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid methyl ester, 4-amino-4-cyano-biphenyl (commercially available from TCI) and methyl 2-(2,5-dimethoxy-tetrahydrofuran-3-yl)acetate were condensed in 6 hours at 80° C. to give a crude product. Successive flash column chromatography with EtOAc/CH2Cl2/hex gave in 60% yield 2-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-acetic acid methyl ester as an amorphous solid. 1H NMR: δ 7.75 (d, 2H, J=8.8 Hz), 7.69 (d, 2H, J=8.8 Hz), 7.64 (d, 2H, J=8.5 Hz), 7.48 (d, 2H, J=8.8 Hz), 7.10-7.09 (m, 2H), 6.33 (t, 1H, J=2.2 Hz), 3.73 (s, 3H), 3.58 (s, 2H). Anal. Calculated for C20H16N2O2: C, 75.93; H, 5.10; N, 8.86. Found: C, 75.86; H, 5.14; N, 8.90.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8](I)=[CH:9][N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[NH:22][CH:23]=[CH:24]4)=[CH:9][N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:4][CH:3]=1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3nc(Br)cnc32)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 2-bromo-7-iodo-5-tosyl-5H-pyrrolo[3,2-b]pyrazine [Intermediate AU] (0.25 g, 0.52 mmol) and 1H-indol-5-ylboronic acid (0.10 mg, 0.62 mmol) in CH3CN (20 mL) was added 1 M Na2CO3 (20 mL) followed by bis(triphenylphosphine)-palladium(II) dichloride (60 mg, 0.086 mmol). The resulting mixture was stirred for 2 h at 60° C. The title compound was isolated as a yellow solid via filtration from the CH3CN layer (0.23 g, 94%). HPLC retention time: 3.23 minutes. MS ESI (m/z): 467.2/469.2 (M+H)+, calc. 466.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH:8]=[CH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=1)([O-])=O>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[S:10]1(=[O:11])(=[O:12])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:14]=[CH:13][C:7]=2[CH2:8][CH2:9]1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)C=C2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)S(=O)(=O)CC2
Yield: 121.9 %

Procedure:
A solution of 6-nitro-1-benzothiophene 1,1-dioxide (1.04 g) in acetic acid (50 ml) and ethyl acetate (50 ml) was hydrogenated over (10% palladium on carbon (130 mg, 50% wet). The catalyst was removed by filtration and washed with ethyl acetate. The filtrate and washings were evaporated under reduced pressure to give the title compound (1.1 g). LCMS RT=1.50 min
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[C:29]1(=[O:35])[O:34][C:32](=[O:33])[CH2:31][CH2:30]1.Cl>O1CCOCC1.CN(C)C1C=CN=CC=1>[C:29]([OH:34])(=[O:35])[CH2:30][CH2:31][C:32]([OH:19])=[O:33].[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: O=C1CCC(=O)O1
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7.6 grams of cholesterol and 2.36 grams of succinic anhydride were dissolved in 100 ml of 1,4-dioxane in a round-bottomed flask. A reaction catalyst, 2.9 grams of 4-(dimethylamino)pyridine (DMAP), was added thereto, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was introduced into an HCl solution in order to precipitate the cholesterol succinate (9.1 g; yield=95%).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].[C:63]1(=[O:69])[O:68][C:66](=[O:67])[CH2:65][CH2:64]1>N1C=CC=CC=1.CC#N>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].[C:63]([OH:68])(=[O:69])[CH2:64][CH2:65][C:66]([OH:6])=[O:67]
Reactant: O=C1CCC(=O)O1
Agent: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(O)CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Paclitaxel (50 mg, 1 equivalent) was introduced into a 50 ml round bottomed flask and dissolved in pyridine (3 ml). Next, succinic anhydride (30 mg, 5.1 equivalents) was added thereto. After stirring at room temperature for 16 hours, the mixture was diluted with 30% MeCN (30 ml). Then it was filtered and purified by high performance liquid chromatography (HPLC). After freeze-drying, paclitaxel-succinic acid (51.86 mg, yield 92.2%) was obtained.
Reaction SMILES: [OH:1][CH:2]([CH2:18][CH3:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:5]1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1.N1C=CC=CC=1.O>C(Cl)Cl>[C:20]([OH:25])(=[O:26])[CH2:21][CH2:22][C:23]([OH:1])=[O:24].[OH:1][CH:2]([CH2:18][CH3:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][CH2:7][C:6]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[N:5]1.[OH:1][CH:2]([CH2:18][CH3:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][CH2:7][C:6]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[N:5]1
Reactant: O=C1CCC(=O)O1
Agent: CCC(O)CN1N=C(c2ccc(Cl)cc2)CCC1=O
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)O

Procedure:
A mixture of 25 grams (0.089 mol) of 2-(2-hydroxy-butyl)-6-(p-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone, 25 grams (0.25 mol) of succinic anhydride and 50 milliliters of pyridine are stirred and heated at 90° for 2.5 hours. The mixture is poured into 100 milliliters of water and 100 milliliters of methylene chloride. The organic layer is separated and washed twice with 100 milliliters of water following which it is treated with anhydrous magnesium sulfate and activated charcoal, filtered through celite and concentrated under vacuum. The residue is dissolved in a mixture of ethanol methylene dichloride and concentrated to about 80 milliliters volume. The precipitate formed (11.4 grams of bis-[2-(2-hydroxy-butyl)-6-(p-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone] succinate; m.p. 142° ) is removed by filtration. The remaining filtrate is concentrated to a syrup (17 grams) and dissolved in 100 milliliters of diethyl ether. The solution is added dropwise to an ice-coated solution of diethylether saturated with dry ammonia gas. The white solid formed is filtered off, washed with diethyl ether and dissolved in CH2Cl2. The solution is filtered and then treated with petroleum ether yielding 6.0 grams of [2-(2-hydroxybutyl)-6-(p-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone] succinic acid ester (m.p. 90°-93° )
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:13]([O:15][C:16](=[O:22])[C:17](OCC)=[O:18])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16](=[O:22])[C:17](=[O:18])[CH2:2][C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)=[O:3])[CH3:14]
Reactant: CC(=O)c1ccco1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1ccco1
Reaction time: 18 h

Procedure:
2-acetylfuran was slowly added to a solution of sodium ethoxide (6.81 g) dissolved in absolute ethanol (200 mL) at 0° C. (5.01 mL). This solution was stirred at 0° C. for 2 hrs before oxalic acid diethyl ester (9.30 mL) was slowly added thereto. After stirring for 18 hrs, the reaction was terminated with 1N HCl. The resulting solution was concentrated under reduced pressure to remove the ethanol, followed by extraction with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 10.0 g of 4-furan-2-yl-2,4-dioxo-butyric acid ethyl ester. This concentrate was used in the next step without further purification.
Reaction SMILES: [Na].[OH:2][C:3]1[CH2:4][CH:5]([C:10]([OH:12])=[O:11])[CH2:6][C:7](=[O:9])[CH:8]=1.[Cl-].[C:14]1([N+:20]#[N:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.NC1C=CC=CC=1.Cl.N([O-])=O.[Na+]>O.CO>[OH:2][C:3]1[CH2:4][CH:5]([C:10]([OH:12])=[O:11])[CH2:6][C:7](=[O:9])[C:8]=1[N:21]=[N:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C=C(O)CC(C(=O)O)C1
Reactant: N#[N+]c1ccccc1
Agent: Cl
Agent: O=N[O-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: Nc1ccccc1
Product: O=C1CC(C(=O)O)CC(O)=C1N=Nc1ccccc1

Procedure:
13.8 G. of sodium were dissolved in 900 ml. of methanol. 46.8 G. of 3-hydroxy-5-keto-3-cyclohexenecarboxylic acid were added to this solution. The mixture was stirred, maintained between -4° C. and -8° C. with a cooling bath and treated over a period of 30 minutes with a phenyl diazonium chloride solution prepared from 27.9 g. of aniline, 450 ml. of water, 72 ml. of concentrated hydrochloric acid and 21.0 g. of sodium nitrite in 90 ml. of water. The mixture was stirred -5° C. to -10° C. for an additional hour. The resulting red precipitate was removed by filtration under vacuum and washed with about 1000 ml. of water, thereby there was obtained 3-hydroxy-5-keto-4-phenylazo-3-cyclohexenecarboxylic acid of melting point 218° C.
Reaction SMILES: CC1(C)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC=2C(=O)CC1.[CH3:25][C:26]1([CH3:50])[C:35]2[CH:34]=[CH:33][C:32]([C:36]#[C:37][C:38]3[CH:48]=[CH:47][C:41]([C:42]([O:44]CC)=[O:43])=[CH:40][N:39]=3)=[CH:31][C:30]=2[C:29](=[O:49])[CH2:28][CH2:27]1.CC1(C)C2C=CC(CCC3C=CC(C(OCC)=O)=CN=3)=CC=2C(=O)CC1>>[CH3:25][C:26]1([CH3:50])[C:35]2[CH:34]=[CH:33][C:32]([C:36]#[C:37][C:38]3[CH:48]=[CH:47][C:41]([C:42]([OH:44])=[O:43])=[CH:40][N:39]=3)=[CH:31][C:30]=2[C:29](=[O:49])[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)nc1
Agent: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Agent: CCOC(=O)c1ccc(CCc2ccc3c(c2)C(=O)CCC3(C)C)nc1
Product: CC1(C)CCC(=O)c2cc(C#Cc3ccc(C(=O)O)cn3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl]ethynyl]benzoic acid (Compound 7), 300 mg (0.86 mmol ) of ethyl 6-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]nicotinate (Compound 3) was converted into the title compound (pale yellow solid) using 8.6 ml (8.6 mmol) of LiOH (1M aqueous solution).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH3:27])[CH:22]=[C:21]2[CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH3:27])[CH:22]=[C:21]2[CH2:28][CH2:29][NH:30][C:11]([C:8]1[CH:7]=[C:6]([CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)[O:10][N:9]=1)=[O:13]
Reactant: O=C(O)c1cc(Cc2cccc(F)c2)on1
Reactant: Cn1cc(CCN)c2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(CCNC(=O)c2cc(Cc3cccc(F)c3)on2)c2cc(Cl)ccc21
Yield: 36.8 %

Procedure:
A solution of 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid (0.057 g; 0.257 mmol), 2-(5-chloro-1-methyl-1H-indol-3-yl)ethanamine (0.060 g; 0.284 mmol), HATU (0.108 g; 0.284 mmol) and N,N-diisopropylethylamine (0.112 mL; 0.649 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.039 g (36%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[OH-].[Na+].Cl>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(Br)ccc1C(=O)O
Yield: 97.6 %

Procedure:
Methyl 4-bromo-2-methoxybenzoate (10 g) was dissolved in methanol (80 mL), 1N aqueous sodium hydroxide solution (80 mL) was added, and the mixture was refluxed for 3 hr. After cooling, 1N hydrochloric acid (80 mL) was added, and the mixture was filtered to give 4-bromo-2-methoxybenzoic acid (9.2 g). By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-methoxybenzoic acid (3.1 g) and 1-(2,4-dimethylphenyl)piperazine (2.7 g), the title compound (4.4 g) was obtained.