Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[N:28]([CH3:36])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)(=O)=O.[NH:39]1[CH:43]=[CH:42][N:41]=[CH:40]1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][CH2:6][N:39]3[CH:43]=[CH:42][N:41]=[CH:40]3)[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[N:28]([CH3:36])[C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=3)[C:11]=12
Reactant: c1c[nH]cn1
Reactant: COc1cc(-c2nn(CCOS(C)(=O)=O)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(-c2nn(CCn3ccnc3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 70 °C
Yield: 44.7 %

Procedure:
A mixture of 2-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl methanesulfonate (Intermediate 4) (0.080 g, 0.15 mmol), imidazole (0.011 g, 0.15 mmol), triethylamine (0.021 mL, 0.15 mmol), and sodium iodide (0.021 g, 0.15 mmol) in DMF (2.5 mL) was heated at 70° C. for 15 h. Imidazole (0.011 g, 0.15 mmol) was added and the reaction mixture was heated at 70° C. for 60 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Water (5 mL) was added and the resulting precipitate was collected by filtration to afford a beige solid which was taken up in hot ethyl acetate then allowed to slowly cool to ambient temperature. The filtrate was concentrated to afford N2-(4-{4-amino-1-[2-(1H-1-imidazolyl)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide (0.034 g, 0.067 mmol): RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.45 min. MS: M+ 508.2.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(C#N)cc2)CC1
Yield: 22 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 140, intermediate a)), 4-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as an off-white foam (22%).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.[ClH:43]>ClCCl.C(#N)C>[ClH:43].[ClH:43].[F:41][C:2]([F:1])([F:42])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1
Reactant: COCCOc1ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Product: COCCOc1ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(7-(2-methoxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.20 g, 0.33 mmol) in dichloromethane (1 mL) was added hydrochloric acid (5-6M in 2-propanol; 8.3 mL, 0.61 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed under reduced pressure, and the solid obtained was suspended in acetonitrile (3 mL) and stirred at ambient temperature for 5 minutes. The solid formed was collected by vacuum filtration to give the title compound (0.17 g, 91%). LCMS APCI (+) m/z 487 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[C:24]2[Cl:30]>>[Cl:30][C:24]1[C:23]2[C:27](=[CH:28][CH:29]=[C:21]([NH:20][C:17]([C:9]3[CH:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]=3[CH3:16])=[O:19])[CH:22]=2)[NH:26][N:25]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2)CC(=O)N1C
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc(Cl)cc2)CC(=O)N1C

Procedure:
The title compound was prepared from the product of Example 56, Step 2 and 5-amino-3-chloroindazole using the method described in Example 56, Step 3. MS (ES+) m/e 430 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][C:10](O)=O.P(Cl)(Cl)([Cl:22])=O.CN(C)[CH:27]=[O:28]>>[Cl:22][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:9]=1[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: O=C(O)CC(Sc1ccccc1)c1ccccc1F
Reactant: O=P(Cl)(Cl)Cl
Product: O=CC1=C(Cl)c2ccccc2SC1c1ccccc1F

Procedure:
As in example 18, but using 5.4 g 3-(2-fluorophenyl)-3-phenylmercapto-propionic acid, 40 ml dimethylformamide and 15 ml phosphorous oxychloride. After hydrolysis a precipitate forms which is filtered, washed with water and dried over phosphorous pentoxide. The residual solid is recrystallized in hexane and pure yellow crystalline 4-chloro-2'-fluoro-3-formyl-thioflav-3-ene is obtained; m.p. 119°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.[CH3:22]CN=C=NCCCN(C)C.C1C=C[C:36]2[N:41]([OH:42])N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:22][O:42][N:41]([CH3:36])[C:19]([C:18]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)=[O:21]
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.2 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (70 mg, 0.176 mmol) and N—O-dimethyl-hydroxylamine (21 mg, 0.21 mmol) in DMF (3 mL) was added EDCI (40 mg, 0.21 mmol), HOBt (28 mg, 0.21 mmol) and DIPEA (70 μL, 0.42 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate then water, dried (Na2SO4), filtered and concentrated in vacuo then azeotroped with diethyl ether to give a pale tan foam (35 mg, 45%). LCMS (Method A): RT=9.63 min, [M+H]+=441. 1H NMR (DMSO-d6, 400 MHz) 13.16 (1 H, s), 8.25 (1 H, s), 7.59-7.51 (2 H, m), 7.34-7.28 (2 H, m), 7.14 (1 H, d, J=8.55 Hz), 6.71 (1 H, t, J=8.73 Hz), 3.38 (3 H, s), 3.10 (3 H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([Cl:29])=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[Cl:21][C:22]1[N:27]=[C:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)[C:25]([Cl:29])=[CH:24][N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3nc(Cl)ncc3Cl)cc2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A mixture of (5)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (100 mg, 0.36 mmol), 2,4,5-trichloropyrimidine (66 mg, 0.36 mmol) and diisopropylethylamine (70 mg, 0.54 mmol) was dissolved in 2-propanol (1.5 ml) and stirred at 80° C. overnight. For work-up most of the solvent was evaporated, then aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The aqueous phase was re-extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (20 g silica gel, 10 to 30% ethyl acetate in heptane) to yield a white solid (141 mg, 92%). MS (ISP): 425.1 ([{35Cl}M+H]+), 427.1 ([{37Cl}M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[CH2:32][CH2:33][CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[CH2:32][CH2:33][CH2:34][NH:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: O=CCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCN1C(=O)c2ccccc2C1=O
Reaction time: 0.33 h

Procedure:
A solution of ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (1.00 g, 3.65 mmol) and 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanal (0.929 g, 4.57 mmol) under nitrogen in glacial acetic acid (10 mL) was treated with sodium triacetoxyborohydride (1.55 g, 7.31 mmol) at ambient temperature. After stirring for 20 min., the reaction was evaporated in vacuo and the residue was partitioned between EtOAc and 5% w/v aq. K2CO3. After separating the layers, the aqueous phase was diluted with sat. aq. NaCl and back-extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl, dried over MgSO4, filtered and evaporated in vacuo. The residue was dissolved in warm Et2O leaving a small residue of insolubles. The Et2O was decanted and evaporated to approximately half volume where precipitation occurred. The product was collected by filtration and dried under high vacuum: 1H NMR (d6-DMSO) δ 7.78-7.86 (4H, m), 7.73 (1H, s), 7.65 (1H, t, J=7 Hz), 7.25-7.30 (2H, m), 7.06-7.12 (3H, m), 4.18 (2H, q, J=7 Hz), 3.90 (2H, s), 3.65 (2H, t, J=6 Hz), 3.24 (2H, q, J=5 Hz), 1.80-1.89 (2H, m), 1.24 (3H, t, 7 Hz); ES+ MS: 462 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:11]([O:12]C)=[C:10]([F:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].B(Br)(Br)Br.C(OCC)(=O)C.O>C(Cl)Cl>[F:1][C:2]1[C:11]([OH:12])=[C:10]([F:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(F)c(OC)c1F
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(F)c(O)c1F
Yield: 72.5 %

Procedure:
In 20 ml of methylene chloride was dissolved 2.00 g of methyl 2,4-difluoro-3-methoxy-benzoate, and to the solution was added 12.8 ml of a 1 M solution of boron tribromide in methylene chloride at -30° C., after which the resulting mixture was stirred under ice-cooling for 2 hours. The reaction mixture was added to a mixed solvent of 150 ml of ethyl acetate and 150 ml of water and the organic layer was separated. The organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a column chromatography (eluent; n-exane:ethyl acetate=3:1) to obtain 1.35 g of methyl 2,4-difluoro-3-hydroxybenzoate as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=O.[Br:20][C:21]1[C:22]([C:27]2[NH:31][N:30]=[CH:29][N:28]=2)=[C:23]([NH2:26])[S:24][CH:25]=1>>[Br:20][C:21]1[C:22]([C:27]2[NH:31][N:30]=[CH:29][N:28]=2)=[C:23]([NH:26][C:17](=[O:19])[CH2:16][N:3]2[C:4]3[C:9](=[N:8][C:7]([C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:24][CH:25]=1
Reactant: O=C(O)Cn1c(=O)ccc2nc(C(F)(F)F)ccc21
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cn1c(=O)ccc2nc(C(F)(F)F)ccc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetic acid (66 mg, 0.245 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (30 mg, 0.122 mmol) according to protocol A. Retention time (min)=5.195, method [7], MS (ESI) 499.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.26-8.21 (m, 3H), 7.96 (d, J=8.9 Hz, 1H), 7.17-7.13 (m, 2H), 5.37 (s, 2H).
Reaction SMILES: [CH:1]1([N:5]2[C:9]([NH2:10])=[CH:8][C:7]([CH3:11])=[N:6]2)[CH2:4][CH2:3][CH2:2]1.[CH:12]1([C:15](=O)[CH2:16][C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1>C1C=CC=CC=1>[CH:1]1([N:5]2[C:9]3[N:10]=[C:15]([CH:12]4[CH2:13][CH2:14]4)[CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]=3[C:7]([CH3:11])=[N:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc(N)n(C2CCC2)n1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCC1
Reaction time: 4 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 33 using 1-cyclobutyl-3-methyl-1H-pyrazol-5-amine (400 mg, 2.65 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (487 mg, 2.65 mmol) and benzene (50 mL), wherein the reaction time was 4 h. The final product was collected as 0.556 g (70%). LCMS E-S (M+H)=300.6 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02-1.22 (m, 4 H) 1.47 (t, J=7.07 Hz, 3 H) 1.80-2.01 (m, 2 H) 2.15-2.28 (m, 1 H) 2.38-2.51 (m, 2 H) 2.70 (s, 3 H) 2.82 (td, J=9.85, 2.53 Hz, 2 H) 4.49 (q, J=7.07 Hz, 2 H) 5.32-5.57 (m, 1 H) 7.41 (s, 1 H).
Reaction SMILES: [NH2:1][C@H:2]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:24][Si:25]([CH3:28])([CH3:27])Cl.C(N(CC)CC)C>C(OCC)C>[CH3:24][Si:25]([CH3:28])([CH3:27])[NH:1][C@H:2]([C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The dibenzyl (S)-aspartate in anhydrous diethyl ether (200 ml) is cooled in an ice-bath under a nitrogen atmosphere. Trimethylchlorosilane (12.7 ml, 0.1 mole) is added to the stirred solution to give a white precipitate. Triethylamine (14.0 ml, 0.1 mole) is then added to the mixture. The cooling bath is removed and the mixture is stirred at room temperature (22°-25° C.) for 2 hrs. The mixture is then filtered directly into a 3-neck, 1.0 liter, round bottom flask fitted with a sintered glass funnel, magnetic stirrer, and a vacuum-nitrogen inlet. This operation is carried out under a blanket of nitrogen, care being taken to exclude atmospheric moisture. The sintered glass funnel is replaced by a stopper and the ether is evaporated under vacuum with stirring to provide dibenzyl (S)-N-trimethylsilylaspartate (35.5 g, 0.092 mole) as a slightly hazy oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@@H:12]1[CH2:14][C@H:13]1[C:15](OCC)=[O:16].[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@@H:12]1[CH2:14][C@H:13]1[CH2:15][OH:16]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1c(F)ccc2nn(C)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc2c([C@@H]3C[C@H]3CO)c(F)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of trans-ethyl 2-(5-fluoro-2-methyl-2H-indazol-4-yl)cyclopropanecarboxylate (2.00 g, 7.63 mmol) in tetrahydrofuran (76 mL) was slowly added a solution (1 M, 22.9 ml, 22.9 mmol) of diisobutylaluminum hydride in hexane at −78° C., and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (1.51 g, yield 90%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.ClC[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[CH:15]=1.[C:20](=O)([O-])[O-].[Na+].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:20][C:15]2[C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[S:12][CH:11]=2)[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: ClCc1cc2ccccc2s1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1Cc1csc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
A stirred suspension of 5-chloropyrimidin-2-one (522 mg), 2-chloromethyl benzothiophene (910 mg), anhydrous sodium carbonate (850 mg) and benzyltrimethylammonium chloride (15 mg) in dry N,N-dimethylformamide (15 ml) was stirred at room temperature for 1 h and then at 80° C. for 45 min. The reaction mixture was then diluted with water (25 ml) and extracted with ethyl acetate (75 ml, 2×25 ml). The combined extracts were washed with water (2×50 ml), dried (MgSO4) and evaporated to a pale yellow solid which was crystallised twice from ethyl acetate to give white crystals of the title pyrimidinone (760 mg), m.p. 138°-140° C., λmax (EtOH) 227.5 nm (ε 32,540), 290.5 nm (ε 3,150), 298.5 nm (ε 3,760), 333.5 nm (ε 2,660).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][C:25](O)=[O:26])=[CH:22][N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1.O1CCCC1.B.O1CCCC1.Cl>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][CH2:25][OH:26])=[CH:22][N:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2CC(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2CCO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a mixture of {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}acetic acid (0.52 g) and tetrahydrofuran (10 mL) was added borane-tetrahydrofuran (1.02 M tetrahydrofuran solution, 2.0 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (5 mL) and water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethanol as colorless crystals (0.31 g, yield 62%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 123-124° C.
Reaction SMILES: C1(C)C=CC(S([NH:10][C:11]2[CH:19]=[CH:18][C:14]([NH:15][CH2:16][CH3:17])=[CH:13][C:12]=2[CH3:20])(=O)=O)=CC=1.[CH3:22][S:23]([NH:26][CH2:27][CH2:28]Cl)(=[O:25])=[O:24].C(=O)([O-])O.[Na+].S(=O)(=O)(O)O>C(O)(C)C.CO.O>[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([N:15]([CH2:28][CH2:27][NH:26][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:16][CH3:17])=[CH:13][C:12]=1[CH3:20]
Reactant: CCNc1ccc(NS(=O)(=O)c2ccc(C)cc2)c(C)c1
Reactant: CS(=O)(=O)NCCCl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: CCN(CCNS(C)(=O)=O)c1ccc(N)c(C)c1

Procedure:
A mixture of 7g of 4-(N-p-toluenesulfonyl)amino-3-methyl-N-ethylaniline, 4g of β-methanesulfonamidoethyl chloride, 2.1g of sodium hydrogen carbonate, 16g of water and 30ml of methanol were refluxed for 5 hours, and then 16g of sulfuric acid were added thereto and the entire reaction system was again refluxed. Next, the reaction solution was condensed to half the original volume and 300ml of isopropyl alcohol were added thereto to separate crystals. The crystals were filtered out and dried to obtain 1.5g of 4-amino-3-methyl-N-(β-methanesulfonamidoethyl)-N-ethylaniline. sesquisulfate. H2O.
Reaction SMILES: CC1C=C[C:5]([S:8]([N-]Cl)(=O)=O)=CC=1.O.O.O.[Na+].Cl.[Br:18][C:19]1[C:20]([NH:34][CH:35]([CH3:37])[CH3:36])=[N:21][C:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29](C)=[CH:28][C:27]=2S)=[N:23][CH:24]=1>C(#N)C.C(OCC)(=O)C>[Br:18][C:19]1[C:20]([NH:34][CH:35]([CH3:37])[CH3:36])=[N:21][C:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:8][CH3:5])=[CH:28][CH:27]=2)=[N:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Reactant: Cc1ccc(Nc2ncc(Br)c(NC(C)C)n2)c(S)c1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ccc(Nc2ncc(Br)c(NC(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.36 g (4.8 mmol) of chloramine-T trihydrate (Aldrich) are added to a suspension of 1.56 g (4.0 mmol) of the hydrochloride of 5-bromo-N4-isopropyl-N2-(4-methyl-sulphanylphenyl)pyrimidine-2,4-diamine in 20 ml of acetonitrile at room temperature. The mixture is stirred at room temperature for 16 hours and then diluted with ethyl acetate. The mixture is filtered with suction and the filter cake is washed with ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated. The resulting residue is purified by HPLC:
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]2[NH:27][N:28]=[C:29]([NH2:30])[C:21]=12>O1CCCC1>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]2[NH:27][N:28]=[C:29]([NH:30][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[C:21]=12
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Cc1cc(C)c2c(N)n[nH]c2n1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(NC=C3C(=O)Nc4ccccc43)n[nH]c2n1

Procedure:
The named compound is prepared by substituting 4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2118 gms. of 4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-ylamine by refluxing in tetrahydrofuran (2.5 mL).