Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH:11]=[CH:10][C:9]=2[NH2:22])=[CH:4][CH2:3]1.[K+].[C:25]([C:27]1[N:28]=[C:29]([C:40]([O-])=[O:41])[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=1)#[N:26].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:1][C:2]1([CH3:23])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH:11]=[CH:10][C:9]=2[NH:22][C:40]([C:29]2[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[C:27]([C:25]#[N:26])[N:28]=2)=[O:41])=[CH:4][CH2:3]1
Reactant: COc1ccc(-c2ccc(N)c(C3=CCC(C)(C)CC3)c2)cn1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCC(C)(C)CC3)c2)cn1

Procedure:
The title compound was prepared from 2-(4,4-dimethyl-cyclohex-1-enyl)4-(6-methoxy-pyridin-3-yl)-phenylamine (as prepared in the previous step, 16.4 mg, 0.0530 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 23 mg, 0.074 mmol), PyBroP (40 mg, 0.084 mmol) and DIEA (23 μL, 0.13 mmol) according to the procedure in Example 11, step (f) (20 mg, 68%). Mass spectrum (ESI, m/z): Calcd. for C31H39N5O3Si, 558.2 (M+H), found 558.3.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[NH:4][N:3]=1.Br[CH2:13][CH2:14][CH3:15]>>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([CH2:13][CH2:14][CH3:15])[N:3]=1
Reactant: CCCBr
Reactant: Cc1ccc2[nH]nc(I)c2c1
Product: CCCn1nc(I)c2cc(C)ccc21
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield from 3-iodo-5-methyl-indazole and 1-bromopropane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.92 (3H, t, J=7.2 Hz), 1.90-1.96 (2H, m), 4.32 (2H, t, J=7.2 Hz), 7.22-7.28 (3H, m).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].[Br:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=[O:26])[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20].N1CCOCC1>CO>[Br:12][C:13]1[CH:14]=[C:15]([CH:23]2[C:10]3[C:2](=[C:3]4[CH:4]=[CH:5][N:6]([CH3:11])[C:7]4=[CH:8][CH:9]=3)[O:1][CH:25]([OH:26])[CH2:24]2)[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20]
Reactant: Cn1ccc2c(O)cccc21
Reactant: COc1cc(C=CC=O)cc(Br)c1OC
Solvent: CO
Solvent: C1COCCN1
Product: COc1cc(C2CC(O)Oc3c2ccc2c3ccn2C)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
A mixture of 4-hydroxy-N-methyl indole (11 mg, 0.075 mmol) and 3-(3-bromo-4,5-dimethoxyphenyl)-propenal (20 mg, 0.074 mmol) in methanol (0.6 ml) containing morpholine (7 μl, 0.08 mmol) was held under reflux for 2 h and the mixture was allowed to stir at room temperature overnight. The solvent was evaporated to dryness. The residue was dissolved in acetic acid (0.8 ml) and water was added until the mixture became turbid. It was held at 50° C. for 10 minutes. It was cooled and added slowly to saturated sodium bicarbonate solution. The product was extracted with dichloromethane, washed with saturated sodium chloride solution and dried over sodium sulphate. The solvent was evaporated and the crude product was passed through a bond-elute (hexane:ethyl acetate=9:1 and 8:2 as eluents), giving the title compound (16 mg, 52%). 1H NMR (acetone-d6): 7.09 and 7.08 (d each, J=2.9 Hz; 1H), 7.00 and 6.98 (d each, J=1.7 Hz; 1H), 6.95 and 6.93 (d each, J=1.7 Hz; 1H), 6.85 and 6.83 (d each, J=8.6 Hz; 1H), 6.55 and 6.50 (d each, J=8.5 Hz; 1H), 6.42 and 6.41 (d each, J=3.3 Hz; 1H), 6.15 (fine split doublet, J=6.8 Hz) and 6.08 (d, J=4.9 HZ) (1H), 5.67-5.70 and 5.54-5.58 (m each, 1H), 4.34 (overlapping dd, J=5.8, 10.1 Hz; 1H), 3.84, 3.81, 3.78 and 3.75 (s each, 9H), 2.38-2.43 and 2.09-2.25 (m each, 2H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:48](=[O:49])[N:30]2[CH:31]([C:35]([O:37]CC3C=CC([N+]([O-])=O)=CC=3)=[O:36])[C:32](=O)[CH2:33][C@H:29]12)[CH3:27].[CH3:50][N+:51]1([CH3:57])[CH2:55][CH2:54][C@H:53]([SH:56])[CH2:52]1>C(#N)C>[CH3:50][N+:51]1([CH3:57])[CH2:55][CH2:54][C@H:53]([S:56][C:32]2[CH2:33][C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:48](=[O:49])[N:30]3[C:31]=2[C:35]([O-:37])=[O:36])[CH2:52]1
Reactant: C[N+]1(C)CC[C@H](S)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3CC[N+](C)(C)C3)C[C@H]12
Reaction time: 1 h
Yield: 18.4 %

Procedure:
183 μl of diisopropylethylamine and 218 μl of diphenylphosphoryl chloride were simultaneously added, whilst ice-cooling, to a solution of 348 mg of 4-nitrobenzyl (5R, 6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate dissolved in 4 ml of dry acetonitrile and the mixture was stirred at the same temperature for 1 hour. At the end of this time, a solution of 338 mg of the crude (3S)-1,1-dimethyl-3-mercaptopyrrolidinium salt prepared as described in Example 5-(1) in 4 ml of dry acetonitrile and 209 μl of diisopropylethylamine were added to the mixture, whilst ice-cooling. The mixture was then allowed to stand at the same temperature for 1 hour and then for two days in a refrigerator. At the end of this time, the reaction mixture was washed by decantation with diethyl ether. The resulting product was dissolved in a mixture of 30 ml of tetrahydrofuran and 30 ml of a 0.1M phosphate buffer (pH 7.0) and hydrogenated at room temperature for 2.5 hours in the presence of 400 mg of 10% w/w palladium-on-charcoal. At the end of this time, an insoluble material was removed by filtration and the filtrate was washed with diethyl ether. The aqueous layer was concentrated by evaporation under reduced pressure and then subjected to column chromatography through Diaion HP-20AG (Mitsubishi Chemical Industries, Inc.). The title compound was prepared as a crude product from the fractions eluted with water. The crude compound was then further purified by chromatography through a Lobar column (Merck Co. LiChroprep RP-8, size B) and the fractions eluted with 5% by volume aqueous methanol were collected, concentrated by evaporation under reduced pressure and lyophilized to afford 60 mg of the title compound.
Reaction SMILES: FC1C(C)=CC(O)=C(C=1)C=O.C([O-])([O-])=O.[Cs+].[Cs+].BrCC#N.[F:22][C:23]1[C:32]([CH3:33])=[CH:31][C:26]([O:27][CH2:28][C:29]#[N:30])=[C:25]([CH:34]=O)[CH:24]=1>C(#N)C>[F:22][C:23]1[C:32]([CH3:33])=[CH:31][C:26]2[O:27][C:28]([C:29]#[N:30])=[CH:34][C:25]=2[CH:24]=1
Reactant: Cc1cc(OCC#N)c(C=O)cc1F
Agent: Cc1cc(O)c(C=O)cc1F
Agent: N#CCBr
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Cc1cc2oc(C#N)cc2cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 5-fluoro-2-hydroxy-4-methylbenzaldehyde (500 mg, 3.24 mmol) in 10.5 ml acetonitrile in a microwave vial was added Cs2CO3 (1.268 g, 3.885 mmol), followed by 2-bromoacetonitrile (271 ul, 3.885 mmol). The reaction mixture was stirred at room temperature for 1 hr. LC/MS showed that all the starting material was converted to ring opened intermediate, 2-(4-fluoro-2-formyl-5-methylphenoxy)acetonitrile. LCMS retention time=1.19 minutes (R×NMON-Acidic:ZQ12); MS (m+1)=194.1. Then, the reaction vial was sealed, and the mixture was heated to 150° C. on microwave for 20 min. This reaction was repeated 20 times. The combined reaction mixture was filtered, washed with acetonitrile, the filtrate was concentrated. The residue was purified by silica gel flash chromatography (100% heptane-10% ethyl acetate/heptane) to give 5-fluoro-6-methylbenzofuran-2-carbonitrile (5.55 g). 1H NMR (400 MHz, DMSO-d6) δ 2.38 (d, J=2.2 Hz, 3H), 7.62 (d, J=9.3 Hz, 1H), 7.72 (d, J=6.0 Hz, 1H), 8.04 (d, J=1.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl.C(OCC)C>[Br:18][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1
Reactant: Cc1ccc(F)c(OC(=O)c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(Oc1cc(CBr)ccc1F)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of benzoic acid 2-fluoro-5-methyl-phenyl ester (CAB02145, 2.47 g, 10.0 mmol), N-bromo-succinimide (1.96 g, 11.0 mmol) and dibenzoylperoxide (10 mg) in carbon tetrachloride (25 mL) was heated to reflux for 2 h (TLC monitored). After cooling to room temperature, water (50 mL) and diethyl ether (100 mL) were added. The organic layer was separated, washed with brine (20 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:hexane, 1:25, Rf: 0.28). Yield: 1.80 g (58%), white solid. 1H-NMR (400 MHz, CDCl3) δ=4.48 (s, 2H, —CH2Br), 7.18 (dd, J=9.8, 8.6 Hz, 1H), 7.28 (ddd, J=8.6, 4.3, 2.3 Hz, 1H), 7.34 (dd, J=7.0, 2.3 Hz, 1H), 7.50-7.55 (m, 2H), 7.64-7.69 (m, 1H), 8.18-8.23 (m, 2H). LRMS (FAB+): 229.1 (95), 309.0 (100, [M+]+). Found: C, 54.1, H, 3.22%; C14H10BrFO2 (309.13) requires C, 54.39, H, 3.26%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:53]=[CH:54][CH:55]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]5)=[C:23]([O:40][CH3:41])[CH:22]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:52])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:53]=[CH:54][CH:55]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:29][CH2:28]5)=[C:23]([O:40][CH3:41])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:52])=[N:7]1
Reactant: COc1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cccc(F)c5)c4C)c3c2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 63.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy phenyl)piperazine-1-carboxylate (140 mg, 0.18 mmol) was hydrolyzed by lithium hydroxide (23 mg, 0.554 mmol), THF/Methanol/water (5/5/2 ml) to afford 70 mg of the titled compound. MS: m/z=610.9 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[CH:26][CH:27]=4)[N:19]=3)[CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2ccc3nc(N)nn3c2)cc1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4ccc(-c5ccc(S(C)(=O)=O)cc5)cn4n3)cc2)CC1

Procedure:
[6-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 6-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.173 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (54.0 mg, 0.212 mmol) with 2,2′-Bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a yellow solid (0.009 g, 10%). MP=260-264° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.68-8.67 (m, 1H), 8.09-8.04 (m, 2H), 7.79-7.74 (m, 2H), 7.68 (dd, J=9.1, 1.8 Hz, 1H), 7.55 (d, J=9.3 Hz, 1H), 7.51-7.46 (m, 2H), 7.00-6.95 (m, 2H), 6.64 (s, 1H), 3.20-3.15 (m, 4H), 3.11 (s, 3H), 2.62-2.58 (m, 4H), 2.36 (s, 3H). MS=463 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[CH:16]1([N:21]=[C:22]=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:22](=[O:23])[NH:21][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CO
Reactant: O=C=NC1CCCC1
Solvent: Cc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)NC1CCCC1
Temperature: 120 °C

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol (0.120 g, 0.45 mmol) was mixed with cyclopentyl isocyanate (0.075 g, 0.68 mmol) in toluene and the reaction was heated to 120° C. overnight. After cooling, the crude material was submitted directly to silica gel purification to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([NH:18][CH2:19][C:20](O)=[O:21])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([O:13][C:11]([NH:18][CH2:19][C:20]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:21])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-nitrophenol (1.0 g, 7.19 mmol) in CH2Cl2 (20.0 mL) was added N-Boc glycine (1.38 g, 7.91 mmol) and EDC HCl (2.05 g, 10.785 mmol) and the reaction was stirred at ambient temperature for 24 h. The reaction mixture was diluted with CH2Cl2 and washed with water and saturated brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound as a light brown gummy material that was used in the next step without further purification (1.1 g): 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=9.2 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 5.07 (br, 1H), 4.20 (s, 2H), 1.47 (s, 9H); ESIMS m/z 296.27 ([M+H]+).
Reaction SMILES: C(N(CC)[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:6]=1[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:32][C:33]([CH3:35])=[O:34].[OH-].[K+].Cl>C1COCC1.O1CCOCC1.C(OCC)(=O)C>[F:12][C:7]1[C:8]([F:11])=[CH:9][CH:10]=[C:5]2[C:6]=1[CH:13]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[C:33]([CH3:35])([CH3:32])[O:34][C:4]2=[O:19]
Reactant: CCN(CC)C(=O)c1ccc(F)c(F)c1Cn1ccnc1
Reactant: CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(C)OC(=O)c2ccc(F)c(F)c2C1n1ccnc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
N,N-Diethyl-3,4-difluoro-2-imidazol-1-ylmethyl-benzamide (0.832 g, 2.695 mmol) is dissolved in THF (15 mL) and cooled to −78° C. LHMDS (1.0M in THF, 4.0 mL, 4.0 mmol) is added over 5 min, resulting in a dark brown solution. After another 10 min, acetone (0.79 g, 13.47 mmol) is added. After 30 min, the mixture is quenched with a pH 7 aqueous buffer and extracted twice with ethyl acetate. The combined organic phase is dried over magnesium sulfate and concentrated in vacuo to give a brown residue, which is redissolved in dioxane (25 mL). 1M aqueous KOH (13.5 mL, 13.5 mmol) is added. The solution is heated to 65° C. After 3 h, the mixture is cooled with a water bath, and acidified to pH=1 with conc. HCl. The mixture is heated to 65° C. After 1 h, the mixture is diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate and filtered through a cotton plug. Concentration in vacuo gives a residue which is purified by silica gel flash chromatography (methylene chloride-methanol, 49:1 to 97:3) to give 5,6-difluoro-4-imidazol-1-yl-3,3-dimethyl-isochroman-1-one as an oil, which is converted to its HCl salt to give a solid; MS (ESI) m/z 279.1 (M+H); 1H NMR (400 MHz, MeOD) of the HCl salt, δ ppm 1.34 (s, 3 H), 1.61 (s, 3 H), 6.29 (s, 1 H), 7.46 (br. s., 1 H), 7.53 (br. s., 1 H), 7.66-7.75 (m, 1 H), 8.20 (ddd, J=8.8, 4.6, 1.6 Hz, 1 H), 8.79 (br. s., 1 H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[NH:11][N:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[NH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n[nH]c3nc(N)sc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1nc2[nH]nc(-c3ccc(O)cc3)c2s1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
To a stirring suspension of 3-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]thiazol-5-ylamine (100 mg, 0.41 mmol) in CH2Cl2 (2 mL) at −78° C. was added a 1 M solution of BBr3 in CH2Cl2 (2.1 mL, 2.1 mmol) dropwise. The reaction mixture was slowly warmed up to room temperature overnight, then it was quenched with water, and the reaction mixture was neutralized to pH 6 with 1 N aqueous NaOH. The resulting precipitate was filtered, washed with water, and dried in vacuo to afford 70 mg (74% yield) of 3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]thiazol-5-ylamine as an off-white solid. 1H-NMR (d6-DMSO) δ: 9.8 (broad s, 1H), 7.57 (broad s, 2H), 7.42 (d, 2H), 6.85 (d, 2H); HPLC/MS m/z: 233.0 [MH]+.
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.C([Li])(C)(C)C.CCCCC.[F:27][C:28]1[CH:35]=[CH:34]C(C#N)=[CH:30][CH:29]=1>C1COCC1>[F:27][C:28]1[CH:35]=[CH:34][C:16]([C:15]2[N:3]=[C:4]([OH:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)=[CH:30][CH:29]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc2c(O)nc(-c3ccc(F)cc3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.5 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (500 mg, 2.259 mmol) in THF (4.52 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (1.59 ml, 2.71 mmol) and the solution was stirred for 0.5 h before addition of 4-fluorobenzonitrile (274 mg, 2.259 mmol) in THF (4.52 ml). The resulting solution was warmed to RT and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid was collected and washed with water to give 3-(4-fluorophenyl)-6-methoxyisoquinolin-1-ol (350 mg, 58% yield) as a solid after drying.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH3:18])=[C:10]([CH:14]=1)[C:11]([NH2:13])=[NH:12].[CH2:19]([CH:21]([C:26](=O)[CH2:27][CH3:28])[C:22](OC)=[O:23])[CH3:20]>>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH3:18])=[C:10]([C:11]2[NH:13][C:22](=[O:23])[C:21]([CH2:19][CH3:20])=[C:26]([CH2:27][CH3:28])[N:12]=2)[CH:14]=1
Reactant: CCCOc1ccc(-c2nnco2)cc1C(=N)N
Reactant: CCC(=O)C(CC)C(=O)OC
Product: CCCOc1ccc(-c2nnco2)cc1-c1nc(CC)c(CC)c(=O)[nH]1

Procedure:
The title compound was prepared by reacting the compound of example 8 with methyl 2-ethyl-3-oxovalerate in the same manner as that of example 1. 1H NMR (CDCl3) δ: 8.69 (1H, d), 8.51 (1H, dd), 7.05 (1H, d), 4.14 (2H, t), 2.69 (4H, m), 1.92 (2H, m), 1.31 (3H, t), 1.21 (3H, t), 1.12 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([NH:13][C:14]2([C:18](OC)=[O:19])[CH2:17][CH2:16][CH2:15]2)(=[O:12])=[O:11])=[C:5]([CH3:22])[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[OH:19][CH2:18][C:14]1([NH:13][S:10]([C:6]2[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:22])(=[O:12])=[O:11])[CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)C1(NS(=O)(=O)c2c(C)cc(OC)cc2C)CCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)NC2(CO)CCC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Methyl 1-(4-methoxy-2,6-dimethylphenylsulfonamido)cyclobutanecarboxylate (4.58 mmol, 1.0 equiv.) was dissolved in THF p.a. (40 ml) and slowly added dropwise, under nitrogen, at 0° C., to a suspension of LiAlH4 (11.4 mmol, 2.5 equiv.) in THF p.a. (20 ml). The reaction mixture was stirred for 1 hour at 25° C., then saturated Na2SO4 solution was added and the mixture was filtered off over Celite. The filtrate was concentrated and the desired product was precipitated in the form of a white solid from hexane. Yield: 92%
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C([Li])CCC.[CH2:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24](Cl)(=[O:26])=[O:25])[CH2:14][CH2:13]1>O1CCCC1.CCCCCC>[CH2:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])(=[O:26])=[O:25])[CH2:16][CH2:17]1
Reactant: O=C1CCCN1
Reactant: O=S(=O)(Cl)c1ccccc1C1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCCN1S(=O)(=O)c1ccccc1C1CCCCC1
Yield: 42.2 %

Procedure:
The operation is carried out as in Example 12, using 1.97 g of 2-pyrrolidinone in 100 cm3 of tetrahydrofuran, 15.5 cm3 of a 1.5M solution of n-butyllithium in hexane, and 6 g of (4-cyclohexyl)benzene-sulphonyl chloride [J. Am. Chem. Soc. 62, 513 (1940)] in 24 cm3 of tetrahydrofuran. 3 g of expected product is obtained.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[CH:1]1([CH2:7][NH:8][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 113.3 %

Procedure:
Cyclohexylmethylamine (2.86 mL, 2.49 g, 22.0 mmol) was added to a mixture of N-(4-fluoro-3-nitrophenyl)acetamide (3.96 g, 20.0 mmol) and sodium carbonate (4.66 g, 44 mmol) in EtOH (50 mL) at room temperature. The reaction mixture was heated for 48 h at 60° C., and diluted with H2O (800 mL). The orange solid was precipitated out and collected to give the desired title product (6.60 g, 100%). MS (ESI) (M+H)+: 292.32.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[N:5][CH:4]=1.[CH2:18]([C:25]1([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:18]([C:25]1([OH:31])[CH2:30][CH2:29][N:28]([C:11]([C:10]2[C:9]([C:6]3[CH:7]=[CH:8][N:3]=[CH:4][N:5]=3)=[N:17][CH:16]=[CH:15][CH:14]=2)=[O:13])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1cccnc1-c1ccncn1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1-c1ccncn1)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
A suspension of 2-(pyrimidin-4-yl)nicotinic acid dihydrochloride (0.24 g), 4-benzyl-4-hydroxypiperidine (0.20 g), HATU (0.50 g) and triethylamine (0.74 mL) in DMF (6 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (0.085 g).