Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][C:25]=3[CH3:37])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[N:10]=[C:9]1[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([O:48]CC2C=CC=CC=2)[CH:39]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])=[CH:26][C:25]=3[CH3:37])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[N:10]=[C:9]1[C:38]1[CH:43]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:41]=[C:40]([OH:48])[CH:39]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(OCc3ccccc3)cc(C(F)(F)F)c1)N(C(=O)OC(C)(C)C)C2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(O)cc(C(F)(F)F)c1)N(C(=O)OC(C)(C)C)C2=O

Procedure:
2-(3-Benzyloxy-5-trifluoromethyl-phenyl)-8-[2-(4-tert-butoxycarbonyl-2-methyl-phenyl)-ethanesulfonyl]-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-3-carboxylic acid tert-butyl ester (1.11 g, 1.41 mmol) was dissolved in ethyl acetate (45.0 ml)-THF (15.0 ml). Pd—C (222 mg) was added and the mixture was stirred at room temperature and for one hour in a hydrogen atmosphere. After completion of the reaction, the black solid was filtered off through celite, and the filtrate was concentrated under reduced pressure to give 8-[2-(4-tert-butoxycarbonyl-2-methyl-phenyl)-ethanesulfonyl]-2-(3-hydroxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-3-carboxylic acid tert-butyl ester as an amorphous (1.01 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C@:5]2(NC(N)=O)C(O)=O.[Mn]([O-])(=O)(=O)=[O:20].[K+]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:20]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: NC(=O)N[C@]1(C(=O)O)CCOc2ccc(F)cc21
Agent: [K+]
Product: O=C1CCOc2ccc(F)cc21

Procedure:
The title compound can be prepared by oxidation of (R)-6-fluoro-4-ureidochroman-4-carboxylic acid with potassium permanganate, using the procedure of Example 1.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[C:25]([CH3:36])[NH:24][C:23]=1[CH:37]=O>C(O)C.N1CCCCC1>[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[O:28])=[C:25]([CH3:36])[NH:24][C:23]=1[CH:37]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=2)[NH:13][C:12]1=[O:18]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The solvent was evaporated and the solid was washed by ether for three times to provide pure product 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (96.5 mg, 76%).
Reaction SMILES: [Cl:1][C:2]([C:6]1[CH:7]=[C:8]([CH3:17])[CH:9]=[C:10]([C:12]([Cl:16])=[C:13]([Cl:15])[Cl:14])[CH:11]=1)=[C:3]([Cl:5])[Cl:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]([C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([C:12]([Cl:16])=[C:13]([Cl:15])[Cl:14])[CH:11]=1)[CH2:17][Br:36])=[C:3]([Cl:5])[Cl:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: ClC(Cl)=C(Cl)c1cc(CBr)cc(C(Cl)=C(Cl)Cl)c1

Procedure:
A solution of 3,5-di(trichlorovinyl)toluene (6.0 g) and dibenzoyl peroxide (200 mg) in 150 ml of benzene was heated at reflux. N-Bromosuccinimide (3.6 g) was added in portions and the reaction mixture stirred at reflux for 3 hours. The mixture was evaporated and the residue triturated with 200 ml of hexane. The precipitated succinimide was collected and the filtrate concentrated to five 7.9 g of crude benzyl bromide.
Reaction SMILES: CC(OC([N:8]1[C@@H:12]2[CH2:13][C:14]([CH2:16][C@H:9]1[CH2:10][CH2:11]2)=[O:15])=O)(C)C.Cl.O1CCOCC1>ClCCl>[CH:9]12[NH:8][CH:12]([CH2:11][CH2:10]1)[CH2:13][C:14](=[O:15])[CH2:16]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)C2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1CC2CCC(C1)N2
Reaction time: 60 h
Yield: 128.2 %

Procedure:
A solution of N-Boc nortropinone (0.73 g, 3.24 mmol) in a minimal amount of dichloromethane (1 mL) was treated with a solution of 4 M hydrochloric acid in dioxane (3.2 mL, 12.8 mmol). After stirring for 2.5 days, the reaction was complete by TLC analysis. Solvent was removed under reduced pressure to give 0.52 g of 8-azabicyclo[3.2.1]octan-3-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH:15](Br)C.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O.C(Cl)(Cl)Cl>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(Br)CCBr
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(OCCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
A solution of N-(4-hydroxyphenyl)acetamide (paracetamol) (1) (1.50 g) and 1,3-dibromobutane (14) (10.0 ml) in ethyl methyl ketone (25.0 ml) containing potassium carbonate (5.0 g) was stirred overnight at room temperature. The reaction mixture was filtered, residue washed with ethyl methyl ketone and solvent evaporated under reduced pressure to get the residue. The residue was dissolved in chloroform (200.0 ml), washed with 5% NaOH solution (3×100 ml), water (3×50 ml), dried, filtered and crystallized from methanol to get the desired product N-[4-(3-Bromo-propoxy)-phenyl]-acetamide (16) (2.01 g, 75.8%), mp 115-118° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:10])=[N:2]1.[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:10][C:13](=[O:14])[N:12]([CH3:11])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:2]1
Reactant: Oc1noc2ccccc12
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1noc2ccccc12)c1ccccc1

Procedure:
The title product was prepared from benzo[d]isoxazol-3-ol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (53%, colorless oil). HPLC-MS: m/z=291.1 (M+23); Rt: 4.05 min.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.O>N1C=CC=CC=1>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])#[N:5]
Reactant: N#Cc1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 2-aminobenzonitrile (2.36 g (20.0 mmol in pyridine (10.0 ml), p-toluenesulfonyl chloride (4.20 g (22.0 mmol) was added with stirring at room temperature. After 15 hours' stirring at room temperature, water (100 ml) was added to the reaction mixture and stirring was continued for another 30 minutes. The crystals separated were filtered, washed with water and re-dissolved in chloroform. The soluble part in 1% aqueous sodium hydroxide solution was extracted from the chloroform solution. The extract was made acidic with hydrochloric acid and re-extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a product which then crystallized. The crystals were washed with diisopropyl ether and filtered to give 4.83 g (89%) of 2′-cyano-p-toluenesulfonanilide as white crystals.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][NH:14][CH3:15].C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:14]([CH3:15])[CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(Bromomethyl)benzenesulfonyl chloride (5.0 g, 18.6 mmol) was dissolved in tetrahydrofuran. N,N-dimethylamine (7.7 mL, 15.5 mmol, 2M in tetrahydrofuran) and N,N-diisopropylethylamine (3.5 mL, 20.1 mmol) were added, and the reaction was allowed to stir at ambient temperature for 2 hours. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The resulting filtrate was concentrated to an oil which deposited needles that were a mixture of the title compound and 4-chloromethyl N,N-dimethylbenzenesulfonamide The resulting needles were collected and dried (2.3 g, 44%). ES-MS m/z 534 (M+H) and 578 (M+H).
Reaction SMILES: N#N.[CH2:3]([O:5][C:6](=[O:11])[CH2:7][CH2:8][CH2:9]Br)[CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([O:22][C:23]([NH:25][C:26]1[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29])=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]([CH2:9][CH2:8][CH2:7][C:6]([O:5][CH2:3][CH3:4])=[O:11])[C:26]1[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)c1cc(C)cc(C)c1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)CCCBr
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(C(=O)OC(C)(C)C)c1c(C)cc(C)cc1C(=O)OC
Temperature: 55 °C
Reaction time: 48 h
Yield: 113.6 %

Procedure:
Charge a 22 L flask, equipped with overhead agitation, heating mantle, condenser and a N2 purge, with DMF (10 L), ethyl-4-bromobutyrate (1.07 kg, 787.8 mL, 5.32 moles), cesium carbonate (2.92 kg, 22.5 moles), and methyl 2-(tert-butoxycarbonylamino)-3,5-dimethylbenzoate (1,000.0 g, 3.54 moles). Heat the resulting mixture to about 55° C. and stir for about 48 hours. Cool; filter off the solid; and wash the solid with MTBE (2×4 L). Combine the filtrate and the MTBE washings into a 50 L flask and cool to less than about 5° C. Add water (6 L) to quench the reaction. Separate the layers. Wash the aqueous layer with MTBE (3 L); combine the organic layers; and wash the resulting organic solution with brine (2×3 L). Dry the organic solution over Na2SO4; filter; and wash the collected solids with MTBE to yield 1.582 kg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[CH:26]1([C:31]2[CH:35]=[C:34]([NH:36][C:37](=O)[O:38]C3C=CC=CC=3)[O:33][N:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>>[CH:26]1([C:31]2[CH:35]=[C:34]([NH:36][C:37]([NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH:20]=3)=[O:38])[O:33][N:32]=2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C(Nc1cc(C2CCCC2)no1)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5CCCC5)no4)c3)c2cc1OC
Yield: 28 %

Procedure:
The title compound was prepared as described in Example 113C by using 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (104 mg, 0.35 mmol), phenyl 3-cyclopentylisoxazol-5-ylcarbamate described in Example 163A (124 mg, 0.45 mmol) and N,N-diisopropylethylamine (73 μl, 0.42 mmol) to give 1-(3-cyclopentylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (51.72 mg, 28%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.05 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.50-7.35 (m, 2H), 7.30 (d, 1H), 7.00 (d, 1H), 5.95 (s, 1H), 4.34 (bs, 2H), 3.99 (s, 3H), 3.77 (bs, 2H), 3.34 (s, 3H), 3.11-2.99 (m, 1H), 2.10-1.80 (m, 2H), 1.75-1.50 (m, 6H); LC-MS (ESI) m/z 520 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([CH3:15])[CH:8]=1)(=[O:5])[CH3:4]>CO>[C:3]([NH:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[C:9]([CH3:15])[CH:8]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1ccc(C=O)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ccc(CO)c(C)c1
Reaction time: 3 h
Yield: 85.1 %

Procedure:
Sodium borohydride (0.248 g) was added portionwise to a solution of 4-acetamido-2-methyl benzaldehyde (2.58 g) in methanol (26 ml) with ice-cooling. After being stirred for 3 hours, the mixture was evaporated in vacuo and the residue was washed with water and dried to give 4-acetamido-2-methylbenzyl alcohol (2.22 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:30][C@@H:31]1[CH2:36][CH2:35][C@H:34]([C:37]([OH:39])=O)[CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:37]([C@H:34]2[CH2:33][CH2:32][C@@H:31]([OH:30])[CH2:36][CH2:35]2)=[O:39])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Product: CN(C(=O)[C@H]1CC[C@@H](O)CC1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound cis-4-hydroxy-cyclohexanecarboxylic acid {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using cis-4-hydroxycyclohexanecarboxylic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 564.4 [M]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12.[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:18][C:2]2[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]3=[N:10][CH:11]=[CH:12][C:3]=23)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CSc1nc(Cl)c2ccnc-2[nH]1
Reactant: NC1CCCC1
Product: CSc1nc(NC2CCCC2)c2ccnc-2[nH]1

Procedure:
To 100 mg of 4-chloro-2-methylthiopyrrolo[2,3-d]pyrimidine was added 2 ml of cyclopentylamine. The solution was heated at reflux under nitrogen for 2 hours. The resulting dark oil was purified by chromatography on 30 g of Sephadex LH-20, elution with H2O and then with increasing concentrations of EtOH up to 40% EtOH. The appropriate fractions were combined and evaporated to dryness and the solid residue was crystallized from EtOH/H2O to afford tan crystals of product, yield 50 mg (40%), m.p. 190°-191° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:8]=2[O:7]1)=[O:5])[CH3:2].[C:16]1([S:22](Cl)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl.ClC(Cl)C>[CH2:1]([O:3][C:4]([CH:6]1[O:7][C:8]2[CH:14]=[C:13]([CH3:15])[C:12]([S:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:23])=[CH:11][C:9]=2[O:10]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Oc2ccc(C)cc2O1
Reactant: O=S(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: CCOC(=O)C1Oc2cc(C)c(S(=O)c3ccccc3)cc2O1
Temperature: 0 °C

Procedure:
20.8 g (0.1 mol) of 5-methyl-1,3-benzodioxole-2-carboxylic acid ethyl ester Example 2b) and 19.2 g (0.125 mol) of phenylsulphinic acid chloride are dissolved in 200 ml of 1,2-dichloroethane and cooled to 5° using an ice-bath. 13.3 g (0.1 mol) of aluminium chloride are introduced in the course of approximately 15 minutes at from 5°-10° while stirring. The mixture is stirred for a further hour in the ice-bath and is then poured out onto ice-water. The resulting emulsion is diluted with 200 ml of dichloroethane and filtered across a layer of a filter aid (for example Hyflo). The filtrate is introduced into a separating funnel and the layers are separated. The organic phase is dried over sodium sulphate, filtered and concentrated to dryness by evaporation. A light brown honey-like product, 5-phenylsulphinyl-6-methyl-1,3-benzodioxole-2-carboxylic acid ethyl ester, is obtained.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[C:9]([O:15][CH3:16])[CH:8]=3)[N:4]([CH2:17][CH2:18][N:19](C)[CH3:20])[N:3]=1.ClC(OC(Cl)C)=O>C(Cl)Cl>[Br:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[C:9]([O:15][CH3:16])[CH:8]=3)[N:4]([CH2:17][CH2:18][NH:19][CH3:20])[N:3]=1
Reactant: COc1ccc2cc3c(Br)nn(CCN(C)C)c3nc2c1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: CNCCn1nc(Br)c2cc3ccc(OC)cc3nc21

Procedure:
3-Bromo-7-methoxy-1-(2-methylaminoethyl)-1H-pyrazolo[3,4-b]quinoline was prepared by demethylation of 3-bromo-1-[2-(dimethylamino)ethyl]-7-methoxy-1H-pyrazolo[3,4-b]quinoline (Example 37) by the method of J. Org. Chem. 49, 2081 (1984), as follows: to a mixture of 15 g of the compound of Example 37 and 150 ml methylene dichloride at 0° C. was added dropwise a solution of 6.7 g α-chloroethyl chloroformate in 30 ml methylene dichloride. The reaction mixture was heated at reflux for one hour and then concentrated to remove solvent. The residue in 300 ml methanol was heated at reflux for one hour. The methanol was removed, ice-water and concentrated ammonium hydroxide added to the residue, and the product collected and recrystallized from ethyl acetate to give 7.12 g 3-bromo-7-methoxy-1-(2-methylaminoethyl)-1H-pyrazolo[3,4-b]quinoline, light yellow powder, m.p. 100°-101° C.
Reaction SMILES: C(O[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C.CC(C)=[O:15]>>[CH2:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:15])=[CH:9][CH:8]=1
Reactant: CC(C)=O
Reactant: CC(=O)OC=Cc1ccccc1
Product: C=Cc1ccc(O)cc1
Temperature: 127.5 °C
Reaction time: 48 h

Procedure:
Acetoxystyrene (75.0 g, 0.463 mol) was placed in a 250 mL round bottom flask and purged with N2. The unimolecular initiating system 1-phenyl-1-(2',2',6',6'-tetramethyl-1'-piperidinyloxy)-ethane (1.21 g, 0.00463 mol) (with no separate free radical initiator used) was then added to the monomer. After addition of the initiator, the polymerization mixture was heated to 125-130° C., under N2, and stirred for 48 hours. During the polymerization the polymer solidified in the reaction vessel. The reaction was then cooled to room temperature and the polymer dissolved in acetone (225 mL), and isolated by precipitation into hexanes (2250 mL). The polymer was then filtered, washed with hexanes and dried in a vacuum oven at 60° C. overnight. Isolated yield was 90% of theory, Mn =8997, Mw /Mn =1.10.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C=O)C>[C:16]([Si:19]([CH3:21])([CH3:20])[O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[NH2:1])([CH3:18])([CH3:17])[CH3:15]
Reactant: Cc1ccc(N)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
To a solution of 2-amino-5-methyl-phenol (500 mg, 4.0 mmol) and imidazole (298 mg, 4.4 mmol) in DMF (5 ml) was added TBDMSCl (660 mg, 4.4 mmol). The reaction mixture was stirred at RT for 3 h then diluted into water and extracted with AcOEt. The organic fraction was dried over Na2SO4, filtered and evaporated to dryness. The resulting residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/TBME containing 5% of 7M NH3 in MeOH 95:5→8:2) to yield the title compound (724 mg, 3.1 mmol, 77%) as a reddish oil. TLC: RF=0.94 (heptane/DCM/TBME 1:1:2 containing 5% of 7M NH3 in MeOH); HPLC: AtRet=1.80 min; API-MS: m/z 238.1 [M+H]+; 1H NMR (400 MHz, CDCl3): 0.26 (s, 6H), 1.04 (s, 9H), 2.23 (s, 3H), 3.56 (br. s., 1H), 6.56-6.67 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1.O.[Li]CCCC>[C:27]([O:26][C:24](=[O:25])[CH2:23][CH:22]([S:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:21][CH2:20][CH2:19][CH2:18][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1ccc(S)cc1OC
Reactant: CC(C)(C)OC(=O)C=CCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(SC(CCCCc2ccccc2)CC(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
To a solution of 3,4-dimethoxythiophenol (8.25 mL, 57.6 mmol) in anhydrous THF (100 mL) at 0° C., is added n-BuLi (2.5 M in hexane, 0.77 mL, 1.92 mmol) and the solution is stirred for 15 minutes under a nitrogen atmosphere. t-butyl 7-phenyl-2-heptenoate (10 g, 38.4 mmol) in THF (100 mL) is added dropwise and the mixture is allowed to warm to room temperature and stir overnight. TLC analysis indicated complete reaction. The reaction mixture is diluted with water (300 mL) and extracted with ether (3×250 mL). Combined organic extracts are washed successively with sat. Na2CO3 solution (4×200 mL), water (200 mL) and brine (200 mL) then dried over MgSO4 and concentrated to afford a pale yellow oil which is chromatographed on silica gel (pet-ether/EtOAc, 9:1) to afford 14.9 g of (±)-t-butyl-3-(3,4-dimethoxyphenyl)sulfanyl-7-phenylheptanoate (90%) as a colorless oil. TLC analysis [pet-ether/EtOAc, 9:1, Rf (heptenoate)=0.80, Rf (heptanoate)=0.50]. 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.48-1.68 (m, 6H), 2.42 (dABq, 2H), 2.60 (t, 2H), 3.28 (t, 1H), 3.85 (d, 6H), 6.75 (d, 1H), 7.0 (dd, 2H), 7.15 (d, 3H), 7.25 (t, 2H) ppm. Mass spectrum (FAB) m/z 447 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1>CCOC(C)=O.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)N1CCN(c2ccc(N)cc2F)CC1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of Example 119B (3.0 g, 10.59 mmol) in EtOAc (40 mL) was added 10% palladium on carbon (300 mg) and the solution was stirred under a balloon of H2 gas for 1.5 h. The solution was filtered through Celite, the catalyst washed with EtOAc, and the filtrate concentrated in vacuo to give the title compound (2.68 g, 10.59 mmol, 100%).