Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[CH:3]1.[CH3:13][I:14].[C:15]1(C)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[I-:14].[CH3:1][N+:2]1[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]([CH3:13])[CH:3]=1
Reactant: CI
Reactant: Cn1cnc(-c2ccccc2)c1
Reactant: Cc1ccccc1
Product: Cn1c[n+](C)c(-c2ccccc2)c1-c1ccccc1
Product: [I-]
Yield: 98 %

Procedure:
In a 25 ml one-necked flask, there is dissolved 0.240 g (1.024 mmol) of 1-methyl-4-phenylimidazole, which was obtained according to W. Collibee et al., Tetrahedron Letters (1985), 62(6), 1595-96, in 7 ml of toluene and then 100 μl of methyl iodide are added. After 15 days of heating under reflux while adding 100 μl of methyl iodide every day, the reaction medium is concentrated under reduced pressure. The residue is taken up in 50 ml of diisopropyl ether. The precipitate formed is drained, washed twice with 5 ml of diisopropyl ether, and then dried under reduced pressure. 0.370 g (98%) of 1,3-dimethyl-4,5-diphenylimidazolium iodide is thus obtained in the form of a pale yellow solid whose characteristics are the following:
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH:14]1[CH2:15][O:16]1
Reactant: ClCC1CO1
Reactant: Oc1ccc2c(c1)CCCC2
Product: c1cc2c(cc1OCC1CO1)CCCC2

Procedure:
The title compound was prepared from 5,6,7,8-tetrahydro-naphthalen-2-ol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH:11][C:12]2[CH:16]=[CH:15][NH:14][C:13]=2[C:17]([O:19]CC)=O)=[CH:2]1.C([N:30]=[C:31]=[S:32])(=O)C1C=CC=CC=1>CO.C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][N:11]2[C:12]3[CH:16]=[CH:15][NH:14][C:13]=3[C:17](=[O:19])[NH:30][C:31]2=[S:32])=[CH:2]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCOC(=O)c1[nH]ccc1NCc1c[nH]c2ccccc12
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(Cc2c[nH]c3ccccc23)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.7 %

Procedure:
A crude mixture of ethyl 3-[(1H-indol-3-ylmethyl)amino]-1H-pyrrole-2-carboxylate (max 0.49 mmol) was added to CH2Cl2 (5 mL). A few drops of methanol were added to increase solubility. Benzoylisothiocyanate (0.072 g, 0.53 mmol) was added and the mixture was stirred at r.t. for 1 h. The mixture was concentrated in vacuo. Ammonia (7N in methanol, 3 mL) was added and the mixture was heated at 80° C. for 2 h. The mixture was concentrated and purified by preparative HPLC, obtaining the title compound (0.030 g, 21%) as a solid.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:21]([NH2:26])[CH2:22][CH:23]([CH3:25])[CH3:24].C1COCC1.[BH3-]C#N.[Na+]>CO.Cl[Ti](Cl)(Cl)Cl>[CH3:24][CH:23]([CH3:25])[CH2:22][CH2:21][NH:26][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(C)CCN
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CCNC1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
Add Ti(iPrO)4 (1.70 g, 6.00 mmol) to a suspension-of 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 805 mg, 3.00 mmol), isoamyl amine (314 mg, 3.60 mmol) and THF (10 ml) and stir overnight under a nitrogen atmosphere at ambient temperature. Treat the reaction mixture with a solution of TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol) and stir at ambient temperature for three hours before adding NaBH3CN (377 mg, 6.00 mmol) dissolved in MeOH (5 ml). After an additional three hours, quench the reaction with 2N aq. NaOH, making the suspension basic. Stir the suspension for one hour and filter through a filter aid to remove solids, washing them with EtOAc. Separate layers in the filtrate/wash and wash the organic layer with brine before drying (MgSO4) and concentrating. Purify on silica gel (5%(1N NH3/MeOH)/45% EtOAc/DCM) to obtain 491 mg of the title compound as a light yellow solid. Mass spectrum (ion spray): m/z=340 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.16 (d, 1H), 7.39 (d, 1H), 7.00 (s, 1H), 6.97-6.94 (m, 2H), 5.87 (br. S, 2H), 4.25 (t, 1H), 3.02 (m, 1H), 2.83 (m, 1H), 2.75 (t, 2H), 2.46 (m, 1H), 1.89 (m, 1H), 1.67 (m, 1H), 1.44 (m, 2H), 0.92 (d, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=3)[N:9]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:8]=2)[CH2:3][CH2:2]1>CO.[Pd]>[O:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH2:16])[CH:14]=3)[N:9]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:8]=2)[CH2:5][CH2:6]1.[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH2:16])[CH:14]=3)[N:9]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(C1=CCOCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)c(C1=CCOCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Nc1ccc2c(c1)c(C1CCOCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 3-(3,6-Dihydro-2H-pyran-4-yl)-5-nitro-1-trityl-1H-indazole (100 mg, 0.2 mmol) in methanol was added and Pd/C (10%, 20 mg). The reaction mixture was evacuated under vacuum and hydrogen gas was filled. After repeated three times the reaction was kept under hydrogen atmosphere overnight at room temperature. LCMS showed the starting material was consumed completely and both 3-(3,6-dihydro-2H-pyran-4-yl)-1-trityl-1H-indazol-5-ylamine and 3-(tetrahydro-pyran-4-yl)-1-trityl-1H-indazol-5-ylamine were obtained. The two products were separated using prep-HPLC to give both product in 60% and 40% yield respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:6]([CH2:12]Cl)=[N:7]2.O.[N:23]1[C:31](=[S:32])[C:30]2[NH:29][CH:28]=[N:27][C:26]=2[NH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:6]([CH2:12][S:32][C:31]1[N:23]=[CH:24][N:25]=[C:26]3[C:30]=1[N:29]=[CH:28][NH:27]3)=[N:7]2
Reactant: S=c1nc[nH]c2nc[nH]c12
Reactant: Cc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1c(CSc2ncnc3[nH]cnc23)nc2cccc(Cl)c2c1=O
Yield: 52.6 %

Procedure:
Prepared according to Procedure C using Intermediate 2j (200 mg, 0.626 mmol), 6-kinases -mercaptopurine monohydrate (93 mg, 0.546 mmol), K2CO3 (95 mg, 0.689 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 125 mg of an off-white solid (46%), mp 213.9° C. 1H NMR (DMSO-d6) δ: 13.53 (br s, 1H); 8.49 (s, 1H); 8.44 (s, 1H); 7.78 (t, J=7.9 Hz, 1H); 7.63 (d, J=8.2 Hz, 1H); 7.59 (d, J=7.7 Hz, 1H); 7.49 (d, J=6.9 Hz, 1H); 7.24-7.41 (m, 3H); 4.32-4.45 (m, 2H); 2.14 (s, 3H). 13C NMR (DMSO-d6) ppm: 158.9, 157.2, 154.2, 151.5, 149.7, 149.6, 143.5, 136.1, 135.9, 135.1, 133.2, 131.3, 130.3, 130.0, 129.9, 129.1, 127.6, 127.1, 117.8, 32.4, 17.5. MS (ES): m/z 438.0 (M+). Anal. calcd. for C21H15ClN6OS: C, 58.00; H, 3.48; Cl, 8.15; N, 19.32; S, 7.37. Found: C, 58.05; H, 3.38; Cl, 8.89; N, 18.38; S, 7.00.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH:12]([NH:14][NH:15][CH:16]=O)=O.[Si](Cl)(C)(C)C.CCN(CC)CC>N1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[N:4]1[CH:16]=[N:15][N:14]=[CH:12]1
Reactant: O=CNNC=O
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(F)c(-n2cnnc2)c1
Temperature: 100 °C
Yield: 37.4 %

Procedure:
A solution of 2-fluoro-5-nitroaniline (415 mg, 2.7 mmol) in pyridine (15 mL) was treated with N′-formylformohydrazide (703 mg, 7.98 mmol), and TMS-Cl (5.10 mL, 39.9 mmol) was then added dropwise. After the addition, Et3N (2.60 mL, 18.6 mmol) was added, and the reaction mixture was heated to 100° C. for 4 hours. The reaction mixture was then cooled to room temperature and concentrated to dryness. The resulting solid was suspended in H2O (25 mL) and filtered. The filtrate was extracted with EtOAc (4×20 mL), and the organics were dried (Na2SO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, hexanes to 100% EtOAc, 40 g column, 40 min. gradient) to afford Intermediate 28A (210 mg, 37.9%). HPLC: Rt=1.497 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=209.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.05 (1H, s), 9.05 (1H, s), 8.72 (1H, dd, J=6.55, 2.77 Hz), 8.39-8.45 (1H, m), 7.85 (1H, t, J=9.57 Hz).
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[C:13]([Cl:23])=[CH:14][C:15]([Cl:22])=[C:16]([C:18](=[O:21])[CH2:19][Br:20])[CH:17]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][NH:25][C:26]([NH:28][CH3:29])=[S:27]>>[BrH:20].[CH2:1]([NH:8][S:9]([C:12]1[C:13]([Cl:23])=[CH:14][C:15]([Cl:22])=[C:16]([C:18]2([OH:21])[CH2:19][S:27][C:26](=[N:25][CH3:24])[N:28]2[CH3:29])[CH:17]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=S)NC
Reactant: O=C(CBr)c1cc(S(=O)(=O)NCc2ccccc2)c(Cl)cc1Cl
Product: Br
Product: CN=C1SCC(O)(c2cc(S(=O)(=O)NCc3ccccc3)c(Cl)cc2Cl)N1C

Procedure:
2,2 g of 5'-benzylsulfamoyl-2-bromo-2',4'dichloro-acetophenone were reacted in a manner analogous to the method described in Example 10 with 0.5 g of 1,3-dimethyl-thiourea. M.p. 201° C (decomposition).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:25][C:26](C)([O-:28])C.[K+].ClCCO>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][OH:28])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)[O-]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Agent: OCCCl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(OCCO)cccc2c1Nc1ccccc1C
Reaction time: 48 h
Yield: 32.4 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)8-hydroxyquinoline (3.2 g, 10 mmol) was dissolved in tetrahydrofuran (150 ml), potassium t-butoxide (1.83 g, 15 mmol) added, stirred to dissolve, then 2-chloroethanol (1.3 ml, 20 mmol) added and the mixture heated at reflux overnight. A further portion of potassium t-butoxide (1.83 g) and of 2-chloroethanol (1.3 ml) was added and heating continued for 2 days. The tetrahydrofuran was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Recrystallization from ethyl acetate/petroleum ether gave 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline (1.18 g, 32%), m.p. 125°-127°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH3:12])=[C:5]2[CH3:13].[C:14](Cl)([Cl:16])=[O:15].[NH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[ClH:16].[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:14]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:15])=[CH:10][CH:9]=2)[C:5]([CH3:13])=[C:6]1[CH3:12]
Reactant: Cc1c(C)n(C)c2ccc(N)cc12
Reactant: O=C(Cl)Cl
Reactant: Nc1cccnc1
Product: Cc1c(C)n(C)c2ccc(NC(=O)Nc3cccnc3)cc12
Product: Cl
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield from 5-amino-1,2,3-trimethyl-1H-indole (D6), phosgene and 3-aminopyridine using a procedure similar to that in Example 1, m.p. 330° C.
Reaction SMILES: [CH3:1][CH:2]([OH:13])[CH2:3][C:4]([CH3:12])([O:6][O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:5].N1C2C(=CC=CC=2)C=CC=1.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26].Cl.N1C2C(=CC=CC=2)C=CC=1>CCCCC>[C:25](=[O:26])([O:27][CH:28]([CH3:30])[CH3:29])[O:13][CH:2]([CH3:1])[CH2:3][C:4]([CH3:12])([O:6][O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:5]
Reactant: CC(O)CC(C)(C)OOC(C)(C)C
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CCCCC
Product: CC(C)OC(=O)OC(C)CC(C)(C)OOC(C)(C)C
Reaction time: 72 h

Procedure:
A four-necked 500 ml. round-bottomed flask was equipped with a mechanical stirrer, reflux condenser surmounted by calcium chloride drying tube, addition funnel and thermometer. A solution of 19 g. (0.1 mole) 1,3-dimethyl-3-(t-butylperoxy)butyl alcohol and 13.3 g (slightly over 0.1 mole) quinoline in 250 ml. pentane was placed in the flask which was placed in a water bath at 221/2 ° C. Then 12.3 g (0.1 mole) isopropyl chloroformate was added dropwise over 5 minutes; the temperature did not rise over 23° C. Reaction was not complete after 3 days. Another 3 g. of quinoline was added, and the reaction was completed after another 3 days as indicated by the fact that no further precipitate of quinoline hydrochloride formed when an aliquot of clean pentane solution was withdrawn from the reaction mixture and allowed to stand for 15 minutes. The quinoline hydrochloride was filtered off and washed with 25 ml pentane which was added to the pentane solution. This solution was then successively washed with 25 ml. of 7% hydrochloric acid, two 50 ml. portions of water, and finally dried over sodium sulfate. After removal of drying agent and pentane, a yield of 23.8 g. (86.4%) of material found to be 1,3-dimethyl-3-(t-butylperoxy)butyl isopropyl carbonate by infrared analysis, was obtained.
Reaction SMILES: [CH3:1][CH:2]([OH:16])[CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=[CH:8][CH2:7][CH:6]=[CH:5]1.[S:17](Cl)([CH3:20])(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:1][CH:2]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH2:7][CH:8]=[CH:9]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CC1(c2ccccc2)C=CCC=C1
Solvent: c1ccncc1
Product: CC(CC1(c2ccccc2)C=CCC=C1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8 g. of α-methyl-1-phenyl-2,5-cyclohexadien-1-ethanol are dissolved in 50 ml. of pyridine and 6.4 g. of mesyl chloride are added dropwise at 0°-5° C. After stirring at room temperature for 2 hours, the mixture is worked-up as follows: The mixture is treated with ice-water and extracted with ether. The ether phase is washed with 3 N aqueous hydrochloric acid, then washed neutral, dried and concentrated. The crude product obtained is chromatographed on 100 g. of silica gel with ether/petroleum ether (1:1). There is obtained an oily product which crystallizes in the cold. After crystallization from methylene chloride/hexane, there is obtained methanesulfonic acid 1-methyl-2-(1-phenyl-2,5-cyclohexadien-1-yl)-ethyl ester having a melting point of 51°-53° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:22])[N:15]([CH2:18][CH2:19][C:20]#[N:21])[CH2:16][CH2:17][C:12]=3[C:11]([C:23]([F:26])([F:25])[F:24])=[N:10]2)=[CH:5][CH:4]=1.C(O)(=O)C>CO.[Pt]=O>[NH2:21][CH2:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][C:12]2[C:11]([C:23]([F:26])([F:25])[F:24])=[N:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:13]=2[C:14]1=[O:22]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCC#N)CC3)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCN)CC3)cc1
Yield: 85.2 %

Procedure:
3-[1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-propionitrile (0.050 g, 0.137 mmol) was dissolved in methanol (20 mL) in a Parr bottle. Platinum oxide (0.005 g, 10%) and acetic acid (5 mL) were added and the reaction was hydrogenated under pressure overnight, filtered over Celite®, washed with methanol, concentrated, and purified with reverse phase HPLC and freeze-drying to afford the title compound (0.043 g, 85%): 1H NMR (CDCl3) δ 8.22 (bs, 2H), 7.39 (d, j=8.8 Hz, 2H), 6.95 (d, j=8.8 Hz, 2H), 3.83 (s, 3H), 3.71 (t, j=6.8 Hz, 2H), 3.61–3.58 (m, 2H), 3.05 (t, j=6.8 Hz, 2H), 2.91 (bs, 2H), 1.99 (bs, 2H) ppm; Mass Spec 369.3(M+H)+.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]=O.[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[C:22]#[CH:23])[CH3:19]>O1CCOCC1>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:23]#[C:22][CH:21]([O:24][CH2:25][CH3:26])[O:20][CH2:18][CH3:19])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: C#CC(OCC)OCC
Solvent: C1COCCO1
Product: CCOC(C#CCN1CCC(NC(=O)c2ccccc2)CC1)OCC
Reaction time: 24 h

Procedure:
4-Benzamidopiperidine (62 g.) was added to a stirred suspension of 1.1 g. cupric acetate and 9.5 g. paraformaldehyde in 300 ml. dry dioxane, followed by propiolaldehyde diethylacetal (38.6 g.). Stirring was continued for 24 hours at 80° C under nitrogen. The hot reaction mixture was filtered and the filtrate was evaporated. Recrystallisation ofthe solid residue from ethyl acetate-petroleum ether (bp. 60°-80° C) gave 4-benzamido-1-(4,4-diethoxybut-2-ynyl)piperidine as colourless shining leaflets. (84.6 g.), m.p. 130° C. (Found: C, 69.5; H, 8.3; N, 8.3 C20H28N2O3 requires C, 69.7; H, 8.2; N, 8.1%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[C:4]([Cl:9])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Br)cc1Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 109 %

Procedure:
4-bromo-2-chlorophenol (1.0 g, 4.82 mmol) was dissolved in MC (30 ml), followed by addition of tert-butyldimethylsilyl chloride (1.09 g, 7.23 mmol) and imidazole (492 mg, 7.23 mmol), and then the resulting mixture was stirred at room temperature under nitrogen stream for 24 hours. The resulting reaction liquid was sequentially washed with distilled water (15 ml) and a saturated aqueous NaHCO3 solution (15 ml), and then dried over anhydrous magnesium sulfate, followed by filtration and concentration. The residue thus obtained was subjected to MPLC (5% EtOAc/Hexanes), to obtain 1.69 g of colorless oil (99%).
Reaction SMILES: [CH3:1][C:2]([CH:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O)([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4]>FC(F)(F)C(O)=O.[Pd].C(OCC)(=O)C>[CH3:1][C:2]([CH:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C(=O)OC)C(Cc1ccccc1[N+](=O)[O-])c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C)(C(=O)OC)C(Cc1ccccc1N)c1ccc(OC)cc1
Yield: 95.8 %

Procedure:
A solution of α-methyl-[2-(2-nitrophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (2.47 g, 6.38 mmol) in 24 ml of trifluoroacetic acid was catalytically hydrogenated (42 psi, 0.25 g of 10% palladium on charcoal) for 11/2 hours. The reaction suspension was filtered through a pad of Celite and concentrated in vacuo to yield a viscous brown oil. The crude product was dissolved in ethyl acetate and washed several times with saturated aqueous potassium carbonate solution. Evaporation of the ethyl acetate layer in vacuo yielded 2.27 g of a light tan solid. Recrystallization from methanol (3 crops) yielded 1.82 g of an off-white solid, melting point 165°-167° C.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]=[C:14]2[NH2:17])=[CH:9][CH:8]=1.N>ClCCl>[NH2:17][C:14]1[C:15]2[C:10](=[CH:9][CH:8]=[C:7]([OH:6])[CH:16]=2)[CH:11]=[CH:12][N:13]=1
Reactant: COc1ccc2ccnc(N)c2c1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Nc1nccc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 97.2 %

Procedure:
Boron tribromide (35 mL) in 50 mL of dichloromethane was added dropwise to a stirred solution of 7-methoxy-isoquinolin-1-ylamine (21.6 g) in 70 mL of dichloromethane at 10° C. After stirring for 4 d at ambient temperature the reaction mixture was poured on ice and the pH adjusted to pH 9 by adding concentrated aqueous ammonia. The precipitated material was collected by filtration and dried in vacuo to give 19.3 g (97%) of the title compound as a light brownish solid. M.p. 260° C. (decomp.); EI-MS: 160 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[Cl:18][C:19]1[C:20]2[CH:28]=[C:27]([N:29]([CH3:31])[CH3:30])[N:26]=[CH:25][C:21]=2[N:22]=[CH:23][N:24]=1>>[ClH:18].[CH3:30][N:29]([CH3:31])[C:27]1[N:26]=[CH:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([NH:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:9]=[CH:10]4)[C:20]=2[CH:28]=1
Reactant: CN(C)c1cc2c(Cl)ncnc2cn1
Reactant: Nc1ccc2c(cnn2Cc2ccccn2)c1
Product: CN(C)c1cc2c(Nc3ccc4c(cnn4Cc4ccccn4)c3)ncnc2cn1
Product: Cl

Procedure:
Prepared according to Procedure A from 1-(2-Pyridylmethyl)indazol-5-ylamine and 4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.75(1H,s), 9.92(1H,s), 8.62(1H,s), 8.55(1H,d), 8.24(1H,s), 8.14(1H,s), 7.75(4H,m), 7.33(1H,m), 7.08(1H,d), 5.82(2H,s), 3.20(6H,s); m/z (M+1+) 397.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1([CH3:20])[C:18]2[CH:13]([O:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[S:11]1>ClCCl>[Br:1][C:16]1[CH:17]=[C:18]2[C:10]([CH3:20])([CH3:9])[S:11][C:12](=[O:19])[CH:13]2[O:14][CH:15]=1
Reactant: CC1(C)SC(=O)C2OC=CC=C21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC1(C)SC(=O)C2OC=C(Br)C=C21

Procedure:
N-Bromosuccinimide (15.0 g, 84.3 mmol) was added to a solution of 5,6-dihydro-5,5-dimethyl-7H-thieno-[3,4-b]pyran-7-one (15.0 g, 82.6 mmol) in dichloromethane (300 mL) at 0° C., and the resultant solution was stirred for 2 h at 0° C. The solution was washed with water and dried over magnesium sulfate. The solvent was evaporated in vacuo to give the product as a dark grey solid, 15.1 g (70%), mp 63°-72° C.; IR(neat): 1694, 1558 and 1438 cm-1 : MS: m/z 261 (MH+); 1H NMR(CDCl3): δ 1.47 (s, 6H), 2.63 (s, 2H),7.99 (s, 1H).
Reaction SMILES: [OH:1][C:2]([CH3:10])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.CN(C)C=O.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23]>CCCCCC>[CH3:10][C:2]([O:1][Si:22]([CH3:25])([CH3:24])[CH3:23])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(C)(O)CCCC
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CCC(C)(CCCC)O[Si](C)(C)C
Reaction time: 8 h

Procedure:
To a stirred solution of 75.4 g (0.537 moles) of 4-hydroxy-4-methyl-1-octyne (Example 122), 104.9 g (1.54 moles) of imidazole, and 325 ml of dimethylformamide is added 65.2 g (0.60 moles) of chlorotrimethylsilane. After standing overnight the mixture is poured into 800 ml of hexane. The mixture is washed thoroughly with water followed by sodium bicarbonate solution and brine. The solution is dried over magnesium sulfate, filtered, and evaporated to give a liquid, p.m.r. spectrum, δ 1.26 (singlet, 3, CH3), 1.92 (triplet, 1, HC), 2.30 (doublet, 2, CH2).