Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)[N:5]([CH2:6][C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH:13]=3)[CH:8]=2)C(=O)C2=CC=CC=C12>CN.CO>[NH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH:13]=2)[CH:8]=1
Reactant: CCCN(CCC)CCCCc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2c1
Agent: CN
Solvent: CO
Product: CCCN(CCC)CCCCc1ccc2cc(CN)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 127.5 %

Procedure:
The compound (75.0 mg) obtained in Example 124-3 was dissolved in a 40% methylamine/methanol solution (2.0 ml) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off and then the residue was added with a 1 mol/l sodium hydroxide aqueous solution and stirred. The solution was subjected to extraction with chloroform and the extract was then washed with saturated saline solution. Subsequently, the organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off, thereby obtaining the subject compound (67.5 mg) as a colorless oily substance.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)=[CH2:9])(=[O:4])=[O:3].[N+](=[C:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[N-]>ClC1C=CC=CC=1.C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Cl:17][C:12]1[CH:11]=[C:10]([C:8]2([CH2:7][CH2:6][O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:9][C:20]2([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: C=C(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: COC(=O)C1(C(=O)OC)CC1(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
In a round-bottomed flask, 3-(3,4-dichlorophenyl)-3-buten-1-yl methanesulfonate (P62, 90.8 g, 308 mmol) was dissolved in chlorobenzene (200 ml) to give a green solution. Rhodium acetate dimer (6.80 g, 15.38 mmol) was added. The suspension was warmed to an internal temperature of +65° C. and dimethyl diazopropanedioate (78 g, 492 mmol, for a reference procedure of preparation see Synthetic Communication 1987, 17 (14), 1709-1716) dissolved in chlorobenzene (150 ml) was added dropwise (during 2.5 hrs), keeping the internal temperature below 65-67° C. At the end of the addition, the mixture was cooled to room temperature. It was diluted with DCM (300 ml) and filtered over a celite pad to separate the catalyst.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:26])[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)=[CH:14][CH:13]=1)C>C(O)C>[C:18]1([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:26])=[O:5])=[CH:17][CH:16]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: CCOC(=O)CCCCOc1ccc(C2=CCCCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCOc1ccc(C2=CCCCCCC2)cc1
Reaction time: 48 h

Procedure:
20 ml of 2 N sodium hydroxide solution are added to a solution of 15 g of 5-[p-(1-cyclooctenyl)-phenoxy]-pentanoic acid ethyl ester in 150 ml of ethanol and the mixture is left to stand at room temperature for 48 hours. It is then evaporated in vacuo to a volume of about 30 ml and the evaporation residue is distributed, at 5° C, between 100 ml of 2 N hydrochloric acid and twice 200 ml of ether. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Crystallisation of the evaporation residue from ether-petroleum ether gives 5-[p-(1-cyclooctenyl)-phenoxy]-pentanoic acid of melting point 94- 96° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]1[C:12]([Cl:13])=[CH:11][N:10]=[C:9]([Cl:14])[N:8]=1.Cl.C(N(CC)CC)C.[N+:26]([C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1)([O-:28])=[O:27]>C1COCC1>[Cl:14][C:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][S:35]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=3)(=[O:36])=[O:37])[CH:17]=[CH:16][CH:15]=2)[C:12]([Cl:13])=[CH:11][N:10]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1cccc(CNc2nc(Cl)ncc2Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2cccc(CNc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a mixture of N-(3-aminobenzyl)-2,5-dichloropyrimidin-4-amine.hydrogen chloride (0.20 g, 0.58 mmol) and triethylamine (0.32 mL, 2.3 mmol) in THF (3 mL) was added slowly m-nitrobenzenesulfonyl chloride (0.13 g, 0.58 mmol). The resulting mixture was stirred at rt for 2 hours and the solvent was removed under vacuum. The residue was treated with EtOAc and water. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to provide the desired product (0.30 g, 95%). LCMS for C17H14Cl2N5O4S (M+H)+: m/z=453.9, 455.9.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7]2.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.O>CN(C=O)C>[C:9]1(=[O:13])[C:10]2[C:6](=[CH:5][C:4]([O:3][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[CH:12][CH:11]=2)[CH2:7][NH:8]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C1NCc2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCc2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 89 %

Procedure:
To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0° C. was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room temp. and was stirred for 45 min., then 4-fluoro-1-nitrobenzene was added and then mixture was heated at 70° C. for 3 h. The mixture was cooled to 0° C. and treated with water dropwise until a precipitate formed. The resulting solids were collected to give 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) Rf 0.35.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:7]([C:3]1[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=1)=[O:8]
Reactant: Clc1ccc(Cl)cc1
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cccc(C(=O)c2cc(Cl)ccc2Cl)c1
Yield: 53 %

Procedure:
The procedure of Example 2 was followed, using 22 ml (0.17 mol) of 3-toluoyl chloride and 60 g (0.45 mol) of aluminum chloride in 120 g (0.82 mol) of 1,4-dichlorobenzene. (The molar ratio of reactants was 2.6:4.8:1.0 (AlCl3 :Dichlorobenzene:3-Toluoyl Chloride)). Pure 2,5-dichloro-3'-methyl-benzophenone was isolated in 53% yield after the crude product was recrystallized twice from hexane.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([CH2:11][CH:12](O)[CH:13]=[CH2:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O>CCOCC>[Cl:3][CH2:14]/[CH:13]=[CH:12]/[CH2:11][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C=CC(O)CC1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: ClC/C=C/CC1CCCCC1
Reaction time: 8 h

Procedure:
Thionyl chloride (50.5 ml) was added dropwise over 1 hour to a stirred solution of 1-cyclohexyl-3-buten-2-ol (50 g) (obtained as described in European Patent Application, Publication No. 258183) in dry ether (1 litre). The solution was allowed to stand overnight and then water (750 ml) was added, and the mixture was stirred for 1 hour. The organic phase was separated, washed with water (500 ml) and saturated sodium chloride solution (2×250 ml) and dried (MgSO4). The solvent was removed by evaporation and the residual liquid distilled under high vacuum to give (2E)-1-chloro-4-cyclohexylbut-2 -ene (B), as a clear liquid (42.2 g), b.p. 64-68° C. at 0.5 mm Hg; NMR: 0.8-1.8(complex m, 11H), 2.0(t, 2H), 4.0(d, 2H), 5.5-5.9(complex m, 2H); microanalysis, found: C, 69.5; H, 10.0; Cl, 20.3%; C10H17Cl requires: C, 69.5; H, 9.9; Cl, 20.5%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[C:13]([NH:18][C:19]3[C:28]4[CH2:27][CH2:26][NH:25][CH2:24][C:23]=4[CH:22]=[CH:21][N:20]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])[N:2]=1.CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[C:13]([NH:18][C:19]3[C:28]4[CH2:27][CH2:26][N:25]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:24][C:23]=4[CH:22]=[CH:21][N:20]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])[N:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(Nc2nccc3c2CCNC3)cc1-c1cc2ccccc2cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(Nc2nccc3c2CCN(S(C)(=O)=O)C3)cc1-c1cc2ccccc2cn1
Reaction time: 8 h

Procedure:
To a solution of N-(3-(isoquinolin-3-yl)-4-methylphenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine (37 mg, 0.1 mmol) in THF (2 mL) is added DIEA (26 mg, 0.2 mmol) and methylsulfonyl chloride (14 mg, 0.12 mmol) subsequently. The reaction mixture is stirred overnight. After removing solvent by rotary evaporation, the residue is purified by HPLC to afford N-(3-(isoquinolin-3-yl)-4-methylphenyl)-6-(methylsulfonyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine as a white solid. MS m/z 445.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.34 (s, 1H), 8.11 (d, 1H, J=8.0 Hz), 7.97 (d, 1H, J=7.6 Hz), 7.88-7.85 (m, 3H), 7.76-7.71 (m, 2H), 7.66-7.63 (m, 2H), 7.16 (d, 1H, J=8.4 Hz), 6.57 (d, 1H, J=5.2 Hz), 4.24 (s, 2H), 3.45 (t, 2H, J=6.0 Hz), 2.91 (s, 3H), 2.75 (t, 2H, J=6.0 Hz), 2.26 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:44])[C@H:4]([CH2:40][CH2:41][S:42][CH3:43])[NH:5][C:6](=[O:39])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:9][C:8]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38].O.[OH-].[Li+:47]>>[Li+:47].[CH:17]1([CH2:16][CH2:15][CH:14]([S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([O-:44])=[O:2])[CH2:40][CH2:41][S:42][CH3:43])=[O:39])=[C:8]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[CH:9]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CC(CCC2CCCCC2)S(=O)(=O)c2ccccc2)cc1-c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CSCC[C@H](NC(=O)c1ccc(CC(CCC2CCCCC2)S(=O)(=O)c2ccccc2)cc1-c1ccccc1C)C(=O)[O-]

Procedure:
The product from Example 1302C (107 mg, 0.17 mmol) was allowed to react with lithium hydroxide monohydrate (8 mg, 0.18 mmol) in a manner similar to that described in Example 608E to afford the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 0.54-0.70 (m, 2H), 0.85-1.10 (m, 6H), 1.30-2.04 (m, 16H), 2.14 (m, 1H), 2.80 (m, 1H), 3.16 (m, 1H), 3.60-3.73 (m, 2H), 6.85-7.26 (m, 6H), 7.43 (d, J=8 Hz, 1H), 7.62-7.68 (m, 2H), 7.75 (m, 1H), 7.93 (d, J=7 Hz, 2H); MS (APCI(−)) m/z: (M−H)− 620; Anal. Calcd for C35H42LiNO5S2.3.20 H2O: C, 61.33; H, 7.12; N, 2.04. Found: C, 61.31; H, 6.63; N, 1.70.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH:17]=2)[C:11]([O:13]C)=[O:12])=[N:6][CH:7]=1.CO.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH:17]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(C)cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a round-bottom flask were charged methyl 3-(5-methylpyridin-2-yl)-5-(pyrrolidine-1-carbonyl)benzoate (0.80 g, 2.47 mmol), methanol (40 mL), sodium hydroxide (0.20 g, 5.0 mmol) and water (10 mL). The mixture was stirred at room temperature for 1 h. The volatiles were removed under reduced pressure. The residue was treated with 1N HCl (10 mL), concentrated, and purified via preparative HPLC to afford the desired product. LC-MS: 311.5 [M+1]+; 1H NMR (400 MHz, DMSO-d6): 8.61 (t, J=1.7 Hz, 1H), 8.52 (t, J=0.8 Hz, 1H), 8.16 (t, J=1.8 Hz, 1H), 7.99 (t, J=1.5 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.72-7.69 (m, 1H), 3.50 (t, J=6.7 Hz, 2H), 3.41 (t, J=6.5 Hz, 2H), 2.35 (s, 3H), 1.91-1.81 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:16])[CH:13]=2)[O:8][CH2:7]1.[H-].[Na+].Cl[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][C:28]([Cl:34])=[CH:29][CH:30]=2)[N:25]=1.O>CN(C)C=O.C(OCC)(=O)C>[Cl:34][C:28]1[CH:27]=[C:26]2[C:31]([CH:32]=[CH:33][C:24]([CH2:23][O:16][C:12]3[CH:13]=[C:14]4[C:9](=[CH:10][CH:11]=3)[O:8][CH2:7][CH:6]([CH2:5][C:4]3[CH:3]=[C:2]([NH2:1])[CH:19]=[CH:18][CH:17]=3)[CH2:15]4)=[N:25]2)=[CH:30][CH:29]=1
Reactant: ClCc1ccc2ccc(Cl)cc2n1
Reactant: Nc1cccc(CC2COc3ccc(O)cc3C2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc(CC2COc3ccc(OCc4ccc5ccc(Cl)cc5n4)cc3C2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a stirred solution of 350 mg (1.37 mmole) of the product from Example 140 in 10 mL dimethylformamide at 0° C. was added 60 mg (1.51 mmole) sodium hydride. The mixture was stirred at 0° C. for 30 minutes, then 349 mg (1.64 mmole) 2-(chloromethyl)-7-chloroquinoline was added. The mixture was warmed to room temperature and stirred for 72 hours. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine, dried (MgSO4) and concentrated to give an oil. Flash chromatography on silica gel eluting with 40% ethyl acetate in hexanes yielded 476 mg (81%) of the title product as a solid, mp 128°-130° C. Analysis calculated for C26H23N2O2Cl: C, 72.47; H, 5.38; N, 650. Found: C, 72.47; H, 5.12; N, 6.43.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C2CCN(c3ccncc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C2CCN(c3ccncc3)CC2)cc1
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A mixture of the product from part (i) (0.24 g) and 5% palladium/carbon (25 mg) in methanol (20 ml) was hydrogenated at 3.5 bars and 21° for 3 hours. The catalyst was filtered off and the filtrate was evaporated to give the title compound, (0.21 g), m.p. 196°-197° (from ethyl acetate/hexane).
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:3][C:4]#[N:5].[CH3:12][NH:13][NH2:14]>C(O)C>[CH3:12][N:13]1[C:4]([NH2:5])=[CH:3][C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:14]1
Reactant: N#CCC(=O)c1ccccn1
Reactant: CNN
Solvent: CCO
Product: Cn1nc(-c2ccccn2)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of crude 3-oxo-3-(2-pyridyl)propanenitrile (48.6 g, 331 mmol) in ethanol (500 mL) was added methyl hydrazine (25 g, 543 mmol). The resulting mixture was stirred for about 30 min at rt and then heated at about 75° C. for about 18 h. After cooling to rt the reaction mixture was concentrated in vacuo. The residue was treated with toluene (300 mL). The formed solid was collected by filtration and washed with toluene (150 mL). The solid was dried under vacuum to give 1-methyl-3-(2-pyridyl)pyrazol-5-amine (36.2 g, 208 mmol, 63%). 1H-NMR (CDCl3, Bruker 400 MHz) δ 3.62 (3H, s); 5.34 (2H, br s); 5.90 (1H, s); 7.21 (1H, m); 7.73 (1H, dt, J=10 Hz, 2 Hz); 7.83 (1H, dt, J=10 Hz, 1 Hz); 8.51 (1H, dt, J=6 Hz, 2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.C1C=CC=CC=1.C[Si]([C:24]#[N:25])(C)C.P(Cl)(Cl)(Cl)=O>[I-].[Zn+2].[I-].N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[C:24]#[N:25])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(C#N)=CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 7-methoxy-1-tetralone (39.65 g, 0.23 mol), zinc iodide (1.73 g, 5.4 mmol), and benzene (100 mLs) was added trimethylsilylcyanide (25.0 g. 0.25 mol). The mixture was stirred overnight at room temperature. Pyridine (350 mL) was added and phosphorous oxychloride (100 mL) was then added dropwise, with a slight temperature increase. The mixture was heated to reflux and held for 6 hr. TLC showed one mid-Rf spot for the desired product. The mixture was stirred overnight at room temperature. The mixture was carefully poured onto ice/hydrochloric acid (about 1.5 liter of 10% HCl). The total volume was 2 liters. This mixture was extracted with ethyl acetate (3×500 mLs), the organics combined and washed with water (2×500 mLs) and then brine (500 mLs). The ethyl acetate was dried over magnesium sulfate and evaporated off provide a liquid which on standing solidified. This crude solid was slurried in hexane and filtered to give 31.3 g (74%) of a tan solid. Some of this material, was purified by silica gel chromatography (10% ethyl acetate-hexanes) to provide a solid: mp 47–49° C.; 1H NMR (DMSO-d6): δ 2.44–2.50 (2H, m), 2.72 (2H, t, J=8.4 Hz), 6.81 (1 H, d, J=2.6 Hz), 6.90 (1H, dd, J=2.9 Hz, J=8.2 Hz), 7.17–7.19 (2H, m); MS m/z 168 ([M−H]−);
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28]1(B(O)O)[CH2:30][CH2:29]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1([PH+](C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([CH:28]4[CH2:30][CH2:29]4)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: [Pd+2]
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(C4CC4)c23)C1
Temperature: 80 °C
Yield: 29 %

Procedure:
A suspension of Intermediate 1a (200 mg) obtained in Example 1-1, Step A, cyclopropylboronic acid (57 mg, Aldrich), anhydrous potassium phosphate (372 mg, Aldrich), and tricyclohexylphosphonium tetrafluoroborate (33 mg, Aldrich) in toluene (2 ml) was added with palladium acetate (10 mg, Wako Pure Chemical Industries), and the mixture was stirred at 80° C. with heating for 14 hours under a nitrogen gas atmosphere. The reaction mixture was cooled to room temperature, and then added with ethyl acetate (5 ml), and the insoluble solids were removed by filtration through Celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (53 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.Br[C:16]1[CH:17]=[C:18]([C:21]#[N:22])[S:19][CH:20]=1>>[CH3:11][CH:9]1[O:8][C:7]([CH3:13])([CH3:12])[C:6]2[CH:14]=[C:2]([C:16]3[CH:17]=[C:18]([C:21]#[N:22])[S:19][CH:20]=3)[CH:3]=[CH:4][C:5]=2[NH:10]1
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Reactant: N#Cc1cc(Br)cs1
Product: CC1Nc2ccc(-c3csc(C#N)c3)cc2C(C)(C)O1

Procedure:
Prepared according to the procedure for Example 13 from 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine and 4-bromo-2-thiophenecarbonitrile. An off-white solid: mp 175-176° C.; 1H-NMR (DMSO-d6) δ 8.39 (d, 1H, J=1.5 Hz), 8.13 (d, 1H, J=1.5 Hz), 7.47 (d, 1H, J=1.9 Hz), 7.36 (dd, 1H, J=8.4, 1.9 Hz), 6.59 (d, 1H, J=8.4 Hz), 6.41 (s, 1H), 4.78 (m, 1H), 1.51 (s, 3H), 1.47 (s, 3H), 1.28 (d, 3H, J=5.4 Hz); MS (ESI) m/z 285 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:10]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:10][NH:1][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCNCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
3-Aminopropanol (1.5 g, 20 mmol) was dissolved in dry DMF and treated with 3,4-dichlorobenzyl chloride (2.62 ml, 19 mmol) followed by anhydrous potassium carbonate (1.38 g, 10 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was partitioned between 1M HCl and dichloromethane, the layers separated and the aqueous phase washed with dichloromethane. The aqueous phase was adjusted to pH 12 with 1M NaOH, and extracted with dichloromethane. The organic extract was dried (MgSO4) and evaporated to afford the title compound as a colourless oil (0.96 g 22%); δH (CDCl3) 1.68-1.77 (2H, m), 2.87 (2H, t, J=5.7 Hz), 3.75 (2H, s), 3.80 (2H, t, J=5.3 Hz), 7.12-7.41 (3H, m); MS (ES+) 234 (5%, MH+), 159 (100).
Reaction SMILES: BrC1C=C2C(=CC=1)C(CC(O)=O)OCC2.O.Cl.Cl.C1(CCN2CCN(C3C=CC=CC=3OC)CC2)C2C(=CC=CC=2)CCO1.[CH2:45]([O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[N:54]1[CH2:59][CH2:58][N:57]([C:60](=O)[CH2:61][CH:62]2[C:71]3[C:66](=[CH:67][C:68]([Br:72])=[CH:69][CH:70]=3)[CH2:65][CH2:64][O:63]2)[CH2:56][CH2:55]1)[CH3:46]>>[CH2:45]([O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[N:54]1[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][CH:62]2[C:71]3[C:66](=[CH:67][C:68]([Br:72])=[CH:69][CH:70]=3)[CH2:65][CH2:64][O:63]2)[CH2:56][CH2:55]1)[CH3:46]
Reactant: CCOc1ccccc1N1CCN(C(=O)CC2OCCc3cc(Br)ccc32)CC1
Agent: COc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Agent: Cl
Agent: O=C(O)CC1OCCc2cc(Br)ccc21
Solvent: O
Product: CCOc1ccccc1N1CCN(CCC2OCCc3cc(Br)ccc32)CC1

Procedure:
(6-Bromoisochroman-1-yl)acetic acid (EXAMPLE 22, LXVIII) is coupled with 2-ethoxyphenylpiperazine (XI) and the resulting amide, 1-(2-ethoxyphenyl)-4-[2-(6-bromoisochroman-1-yl)]acetyl piperazine (LXIII, 3.7 mmol) is reduced following the general procedure of EXAMPLE 50 making non-critical variations, to give the title compound, IR (neat) 2816, 1501, 1480, 1448, 1240, 1143, 1124, 1046, 1110 and 748 cm-1 ; NMR (300 MHz, CDCl3) 7.31-7.26, 7.00-6.90, 6.85°6.83, 4.78, 4.14-4.03, 3.78-3.70, 3.13, 3.00-2.90, 2.13, 1.99, 1.45; CMR (75 MHz, CDCl3) 151.37, 141.19, 137.0, 136.1, 131.5, 129.1, 126.4, 122.5, 120.8, 119.8, 117.9, 112.2, 74.2, 63.4, 62.6, 54.6, 53.5, 50.4, 33.0, 28.7 and 14.8δ; HRMS Calcd for C23H29N2O2Br1 =444.1413, found=444.1400.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27]C)[CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([S:29][CH3:30])[NH:11]1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([S:29][CH3:30])[NH:11]1
Reactant: COc1cccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(SC)c-3c(=O)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CSc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3cccc(O)c3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 101.1 %

Procedure:
To a stirred solution of 55 mg (0.11 mmol) of 1-(2,4,6-trichlorophenyl)-3-(methylthio)-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of CH2Cl2 was added 1 mL (1 mmol) of 1 M boron tribromide in CH2Cl2. The solution was stirred 35 min. at ambient temperature, and it was then cooled to 0° C. The reaction was quenched with 4 mL of 1 M aq. HCl. The mixture was poured into water and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure to afford 52 mg (98%) of 1-(2,4,6-trichlorophenyl)-3-(methylthio)-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid, m.p. 264-266° C. Mass spec. Calc'd for C19H13N4O2SCl3: 465.9825(M)+. Found: 465.9798.