Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[O:19][CH3:20].[N+:21]([O-])([OH:23])=[O:22]>CC(C)=O>[OH:1][C:2]1[C:11]([N+:21]([O-:23])=[O:22])=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: O=[N+]([O-])O
Reactant: COc1cc2cc(-c3ccccc3)c(=O)oc2cc1O
Solvent: CC(C)=O
Product: COc1cc2cc(-c3ccccc3)c(=O)oc2c([N+](=O)[O-])c1O
Reaction time: 0.33 h

Procedure:
To a solution of 7-hydroxy-6-methoxy-3-phenyl-chromen-2-one (1.34 g) in acetone (40 ml) was added nitric acid (0.22 ml in 5 ml of CH2Cl2) and the resulting mixture stirred for 20 minutes. After evaporation of the solvents the product was recrystallized from ethanol. Yield: 0.85 g.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:27])[C:17]=2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:12]=1.CS(O[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=1)(=O)=O>CN(C)C=O>[F:27][C:16]1[C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=3)[CH2:23][CH2:22]2)=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:10])[CH:20]=[CH:19]2
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc2c(N3CCNCC3)c(F)ccc2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)c(F)ccc2n1
Temperature: 100 °C
Yield: 42 %

Procedure:
N,N-Diisopropylethylamine (0.15 mL; 3 eq) was added to a solution of 2-methyl-5-(1-piperazinyl)-6-fluoro quinoline (0.075 g; 1 eq) and 2-(3-nitrophenyl)ethyl methanesulfonate (D4) (0.08; 1.1 eq) in dimethylformamide (3.0 mL). The reaction mixture was heated to 100° C. for 10 hours. The dark solution was concentrated under reduced pressure, diluted with water (3 mL) and brine (1 mL) and extracted into ethyl acetate (3×3 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel, eluting with a gradient from dichloromethane to dichloromethane-methanol (98:2) affording the title compound in 42% yield (0.05 g).
Reaction SMILES: C(OC([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:41])[CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[C:27](=[O:39])[C:26]2=[O:40])=[CH:16][CH:15]=1)=[NH:13])=O)C1C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:12]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:41])[CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]([OH:34])=[O:33])[C:27](=[O:39])[C:26]2=[O:40])=[CH:18][CH:19]=1)(=[NH:11])[NH2:13]
Reactant: CC(C)(C)OC(=O)CN1CCN(CCCC(=O)Nc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(NC(=O)CCCN2CCN(CC(=O)O)C(=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.1 %

Procedure:
To a solution of 0.28 g of tert-butyl [4-[4-(4-benzyloxycarbonylamidinophenylamino)-4-oxobutyl]-2,3-dioxopiperazin-1-yl]acetate in 2.8 ml of methylene chloride was added 1.4 ml of trifluoroacetic acid, and the resulting mixture was stirred at room temperature for 12 hours and then distilled under reduced pressure to remove the solvent. To the resulting residue were added 0.08 g of 5% palladium-carbon and 5.6 ml of N,N-dimethylformamide, followed by hydrogenation at ordinary temperature and atmospheric pressure for 3 hours. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. To the resulting concentrate were added 5 ml of water and 0.042 g of sodium hydrogencarbonate to obtain a homogeneous solution. This solution was purified by a reversed phase column chromatography (eluent: a 10% aqueous acetonitrile solution) to obtain 0.08 g of [4-[4-(4-amidinophenylamino)-4-oxobutyl]-2,3-dioxopiperazin-1yl]acetic acid as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[Li]CCCC.CN([CH:24]=[O:25])C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:3]=1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cc(F)ccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(F)c1C=O
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a stirred solution of tert-butyl 4-fluoropyridin-2-ylcarbamate (1 g, 4.72 mmol) in THF (20 mL) was added dropwise n-BuLi (4.7 mL, 11.8 mmol) at −78° C. After stirring for 0.5 h, a solution of DMF (2 mL) in THF (2 mL) was added dropwise at −78° C. TLC indicated the reaction was completed. The reaction was quenched with 1N HCl at −78° C. to pH=4. Then water (20 mL) was added and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:PE=1:2) to give the title compound (0.65 g, 57%) as a white solid. 1H-NMR (600 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.99 (s, 1H), 8.58-8.56 (m, 1H), 7.23-7.21 (m, 1H), 1.46 (s, 9H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[N:7]=1.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O:13][CH3:14])=[O:12]>ClCCCl>[Cl:8][C:6]1[N:7]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:23])=[O:22])=[O:26])[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Cl)nc(N)c1=O
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)cn(C)c1=O

Procedure:
To a mixture of 3-amino-5-chloro-1-methyl-2(1H)-pyrazinone (0.40 g, 0.0025 mol) in anhydrous 1,2-dichloroethane (4 mL) under nitrogen was added a solution of 2-carbomethoxybenzenesulfonyl isocyanate (0.84 g, 0.0035 mol) in anhydrous 1,2-dichloromethane (3 mL). The mixture was heated at reflux for 2 hours. The solvent was rotary evaporated, and the residue was purified by chromatography on a column of silica gel using a solvent mixture of 1:1 hexanes-acetone containing a little acetic acid as eluant. Rotary evaporation of the appropriate fractions left 0.34 g of methyl 2-[[(6-chloro-3,4-dihydro-4-methyl-3-oxo-2-pyrazinylamino)carbonylamino]sulfonyl]benzoate as a crystalline powder melting at 173°-176° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1.[OH:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)\[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[C:29]1(/[C:22](=[N:21]/[O:20][CH2:19][C:18]2[CH:35]=[CH:36][C:15]([O:14][CH2:2][C:3]3[N:4]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[O:6][CH:7]=3)=[CH:16][CH:17]=2)/[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClCc1coc(-c2ccccc2)n1
Reactant: COC(=O)CC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2coc(-c3ccccc3)n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.8 %

Procedure:
A mixture of 4-(chloromethyl)-2-phenyloxazole (250 mg), methyl E-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (369 mg), potassium carbonate (325 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 17 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl E-4-phenyl-4-[4-(2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (320 mg, yield 58%) as a colorless oil from an ethyl acetate-hexane (2:9, v/v)-eluted fraction.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN(C)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1OCCCN(C)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (150 mg, 0.42 mmol), (prepared as described for the starting material in Example 152), potassium carbonate (90 mg, 0.63 mmol) and 7hydroxyquinoline (67 mg, 0.46 mmol) in DMF (5.0 ml) was stirred at 100° C. for 2 hours and allowed to cool to ambient temperature. The solvent was removed by evaporation and the residue taken up in 2N. aqueous sodium hydroxide solution. The precipitate was filtered off, dried, taken up in dichloromethane and the solution filtered through phase separating paper. The filtrate was then evaporated to dryness. The resulting solid was recrystallised from acetonitrile, filtered and washed with diethyl ether to give 6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)-4-(quinolin-7-yloxy)quinazoline (122 mg, 63%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C@H:38]([OH:45])[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([C@H:38]([OH:45])[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N+:40]=5[O-:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4ccccn4)cc2)CCN3S(C)(=O)=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(2-pyridyl)methyl]phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.45 g) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 0.21 g) at 0° C. and the mixture was stirred for 20 hours at room temperature. To the reaction solution was added sodium thiosulfate solution, and the mixture was stirred for several minutes and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 94) (292.1 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:22])[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.I[CH3:24]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:22])[N:14]([CH3:24])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: O=c1[nH]c2ccccc2cc1-c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2c(Cl)ccc([N+](=O)[O-])c2Cl)cc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
To a solution of 3-(2,6-dichloro-3-nitro-phenyl)-1H-quinolin-2-one (0.21 g, 0.6266 mmol) in DMF (5.0 mL) is added HNa (30.1 mg, 60%, 0.752 mmol) and IMe (120.1 mg, 0.846 mmol) at 0° C. After the mixture is stirred for two hours at 0° C., the mixture is diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by flash silica gel column, eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (2N NH3) (95/5), t give the titled intermediate as a solid (78 mg, 35.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][CH:13]=[N:12][C:11]=2[CH:15]([CH3:17])[CH3:16])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:20])[CH:13]=[N:12][C:11]=2[CH:15]([CH3:17])[CH3:16])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2[nH]cnc2C(C)C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Sc2c(C(C)C)ncn2C)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
In 10 ml of dry N,N-dimethylformamide was dissolved 1.0 g (4.1 mmol)of 5-(3,5-dimethylphenylthio)-4-isopropyl-1H-imidazole (X=Y=Me)(9), followed by addition of 330 mg (8.3 mmol)of 60% sodium hydride under ice-cooling. After 5 minutes, 690 mg (4.9 mmol)of methyl iodide was added and the mixture was stirred for 10 minutes. This reaction mixture was poured in ice-water and extracted with diethyl ether. The organic layer was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was fractionated by alumina chromatography (ethyl acetate:n-hexane,=1:1). From the first fraction, 833 mg (yield 79%)of 5-(3,5-dimethylphenylthio)-4-isopropyl-1-methyl-1H-imidazole (X=Y=Me) (10)was recovered as oil.
Reaction SMILES: [Br-].[ClH:2].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10]/[C:11](/[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[N:12]\[OH:13])[CH2:6][CH2:5]1.Cl.CN1CCN(C/C(/C2C=CC(OCC3C=CC=CC=3)=CC=2)=N/O)CC1>>[ClH:2].[CH3:3][N:4]1[CH2:5][CH2:6][N:7]([CH2:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[N:12][OH:13])[CH2:8][CH2:9]1
Reactant: CN1CCN(C/C(=N\O)c2ccc(OCc3ccccc3)cc2)CC1
Agent: CN1CCN(C/C(=N/O)c2ccc(OCc3ccccc3)cc2)CC1
Agent: Cl
Agent: [Br-]
Product: CN1CCN(CC(=NO)c2ccc(OCc3ccccc3)cc2)CC1

Procedure:
After dissolving 4.0 g of 4-benzyloxyacetophenone into 20 ml of 1,4-dioxane and 20 ml of tetrahydrofuran, 0.1 g of anhydrous aluminum chloride and 3.1 g of bromine were added under ice cooling and stirring. Further, after stirring for 5 hours under ice cooling, the reaction solution was concentrated to solid. Water and chloroform were added to the residue to separate liquid layers. Then, the chloroform layer was dried over anhydrous sodium sulfate and then concentrated to solid followed by purification by silica gel column chromatography using benzene/n-hexane (1:1) as an elute, to obtain 4.1 g of 2-bromo-1-(4-benzyloxy-phenyl)-ethanone. Then, using 3.0 g of the thus obtained bromide, 2.2 g of (Z)-2-(4-methyl-piperazin-1-yl)-1-(4-benzyloxy-phenyl)-ethanone oxime hydrochloride with the melting point of from 208° to 210° C. (decomposition) and 0.7 g of (E)-2-(4-methyl-piperazin-1-yl)-1-(4-benzyloxy-phenyl)-ethanone oxime hydrochloride with the melting point of from 210° to 212° C. were obtained in the same manner as in Example 1.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:15]([O-])=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO>[NH2:15][C:10]1[CH:9]=[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][C:11]=1[OH:14]
Reactant: O=[N+]([O-])c1cc(Cc2ccccc2)ccc1O
Agent: [Pd]
Solvent: CO
Product: Nc1cc(Cc2ccccc2)ccc1O
Reaction time: 24 h

Procedure:
10% Palladium on carbon, Pearlman, (50% wet) (2.3 g, 2.2 mmol) and 4-benzyl-2-nitrophenol (5.00 g, 22 mmol) were combined under nitrogen and diluted with 80 mL MeOH delivered via syringe. The vessel was pressurized to 40 psi and shaken in a Parr shaker for ˜24 h. The resulting material was flushed with nitrogen and filtered through Celite, rinsing with MeOH. The filtrate was concentrated in vacuo to give 2-amino-4-benzylphenol as a brown solid. MS (ESI) m/z: Calculated: 199.1; Observed: 200.0 (M++1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][C:8]=1[CH2:17][C:18](OCC)=[O:19].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.O>[N:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][C:8]=1[CH2:17][CH2:18][OH:19]
Reactant: CCOC(=O)Cc1ccc2c(n1)CCCC2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccc2c(n1)CCCC2
Reaction time: 1.5 h

Procedure:
Under N2, 4.56 mL (4.56 mmol) of lithium aluminium hydride (1M in THF) was cooled to 0° C. and ethyl 2-(5,6,7,8-tetrahydroquinolin-2-yl)acetate (1 g, 4.56 mmol) dissolved in a small quantity of THF was slowly added. The mixture was allowed to stir for 1.5 h. To the reaction mixture 173 mg of H2O in THF, 173 mg of 10% ige NaOH and 3×173 mg of H2O were added. The mixture was then stirred for 30 min. Magnesium sulfate was added. After removal of the solvent, the crude product (0.78 g, 96%) was purified by chromatography (eluent: EA/heptane 3/1) to give the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].C(O)(=O)C.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:33](=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:23]([C:28](OCC)=[O:29])[N:24]2[CH3:27])=[CH:20][CH:19]=1>O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:10][N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=4)[C:28](=[O:29])[C:23]=3[N:24]([CH3:27])[C:25]=2[CH:26]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)c1c(C(=O)OCC)n(C)c2cc(Cl)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1nn(-c2cccc(Cl)c2)c(=O)c2c1c1ccc(Cl)cc1n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
7.0 g (39.1 mmol) of 3-chlorophenylhydrazine hydrochloride are dissolved in 50 ml of water and 5 ml of a 35% sodium hydroxide solution. Extraction is carried out with diethyl ether. The organic phase is dried over sodium sulphate, filtered and concentrated under reduced pressure. An oil is obtained, to which are added 100 ml of acetic acid and 4.0 g (12.35 mmol) of ethyl 6-chloro-2-(ethoxycarbonyl)-1-methyl-α-oxo-1H-indole-3-acetate. The reaction mixture is stirred for 30 min at room temperature and then for 6 h at reflux. The mixture is cooled, 100 ml of water are added and an insoluble material is collected by filtration, washed with water and purified by chromatography on a silica column (eluant: dichloromethane/ethyl acetate: 98/2). 4.59 g (11 mmol) of compound are isolated in the form of a white solid.
Reaction SMILES: I[C:2]1[CH:23]=[C:22]([CH3:24])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:8]=2)=[C:4]([CH3:25])[CH:3]=1.[CH2:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][OH:41])[C:27]#[CH:28].C(N(CC)CC)C>CN(C=O)C.C1COCC1.C(Cl)Cl.CO.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:26][C:27]#[C:28][C:2]1[CH:23]=[C:22]([CH3:24])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:8]=2)=[C:4]([CH3:25])[CH:3]=1
Reactant: C#CCOCCOCCOCCOCCO
Reactant: Cc1cc(I)cc(C)c1Oc1ccnc(Nc2ccc(C#N)cc2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C#CCOCCOCCOCCOCCO)cc(C)c1Oc1ccnc(Nc2ccc(C#N)cc2)n1
Yield: 85.4 %

Procedure:
To a deoxygenated solution of iodopyrimidine 3 (494 mg, 1.12 mmol) and 2-(2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethoxy)ethanol (Veciani, et al., Ibid.) (780 mg, 3.36 mmol) in dry DMF (1.5 mL) and dry THF (3.0 mL) were added successively dry triethylamine (562.0 mg, 5.55 mmol, 0.80 mL), copper (1) iodide (105.7 mg, 0.56 mmol), and tetrakis(triphenylphosphine)palladium (0) (128.3 mg, 0.11 mmol). The reaction mixture was stirred at 25° C. under a nitrogen atmosphere for 3 hours after which TLC (DCM/methanol=3:97) revealed a more polar product and consumption of starting material 3. The mixture was poured into EDTA solution (20 mL, 5%) and the organic product extracted into EtOAc (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and the solvent evaporated in vacuo to furnish a residue that was subjected to silica-gel column chromatography using DCM/MeOH (95:5) as eluent to produce 4 as a light-brown oil (522.0 mg, 0.956 mmol, 85%).
Reaction SMILES: [N:1]([CH2:4][CH:5]([CH:7]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:8][CH:9]([CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[C:17]2[CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:10]([CH3:12])[CH3:11])[OH:6])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH:5]([CH:7]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:8][CH:9]([CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[C:17]2[CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:10]([CH3:11])[CH3:12])[OH:6]
Reactant: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CN=[N+]=[N-])C(C)C)cc12
Agent: [Pd]
Solvent: CO
Product: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CN)C(C)C)cc12

Procedure:
The solution of 0.51 g of tert-butyl {1-(2-azido-1-hydroxyethyl)-3-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-ylmethyl]-4-methylpentyl}carbamate in 15 ml of methanol is hydrogenated in the presence of 0.11 g of 10% Pd/C over 1 hour. The reaction mixture is clarified by filtration and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])=[O:17].[CH3:25][CH:26]([CH3:42])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:31]=1)=[O:28]>>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:39]1[CH2:40][CH2:41][CH:36]([C:32]2[CH:31]=[C:30]([NH:29][C:27](=[O:28])[CH:26]([CH3:25])[CH3:42])[CH:35]=[CH:34][CH:33]=2)[CH2:37][CH2:38]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCCCl)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(=O)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using K2CO3 instead of Na2CO3 and NaI instead of KI and 7-chloro-1-(2-fluorophenyl)-1-heptanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3), δ 8.17 (s, br, 1H), 8.06-6.88 (m, 8H), 3.08-2.94 (m, 4H), 2.62-2.48 (m, 1H), 2.48-2.38 (m, 1H) 2.38-2.15 (m, 2H), 2.02-1.92 (m, 2H), 1.84-1.77 (m, 4H), 1.77-1.66 (m, 2H), 1.62-1.46 (m, 2H), 1.46-1.29 (M, 4H), 1.21 (d, 6H, J=6.8 Hz); ESMS m/e: 453.2 (M+H)+.