Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[N:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][C:69](O)=[O:70])=[C:64]([F:72])[CH:63]=1>CN(C)C(=O)C>[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][C:69]([NH:1][C:2]2[CH:3]=[CH:4][N:5]([CH3:27])[C:6]3[C:7]=2[CH:8]=[N:9][C:10]2[N:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:18][CH:17]=[C:12]4[NH:13][C:14](=[O:16])[C:15]=3[C:11]=24)=[O:70])=[C:64]([F:72])[CH:63]=1
Reactant: CN1C=CC(N)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: O=C(O)Cc1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN1C=CC(NC(=O)Cc2ccc(Cl)cc2F)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1

Procedure:
A stock solution of Example 14e and N,N-diisopropylethylamine (0.11 M and 0.33 M in N,N-dimethylacetamide, respectively, 350 μL, 0.038 mmol Example 14e and 0.11 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.13 M in N,N-dimethylacetamide, 350 μL, 0.046 mmol), and 2-(4-chloro-2-fluorophenyl)acetic acid (0.40 M in N,N-dimethylacetamide, 113 μL, 0.050 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to yield the title compound as an impure mixture. The material was dissolved in methanol (1 mL) and manually injected into the HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0036 g (19%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.52 (d, J=2.75 Hz, 1H), 8.43 (d, J=2.75 Hz, 1H), 7.76 (s, 1H), 7.47 (t, J=8.24 Hz, 1H), 7.42 (dd, J=9.77, 1.83 Hz, 1H), 7.30 (dd, J=8.09, 1.68 Hz, 1H), 7.07 (s, 1H), 6.87 (m, 2H), 6.58 (m, 2H), 4.61 (s, 2H), 4.05 (s, 3H), 3.82 (s, 2H). MS (APCI+) m/z 532.0 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH3:38])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19]Br)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[SH:39][C:40]1[NH:41][CH:42]=[CH:43][N:44]=1.[H-].[Na+].O>CN(C=O)C.C(OCC)C>[OH:1][CH:2]([CH3:38])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][S:39][C:40]2[NH:41][CH:42]=[CH:43][N:44]=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]
Reactant: Sc1ncc[nH]1
Reactant: CCCOc1c(OCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(OCCSc2ncc[nH]2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of trans-2-[3-(2-hydroxy-n-propylsulfonyl)-4-n-propoxy-5-(2-bromoethoxy)phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (47 mg, 0.07 mmol)(Example 19A) in DMF (250 mL) was added to a mixture of 2-mercaptoimidazole (25 mg, 0.25 mmol) and NaH (56%; 10 mg, 0.25 mmol) in DMF (0.5 mL) under nitrogen, and the mixture was stirred at room temperature for 30 min. Water (5 mL) and ethyl ether (5 mL) were added, and the mixture was stirred for another 5 min. The ethereal layer was separated, dried over MgSO4, and filtered. The filtrate was evaporated to a residue, which was purified by preparative TLC (EtOAc) to give the title compound: Rf 0.5; MS, m/z 636 M+. ; NMR (CDCl3) δ 1.02 (t, CH2CH2CH3), 1.24 (d, CH2CHOHCH3), 1.85 (m, CH2CH2CH3), 2.0 and 2.49 (2 m, H-3 and H-4), 3.42 (m, CH2S), 3.54 (m, CH2CHOH) 3.84 and 3.88 (2 s, 3 OCH3), 4.18 (m, CH2CH2S), 4.3 (m, CH2CHOH), 4.38 (t, CH2CH2CH3), 5.22 (m, H-2 and H-5), 6.62 (s, C5ArH), 6.96 (s, NH), 7.1 (s, imidazole), 7.32 and 7.50 (2 d, J=1.5 Hz, C2ArH).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]([CH3:15])([CH3:14])[C:6](=O)[CH:7]=[C:8](SC)[S:9][CH3:10].CS>C(O)C>[C:5]([C:6]1[CH:7]=[C:8]([S:9][CH3:10])[NH:3][N:2]=1)([CH3:15])([CH3:14])[CH3:4]
Reactant: NN
Reactant: CSC(=CC(=O)C(C)(C)C)SC
Agent: CS
Solvent: O
Solvent: CCO
Product: CSc1cc(C(C)(C)C)n[nH]1
Yield: 48 %

Procedure:
Hydrazine hydrate (4 g, 3.9 ml) was added dropwise to a cooled solution of the product of Example 1 (15 g) in ethanol (75 ml). The reaction mixture was refluxed until evolution of methyl mercaptan ceased (2 hours), and allowed to cool. Most of the ethanol was evaporated off, and the residue was pitched into water, and ether extracted. The ethereal solution was dried over magnesium sulphate, and evaporated to give a pale yellow solid, which was recrystallised from 1:1 benzene/60°-80° petrol to give 3-t-butyl-5-(methylthio)pyrazole, 6.0 g, (48% yield), melting point 142°-4°.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:15]([CH:17]=[C:18]([NH:20][C:21]([CH:23]4[CH2:25][CH2:24]4)=[O:22])[N:19]=3)[CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.C(OCC)(=O)C>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:15]([CH:17]=[C:18]([NH:20][C:21]([CH:23]4[CH2:24][CH2:25]4)=[O:22])[N:19]=3)[CH:16]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1cn2cc(Oc3ccc([N+](=O)[O-])nc3)ccc2n1)C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cn1
Yield: 44.7 %

Procedure:
A mixed solution of N-{6-[(6-nitropyridin-3-yl)oxy]imidazo[1,2-a]pyridin-2-yl}cyclopropanecarboxamide (184 mg, 0.542 mmol), reduced iron (173 mg, 2.95 mmol) and ammonium chloride (315 mg, 5.89 mmol) in ethanol (2 mL) and water (0.5 mL) was stirred at 80° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, and filtered through celite. Water was added to the filtrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-÷ethyl acetate/methanol=95/5) to give the title compound (75 mg, 45%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=[N:5]1)[CH3:3].[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C>C(O)(=O)C>[F:15][C:7]1[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1ccnn1C(C)C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(F)cnn1C(C)C
Temperature: 100 °C

Procedure:
A microwave vial was charged with ethyl 1-(1-methylethyl)-1H-pyrazole-5-carboxylate (0.15 g) and Selectfluor™ (0.38 g) followed by acetonitrile (3 ml) and acetic acid (1 ml). The mixture was heated at 100° C. under microwave irradiation for 180 min. Selectfluor™ (0.076 g) was added and the mixture heated at 100° C. under microwave irradiation for 60 min. Further Selectfluor™ (0.15 g) was added and the mixture heated at 100° C. under microwave irradiation for 60 min. Further Selectfluor (0.38 g) was added and the mixture heated at 100° C. under microwave irradiation for 60 min. The solvent was removed in vacuo and the residue was partitioned between DCM (15 ml) and water (15 ml) and separated using a hydrophobic frit. The aqueous layer was extracted with dichloromethane (2×5 ml) and the combined organic layers were concentrated in vacuo. Purification by chromatography on silica gel (20 g silica cartridge), eluting with a gradient of 0-50% DCM in cyclohexane over 20 minutes gave the title compound (100 mg) as a colourless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[CH2:12]([N:14]=[C:15]=[S:16])[CH3:13]>>[CH2:12]([NH:14][C:15]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[S:16])[CH3:13]
Reactant: CCN=C=S
Reactant: NCCNCc1cnccn1
Product: CCNC(=S)NCCNCc1cnccn1

Procedure:
Reacting N-(2-pyrazinylmethyl)ethylenediamine with ethyl isothiocyanate by the procedure of Example 3 and chromatographing gives N-ethyl-N'-[2-(2-pyrazinylmethylamino)ethyl]thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3 gives N-cyano-N'-ethyl-N"-[2-(2-pyrazinylmethylamino)ethyl]guanidine.
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH3:10])[C@@H:3]([C:5]([N:7]([CH3:9])[CH3:8])=[O:6])[NH2:4].S=[C:13]1[CH2:17][S:16][C:15](=[O:18])[NH:14]1>C(O)C>[OH:1][C:2]([CH3:11])([CH3:10])[C@@H:3]([C:5]([N:7]([CH3:9])[CH3:8])=[O:6])[NH:4][C:13]1[CH2:17][S:16][C:15](=[O:18])[N:14]=1
Reactant: O=C1NC(=S)CS1
Reactant: CN(C)C(=O)[C@@H](N)C(C)(C)O
Solvent: CCO
Product: CN(C)C(=O)[C@@H](NC1=NC(=O)SC1)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the crude product containing 3-hydroxy-N,N-dimethyl-L-valinamide obtained in C) in ethanol (5 mL) was added 4-thioxothiazolidin-2-one (380 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (300 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([C:6]1(O)[C:15]2[CH:14]=[N:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[CH2:5].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:19][N:2]([CH3:1])[CH2:3][C:4]([C:6]1[C:15]2[CH:14]=[N:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]=1)=[CH2:5]
Reactant: C=C(CN(C)C)C1(O)CCCc2cc(OC)ncc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C=C(CN(C)C)C1=CCCc2cc(OC)ncc21

Procedure:
The 11β-alkyl compounds are produced by reacting 7-aza-6-methoxy-1-tetralone with a solution containing butyl lithium and 2-bromo-3-dimethylaminopropene to yield N,N-di-methyl-N-(2-[5,6,7,8-tetrahydro-8-hydroxy-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine. The hydroxyl substituent is removed with a phosphorous oxyhalide, such as phosphorous oxychloride in pyridine or in concentrated sulfuric acid, to yield the N,N-dimethyl-N-(2-[5,6-dihydro-3-substituted-isoquinol-8-yl]alk-2-en-1-yl)amine. For example, N,N-dimethyl-N-(2-[5,6,7,8-tetrahydro-8-hydroxy-3-methoxyisoquinol-8-yl]-prop-2-en-1-yl)amine is contacted with phosphorous oxychloride in pyridine to obtain N,N-dimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine. Quaternarization of the amines with an alkyl halide, e.g. methyl iodide, yields the quaternary salts, which are subsequently reacted with silver oxide and then with 2-(lower alkyl)cyclopentane-1,3-dione to yield the appropriate 5,6-dihydro-3-substituted-8-[3-(2-methyl-1,3-dioxocyclopent-2-yl)alk-1-en-2-yl]isoquinoline. In that manner, the aforementioned N,N-dimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine is treated with methyl iodide to afford the corresponding trimethyl ammonium iodide. Subsequent treatment with silver oxide and 2-(lower alkyl)cyclopentane-1,3-dione produces 5,6-dihydro-3-methoxy-8-[3-(2-methyl-1,3-dioxocyclopent-2-yl)-prop-1-en-2-yl]isoquinoline. Cyclization of the diketones is effected conveniently with sulfuric acid to afford the corresponding dl-2-aza-3-substituted-11β-methylestra-1,3,5(10),8(14),9(11),15-hexaen17-ones. Representative thereof is the formation of dl-2-aza-3-methoxy-11α-methylestra-1,3,5-(10), 8(14), 9(11), 15-hexaen-17-one upon contacting the aforementioned isoquinoline derivative with sulfuric acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C(=[NH:28])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl>C1(C)C=CC=CC=1.O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:28][C:2]1[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CCc1cc(Br)cc2c1OCC2(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(N)cc2c1OCC2(C)C

Procedure:
Following general procedure D and using 5-bromo-3,3-dimethyl-7-ethyl-2,3-dihydro-benzofuran (Compound 9, 1.2 g, 4.72 mmol obtained substantially in accordance with J Med. Chem. 1998, 41, 1124-1137), benzophenone imine (0.94 g, 5.2 mmol), sodium-tert-butoxide (0.63 g, 6.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.020 g, 0.021 mmol) and (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.040 g, 0.064 mmol) in 10 mL of anhydrous toluene, followed by hydrolysis of the intermediary imine with 2M hydrochloric acid in tetrahydrofuran, the title compound was obtained as an oil (0.7 g, 78%). 1H NMR (300 MHz, CDCl3): δ 6.37 (d, 1H, J=2.3 Hz), 6.35 (d, 1H, J=2.3 Hz), 4.17 (s, 2H), 3.15 (br s, 2H), 2.54 (q, 2H, J=7.6 Hz), 1.30 (s, 6H), 1.20 (t, 3H, J=7.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[H-].[Na+].Br[CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34].C(=O)(O)[O-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:21][CH:22]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COCCOCCBr
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COCCOCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6.59 g (20 mmol) of N-benzyloxycarbonyl-tyrosine-methyl ester is dissolved in 25 ml of anhydrous N,N-dimethylformamide and mixed at 0° C. under argon with 0.81 g (20.5 mmol) of sodium hydride dispersion (60% in mineral oil). The batch is allowed to stir for 10 minutes, then 3.75 g (20.5 mmol) of 1-bromo-2-(2-methoxyethoxy)-ethane is added, the reaction temperature is allowed to increase to room temperature and stirred for another three hours. For working-up, the batch is taken up in toluene and shaken out several times against aqueous sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate, filtered and concentrated by evaporation. The oily residue is chromatographed for purification on silica gel with hexane/diethyl ether/triethylamine.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]([O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1.C([Li])CCC.[C:26]1([P:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)Cl)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-].[Li+]>O1CCCC1.CCCCCC>[C:17]([C:4]1[CH:3]=[C:2]([P:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])([CH3:20])([CH3:19])[CH3:18]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O[Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1cc(P(c2ccccc2)c2ccccc2)cc(C(C)(C)C)c1O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 107.3 %

Procedure:
A stirred suspension of 20.0 g (56 mmol) of 4-bromo-2,6-di-tert-butylphenoxy(trimethyl)silane in 80 ml of dry tetrahydrofuran at -78° C. is admixed dropwise with 38 ml (56 mmol) of a 1.55M solution of n-butyllithium in hexane. The resulting homogeneous solution is stirred for 1 hour at -78° C. and then 12.36 g (56 mmol) of diphenylchlorophosphine is added dropwise. The reaction mixture is stirred for 24 hours at room temperature, and then the suspension of lithium chloride is removed by filtration. The solvent is removed in vacuo. The residue is dissolved in 250 ml of diethyl ether and extracted (3×250 ml) with water. The organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo to give 27.8 grams of a yellow liquid. The crude product is purified by preparative HPLC (silica gel, 99:1 heptane:ethyl acetate eluent) to give 10.7 grams (41%) of a white solid, m.p. 76°-80° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10].[CH3:22][O:23][CH:24]([O:41][CH3:42])[C:25]1[C:30]([O:31][CH2:32][O:33][CH3:34])=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=[CH:27][C:26]=1[CH2:39]O>>[CH3:42][O:41][CH:24]([O:23][CH3:22])[C:25]1[C:30]([O:31][CH2:32][O:33][CH3:34])=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=[CH:27][C:26]=1[CH2:39][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])=[C:2]([F:1])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: COCOc1c(C(F)(F)F)ccc(CO)c1C(OC)OC
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(O)cc2)cc1F
Product: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCOC)c3C(OC)OC)cc2)cc1F

Procedure:
According to a method similar to Example (6-7), from allyl (3-fluoro-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (3.10 g, 10.9 mmol) obtained in Example (11-3) and [2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)phenyl]methanol (3.70 g, 12.0 mmol) obtained in Example (6-6), allyl (4′-{[2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl]oxy}-3-fluoro-1,1′-biphenyl-4-yl)acetate was obtained as a pale yellow oil (3.89 g, yield: 61%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH:28]=O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH:1]1([N:6]2[C:10]3=[N:11][C:28]([C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[O:25][CH2:24][CH2:23][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1ccccc1OCCN1CCOCC1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccccc3OCCN3CCOCC3)nc(=O)c1-2
Temperature: 120 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.95 g, 4.28 mmol), 2-[2-(4-morpholinyl)ethoxy]benzaldehyde (1.51 g) and xylenes (15 ml) was heated to 120° C. for 1 hour, then to 160° C. until the reaction was complete. The reaction mixture was then cooled to room temperature, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography eluting with ethyl acetate (100%), followed by ethanol/ethyl acetate (1/1) to afford 1-cyclopentyl-3-ethyl-6-[2-[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one (Example 11(b)), as an oil. The free base was then converted into its hydrochloride salt, which was recrystallized from ethanol and dried at 110° C. under high vacuum to afford 0.5 g of 1-cyclopentyl-3-ethyl-6-[2-[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one monohydrochloride, as an off-white powder, m.p. 235°-237° C., labelled as Example 11(c).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:12].I(C1C=CC=C(C[C:22]([O-])=[O:23])C=1CC([O-])=O)=O.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([O:23][CH3:22])=[CH:5][NH:6][C:7]2=[O:12]
Reactant: O=c1[nH]ccc2c(Cl)cccc12
Reactant: O=Ic1cccc(CC(=O)[O-])c1CC(=O)[O-]
Agent: CS(=O)(=O)O
Solvent: CO
Product: COc1c[nH]c(=O)c2cccc(Cl)c12
Yield: 87.8 %

Procedure:
To a solution of 5-chloroisoquinolin-1(2H)-one (3.8 g, 21.2 mmol) in methanol (70 ml) was added iodosobenzenediacetate (7.5 g, 23.4 mmol) followed by methane sulphonic acid (2.45 g, 25.5 mmol) at room temperature. The reaction mass was heated at reflux for 3 h. The solvent was evaporated and the residue was diluted with cold water. The precipitated solid was filtered, washed with water to get crude compound (3.9 g, 88%) as a light red colored solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.06-8.03 (d, J=12 Hz, 1H), 7.60-7.57 (d, J=12 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.01-6.99 (br s, 1H), 3.51 (s, 3H); MS: MS m/z 209.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:10]3[CH:9]([OH:18])[N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.S(=O)(=O)(O)O.[CH3:31]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:10]3[CH:9]([O:18][CH3:31])[N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1
Reactant: NC(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC1N=C(c2ccccc2)c2cc(Cl)ccc2-n2nc(C(N)=O)nc21

Procedure:
To a solution of 8-chloro-4-hydroxy-6-phenyl-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide (3/2 hydrate) in methanol is added a small amount of concentrated sulfuric acid, and the mixture is treated in the same manner as that of Example 3 to give 8-chloro-4-methoxy-6-phenyl-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide as crystals (1/3 hydrate). This product is identical with the product in Example 3 with respect to melting point and infrared absorption spectrum.
Reaction SMILES: C([N:9]1[CH2:21][C:20](=O)[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:23])[CH:17]=3)[NH:12][C:11]=2[CH2:10]1)(=O)C1C=CC=CC=1.[NH2:24]N>>[NH2:24][C:20]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:23])[CH:17]=3)[NH:12][C:11]=2[CH:10]=[N:9][CH:21]=1
Reactant: O=C1CN(C(=O)c2ccccc2)Cc2[nH]c3ccc(Cl)cc3c21
Reactant: NN
Product: Nc1cncc2[nH]c3ccc(Cl)cc3c12
Temperature: 130 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
Crude 2-benzoyl-6-chloro-1,2,3,9-tetrahydro-β-carbolin-4-one (4 g) was dissolved in 30 ml of anhydrous hydrazine and stirred at reflux (130° C. oil bath) under N2 for 6 hours, after which the reaction mixture was allowed to cool to room temperature and sit overnight. The precipitated yellow solids were removed by filtration and washed with water, 2×5 ml, to yield 785 mg (30%) of 4-amino-6-chloro β-carboline as an off white solid. Additional water was added to the combined filtrates until no further precipitation occurred. These solids were also removed by filtration to give 1.056 g (39%) of 4-amino-6-chloro β-carboline as yellow solids, (69% total yield).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:18]([O:22][C:23](=[O:48])[CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH:34][S:35]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])=[CH:33][C:28]=2[N:27]=[C:26]1[CH2:45][CH2:46][CH3:47])([CH3:21])([CH3:20])[CH3:19]>CC#N.CCOC(C)=O.O>[C:18]([O:22][C:23](=[O:48])[CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][C:32]([N:34]([S:35]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)(=[O:36])=[O:37])[CH2:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:33][C:28]=2[N:27]=[C:26]1[CH2:45][CH2:46][CH3:47])([CH3:21])([CH3:20])[CH3:19]
Reactant: BrCCCOc1ccccc1
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCCc1nc2cc(N(CCCOc3ccccc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Phenoxypropyl bromide (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column.