Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][CH2:19][CH2:20][CH2:21][OH:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>ClCCl.C(N(CC)CC)C>[CH2:11]([O:18][CH2:19][CH2:20][CH:21]=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCOCc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCCOCc1ccccc1
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
Under nitrogen, a solution of DMSO (8.4 mL, 118 mmoles) in dry dichloromethane (125 mL) is cooled to -60° C., and oxalyl chloride (5 mL, 59 mmoles) in CH2Cl2 (40 mL) is added slowly. After stirring for 5 min at -50° C., 3-benzyloxy-1-propanol (14), 8.9 g, 53.7 mmoles) in CH2Cl2 (27 mL) is added at -60° C. Stirring is continued for 15 min, then triethylamine (47 mL) is added slowly at -60° C. After 5 min at this temperature, the mixture is allowed to warm up to room temperature. After addition of 0.5N HCl and phase separation, the organic phase is washed with water until neutral. Drying (Na2SO4) and evaporation gives the crude aldehyde as an oil: 10.6 g. Distillation under vacuum gives pure 15: 6.54 g (74%), bp 170° C. (15 mm Hg).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:10]2=[O:18])=[N:6][C:5]=1[CH3:19])(=O)[CH3:2].COC(OC)[N:23]([CH3:25])C.O.[NH2:29]N>CN(C)C=O>[CH:15]1([CH2:14][N:11]2[CH2:12][CH2:13][N:9]([C:7]3[S:8][C:4]([C:1]4[CH:2]=[CH:25][NH:23][N:29]=4)=[C:5]([CH3:19])[N:6]=3)[C:10]2=[O:18])[CH2:17][CH2:16]1
Reactant: CC(=O)c1sc(N2CCN(CC3CC3)C2=O)nc1C
Reactant: NN
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1-c1cc[nH]n1
Temperature: 110 °C
Yield: 76 %

Procedure:
To a solution of 1-(5-acetyl-4-methylthiazol-2-yl)-3-(cyclopropylmethyl)-imidazolidin-2-one (0.24 g, 0.85 mmol) in N,N-dimethylformamide (10 mL) was added N,N-dimethylformamide dimethyl acetal (0.20 mL, 1.50 mmol). The reaction mixture was heated for 17 hours at 110° C., followed by the addition of hydrazine monohydrate (0.20 mL, 4.11 mmol). The reaction mixture was heated for another 10 minutes at 110° C. and concentrated in vacuo. The residue was washed with water and triturated with ethyl acetate and the title compound was obtained as a white solid in 76% yield (0.20 g): mp 169-171° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 12.8 (s, 1H), 7.74 (br s, 1H), 6.40 (d, J=3.0 Hz, 1H), 3.98-3.92 (m, 2H), 3.62-3.57 (m, 2H), 3.05 (d, J=7.2 Hz, 2H), 2.36 (s, 3H), 0.95-0.84 (m, 1H), 0.49-0.43 (m, 2H), 0.21-0.17 (m, 2H); 1H NMR (75 MHz, DMSO-d6) δ 156.0, 155.5, 142.5, 103.3, 48.2, 42.5, 42.4, 16.9, 9.3, 3.6; MS (ES+) m/z 304.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[C:22]([CH3:34])[N:23]2[CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:19][CH:18]=1.[Cl-].[Cl-].C([Al+2])C>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:12]([C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:13])=[C:22]([CH3:34])[N:23]2[CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)Cl)c2ccccc12
Reactant: COc1ccc2cc(C)n(CCN3CCOCC3)c2c1
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3ccc(C)c4ccccc34)c(C)n(CCN3CCOCC3)c2c1
Temperature: 25 °C

Procedure:
To a solution of 4-methyl-1-naphthoyl chloride (11 mg, 0.055 mmol) and 4-(2-(6-methoxy-2-methyl-1H-indol-1-yl)ethyl)morpholine (15 mg, 0.055 mmol) in 1 mL CH2Cl2 at −70° C. was added dropwise ethyl aluminum dichloride (70 μL, 0.12 mmol, 1.8 M in toluene). The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and cold H2O, and the aqueous layer extracted twice with ethyl acetate. The combined organic extract was washed successively with H2O, 10% K2CO3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 10% MeOH in CH2Cl2 to give CBX006 (4 mg, 0.009 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.46 (s, 3H), 2.50-2.63 (m, 4H), 2.72 (t, J=7.1 Hz, 2H), 2.81 (s, 3H), 3.73 (t, J=4.5 Hz, 4H), 3.87 (s, 3H), 4.23 (t, J=7.1 Hz, 2H), 6.72 (dd, J=8.7 Hz, 2.2 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 7.38 (d, J=7.1 Hz, 1H), 7.44-7.54 (m, 2H), 7.58 (t, J=7.6 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 8.19 (d, J=8.4 Hz, 1H). MS m/z 443.4 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[CH:7]2.Cl.[O:15]=[C:16]1[NH:25][C:24]2[N:23]=[CH:22][C:21](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:20][C:19]=2[CH2:18][CH2:17]1>>[CH3:1][N:2]([CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[CH:7]2)[C:28](=[O:29])[CH:27]=[CH:26][C:21]1[CH:22]=[N:23][C:24]2[NH:25][C:16](=[O:15])[CH2:17][CH2:18][C:19]=2[CH:20]=1
Reactant: CNCc1ccc2c(ccn2C)c1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: Cl
Product: CN(Cc1ccc2c(ccn2C)c1)C(=O)C=Cc1cnc2c(c1)CCC(=O)N2
Yield: 65.1 %

Procedure:
According to the procedure of Example 35g, (methyl-(1-methyl-1H-indol-5-ylmethyl)-amine (155 mg, 0.89 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride (229 mg, 0.90 mmol), were coupled to give crude product. Purification by column chromatography (silica gel, 5% MeOH/CH2Cl2) gave the title compound (217 mg, 65%) as a red solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.63-10.62 (m, 1H), 8.36-8.33 (m, 1H), 8.06 (s, 1H), 7.56-7.51 (m, 1H), 7.43-7.19 (m, 4H), 7.08-7.01 (m, 1H), 6.38 (s, 1H), 4.85-4.67 (m, 2H), 3.76 (s, 3H), 3.06-2.85 (m, 5H), 2.54-2.52 (m, 2H); ESI MS m/z 375 [C22H22N4O2+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39]([CH3:42])(=[O:41])=[O:40])[C:23]=1[CH3:43].Cl.O1CCOCC1>CN1C(=O)CCC1>[F:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:23]([CH3:43])[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[S:39]([CH3:42])(=[O:40])=[O:41])=[N:25]2)=[CH:30][CH:29]=1
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure L using 6-morpholino-2′,3′,5′,6′-tetrahydrospiro-[indoline-3,4′-pyran] (76 mg, 0.28 mmol) (described herein), 4-chloro-7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (97 mg, 0.28 mmol) (described herein), 4.0 M hydrochloric acid in 1,4-dioxane (0.07 mL, 0.28 mmol), and NMP (0.476 mL). After purification 1-(7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran] was obtained as an orange solid. Compound is rotameric. 1H NMR (400 MHz, chloroform-d) δ ppm 8.16-8.30 (1H, m), 7.90 and 8.00 (1H, m), 7.75-7.85 (1H, m), 7.63-7.75 (2H, m), 7.42-7.53 (1H, m), 7.28-7.39 (1H, m), 7.06-7.18 (1H, m), 6.25-6.40 (1H, m), 5.65 and 5.81 (1H, m), 4.21 (1H, m), 3.85-4.09 (3H, m), 3.69-3.83 (5H, m), 3.63 (1H, m), 3.46-3.59 (1H, m), 3.16 (1H, s), 2.91-3.13 (6H, m), 2.09-2.24 (2H, m), 1.95 (2H, m), 1.89 (1H, m), 1.66-1.79 (1H, m). Mass Spectrum (ESI) m/e=588 (M+1).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([Cl:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1=O>C(O)C>[NH2:34][CH:35]1[CH2:38][N:37]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([Cl:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:36]1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(Cl)cc1F
Reactant: NC1CNC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(Cl)cc1F
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To 300 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3-chloro-5-fluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidone, and the mixture was stirred at 90° C. for 30 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 95 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].Br[CH2:15][CH2:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])(=[O:22])[O:19][CH2:20][CH3:21]>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:15][CH2:16][CH2:17][P:18](=[O:22])([O:23][CH2:24][CH3:25])[O:19][CH2:20][CH3:21])[CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4]
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: CCOP(=O)(CCCBr)OCC
Product: CCOP(=O)(CCCn1cnc2c1c(=O)n(C)c(=O)n2C)OCC

Procedure:
The title substance was prepared from 1,3-dimethylxanthine and diethyl 3-bromopropanephosphonate analogously to Example 1.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>CN(C=O)C>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([SH:1])=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1ccc(S)nc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)c1ccc(S)nc1
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
To a solution of 6-mercaptonicotinic acid (0.85 g, 5.48 mmol) in 50 mL of DMF was added 4-fluoroaniline (1.0 mL, 11.0 mmol) and 2-ethyoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ, 1.6 g, 6.6 mmol). The mixture was stirred for 30 minutes and the volatiles removed in vacuo. The resulting residue was diluted with ethyl acetate to yield a light tan solid that was isolated by vacuum filtration to give 0.63 g (47%) of the titled compound: 1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.28 (m, 1H), 7.83 (m, 1H), 7.68 (m, 2H), 7.33 (m, 1H), 7.15 (m, 2H); MS (EI) m/z 247.05 (M−H)−.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([CH3:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].C(OC([NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4][N:3]3[CH2:1][CH3:2])=[C:8]([CH3:16])[C:9]=2[F:15])[CH2:30]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2c(C)c(F)c(F)c(F)c21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2c(C)c(F)c(N3CCC(N)C3)c(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A mixture of 0.36 g (1.25 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.26 g (1.39 mmol) of 3-(t-butoxycarbonyl) aminopyrrolidine, 0.38 g (3.76 mmol) of triethylamine, and 20 mL of acetonitrile was refluxed for 5 hours, then stirred at room temperature overnight. The solids were collected by filtration and washed with acetonitrile and ether. The crude product was dissolved in 5 mL of 6N hydrochloric acid and 5 mL of glacial acetic acid and stirred for 5 hours at room temperature. The solution was concentrated to a solid which was suspended in water, made basic (pH 12), filtered through a fiberglass pad, and neutralized (pH 6.8). The solids were collected by filtration, washed with water, and dried in vacuo to give 0.32 g of white solid, mp 218°-220° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][C:5]1[N:10]=[C:9](F)[N:8]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[N:6]=1>O1CCCC1>[NH2:4][C:5]1[N:10]=[C:9]([N:2]([CH3:3])[CH3:1])[N:8]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[N:6]=1
Reactant: Nc1nc(F)nc(OC(F)(F)F)n1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)c1nc(N)nc(OC(F)(F)F)n1
Temperature: 22 °C
Reaction time: 8 h

Procedure:
5.0 g (0.111 mol) of dimethylamine were passed over the course of 20 minutes into a stirred solution of 11 g (0.055 mol) of 2-amino-4-fluoro-6-trifluoromethoxy-1,3,5-triazine in 150 ml of tetrahydrofuran at 0° C. The mixture was stirred at 0° C. for one hour and at 22° C. overnight. Concentration, washing with water and drying yielded 9.9 g (80.7% of theory) of the title compound of melting point 114-118° C. (decomposition).
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH2:12][CH2:11]2>C(Cl)(Cl)(Cl)Cl>[Br:2][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH2:12][CH2:11]2
Reactant: OCCc1ccc2c(c1)CCC2
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCCc1ccc2c(c1)CCC2
Temperature: 0 °C
Yield: 54 %

Procedure:
Phosphorous tribromide (3.5 ml) was added, dropwise, to an ice-cooled solution of 5-(2-hydroxyethyl)indane (prepared as described in FR-2,139,628) (14.0 g) in carbon tetrachloride (100 ml) and the mixture was heated under reflux for 2 hours, quenched with ice-water and partitioned between dichloromethane and 10% aqueous sodium carbonate solution. The organic layer was washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using dichloromethane as eluant. Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a pale yellow oil, (10.5 g, 54%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:13]([O:20][CH3:21])=[C:14]([OH:19])[CH:15]=[C:16]([F:18])[CH:17]=1.[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[CH3:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(=O)C>[CH3:8][C:7]([N:6]1[C:2]2[N:1]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([O:29][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:31]([CH3:38])[CH:32]=3)[C:17]3[C:16]([F:18])=[CH:15][C:14]([OH:19])=[C:13]([O:20][CH3:21])[C:12]=3[C:3]=2[C:4]([CH3:11])=[N:5]1)([CH3:9])[CH3:10]
Reactant: Cc1cc(C=O)ccc1OCc1ccccc1
Reactant: COc1c(O)cc(F)cc1-c1c(C)nn(C(C)(C)C)c1N
Solvent: CC(=O)O
Product: COc1c(O)cc(F)c2c(-c3ccc(OCc4ccccc4)c(C)c3)nc3c(c(C)nn3C(C)(C)C)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To 3-[5-amino-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-4-yl]-5-fluoro-2-(methyloxy)phenol (150 mg, 0.51 mmol) was added 4-benzyloxy-3-methylbenzaldehyde (115 mg, 0.51 mmol) and acetic acid (2 mL). The mixture was heated to 120° C. and stirred overnight. The acetic acid was removed in vacuo. The residue was purified by flash chromatography (70% hexanes, 30% ethyl acetate) to provide 3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-3H-pyrazolo[3,4-c]isoquinolin-8-ol (207 mg, 0.42 mmol, 81% yield) as an orange foam. 1H NMR (400 MHz, CDCl3): δ 7.52-7.35 (m, 7H), 6.99 (br d, 1H), 6.85 (d, 1H), 5.17 (s, 2H), 3.82 (s, 3H), 2.89 (s, 3H), 2.39 (s, 3H), 1.88 (s, 9H); MS (EI) for C30H30FN3O3: 500 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:19]=1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([Cl:47])[C:33]=1[OH:48]>CO>[ClH:31].[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)[CH:19]=2)=[CH:3][C:2]([C:36]2[CH:35]=[C:34]([Cl:47])[C:33]([OH:48])=[C:32]([Cl:31])[CH:37]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Nc1cccc(CCN2CCCC2)c1)C1CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Solvent: CO
Product: Cl
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1cccc(CCN2CCCC2)c1)C1CC1

Procedure:
Following general procedure F, (6-bromo-4-(3-(2-(pyrrolidin-1-yl)ethyl)phenylamino)quinolin-3-yl)(cyclopropyl)methanone (41 mg, 0.088 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (38 mg, 0.13 mmol) and the desired compound was dissolved in methanol (4 mL) and HCl (2 mL, 1.25 M in methanol). The mixture was concentrated to obtain the desired product (47 mg, 86% over two steps) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.45 (s, 1H), 8.22 (dd, J=8.8, 1.9 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.88 (s, 1H), 7.65-7.58 (m, 1H), 7.57-7.54 (m, 1H), 7.48 (s, 1H), 7.41-7.31 (m, 1H), 7.20 (s, 2H), 3.69-3.65 (m, 2H), 3.45-3.38 (m, 2H), 3.19-3.12 (m, 2H), 3.11-3.07 (m, 2H), 2.93-2.86 (m, 1H), 2.15-2.11 (s, 2H), 2.05-2.01 (s, 2H), 1.24-1.16 (m, 4H); ESI MS m/z 546 [C31H29Cl2N3O2+H]+; HPLC 97.8% (AUC), tR=10.83 min.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9]C)=[C:4]([CH3:11])[CH:3]=1.B(Br)(Br)Br.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:11])[CH:3]=1
Reactant: COc1cc(C)c(F)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(F)c(C)cc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
9.7 g of 4-fluoro-2,5-dimethylanisol was dissolved in 100 ml of dichloromethane and 76 ml of boron tribromide (1.0M dichloromethane solution) was added to the solution at 0° C. The resulting mixture was brought to room temperature, stirred for one hour, and poured into ice-water. 300 ml of ethyl acetate was added to the resultling mixture. The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate and brine successively, dried over magnesium sulfate. After the desiccant was filtered off, the resulting mixture was evaporated. The resulting crude product was purified by silica gel column chromatography to give 8.5 g of the title compound as a pale brown oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:7]([C:8]2[CH:13]=[C:12]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:6]=[C:5]([O:22][C:23]([F:31])([F:30])[CH:24]([F:29])[C:25]([F:28])([F:27])[F:26])[CH:4]=1.ClC1C=CC=C(C(OO)=[O:40])C=1>C(Cl)(Cl)Cl>[F:21][C:9]1[CH:10]=[C:11]([CH3:20])[C:12]([S:14]([CH2:15][C:16]([F:19])([F:18])[F:17])=[O:40])=[CH:13][C:8]=1[N:7]1[C:3]([NH:2][CH3:1])=[CH:4][C:5]([O:22][C:23]([F:30])([F:31])[CH:24]([F:29])[C:25]([F:26])([F:27])[F:28])=[N:6]1
Reactant: CNc1cc(OC(F)(F)C(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CNc1cc(OC(F)(F)C(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 1 h
Yield: 96.8 %

Procedure:
0.4 g of 5-methylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole was dissolved in 10 mL of chloroform, and 190 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 1 hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.4 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)-5-methylaminopyrazole.
Reaction SMILES: [C:1]([Si:5]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[O:6][CH:7]1[CH:11]([CH2:12][O:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:53][Si:54]([Mg]Cl)([CH3:56])[CH3:55].[CH2:59](OCC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([Si:5]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[O:6][C:7]1([CH2:53][Si:54]([CH3:56])([CH3:59])[CH3:55])[CH2:8][CH2:9][CH:10]=[C:11]1[CH2:12][O:13][C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](OC1CC=C(OS(=O)(=O)C(F)(F)F)C1COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)[Mg]Cl
Reactant: CCOCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)[Si](OC1(C[Si](C)(C)C)CCC=C1COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
The enolate compound of formula (X) obtained in Example 1-1 (33.5 g, 45.1 mmol) was dissolved in diethylether (335 ml). Tetrakis(triphenylphosphine)palladium (2.6 g, 2.25 mmol) was added thereto at room temperature and cooled to 0° C. To the resulting mixture, 1 M trimethylsilyl magnesium chloride (90.2 ml, 90.2 mmol) was added and stirred at room temperature for 1 hr. After completion of the reaction, the resulting mixture was cooled to 0° C. The cooled mixture was quenched with saturated sodium bicarbonate (335 ml) and filtered through Celite. The resulting solid was washed with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and condensed under a reduced pressure. The material thus obtained was purified with column chromatography to obtain the title compound (26.99 g, yield: 87.4%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([O:34][CH3:35])[CH:29]=2)=[CH:22][N:21]=1)([O-])=O>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[C:30]([O:34][CH3:35])[CH:29]=3)=[CH:22][N:21]=2)[CH:6]=1)[CH3:1]
Reactant: COc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)ccn1
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Solvent: c1ccncc1
Product: COc1cc(Cc2cnc(NCCSCc3cc(CN(C)C)ccn3)[nH]c2=O)ccn1
Yield: 61.9 %

Procedure:
A solution of 2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamine (1 g) and 2-nitroamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone (1.23 g) was refluxed in pyridine (6 ml) for 10 hours, concentrated in vacuo and chromatographed on silica gel column eluted with ethyl acetate-ethanol-28% W:W aqueous ammonia (by volume 10:15:2). Recrystallisation from acetonitrile:ether (1:5) gave 2-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone (1.21 g) m.p. 65°-74° C.