Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:17])([CH3:16])[CH:5]([OH:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.[H][H]>[Pd].CO>[OH:15][CH:5]1[C:6]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:12][C:3](=[O:2])[C:4]1([CH3:17])[CH3:16]
Reactant: COC(=O)C(C)(C)C(O)c1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)C(=O)Nc2ccccc2C1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.4 %

Procedure:
A mixture of 3-Hydroxy-2,2-dimethyl-3-(2-nitro-phenyl)-propionic acid methyl ester (800 mg), Palladium on carbon (10%, 80 mg) in 5 mL of MeOH under 1 atm hydrogen gas is stirred at room temperature for 4 h. The mixture is filtered through a pad of celite and washed with MeOH. The combined solution is concentrated and the residue is purified by flash column and gives 250 mg colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1>CN(C=O)C>[CH3:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])[CH:18]=1
Reactant: Cc1ccnc(N)c1
Reactant: CN1CC(=O)NC1=NC(=O)O
Solvent: CN(C)C=O
Product: Cc1ccnc(NC(=O)N=C2NC(=O)CN2C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 12.7 %

Procedure:
A mixture of 3.0 g (12.8 mM) of the phenyl carbamate 8 and 2.8 g (25.7 mM) of 2-amino-4-methylpyridine in 25 ml of anhydrous DMF was stirred at 25° C. for 5 hrs., filtered and the filtrate diluted with 150 ml of water. The resulting precipitate was collected and recrystallized from ethanol to give 0.6 g of the above urea as a pale yellow solid, m.p. 231°-232° C. (dec.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][C:34]=2[NH2:39])O1>COCCOC.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(Cl)Cl>[NH2:39][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:33]=1[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1
Reactant: CC1(C)OB(c2ccncc2N)OC1(C)C
Reactant: COc1cc(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: COc1cc(-c2ccncc2N)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 13 %

Procedure:
Method 26 was followed using 4-chloro-N,N-di-BOC-6-methoxypyrimidin-2-amine (1.0 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-3-amine (3.0 equiv.), Pd(dppf)Cl2-DCM (0.10 equiv.) in DME/2M Na2CO3 (0.07M) at 90° C. for 30 min. Purification via SiO2 column chromatography eluting with EtOAc and hexanes (1:1) afforded 4-(3-aminopyridin-4-yl)-6-methoxy-N,N-di-BOC-pyrimidin-2-amine in 13% yield). LCMS (m/z): 418.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:6]2.C(O)(=O)C>[Fe].O>[NH2:11][C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]2[C:7]=1[NH:6][C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4]2
Reactant: CCOC(=O)c1cc2c(Cl)ccc([N+](=O)[O-])c2[nH]1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc2c(Cl)ccc(N)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.8 %

Procedure:
A stirred solution of 2.68 grams (0.01 mole) of 4-chloro-2-ethoxycarbonyl-7-nitroindole, 80 mL of acetic acid, and 15 mL of water was heated to 65° C., and 18.3 grams (0.048 mole) of iron powder was slowly added during a 20 minute period. Upon completion of addition, the reaction mixture was allowed to cool to 25° C. where it stirred for one hour. After this time, the reaction mixture was poured into water, and the resulting mixture was filtered through diatomaceous earth. The filter cake was washed thoroughly with ethyl acetate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure a residue. The residue was purified by column chromatography, yielding 0.4 gram of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13](=[O:24])[NH:14][O:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>>[C:1]1([CH2:11][NH:12][C:13](=[O:24])[NH:14][O:15][CH2:16][C:17]([OH:19])=[O:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CONC(=O)NCc1cccc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CONC(=O)NCc1cccc2ccccc12
Yield: 99.7 %

Procedure:
According to the procedure described in the synthesis method of Compound VI-9, tert-butyl 2-(3-(naphthalen-1-ylmethyl)ureidooxy)acetate (Compound V-7) (50 mg, 0.15 mmol) was reacted with 4N HCl/dioxane (2 ml) to obtain the title compound (41 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH3:17][N:18]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=[N:19]1>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:22]2[N:18]([CH3:17])[N:19]=[CH:20][CH:21]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C(F)(F)F)cc1N
Temperature: 100 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
2-Amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (7 g, 20.29 mmol) and 1-methyl-5-tributylstannanyl-1H-pyrazole (9.03 g, 1.2 equiv) were weighed in air and added in a flame-dried flask. Bis(triphenylphosphine)palladium (II) dichloride (2.18 g, 0.15 equiv) and dioxane (100 mL) were added and the mixture was stirred for 18 h at 100° C. The mixture was evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (4:6)) to provide 2-amino-4-trifluoromethyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (4.6 g, 76%) as an orange solid. (ESI-MS: m/z 300.3 [M+H]+, rt 5.15 min).
Reaction SMILES: [NH3:1].[H][H].[CH3:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH3:11])[CH:6]1[OH:12].[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH3:20])[C:15]1=[O:21]>[Pd].[Zn]>[CH3:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH3:11])[CH:6]1[OH:12].[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH3:20])[C:15]1=[O:21].[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[NH2:1]
Reactant: N
Reactant: [H][H]
Agent: [Pd]
Agent: CC1CCCC(C)C1=O
Agent: CC1CCCC(C)C1O
Product: Cc1cccc(C)c1N

Procedure:
1,000 parts by volume of catalyst are introduced into a fluidised bed reactor having a capacity of 1.2 liters, corresponding to 1,200 parts by volume. The catalyst consists of 0.5% by weight of palladium and 0.2% by weight of zinc on Al2O3 and has a particle size of 0.2 to 0.6 mm. The temperature in the reactor is set to 220° C. and, per hour, a correspondingly preheated mixture of 200,000 parts by volume of ammonia and 200,000 parts by volume of hydrogen is introduced. 50 parts of a mixture consisting of 80% by weight of 2,6-dimethylcyclohexanol and 20% by weight of 2,6-dimethylcyclohexanone is passed continuously, per hour, through the fluidised catalyst bed thus produced. The reaction product is isolated by cooling the exit gases, and is distilled. 100 parts of 2,6-dimethylcyclohexanol/2,6-dimethylcyclohexanone mixture employed give 92 parts of 2,6-dimethylaniline. Yield: 96.5%.
Reaction SMILES: CC(O)(C)C.[K].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[C:10]([C:18](=O)[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH:9]=1>COCCOC>[Br:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[NH:14][C:15](=[O:17])[CH:16]=[C:18]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1
Reactant: CC(=O)Nc1ccc(Br)cc1C(=O)c1cccc(Cl)c1
Agent: [K]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: O=c1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2[nH]1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
2-methyl,2-propanol, potassium salt (1.635 mol) was added portionwise at room temperature to a solution of intermediate (3) (0.328 mol) in DME (1200 ml) and the mixture was stirred at room temperature for one night. The mixture was evaporated till dryness, the residue was poured into water and ice and decanted. The oily residue was taken up in DIPE, the precipitate was filtered off, washed with EtOAc, CH3CN and diethylether and dried, yielding 88.6 g (80.76%) of 6-bromo-4-(3-chlorophenyl)-2(1H)-quinolinone (intermediate 4).
Reaction SMILES: Cl.C(OCC)(=O)C.[CH3:8][S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[N:26]=[CH:25][N:24]=[C:23]([O:27][CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[CH:22]=1)[CH2:16][CH2:15]2)(=[O:11])=[O:10]>C(OCC)(=O)C>[CH3:8][S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[CH:22]=[C:23]([O:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:24]=[CH:25][N:26]=1)[CH2:16][CH2:15]2)(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A 4 N hydrochloric acid-ethyl acetate solution (9.45 mL) was added at 0° C. to an ethyl acetate (3.15 mL) suspension of tert-butyl 4-({6-[5-(methylsulfonyl)indolin-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate (630 mg, 1.33 mmol) produced in Example 1 below, and the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure. To the obtained residue, a 1 N aqueous sodium hydroxide solution (20 mL) was added, and the deposit was collected by filtration and washed with water to obtain the title compound as white powder (489 mg, yield: 99%).
Reaction SMILES: [C:1]([S:20][CH2:21][CH2:22][NH2:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:31][CH2:32][C:33](Br)=[O:34].O>C(Cl)Cl>[C:1]([S:20][CH2:21][CH2:22][NH:23][C:33](=[O:34])[CH2:32][Br:31])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Br)CBr
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
2-(tritylsulfanyl)-1-ethaneamine (0.5 g, 1.6 mmol) was dissolved in methylene chloride (10 ml) and added with triethylamine (0.22 ml, 1.6 mmol). To the solution, bromoacetylbromide (0.14 ml, 1.6 mmol) in methylene chloride (1 ml) was added dropwise. The resulting solution was stirred at room temperature for 15 min and added with water (30 ml). The organic phase was washed with 1 M hydrogen chloride, water, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution in sequence. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a white solid of N1-(2(tritylsulfanyl)ethyl)-2-bromoacetamide (0.67 g, 1.51 mmol, 94.2%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[CH2:27][O:28][CH3:29].FC1C=C(F)C=CC=1N>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][C:21]=1[CH2:27][O:28][CH3:29]
Reactant: COCc1cc(N)ccc1F
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: Nc1ccc(F)cc1F
Agent: [Na+]
Product: COCc1cc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Yield: 46.6 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 900 mg of 4-fluoro-3-(methoxymethyl)aniline prepared previously, in place of the 2,4-difluoroaniline. 168 mg of N-[4-fluoro-3-(methoxymethyl)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:31]([NH2:33])=[O:32])[C:15]3[NH:16][C:17]4[CH:18]=[C:19]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH:20]=[CH:21][C:22]=4[C:23]=3[N:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10]Cl.[I-].[K+].C([O-])([O-])=O.[K+].[K+].[CH2:42]1[CH2:48][O:47][CH2:46][CH2:45][NH:44][CH2:43]1.Cl.C(O)(C(F)(F)F)=O.N>CS(C)=O.CO.O>[O:47]1[CH2:48][CH2:42][CH2:43][N:44]([CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([C:12]3[CH:13]=[C:14]([C:31]([NH2:33])=[O:32])[C:15]4[NH:16][C:17]5[CH:18]=[C:19]([N:25]6[CH2:30][CH2:29][O:28][CH2:27][CH2:26]6)[CH:20]=[CH:21][C:22]=5[C:23]=4[N:24]=3)=[CH:3][C:2]=2[Cl:1])[CH2:45][CH2:46]1
Reactant: NC(=O)c1cc(-c2ccc(OCCCl)c(Cl)c2)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Reactant: C1CNCCOC1
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: NC(=O)c1cc(-c2ccc(OCCN3CCCOCC3)c(Cl)c2)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 70 °C
Yield: 70.7 %

Procedure:
A mixture of 2-(3-chloro-4-(2-chloroethoxy)phenyl)-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (20 mg, 0.041 mmol), potassium iodide (14 mg, 0.082 mmol), K2CO3 (11 mg, 0.082 mmol) and homomorpholine hydrochloride (23 mg, 0.17 mmol) in DMSO (0.2 mL) in a vial was heated at 70° C. for 40 hrs. Preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, gradient of 0 to 60% B over 20 min at 42 mL/min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 2-(4-(2-(1,4-oxazepan-4-yl)ethoxy)-3-chlorophenyl)-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (16 mg, 0.029 mmol, 71% yield) as a yellow solid. MS (ESI) m/z 550.24 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.22 (1H, d, J=8.85 Hz), 8.16 (1H, d, J=2.14 Hz), 8.06 (1H, s), 7.99 (1H, dd, J=8.55, 2.44 Hz), 7.19 (1H, d, J=8.85 Hz), 7.10 (1H, d, J=2.14 Hz), 7.03 (1H, dd, J=8.85, 2.14 Hz), 4.27 (2H, t, J=5.34 Hz), 3.86-3.94 (4H, m), 3.76-3.85 (4H, m), 3.27-3.31 (4H, m), 3.10 (2H, t, J=5.34 Hz), 2.94-3.02 (4H, m), 1.97 (2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[O-2].[Ca+2].C1C2C(=NC3C(C=2)=CC=CC=3)C=CC=1.[P:26](Cl)(Cl)([Cl:28])=[S:27]>C1C=CC=CC=1>[Cl:28][P:26]1(=[S:27])[O:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[O:1]1
Reactant: OCc1ccccc1O
Reactant: S=P(Cl)(Cl)Cl
Agent: [Ca+2]
Agent: [O-2]
Agent: c1ccc2nc3ccccc3cc2c1
Solvent: c1ccccc1
Product: S=P1(Cl)OCc2ccccc2O1
Temperature: 22 °C
Reaction time: 2 h

Procedure:
Into a three-necked, 500 ml flask were placed 31 g (0.25 mole) o-hydroxybenzyl alcohol, 56 g (1.0 moles) calcium oxide, a catalytic amount (0.1 g) of acridine, and 600 ml of benzene. To this reaction mixture was added 46.5 g (0.275 mole) of thiophosphoryl trichloride, dropwise, over a period of 120 minutes with stirring. The temperature was maintained at 22° C by use of a water bath. After the addition of the thiophosphoryl trichloride the mixture was stirred overnight. The mixture was then filtered, the solids washed with four equal portions of benzene (total of 200 ml) and the washings combined with the filtrate. The filtrate was then washed with two equal portions of a 5 percent aqueous bicarbonate solution (total of 100 ml), dried over sodium sulfate, filtered, and the volatiles removed under reduced pressure. The residue crystallized, affording 39 g (71%) pf 2-chloro-4H-1,3,2-benzodioxaphosphorin-2-sulfide, m.p.=44°-45° C. Analysis: %Cl, 16.12 (calculated); 16.42 (Found).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:17]3[CH:22]4[CH2:23][CH2:24][CH:18]3[CH2:19][O:20][CH2:21]4)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([N:17]3[CH:18]4[CH2:24][CH2:23][CH:22]3[CH2:21][O:20][CH2:19]4)=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N3C4CCC3COC4)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c(cc1N1C3CCC1COC3)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown oil. MS (m/e): 231.1 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.Cl>C1COCC1.CO.[Fe]>[F:1][C:2]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline (0.900 g, 2.9 mmol) in THF was added methanol (53 ml, 1297 mmol) and 1N HCl (8.6 ml, 8.6 mmol). The resulting mixture was cooled to 0° C. Iron (2.2 g, 40 mmol) was added, and the reaction was allowed to stir at RT for 3.5 hours. The reaction mixture was then diluted with MeOH, filtered through a pad of Celite, and concentrated in vacuo. The residue was then diluted with sat. NaHCO3 (aq) and CH2Cl2. The aqueous layer was separated and extracted three times with CH2Cl2. The combined organic extracts were dried over sodium sulfate and filtered through a pad of silica gel using 10% MeOH/CH2Cl2. The collected fractions were concentrated in vacuo and purified by silica gel chromatography (80 g column; 2% MeOH/CH2Cl2 for 10 minutes then 3.5% MeOH/CH2Cl2 for 10 minutes). Fractions containing pure product were concentrated to yield 3-fluoro-4-(7-methoxyquinolin-4-yloxy)benzenamine as a tan solid. Calcd for C16H13FN2O2: [M]+=284. Found: [M+H]+=285.
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[NH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([NH2:25])[CH:24]=1)[CH2:20][OH:21]>>[CH:4]1[C:3]2[C:8](=[N:9][C:10]3[C:15]([C:2]=2[NH:16][C:17]2[CH:24]=[C:23]([CH:22]=[C:19]([CH2:20][OH:21])[CH:18]=2)[NH2:25])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1c2ccccc2nc2ccccc12
Reactant: Nc1cc(N)cc(CO)c1
Product: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1

Procedure:
condensing 9-chloroacridine with 3,5-diaminobenzyl alcohol under suitable conditions to form 3-(9-acridinylamino)-5-hydroxymethylaniline (Formula II); ##STR9##
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[O:5][C:6]=1C=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:24]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])OCC>C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[O:5][C:6]=1[CH:24]([O:28][CH2:29][CH3:30])[O:31][CH2:32][CH3:33]
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1oc2ccccc2c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(OCC)c1oc2ccccc2c1Br
Reaction time: 8 h

Procedure:
To a solution of 2.6 g of 3-bromo-2-benzo[b]furancarboxaldehyde (see M. Cugnon de Sevricourt and M. Robba, Bull. Chim. Soc. Fr., 1977, 142) in 2.7 ml of triethyl orthoformate was added 33 mg of para-toluene sulfonic acid and the solution stirred at at roon temperature overnight. The solution was diluted with a 5% sodium carbonate solution and extracted with ether. The ether extracts were dried over sodium sulfate and evaporated to give 3-bromo-2-(diethoxymethyl)-benzo[b]furan as a liquid; 1H-NMR (200 MHz, CDCl3) d 5.76 (CHOEt).
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[C:15]2[C:24]3[C:29]([CH2:30][C:14]1=2)=[CH:28][CH:27]=[CH:26][CH:25]=3.N1C2C(C=CC3C=2C=C2C=3C=CC=C2)=CC=1.[Cl:47][Si:48](Cl)([CH3:50])[CH3:49]>C1COCC1>[Cl:47][Si:48]([CH3:50])([CH3:49])[CH:30]1[C:14]2[N:13]([CH3:12])[C:21]3[C:16]([C:15]=2[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3
Reactant: C[Si](C)(Cl)Cl
Reactant: COc1ccc2c(c1)c1c(n2C)Cc2ccccc2-1
Agent: C1=Nc2c3c(ccc2=C1)=c1ccccc1=C3
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2c(c1)c1c(n2C)C([Si](C)(C)Cl)c2ccccc2-1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
3.4 mL of a 2.5 M solution of n-BuLi in hexane (8.50 mmol) were added dropwise to a solution of 2.22 g of N-methyl-2-methoxy-5,6-dihydroindeno[2,1-b]indole, obtained as reported above, (Mw=249.32, purity 85.8%, 7.64 mmol; indenoindole: n-BuLi=1:1.1) in 50 mL of THF, previously cooled to −78° C. At the end of the addition, the brown solution was allowed to warm up to room temperature and stirred for 5 hours. Then it was cooled again to −78° C. and added dropwise to a solution of dichlorodimethylsilane (Mw=129.06, d=1.064, 0.92 mL, 7.64 mmol; indenoindole: Me2SiCl2=1:1) in 20 mL of THF, previously cooled to −78° C. At the end of the addition, the dark brown solution was allowed to warm up to room temperature and stirred overnight. The solvents were evaporated under reduced pressure to give the desired product, containing few by-products, in the form of a brown sticky solid; this product was used in the following step without further purification.
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:30](=[O:31])[CH2:29][C:24]2([CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23][C:22]1=[O:32].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:22](=[O:32])[CH2:23][C:24]4([CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:29][C:30]3=[O:31])[CH2:3][CH2:2]2)=[N:8]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1

Procedure:
Method A--A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (24.3 g., 0.11 mole) and 8-(4-bromobutyl)-8-azaspiro[4.5]decane-7.9-dione (33.5 g., 0.11 mole), anhydrous potassium carbonate (32.4 g., 0.23 mole) and potassium iodide (3.9 g., 0.023 mole) in 1 liter of acetonitrile is stirred and heated under reflux for a period of 20 hr. The reaction mixture is filtered, concentrated in vacuo and residual material taken up in 350 ml. of chloroform which is filtered and concentrated in vacuo. The residue is triturated with ether, refrigerated and resulting solid collected. This material crystallized from acetonitrile (employing activated charcoal affords a first crop 25.1 g, m.p. 120°-124° C. and a second crop, 6.0 g, m.p. 123°-126° C. for a total yield of 31.1 g. (64% yield) of the free base form of the title compound. Crystallization from acetonitrile affords analytically pure 8-[4-[ 4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione, m.p. 124°-126° C.