Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:24])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]([CH3:17])[C:15]=2[CH3:16])=[O:10])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:40])=[O:39])[CH:33]=1>CN(C=O)C.O>[CH3:17][N:14]1[C:15]([CH3:16])=[C:11]([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][C:32]3[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:40])=[O:39])[CH:33]=3)=[CH:3][CH:4]=2)=[O:10])[C:12](=[O:24])[N:13]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Cc1c(C(=O)Nc2ccc(O)cc2)c(=O)n(-c2ccccc2)n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
To a solution of N-(4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1.80 g, 5.57 mmol) in DMF (35 mL) was added potassium tert-butoxide (1.87 g, 16.7 mmol). The solution was stirred at rt for 20 minutes, followed by the addition of 4-chloropicolinamide (1.046 g, 6.68 mmol). The reaction was heated at 120° C. for 3 hours, then cocentrated to 2 mL in vacuo, and diluted with water (60 mL). The precipitate was obtained by filtration, washed with water (5 mL) and dried. The crude product was washed with DCM (20 mL) to give the title compound as a brown solid (1.8 g, 73%).
Reaction SMILES: [CH2:1]([N:4]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([CH2:15][NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[N:12][C:11]=2[CH:25]=1)=[O:6])[CH2:2][CH3:3].[ClH:33].C(O)C.C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:33].[CH2:1]([N:4]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([CH2:15][NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](=[NH:41])[NH2:24])=[CH:19][CH:18]=3)=[N:12][C:11]=2[CH:25]=1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc2sc(CNc3ccc(C#N)cc3)nc2c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: CCCN(CCC(=O)OCC)C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1
Yield: 83 %

Procedure:
Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 83% of theory, C24H29N5O3 (467.59) Rf value: 0.31 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid) ##EQU6##
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]#[N:16])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][OH:20].C(N(CC)CC)C>C(O)(C)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15](=[NH:16])[NH:19][OH:20])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCN(C#N)CC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCC1CCN(C(=N)NO)CC1

Procedure:
(1-Cyano-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester (2 g, 8.36 mmol), hydroxylamine hydrochloride (3.48 g, 50.14 mmol) and triethylamine (5.92 g, 58.5 mmol) were stirred in 30 ml of isopropanol at room temperature for 4 hours. The mixture was evaporated. After addition of water (pH4) and ethyl acetate, the organic layer was separated and evaporated.
Reaction SMILES: O1CCOCC1.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:15])=[CH:12][C:13]=1[OH:14].C(=O)([O-])[O-].[Ca+2].[Cl:21][CH2:22][C:23](Cl)=[O:24]>O>[OH:14][C:13]1[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=1[NH:7][C:23](=[O:24])[CH2:22][Cl:21]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(NC(=O)CCl)c(O)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To 130 ml of dioxane, were added 20.0 g (163 mmol) of 6-amino-m-cresol and 9.2 g (92 mmol) of calcium carbonate, followed by heating to 60° C. To the obtained solution, there was added 22.1 g (196 mmol) of chloroacetyl chloride over 40 minutes and the mixture was further stirred at 60° C. for 2 hours. After cooling, the mixture was poured into 500 ml of water, extracted with 700 ml of ethyl acetate and dried over anhydrous Glauber's salt. After distilling off the solvent under reduced pressure, the obtained greenish brown solid was recrystallized from acetonitrile. Thus 23.5 g (118 mmol) of N-(2-hydroxy-4-methylphenyl)chloroacetamide was obtained as pale green crystals. The yield was 72%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20](C)[N:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.N1C=CC=C[CH:37]=1>>[CH3:37][C:23]1[C:18]([C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:5]3[CH:6]=[N:7][C:2]([NH:1][S:31]([C:28]4[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=4)(=[O:33])=[O:32])=[CH:3][CH:4]=3)[CH:10]=2)=[O:17])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cccc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)n1
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4ncccc4C)c3)cn2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-6-methylpyridine-2-carboxamide (8.25 g, 25.8 mmol), p-toluenesulfonyl chloride (5.41 g, 28.4 mmol) and pyridine (50 mL) was stirred at 80° C. for 2 hr. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate-hexane to give the title compound (12.1 g, 99%) as a pale-brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:19][CH2:20][CH2:21][OH:22])=[O:18])=[CH:12][CH:11]=1.[CH3:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]([O:19][CH2:20][CH2:21][O:22][C:40](=[O:41])[NH:39][C:36]2[CH:35]=[CH:34][C:33]([O:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:26]([O:25][CH3:24])=[O:42])=[CH:38][CH:37]=2)=[O:18])=[CH:14][CH:15]=1
Reactant: COC(=O)CCCCCOc1ccc(N=C=O)cc1
Reactant: COC(=O)CCCCCOc1ccc(NC(=O)OCCO)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCOc1ccc(NC(=O)OCCOC(=O)Nc2ccc(OCCCCCC(=O)OC)cc2)cc1
Temperature: 60 °C
Yield: 95 %

Procedure:
To a mixture of 6-[4-(2-Hydroxyethoxycarbonylamino)phenoxy]hexanoic acid methyl ester 37 (5 g, 15.38 mmol) in toluene (50 ml) was added 6-(4-Isocyanatophenoxy) hexanoic acid methyl ester 36 (4 g, 15.2 mmol) at room temperature and heated to 60° C. for 2 hours. Toluene was distilled off and water (50 ml) was added. The solid was filtered and dried to give crude 38, which was purified by column chromatography on silica gel using chloroform as eluant to get pure 38 (8.5 g, 94%) as a white powder. M.p: 118-120.5° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:19]O>>[OH:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:19])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: COc1c(O)cccc1CCC(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1cccc(O)c1OC

Procedure:
To a solution of 3-(3-hydroxy-2-methoxyphenyl)propanoic acid (50 mg) in methanol (10 mL) was added dropwise thionyl chloride (2.0 mL) at 0° C. The reaction mixture was heated under reflux for 3 hr. The reaction mixture was concentrated, and ethyl acetate was added. The reaction mixture was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (45 mg) as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[C:13]([C:18]3([O:26][CH3:27])[CH2:22][CH2:21][N:20]([CH2:23][C:24]#[CH:25])[CH2:19]3)[CH:14]=[C:15]([F:17])[CH:16]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:29][OH:30]>>[F:17][C:15]1[CH:16]=[C:11]([S:10][C:7]2[CH:6]=[CH:5][C:4]([C:1](=[N:29][OH:30])[CH3:2])=[CH:9][CH:8]=2)[CH:12]=[C:13]([C:18]2([O:26][CH3:27])[CH2:22][CH2:21][N:20]([CH2:23][C:24]#[CH:25])[CH2:19]2)[CH:14]=1
Reactant: C#CCN1CCC(OC)(c2cc(F)cc(Sc3ccc(C(C)=O)cc3)c2)C1
Reactant: NO
Agent: Cl
Product: C#CCN1CCC(OC)(c2cc(F)cc(Sc3ccc(C(C)=NO)cc3)c2)C1
Yield: 96 %

Procedure:
Using an analogous procedure to that described in Example 27, 3-[3-(4-acetylphenylthio)-5-fluorophenyl]-3-methoxy-1-(prop-2-ynyl)pyrrolidine was reacted with hydroxylamine hydrochloride to give 3-{5-fluoro-3-[4-(1-hydroxyiminoethyl)phenylthio]phenyl}-3-methoxy-1-(prop-2-ynyl)pyrrolidine in 96% yield, m.p. 97°-99° C. (recrystallised from a mixture of hexane and diethyl ether).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]=[O:21])=[CH:19][C:14]=2[CH:13]=[CH:12]1>C1COCC1>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[OH:21])=[CH:19][C:14]=2[CH:13]=[CH:12]1
Reactant: c1cscn1
Reactant: O=Cc1ccc2occc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccc2occc2c1)c1nccs1
Reaction time: 0.75 h

Procedure:
Under argon at −78° C., a mixture of thiazole (1.13 g, 13.2 mmol) in THF (50 mL) was dropwise treated with 2.5M n-BuLi (1.05 equiv., 5.04 mL, in hexanes) over a period of 10 min and stirred for 45 min. The resulting yellow mixture was treated dropwise with a solution of benzofuran-5-carbaldehyde (1.76 g, 12.0 mmol) in THF (10 mL). Cooling was removed after addition. When the mixture reached room temperature, it was treated with EtOAc, washed with 1M aqueous HCl and brine, dried over MgSO4, and evaporated, to give benzofuran-5-yl(thiazol-2-yl)methanol as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.71-7.75 (m, 2H), 7.64 (d, J=2.2 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.39 (dd, J=8.6, 1.7 Hz, 1H), 7.29 (d, J=3.1 Hz, 1H), 6.76-6.75 (m, 1H), 6.17 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[S-:12][C:13]#[N:14].[K+].[NH2:16][C:17]1[CH:37]=[CH:36][C:20]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH:23]=2)=[CH:19][CH:18]=1.CCCCCC>C(#N)C.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:14][C:13](=[S:12])[NH:16][C:17]2[CH:37]=[CH:36][C:20]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:30])[CH:23]=3)=[CH:19][CH:18]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)cc1
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CC#N
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.1 %

Procedure:
2-(4-Fluorophenyl)acetyl chloride (72.5 mg) was dissolved in acetonitrile (2 ml) under a nitrogen atmosphere, and then potassium thiocyanate (81.6 mg) was added thereto at 60° C., followed by stirring at the same temperature for 2 hrs. The reaction mixture was cooled down to room temperature, and then a solution of 4-(4-aminophenoxy)-2-[(pyrrolidin-1-yl)carbonylamino]pyridine (50 mg) in acetonitrile (3 ml) was added thereto, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 to 1:3). Fractions containing the target compound were concentrated to give a residue, which was suspended in diethyl ether (0.5 ml)-hexane (1.5 ml). The solid was filtered off and dried under aeration to provide the titled compound (15.8 mg, 19.1%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[S:21][C:12]=2[N:13]=[C:14]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[O:20]1[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[S:21][C:12]=3[N:13]=2)=[CH:17][CH:18]=[N:19]1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1ccccc1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(isoxazol-5-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-benzylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[CH:4]([CH:8]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20](O)=[O:21])=[O:14])[CH2:9][CH2:10][CH2:11][CH3:12])[O:3]1.CC[N:26](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[CH:4]([CH:8]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20]([NH2:26])=[O:21])=[O:14])[CH2:9][CH2:10][CH2:11][CH3:12])[O:3]1
Reactant: CCCCC(C(=O)N1CCC[C@H]1C(=O)O)C1OC(C)(C)OC1=O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCCCC(C(=O)N1CCC[C@H]1C(N)=O)C1OC(C)(C)OC1=O
Reaction time: 2 h

Procedure:
To 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-carboxypyrrolidin-1-ylcarbonyl)pentane C-2 in DMF was added an amine R14NH2, DIEA and HATU and the solution stirred for 2 h. Aqueous workup followed by silica gel chromatography afforded 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-aminocarbonylpyrrolidin-1-ylcarbonyl)pentane C-3.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@:13]([CH2:16][O:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])([CH2:14][OH:15])[O:12][C@@H:11]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[C@@H:10]1[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][O:39][C:40]1[CH:61]=[CH:60][C:43]([C:44](Cl)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[CH:42][CH:41]=1>N1C=CC=CC=1.ClCCl>[CH2:1]([O:8][C@H:9]1[C@@:13]([CH2:16][O:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])([CH2:14][O:15][C:44]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[C:43]2[CH:42]=[CH:41][C:40]([O:39][CH3:38])=[CH:61][CH:60]=2)[O:12][C@@H:11]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[C@@H:10]1[OH:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@]2(CO)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@H]2OCc2ccccc2)cc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@]2(COS(=O)(=O)c3ccc(C)cc3)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@H]2OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 74.5 %

Procedure:
To a solution of nucleoside 6 (3.66 g, 6.88 mmol) in anhydrous pyridine (25 cm3) was added N,N-(dimethylamino)pyridine (0.84 g, 6.81 mmol) and 4,4′-dimethoxytrityl chloride (3.5 g, 13.2 mmol) and the mixture was stirred for 23 h at room temperature. Additional N,N-(dimethylamino)pyridine (0.250 g, 2.06 mmol) and 4,4′-dimethoxytrityl chloride (0.700 g, 2.06 mmol) was added, and stirring was continued for 36 h at room temperature. Ice cold H2O (50 cm3) was added and the reaction mixture was diluted with dichloromethane (150 cm3). The organic phase was separated and washed with saturated aqueous solutions of sodium hydrogen carbonate (25 cm3×3) and brine (40 cm3×3), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol/pyridine (0.75–1.5% methanol; 0.5% pyridine, v/v/v) as eluent to afford nucleoside 7 (4.28 g, 75%) as a white solid material after evaporation of the solvents under reduced pressure.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O(CCCNC(C)(C)CC1C=CC([O:47][CH3:48])=CC=1)C1C=CC=CC=1.Cl.OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:26].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:47][CH3:48])[CH:23]=[C:22]([Cl:1])[CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cc(Cl)cc(OC)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 378 (M−15,0.1), 275 (5), 274 (34), 273 (16), 272 (100), 163 (5), 121 (17), 114 (8).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12](I)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2].[OH:21][C:22]1[CH:23]=[C:24]([C:28]#[CH:29])[CH:25]=[CH:26][CH:27]=1>C(OCC)(=O)C.CCOCC>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([C:29]#[C:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=3)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2].[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:29][CH2:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=3)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2]
Reactant: C#Cc1cccc(O)c1
Reactant: CCN1c2ncc(I)cc2C(=O)N(C)c2cccnc21
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCN1c2ncc(C#Cc3cccc(O)c3)cc2C(=O)N(C)c2cccnc21
Product: CCN1c2ncc(CCc3cccc(O)c3)cc2C(=O)N(C)c2cccnc21

Procedure:
5,11-Dihydro-11-ethyl-5-methyl-8-(3-hydroxyphenyl)ethynyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.10 g) was prepared by coupling 5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one with 3-hydroxyphenylacetylene by a procedure analogous to that described in Example 42a. Hydrogenation as described in Example 42b afforded 7 mg of the title compound, m.p. 177°-179° C. (ethyl acetate/ether).
Reaction SMILES: O[CH:2]([C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[C:13](=[O:27])[N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:15]([CH2:18][CH2:19][CH3:20])[C:16]=2[CH3:17])=[O:11])=[CH:5][CH:4]=1>C(O)=O.C(OCC)(=O)C.[Zn]>[CH3:39][O:38][C:34]1[CH:33]=[C:32]2[C:37]([C:28]([CH2:2][C:3]3[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]4[C:13](=[O:27])[N:14]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:15]([CH2:18][CH2:19][CH3:20])[C:16]=4[CH3:17])=[O:11])=[CH:7][CH:8]=3)=[CH:29][CH:30]=[N:31]2)=[CH:36][CH:35]=1
Reactant: CCCn1c(C)c(C(=O)Nc2ccc(C(O)c3ccnc4cc(OC)ccc34)cc2)c(=O)n1-c1ccccc1
Agent: [Zn]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CCCn1c(C)c(C(=O)Nc2ccc(Cc3ccnc4cc(OC)ccc34)cc2)c(=O)n1-c1ccccc1
Temperature: 60 °C
Yield: 24.8 %

Procedure:
In a 25 mL round bottom flask was dissolved N-(4-(hydroxy(7-methoxyquinolin-4-yl)methyl)phenyl)-5-methyl-3-oxo-2-phenyl-1-propyl-2,3-dihydro-1H-pyrazole-4-carboxamide (104 mg, 199 μmol) in 4 mL of formic acid and the resultant was then treated with zinc dust (325 mg, 4975 μmol) and heated at 60° C. After 6 h the reaction mixture was diluted with ethyl acetate, filtered over Celite and neutralized with aqueous NaHCO3 (sat.). The aqueous phase was extracted with ethyl acetate, and then the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by MPLC (ISCO, dichloromethane: 1% NH4OH in MeOH, 100:0 to 90:10) to afford N-(4-((7-methoxyquinolin-4-yl)methyl)phenyl)-5-methyl-3-oxo-2-phenyl-1-propyl-2,3-dihydro-1H-pyrazole-4-carboxamide (25 mg, 25% yield) as an off-white solid. MS (ESI pos. ion) m/z: 507 (MH+). Calc'd exact mass for C31H30N4O3: 506. 1H NMR (400 MHz, DMSO-d6) 10.65 (s, 1 H), 8.74 (d, J=4.42 Hz, 1 H), 8.10 (d, J=9.22 Hz, 1 H), 7.57 (t, J=7.52 Hz, 2 H), 7.46-7.52 (m, 3 H), 7.35-7.44 (m, 3 H), 7.14-7.28 (m, 4 H), 4.38 (s, 2 H), 3.90 (s, 3 H), 3.79 (t, J=7.14 Hz, 2 H), 2.72 (s, 3 H), 1.32-1.41 (m, 2 H), 0.66 (t, J=7.39 Hz, 3 H).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:33]CCBr)[CH:29]=2)[CH:24]=1)[C:16]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:16][CH2:15][O:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26]4)[CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: BrCCOc1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CC2CCN(CCOc3ccc4cc(O)ccc4c3)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-Methylbenzyl)-piperidine and and 2-benzyloxy-6-(2-bromo-ethoxy)-naphthalene and potassium carbonate in two steps as a solid, mp 164-166° C. Analysis calculated for CH25H29O2 : C, 79.96; H, 7.78; N, 3.73. Found: C, 79.63; H, 7.84; N, 3.67.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@@H:8]([CH3:33])[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17](=[O:32])[NH:18][C@@H:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][C:25]([Br:31])=[CH:26][CH:27]=3)[N:22]=2)[CH3:20])[NH:12]1)=[O:10])(C)(C)C.Cl.[OH:36][CH2:37][CH2:38][C:39]([CH3:52])([CH:50]=[CH2:51])[C:40]([NH:42][C@@H:43]([CH:47]([CH3:49])[CH3:48])C(O)=O)=[O:41].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C>ClCCl.C(#N)C>[Br:31][C:25]1[CH:24]=[C:23]2[C:28]([CH:29]=[CH:30][C:21]([C@H:19]([NH:18][C:17]([C@@H:13]3[CH2:14][CH2:15][CH2:16][N:11]([C:9](=[O:10])[C@@H:8]([NH:7][C:6](=[O:5])[C@@H:43]([NH:42][C:40](=[O:41])[C:39]([CH2:38][CH2:37][OH:36])([CH3:52])[CH:50]=[CH2:51])[CH:47]([CH3:49])[CH3:48])[CH3:33])[NH:12]3)=[O:32])[CH3:20])=[N:22]2)=[CH:27][CH:26]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=CC(C)(CCO)C(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(C)(CCO)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A cooled (0° C.) solution of ((S)-2-{(S)-3-[(R)-1-(7-bromo-quinolin-2-yl)-ethylcarbamoyl]-tetrahydro-pyridazin-1-yl}-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (432.0 mg, 0.808 mmol) in dichloromethane (30 mL) was treated with a solution of hydrochloric acid (2.4 mL, 9.699 mmol, 4 M in 1,4-dioxane). After stirring for 2 h at room temperature the volatiles were removed in vacuo. Residual water was azeotroped off with toluene to provide a white solid that was combined with (S)-2-[2-(2-hydroxy-ethyl)-2-methyl-but-3-enoylamino]-3-methyl-butyric acid (196.6 mg, 0.808 mmol) and anhydrous acetonitrile (30 mL). This mixture was cooled to 0° C. and subsequently treated with N,N-diisopropylethylamine (0.71 mL, 4.04 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (430.1 mg, 1.131 mmol). The reaction was slowly warmed to room temperature. After stirring at room temperature for 20 h, the volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/acetone 1:0 to 1:1 to afford the title compound (186.4 mg, 35%) as a yellow foam and as a 1:1 mixture of diastereoisomers. LCMS (m/z) 659.2, 661.1 [M+H], Tr=2.21 min.